Lamotrigine

Lamotrigine Manufacturers

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  Lamotrigine | Direct Rx

  

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  2.1 General Dosing Considerations

  Rash: There are suggestions, yet to be proven, that the risk of severe, potentially life-threatening rash may be increased by (1) coadministration of lamotrigine tablets with valproate, (2) exceeding the recommended initial dose of lamotrigine tablets, or (3) exceeding the recommended dose escalation for lamotrigine tablets. However, cases have occurred in the absence of these factors [see Boxed Warning ]. Therefore, it is important that the dosing recommendations be followed closely.

  The risk of nonserious rash may be increased when the recommended initial dose and/or the rate of dose escalation of lamotrigine tablet is exceeded and in patients with a history of allergy or rash to other AEDs.

  It is recommended that lamotrigine tablets not be restarted in patients who discontinued due to rash associated with prior treatment with lamotrigine, unless the potential benefits clearly outweigh the risks. If the decision is made to restart a patient who has discontinued lamotrigine, the need to restart with the initial dosing recommendations should be assessed. The greater the interval of time since the previous dose, the greater consideration should be given to restarting with the initial dosing recommendations. If a patient has discontinued lamotrigine for a period of more than 5 half-lives, it is recommended that initial dosing recommendations and guidelines be followed. The half-life of lamotrigine is affected by other concomitant medications [see Clinical Pharmacology (12.3) ].

  Lamotrigine Tablets Added to Drugs Known to Induce or Inhibit Glucuronidation: Drugs other than those listed in the Clinical Pharmacology section [see Clinical Pharmacology (12.3) ] have not been systematically evaluated in combination with lamotrigine. Because lamotrigine is metabolized predominantly by glucuronic acid conjugation, drugs that are known to induce or inhibit glucuronidation may affect the apparent clearance of lamotrigine and doses of lamotrigine tablets may require adjustment based on clinical response.

  Target Plasma Levels for Patients With Epilepsy or Bipolar Disorder: A therapeutic plasma concentration range has not been established for lamotrigine. Dosing of lamotrigine tablets should be based on therapeutic response [see Clinical Pharmacology (12.3) ].

  Women Taking Estrogen-Containing Oral Contraceptives: Starting Lamotrigine Tablets  in Women Taking Estrogen-Containing Oral Contraceptives: Although estrogen-containing oral contraceptives have been shown to increase the clearance of lamotrigine [see Clinical Pharmacology (12.3) ], no adjustments to the recommended dose-escalation guidelines for lamotrigine tablets should be necessary solely based on the use of estrogen-containing oral contraceptives. Therefore, dose escalation should follow the recommended guidelines for initiating adjunctive therapy with lamotrigine tablets based on the concomitant AED or other concomitant medications (see Table 1 or Table 5). See below for adjustments to maintenance doses of lamotrigine tablets in women taking estrogen-containing oral contraceptives.

  Adjustments to the Maintenance Dose of Lamotrigine Tablets In Women Taking Estrogen-Containing Oral Contraceptives:

  (1) Taking Estrogen-Containing Oral Contraceptives: For women not taking carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin that induce lamotrigine glucuronidation [see Drug Interactions (7), Clinical Pharmacology (12.3)], the maintenance dose of lamotrigine  tablets will in most cases need to be increased, by as much as 2-fold over the recommended target maintenance dose, in order to maintain a consistent lamotrigine plasma level [see Clinical Pharmacology (12.3) ].

  (2) Starting Estrogen-Containing Oral Contraceptives: In women taking a stable dose of lamotrigine tablets and not taking carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin that induce lamotrigine glucuronidation [see Drug Interactions (7), Clinical Pharmacology (12.3)], the maintenance dose will in most cases need to be increased by as much as 2-fold in order to maintain a consistent lamotrigine plasma level. The dose increases should begin at the same time that the oral contraceptive is introduced and continue, based on clinical response, no more rapidly than 50 to 100 mg/day every week. Dose increases should not exceed the recommended rate (see Table 1 or Table 5) unless lamotrigine plasma levels or clinical response support larger increases. Gradual transient increases in lamotrigine plasma levels may occur during the week of inactive hormonal preparation ("pill-free" week), and these increases will be greater if dose increases are made in the days before or during the week of inactive hormonal preparation. Increased lamotrigine plasma levels could result in additional adverse reactions, such as dizziness, ataxia, and diplopia. If adverse reactions attributable to lamotrigine tablets consistently occur during the "pill-free" week, dose adjustments to the overall maintenance dose may be necessary. Dose adjustments limited to the "pill-free" week are not recommended. For women taking lamotrigine tablets in addition to carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin that induce lamotrigine glucuronidation [see Drug Interactions (7), Clinical Pharmacology (12.3)], no adjustment to the dose of lamotrigine tablets should be necessary.

  (3) Stopping Estrogen-Containing Oral Contraceptives: For women not taking carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin that induce lamotrigine glucuronidation [see Drug Interactions (7), Clinical Pharmacology (12.3)], the maintenance dose of lamotrigine tablets will in most cases need to be decreased by as much as 50% in order to maintain a consistent lamotrigine plasma level. The decrease in dose of lamotrigine tablets should not exceed 25% of the total daily dose per week over a 2-week period, unless clinical response or lamotrigine plasma levels indicate otherwise [see Clinical Pharmacology (12.3) ]. For women taking lamotrigine tablets in addition to carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin that induce lamotrigine glucuronidation [see Drug Interactions (7), Clinical Pharmacology (12.3)], no adjustment to the dose of lamotrigine tablets should be necessary.

  Women and Other Hormonal Contraceptive Preparations or Hormone Replacement Therapy: The effect of other hormonal contraceptive preparations or hormone replacement therapy on the pharmacokinetics of lamotrigine has not been systematically evaluated. It has been reported that ethinylestradiol, not progestogens, increased the clearance of lamotrigine up to 2-fold, and the progestin-only pills had no effect on lamotrigine plasma levels. Therefore, adjustments to the dosage of lamotrigine tablets in the presence of progestogens alone will likely not be needed.

  Patients With Hepatic Impairment: Experience in patients with hepatic impairment is limited. Based on a clinical pharmacology study in 24 patients with mild, moderate, and severe liver impairment [see Use in Specific Populations (8.6) , Clinical Pharmacology (12.3) ], the following general recommendations can be made. No dosage adjustment is needed in patients with mild liver impairment. Initial, escalation, and maintenance doses should generally be reduced by approximately 25% in patients with moderate and severe liver impairment without ascites and 50% in patients with severe liver impairment with ascites. Escalation and maintenance doses may be adjusted according to clinical response.

  Patients With Renal Impairment: Initial doses of lamotrigine tablets should be based on patients' concomitant medications (see Tables 1-3 or Table 5); reduced maintenance doses may be effective for patients with significant renal impairment [see Use in Specific Populations (8.7) , Clinical Pharmacology (12.3) ]. Few patients with severe renal impairment have been evaluated during chronic treatment with lamotrigine tablets. Because there is inadequate experience in this population, lamotrigine tablets should be used with caution in these patients.

  Discontinuation Strategy:

  Epilepsy: For patients receiving lamotrigine tablets in combination with other AEDs, a reevaluation of all AEDs in the regimen should be considered if a change in seizure control or an appearance or worsening of adverse reactions is observed.

  If a decision is made to discontinue therapy with lamotrigine tablets, a step-wise reduction of dose over at least 2 weeks (approximately 50% per week) is recommended unless safety concerns require a more rapid withdrawal [see Warnings and Precautions (5.9) ].

  Discontinuing carbamazepine, phenytoin, phenobarbital, primidone or other drugs such as rifampin that induce lamotrigine glucuronidation should prolong the half-life of lamotrigine; discontinuing valproate should shorten the half-life of lamotrigine.

  Bipolar Disorder: In the controlled clinical trials, there was no increase in the incidence, type, or severity of adverse reactions following abrupt termination of lamotrigine tablets. In clinical trials in patients with Bipolar Disorder, 2 patients experienced seizures shortly after abrupt withdrawal of lamotrigine tablets. However, there were confounding factors that may have contributed to the occurrence of seizures in these bipolar patients. Discontinuation of lamotrigine tablets should involve a step-wise reduction of dose over at least 2 weeks (approximately 50% per week) unless safety concerns require a more rapid withdrawal [see Warnings and Precautions (5.9) ].

  2.2 Epilepsy – Adjunctive Therapy

  This section provides specific dosing recommendations for patients greater than 12 years of age and patients 2 to 12 years of age. Within each of these age-groups, specific dosing recommendations are provided depending upon concomitant AED or other concomitant medications (Table 1 for patients greater than 12 years of age and Table 2 for patients 2 to 12 years of age). A weight-based dosing guide for patients 2 to 12 years of age on concomitant valproate is provided in Table 3.

  Patients Over 12 Years of Age: Recommended dosing guidelines are summarized in Table 1.

  Table 1. Escalation Regimen for Lamotrigine Tablets in Patients Over 12 Years of Age With Epilepsy

  a Valproate has been shown to inhibit glucuronidation and decrease the apparent clearance of lamotrigine [see Drug Interactions (7), Clinical Pharmacology (12.3)].

  b These drugs induce lamotrigine glucuronidation and increase clearance [see Drug Interactions (7), Clinical Pharmacology (12.3)]. Other drugs that have similar effects include estrogen-containing oral contraceptives [see Drug Interactions (7), Clinical Pharmacology (12.3)]. Dosing recommendations for oral contraceptives can be found in General Dosing Considerations [see Dosage and Administration (2.1)]. Patients on rifampin, or other drugs that induce lamotrigine glucuronidation and increase clearance, should follow the same dosing titration/maintenance regimen as that used with anticonvulsants that have this effect.

  For  For Patients NOT TAKING  For Patients  Patients Carbamazepine,  TAKING TAKING Phenytoin, Carbamazepine, Valproatea Phenobarbital, Phenytoin,  or Primidoneb,   Phenobarbital, or Valproatea or Primidoneb and NOT TAKING Valproatea Weeks 1 and 2 25 mg every other day 25 mg every day 50 mg/day Weeks 3 and 4 25 mg every day 50 mg/day 100 mg/day
  (in 2 divided doses) Weeks 5 onwards to 
  maintenance Increase by 25 to 
  50 mg/day every 1 to 2 weeks Increase by 50
  mg/day every 1
  to 2 weeks Increase by 
  100 mg/day every 
  1 to 2 weeks. Usual maintenance 
  dose 100 to 200 mg/day
  with valproate alone 225 to 375 mg/day
  (in 2 divided doses). 300 to 500 mg/day
  (in 2 divided doses). 100 to 400 mg/day
  with valproate
  and other drugs that induce glucuronidation (in 1 or 2 divided doses)

  Patients 2 to 12 Years Of Age: Recommended dosing guidelines are summarized in Table 2.

  Smaller starting doses and slower dose escalations than those used in clinical trials are recommended because of the suggestion that the risk of rash may be decreased by smaller starting doses and slower dose escalations. Therefore, maintenance doses will take longer to reach in clinical practice than in clinical trials. It may take several weeks to months to achieve an individualized maintenance dose. Maintenance doses in patients weighing less than 30 kg, regardless of age or concomitant AED, may need to be increased as much as 50%, based on clinical response.

  Table 2. Escalation Regimen for Lamotrigine Tablets in Patients 2 to 12 Years of Age With Epilepsy

  Note: Only whole tablets should be used for dosing.

  a Valproate has been shown to inhibit glucuronidation and decrease the apparent clearance of lamotrigine [see Drug Interactions (7), Clinical Pharmacology (12.3)].

  b These drugs induce lamotrigine glucuronidation and increase clearance [see Drug Interactions (7), Clinical Pharmacology (12.3)]. Other drugs which have similar effects include estrogen-containing oral contraceptives [see Drug Interactions (7), Clinical Pharmacology (12.3)]. Dosing recommendations for oral contraceptives can be found in General Dosing Considerations [see Dosage and Administration (2.1)]. Patients on rifampin, or other drugs that induce lamotrigine glucuronidation and increase clearance, should follow the same dosing titration/maintenance regimen as that used with anticonvulsants that have this effect.

  For Patients TAKING 
  Valproatea For Patients NOT 
  TAKING Carbamazepine, Phenytoin, 
  Phenobarbital, Primidoneb, or 
  Valproatea For Patients TAKING 
  Carbamazepine, Phenytoin, Phenobarbital, or 
  Primidoneb and NOT 
  TAKING Valproatea Weeks 1 and 2 0.15 mg/kg/day
  in 1 or 2 divided doses, rounded down to the 
  nearest whole tablet (see Table 3 for weight 
  based dosing guide). 0.3 mg/kg/day
  in 1 or 2 divided doses, rounded down to the 
  nearest whole tablet. 0.6 mg/kg/day
  in 2 divided doses, rounded down to the 
  nearest whole tablet. Weeks 3 and 4 0.3 mg/kg/day
  in 1 or 2 divided doses,
  rounded down to the 
  nearest whole tablet 
  (see Table 3 for weight 
  based dosing guide). 0.6 mg/kg/day
  in 2 divided doses,
  rounded down to the 
  nearest whole tablet. 1.2 mg/kg/day
  in 2 divided doses, 
  rounded down to the 
  nearest whole tablet. Weeks 5 
  onwards to 
  maintenance The dose should be increased every 
  1 to 2 weeks as follows:
  calculate 0.3 mg/kg/day, round this amount 
  down to the nearest whole tablet, and 
  add this amount to the 
  previously administered daily dose. The dose should be increased every 
  1 to 2 weeks as follows:
  calculate 0.6 mg/kg/day, round this amount 
  down to the nearest whole tablet, and 
  add this amount to the 
  previously administered daily dose The dose should be increased every 
  1 to 2 weeks as follows:
  calculate 1.2 mg/kg/day, round this amount 
  down to the nearest whole tablet, and 
  add this amount to the 
  previously administered daily dose Usual 
  Maintenance 
  Dose 1 to 5 mg/kg/day
  (maximum 200 mg/day 
  in 1 or 2 divided doses).
  1 to 3 mg/kg/day with valproate alone 4.5 to 7.5 mg/kg/day
  (maximum 300 mg/day 
  in 2 divided doses) 5 to 15 mg/kg/day
  (maximum 400 mg/day 
  in 2 divided doses) Maintenance dose in 
  patients 
  less than 30 kg May need to be increased 
  by as much as 50%, 
  based on clinical response May need to be increased 
  by as much as 50%, 
  based on clinical response May need to be increased 
  by as much as 50%, based 
  on clinical response Table 3. The Initial Weight-Based Dosing Guide for Patients 2 to 12 Years Taking Valproate (Weeks 1 to 4) With Epilepsy If the patient’s weight is Give this daily dose, using the most appropriate combination of Lamotrigine 2-mg and 5-mg tablets Greater than And less than Weeks 1 and 2 Weeks 3 and 4 6.7 kg 14 kg 2 mg every other day 2 mg every day 14.1 kg 27 kg 2 mg every day 4 mg every day 27.1 kg 34 kg 4 mg every day 8 mg every day 34.1 kg 40 kg 5 mg every day 10 mg every day

  Usual Adjunctive Maintenance Dose for Epilepsy: The usual maintenance doses identified in Tables 1 and 2 are derived from dosing regimens employed in the placebo-controlled adjunctive studies in which the efficacy of lamotrigine tablets was established. In patients receiving multidrug regimens employing carbamazepine, phenytoin, phenobarbital, or primidone without valproate, maintenance doses of adjunctive lamotrigine tablets as high as 700 mg/day have been used. In patients receiving valproate alone, maintenance doses of adjunctive lamotrigine tablets as high as 200 mg/day have been used. The advantage of using doses above those recommended in Tables 1 through 4 has not been established in controlled trials.

  2.3 Epilepsy – Conversion From Adjunctive Therapy to Monotherapy

  The goal of the transition regimen is to effect the conversion to monotherapy with lamotrigine tablets under conditions that ensure adequate seizure control while mitigating the risk of serious rash associated with the rapid titration of lamotrigine tablets.

  The recommended maintenance dose of lamotrigine tablets as monotherapy is 500 mg/day given in two divided doses.

  To avoid an increased risk of rash, the recommended initial dose and subsequent dose escalations of lamotrigine tablets should not be exceeded [see Boxed Warning].

  Conversion From Adjunctive Therapy With Carbamazepine, Phenytoin, Phenobarbital, or Primidone to Monotherapy With Lamotrigine Tablets: After achieving a dose of 500 mg/day of lamotrigine tablets according to the guidelines in Table 1, the concomitant AED should be withdrawn by 20% decrements each week over a 4-week period. The regimen for the withdrawal of the concomitant AED is based on experience gained in the controlled monotherapy clinical trial.

  Conversion from Adjunctive Therapy With Valproate to Monotherapy With Lamotrigine Tablets:

  The conversion regimen involves 4 steps outlined in Table 4.

  Table 4. Conversion From Adjunctive Therapy With Valproate to Monotherapy With Lamotrigine Tablets in Patients ≥16 Years of Age with Epilepsy Lamotrigine Tablets Valproate Step 1 Achieve a dose of 200 mg/day according to
  guidelines in Table 1
  (if not already on 200 mg/day). Maintain previous stable dose. Step 2 Maintain at 200 mg/day. Decrease to 500 mg/day by decrements no greater than
  500 mg/day/week and then maintain the dose of
  500 mg/day for 1 week. Step 3 Increase to 300 mg/day and maintain for 1 week. Simultaneously decrease to
  250 mg/day and maintain for 1 week. Step 4 Increase by 100 mg/day every
  week to achieve maintenance dose of 500 mg/day. Discontinue.

  Conversion from Adjunctive Therapy With AEDs Other Than Carbamazepine, Phenytoin, Phenobarbital, Primidone, or Valproate to Monotherapy With Lamotrigine Tablets: No specific dosing guidelines can be provided for conversion to monotherapy with lamotrigine tablets with AEDs other than carbamazepine, phenobarbital, phenytoin, primidone, or valproate.

  2.4 Bipolar Disorder

  The goal of maintenance treatment with lamotrigine tablets is to delay the time to occurrence of mood episodes (depression, mania, hypomania, mixed episodes) in patients treated for acute mood episodes with standard therapy. The target dose of lamotrigine tablets is 200 mg/day (100 mg/day in patients taking valproate, which decreases the apparent clearance of lamotrigine, and 400 mg/day in patients not taking valproate and taking either carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin that increase the apparent clearance of lamotrigine). In the clinical trials, doses up to 400 mg/day as monotherapy were evaluated; however, no additional benefit was seen at 400 mg/day compared with 200 mg/day [see Clinical Studies (14.2) ]. Accordingly, doses above 200 mg/day are not recommended. Treatment with lamotrigine tablets is introduced, based on concurrent medications, according to the regimen outlined in Table 5. If other psychotropic medications are withdrawn following stabilization, the dose of lamotrigine tablets should be adjusted. For patients discontinuing valproate, the dose of lamotrigine tablets should be doubled over a 2-week period in equal weekly increments (see Table 6). For patients discontinuing carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin that induce lamotrigine glucuronidation, the dose of lamotrigine tablets should remain constant for the first week and then should be decreased by half over a 2-week period in equal weekly decrements (see Table 6). The dose of lamotrigine tablets may then be further adjusted to the target dose (200 mg) as clinically indicated.

  If other drugs are subsequently introduced, the dose of lamotrigine tablets may need to be adjusted. In particular, the introduction of valproate requires reduction in the dose of lamotrigine tablets [see Drug Interactions (7) , Clinical Pharmacology (12.3) ].

  To avoid an increased risk of rash, the recommended initial dose and subsequent dose escalations of lamotrigine tablets should not be exceeded [see Boxed Warning ].

  Table 5. Escalation Regimen for Lamotrigine Tablets for Patients With Bipolar Disorder

  a Valproate has been shown to inhibit glucuronidation and decrease the apparent clearance of lamotrigine [see Drug Interactions (7), Clinical Pharmacology (12.3)].

  b These drugs induce lamotrigine glucuronidation and increase clearance [see Drug Interactions (7), Clinical Pharmacology (12.3)]. Other drugs which have similar effects include estrogen-containing oral contraceptives [see Drug Interactions (7), Clinical Pharmacology (12.3)]. Dosing recommendations for oral contraceptives can be found in General Dosing Considerations [see Dosage and Administration (2.1)]. Patients on rifampin, or other drugs that induce lamotrigine glucuronidation and increase clearance, should follow the same dosing titration/maintenance regimen as that used with anticonvulsants that have this effect.

  For Patients TAKING 
  Valproatea For Patients NOT TAKING 
  Carbamazepine, Phenytoin, Phenobarbital, 
  Primidoneb, or Valproatea For Patients TAKING 
  Carbamazepine, Phenytoin,
  Phenobarbital, or Primidoneb and NOT TAKING 
  Valproatea Weeks 1 and 2 25 mg every 
  other day 25 mg daily 50 mg daily Weeks 3 and 4 25 mg daily 50 mg daily 100 mg daily, in divided doses Week 5 50 mg daily 100 mg daily 200 mg daily, in divided doses Week 6 100 mg daily 200 mg daily 300 mg daily, in divided doses Week 7 100 mg daily 200 mg daily up to 400 mg daily, in divided doses Table 6. Dosage Adjustments to Lamotrigine Tablets for Patients With Bipolar Disorder Following Discontinuation of Psychotropic Medications Discontinuation of Psychotropic Drugs 
  (excluding Carbamazepine, Phenytoin, 
  Phenobarbital, Primidoneb, or 
  Valproatea) After Discontinuation of 
  Valproatea After Discontinuation of 
  Carbamazepine, Phenytoin, 
  Phenobarbital, or Primidoneb Current dose of lamotrigine tablets
  (mg/day)
  100 Current dose of lamotrigine tablets
  (mg/day)
  400

  a Valproate has been shown to inhibit glucuronidation and decrease the apparent clearance of lamotrigine [see Drug Interactions (7), Clinical Pharmacology (12.3)].

  b These drugs induce lamotrigine glucuronidation and increase clearance [see Drug Interactions (7), Clinical Pharmacology (12.3)]. Other drugs which have similar effects include estrogen-containing oral contraceptives [see Drug Interactions (7), Clinical Pharmacology (12.3)]. Dosing recommendations for oral contraceptives can be found in General Dosing Considerations [see Dosage and Administration (2.1)]. Patients on rifampin, or other drugs that induce lamotrigine glucuronidation and increase clearance, should follow the same dosing titration/maintenance regimen as that used with anticonvulsants that have this effect.

  Week 1 Maintain current dose of lamotrigine tablets 150 400 Week 2 Maintain current dose of lamotrigine tablets 200 300 Week 3 onward Maintain current dose of lamotrigine tablets 200 200

  The benefit of continuing treatment in patients who had been stabilized in an 8- to 16-week open-label phase with lamotrigine tablets was established in two randomized, placebo-controlled clinical maintenance trials [see Clinical Studies (14.2) ]. However, the optimal duration of treatment with lamotrigine tablets has not been established. Thus, patients should be periodically reassessed to determine the need for maintenance treatment.

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  2.1 General Dosing Considerations 

       Rash: There are suggestions, yet to be proven, that the risk of severe, potentially life-threatening rash may be increased by (1) coadministration of lamotrigine with valproate, (2) exceeding the recommended initial dose of lamotrigine, or (3) exceeding the recommended dose escalation for Lamotrigine. However, cases have occurred in the absence of these factors [see Boxed Warning]. Therefore, it is important that the dosing recommendations be followed closely.

       The risk of nonserious rash may be increased when the recommended initial dose and/or the rate of dose escalation for lamotrigine is exceeded and in patients with a history of allergy or rash to other AEDs.

       It is recommended that lamotrigine not be restarted in patients who discontinued due to rash associated with prior treatment with lamotrigine, unless the potential benefits clearly outweigh the risks. If the decision is made to restart a patient who has discontinued Lamotrigine, the need to restart with the initial dosing recommendations should be assessed. The greater the interval of time since the previous dose, the greater consideration should be given to restarting with the initial dosing recommendations. If a patient has discontinued lamotrigine for a period of more than 5 half-lives, it is recommended that initial dosing recommendations and guidelines be followed. The half-life of Lamotrigine is affected by other concomitant medications [see Clinical Pharmacology (12.3)].

       Lamotrigine Added to Drugs Known to Induce or Inhibit Glucuronidation: Because lamotrigine is metabolized predominantly by glucuronic acid conjugation, drugs that are known to induce or inhibit glucuronidation may affect the apparent clearance of lamotrigine. Drugs that induce glucuronidation include carbamazepine, phenytoin, phenobarbital, primidone, rifampin, estrogen-containing oral contraceptives, and the protease inhibitors lopinavir/ritonavir and atazanavir/ritonavir. Valproate inhibits glucuronidation. For dosing considerations for Lamotrigine in patients on estrogen-containing contraceptives and atazanavir/ritonavir, see below and Table 13. For dosing considerations for Lamotrigine in patients on other drugs known to induce or inhibit glucuronidation, see Table 1, Table 2, Table 5, Table 6, and Table 13.

       Target Plasma Levels for Patients With Epilepsy or Bipolar Disorder: A therapeutic plasma concentration range has not been established for lamotrigine. Dosing of Lamotrigine should be based on therapeutic response [see Clinical Pharmacology (12.3)].

       Women Taking Estrogen-Containing Oral Contraceptives: Starting Lamotrigine in Women Taking Estrogen-Containing Oral Contraceptives: Although estrogen-containing oral contraceptives have been shown to increase the clearance of lamotrigine [see Clinical Pharmacology (12.3)], no adjustments to the recommended dose-escalation guidelines for Lamotrigine should be necessary solely based on the use of estrogen-containing oral contraceptives. Therefore, dose escalation should follow the recommended guidelines for initiating adjunctive therapy with Lamotrigine based on the concomitant AED or other concomitant medications (see Table 1 or Table 5). See below for adjustments to maintenance doses of Lamotrigine in women taking estrogen-containing oral contraceptives.

       Adjustments to the Maintenance Dose of Lamotrigine In Women Taking Estrogen-Containing Oral Contraceptives:

       (1) Taking Estrogen-Containing Oral Contraceptives: In women not taking carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin and the protease inhibitors lopinavir/ritonavir and atazanavir/ritonavir that induce lamotrigine glucuronidation [see Drug Interactions (7), Clinical Pharmacology (12.3)], the maintenance dose of lamotrigine will in most cases need to be increased by as much as 2-fold over the recommended target maintenance dose to maintain a consistent lamotrigine plasma level.

       (2) Starting Estrogen-Containing Oral Contraceptives: In women taking a stable dose of Lamotrigine and not taking carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin and the protease inhibitors lopinavir/ritonavir and atazanavir/ritonavir that induce lamotrigine glucuronidation [see Drug Interactions (7), Clinical Pharmacology (12.3)], the maintenance dose will in most cases need to be increased by as much as 2-fold to maintain a consistent lamotrigine plasma level. The dose increases should begin at the same time that the oral contraceptive is introduced and continue, based on clinical response, no more rapidly than 50 to 100 mg/day every week. Dose increases should not exceed the recommended rate (see Table 1 or Table 5) unless lamotrigine plasma levels or clinical response support larger increases. Gradual transient increases in lamotrigine plasma levels may occur during the week of inactive hormonal preparation (pill-free week), and these increases will be greater if dose increases are made in the days before or during the week of inactive hormonal preparation. Increased lamotrigine plasma levels could result in additional adverse reactions, such as dizziness, ataxia, and diplopia. If adverse reactions attributable to Lamotrigine consistently occur during the pill-free week, dose adjustments to the overall maintenance dose may be necessary. Dose adjustments limited to the pill-free week are not recommended. For women taking Lamotrigine in addition to carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin and the protease inhibitors lopinavir/ritonavir and atazanavir/ritonavir that induce lamotrigine glucuronidation [see Drug Interactions (7), Clinical Pharmacology (12.3)], no adjustment to the dose of Lamotrigine should be necessary.

       (3) Stopping Estrogen-Containing Oral Contraceptives: In women not taking carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin and the protease inhibitors lopinavir/ritonavir and atazanavir/ritonavir that induce lamotrigine glucuronidation [see Drug Interactions (7), Clinical Pharmacology (12.3)], the maintenance dose of lamotrigine will in most cases need to be decreased by as much as 50% in order to maintain a consistent lamotrigine plasma level. The decrease in dose of Lamotrigine should not exceed 25% of the total daily dose per week over a 2-week period, unless clinical response or lamotrigine plasma levels indicate otherwise [see Clinical Pharmacology (12.3)]. In women taking Lamotrigine in addition to carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin and the protease inhibitors lopinavir/ritonavir and atazanavir/ritonavir that induce lamotrigine glucuronidation [see Drug Interactions (7), Clinical Pharmacology (12.3)], no adjustment to the dose of Lamotrigine should be necessary.

       Women and Other Hormonal Contraceptive Preparations or Hormone Replacement Therapy: The effect of other hormonal contraceptive preparations or hormone replacement therapy on the pharmacokinetics of lamotrigine has not been systematically evaluated. It has been reported that ethinylestradiol, not progestogens, increased the clearance of lamotrigine up to 2-fold, and the progestin-only pills had no effect on lamotrigine plasma levels. Therefore, adjustments to the dosage of Lamotrigine in the presence of progestogens alone will likely not be needed.

       Patients Taking Atazanavir/Ritonavir: While atazanavir/ritonavir does reduce the lamotrigine plasma concentration, no adjustments to the recommended dose-escalation guidelines for Lamotrigine should be necessary solely based on the use of atazanavir/ritonavir. Dose escalation should follow the recommended guidelines for initiating adjunctive therapy with Lamotrigine based on concomitant AED or other concomitant medications (see Tables 1, 2, and 5). In patients already taking maintenance doses of Lamotrigine and not taking glucuronidation inducers, the dose of Lamotrigine may need to be increased if atazanavir/ritonavir is added, or decreased if atazanavir/ritonavir is discontinued [see Clinical Pharmacology (12.3)].

       Patients With Hepatic Impairment: Experience in patients with hepatic impairment is limited. Based on a clinical pharmacology study in 24 subjects with mild, moderate, and severe liver impairment [see Use in Specific Populations (8.6), Clinical Pharmacology (12.3)], the following general recommendations can be made. No dosage adjustment is needed in patients with mild liver impairment. Initial, escalation, and maintenance doses should generally be reduced by approximately 25% in patients with moderate and severe liver impairment without ascites and 50% in patients with severe liver impairment with ascites. Escalation and maintenance doses may be adjusted according to clinical response.

       Patients With Renal Impairment: Initial doses of Lamotrigine should be based on patients' concomitant medications (see Tables 1-3 or Table 5); reduced maintenance doses may be effective for patients with significant renal impairment [see Use in Specific Populations (8.7), Clinical Pharmacology (12.3)]. Few patients with severe renal impairment have been evaluated during chronic treatment with lamotrigine. Because there is inadequate experience in this population, lamotrigine should be used with caution in these patients.

       Discontinuation Strategy: Epilepsy: For patients receiving lamotrigine in combination with other AEDs, a re-evaluation of all AEDs in the regimen should be considered if a change in seizure control or an appearance or worsening of adverse reactions is observed.

       If a decision is made to discontinue therapy with lamotrigine, a step-wise reduction of dose over at least 2 weeks (approximately 50% per week) is recommended unless safety concerns require a more rapid withdrawal [see Warnings and Precautions (5.9)].

       Discontinuing carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin and the protease inhibitors lopinavir/ritonavir and atazanavir/ritonavir that induce lamotrigine glucuronidation should prolong the half-life of lamotrigine; discontinuing valproate should shorten the half-life of lamotrigine.

       Bipolar Disorder: In the controlled clinical trials, there was no increase in the incidence, type, or severity of adverse reactions following abrupt termination of lamotrigine. In clinical trials in patients with bipolar disorder, 2 patients experienced seizures shortly after abrupt withdrawal of lamotrigine. However, there were confounding factors that may have contributed to the occurrence of seizures in these patients with bipolar disorder. Discontinuation of lamotrigine should involve a step-wise reduction of dose over at least 2 weeks (approximately 50% per week) unless safety concerns require a more rapid withdrawal [see Warnings and Precautions (5.9)].

  2.2 Epilepsy – Adjunctive Therapy

       This section provides specific dosing recommendations for patients older than 12 years and patients aged 2 to 12 years. Within each of these age-groups, specific dosing recommendations are provided depending upon concomitant AEDs or other concomitant medications (see Table 1 for patients older than 12 years and Table 2 for patients aged 2 to 12 years). A weight-based dosing guide for patients aged 2 to 12 years on concomitant valproate is provided in Table 3.

       Patients Older Than 12 Years: Recommended dosing guidelines are summarized in Table 1.

  Table 1 Escalation Regimen for Lamotrigine in Patients Older Than 12 Years With Epilepsy * Valproate has been shown to inhibit glucuronidation and decrease the apparent clearance of lamotrigine [see Drug Interactions ( 7 ), Clinical Pharmacology  ( 12.3 )]. † Drugs that induce lamotrigine glucuronidation and increase clearance, other than the specified antiepileptic drugs, include estrogen-containing oral contraceptives, rifampin, and the protease inhibitors lopinavir/ritonavir and atazanavir/ritonavir. Dosing recommendations for oral contraceptives and the protease inhibitor atazanavir/ritonavir can be found in General Dosing Considerations [see Dosage and Administration (2.1)]. Patients on rifampin and the protease inhibitor lopinavir/ritonavir should follow the same dosing titration/maintenance regimen used with antiepileptic drugs that induce glucuronidation and increase clearance [see Dosage and Administration (2.1), Drug Interactions (7), and Clinical Pharmacology (12.3)].   In Patients TAKING Valproate* In Patients NOT TAKING Carbamazepine, Phenytoin, Phenobarbital, Primidone†,or Valproate* In Patients TAKING Carbamazepine, Phenytoin, Phenobarbital, or Primidone† and NOT TAKING Valproate* Weeks 1 and 2 25 mg every other day 25 mg every day 50 mg/day Weeks 3 and 4 25 mg every day 50 mg/day 100 mg/day
  (in 2 divided doses) Week 5 onward to maintenance Increase by 25 to 50 mg/day every 1 to 2 weeks. Increase by 50 mg/day
  every 1 to 2 weeks. Increase by 100 mg/day every 1 to 2 weeks. Usual maintenance dose 100 to 200 mg/day with valproate alone
  
  100 to 400 mg/day with valproate and other drugs that induce glucuronidation
  (in 1 or 2 divided doses) 225 to 375 mg/day
  (in 2 divided doses) 300 to 500 mg/day  (in 2 divided doses)

        Patients Aged 2 to 12 Years: Recommended dosing guidelines are summarized in Table 2.

        Smaller starting doses and slower dose escalations than those used in clinical trials are recommended because of the suggestion that the risk of rash may be decreased by smaller starting doses and slower dose escalations. Therefore, maintenance doses will take longer to reach in clinical practice than in clinical trials. It may take several weeks to months to achieve an individualized maintenance dose. Maintenance doses in patients weighing less than 30 kg, regardless of age or concomitant AED, may need to be increased as much as 50%, based on clinical response.

  Table 2. Escalation Regimen for Lamotrigine in Patients Aged 2 to 12 Years With Epilepsy * Valproate has been shown to inhibit glucuronidation and decrease the apparent clearance of lamotrigine [see Drug Interactions (7), Clinical Pharmacology  (12.3)]. † Drugs that induce lamotrigine glucuronidation and increase clearance, other than the specified antiepileptic drugs, include estrogen-containing oral contraceptives, rifampin, and the protease inhibitors lopinavir/ritonavir and atazanavir/ritonavir. Dosing recommendations for oral contraceptives and the protease inhibitor atazanavir/ritonavir can be found in General Dosing Considerations [see Dosage and Administration (2.1)]. Patients on rifampin and the protease inhibitor lopinavir/ritonavir should follow the same dosing titration/maintenance regimen used with antiepileptic drugs that induce glucuronidation and increase clearance [see Dosage and Administration (2.1), Drug Interactions (7), and Clinical Pharmacology (12.3)].   In Patients TAKING Valproate* In Patients NOT TAKING Carbamazepine, Phenytoin, Phenobarbital,  Primidone† or
   Valproate* In Patients TAKING Carbamazepine, Phenytoin, Phenobarbital, or Primidone† and NOT TAKING Valproate* Weeks 1 and 2 0.15 mg/kg/day
   in 1 or 2 divided doses, rounded down to the nearest whole tablet (see Table 3 for weight-based dosing guide) 0.3 mg/kg/day
  in 1 or 2 divided doses, rounded down to the nearest whole tablet 0.6 mg/kg/day
  in 2 divided doses, rounded down to the nearest whole tablet Weeks 3 and 4 0.3 mg/kg/day
  in 1 or 2 divided doses, rounded down to the nearest whole tablet (see Table 3 for weight-based dosing guide) 0.6 mg/kg/day
   in 2 divided doses, rounded down to the nearest whole tablet 1.2 mg/kg/day
    in 2 divided doses, rounded down to the nearest whole tablet Week 5 onward to maintenance The dose should be increased every 1 to 2 weeks as follows: calculate 0.3 mg/kg/day, round this amount down to the nearest whole tablet, and add this amount to the previously administered daily dose. The dose should be increased every 1 to 2 weeks as follows: calculate 0.6 mg/kg/day, round this amount down to the nearest whole tablet, and add this amount to the previously administered daily dose. The dose should be increased every 1 to 2 weeks as follows: calculate 1.2 mg/kg/day, round this amount down to the nearest whole tablet, and add this amount to the previously administered daily dose. Usual maintenance dose 1 to 5 mg/kg/day
  (maximum 200 mg/day in 1 or 2 divided doses)
   1 to 3 mg/kg/day with valproate alone 4.5 to 7.5 mg/kg/day
  (maximum 300 mg/day in 2 divided doses) 5 to 15 mg/kg/day
  (maximum 400 mg/day in 2 divided doses) Maintenance dose in patients less than 30 kg May need to be increased by as much as 50%, based on clinical response. May need to be increased by as much as 50%, based on clinical response. May need to be increased by as much as 50%, based on clinical response. Note: Only whole tablets should be used for dosing. Table 3. The Initial Weight-Based Dosing Guide for Patients Aged 2 to 12 Years Taking Valproate (Weeks 1 to 4) With Epilepsy If the patient’s weight is Give this daily dose, using the most appropriate combination of Lamotrigine 2-mg and 5-mg tablets Greater than And less than Weeks 1 and 2 Weeks 3 and 4 6.7 kg 14 kg 2 mg every other day 2 mg every day 14.1 kg 27 kg 2 mg every day 4 mg every day 27.1 kg 34 kg 4 mg every day 8 mg every day 34.1 kg 40 kg 5 mg every day 10 mg every day

        Usual Adjunctive Maintenance Dose for Epilepsy: The usual maintenance doses identified in Tables 1 and 2 are derived from dosing regimens employed in the placebo-controlled adjunctive trials in which the efficacy of lamotrigine was established. In patients receiving multidrug regimens employing carbamazepine, phenytoin, phenobarbital, or primidone without valproate, maintenance doses of adjunctive lamotrigine as high as 700 mg/day have been used. In patients receiving valproate alone, maintenance doses of adjunctive lamotrigine as high as 200 mg/day have been used. The advantage of using doses above those recommended in Tables 1- 4 has not been established in controlled trials.

  2.3 Epilepsy – Conversion From Adjunctive Therapy to Monotherapy

        The goal of the transition regimen is to attempt to maintain seizure control while mitigating the risk of serious rash associated with the rapid titration of lamotrigine.

        The recommended maintenance dose of lamotrigine as monotherapy is 500 mg/day given in 2 divided doses.

        To avoid an increased risk of rash, the recommended initial dose and subsequent dose escalations for lamotrigine should not be exceeded [see Boxed Warning].

        Conversion From Adjunctive Therapy With Carbamazepine, Phenytoin, Phenobarbital, or Primidone to Monotherapy With Lamotrigine: After achieving a dose of 500 mg/day of lamotrigine using the guidelines in Table 1, the concomitant enzyme-inducing AED should be withdrawn by 20% decrements each week over a 4-week period. The regimen for the withdrawal of the concomitant AED is based on experience gained in the controlled monotherapy clinical trial.

        Conversion From Adjunctive Therapy With Valproate to Monotherapy With Lamotrigine: The conversion regimen involves the 4 steps outlined in Table 4.

  Table 4. Conversion From Adjunctive Therapy With Valproate to Monotherapy With Lamotrigine in Patients Aged 16 Years and Older With Epilepsy  

  Lamotrigine

  Valproate

  Step 1

  Achieve a dose of 200 mg/day according to guidelines in Table 1.

  Maintain established stable dose.

  Step 2

  Maintain at 200 mg/day.

  Decrease dose by decrements no greater than 500 mg/day/week to 500 mg/day and then maintain for 1 week.

  Step 3

  Increase to 300 mg/day and maintain for 1 week.

  Simultaneously decrease to 250 mg/day and maintain for 1 week.

  Step 4

  Increase by 100 mg/day every week to achieve maintenance dose of 500 mg/day.

  Discontinue.

        Conversion From Adjunctive Therapy With Antiepileptic Drugs Other Than Carbamazepine, Phenytoin, Phenobarbital, Primidone, or Valproate to Monotherapy With Lamotrigine: No specific dosing guidelines can be provided for conversion to monotherapy with lamotrigine with AEDs other than carbamazepine, phenytoin, phenobarbital, primidone, or valproate.

  2.4 Bipolar Disorder

        The goal of maintenance treatment with lamotrigine is to delay the time to occurrence of mood episodes (depression, mania, hypomania, mixed episodes) in patients treated for acute mood episodes with standard therapy. The target dose of lamotrigine is 200 mg/day (100 mg/day in patients taking valproate, which decreases the apparent clearance of lamotrigine, and 400 mg/day in patients not taking valproate and taking either carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin and the protease inhibitor lopinavir/ritonavir that  increase the apparent clearance of lamotrigine). In the clinical trials, doses up to 400 mg/day as monotherapy were evaluated; however, no additional benefit was seen at 400 mg/day compared with 200 mg/day [see Clinical Studies (14.2)]. Accordingly, doses above 200 mg/day are not recommended. Treatment with lamotrigine is introduced, based on concurrent medications, according to the regimen outlined in Table 5. If other psychotropic medications are withdrawn following stabilization, the dose of lamotrigine should be adjusted. For patients discontinuing valproate, the dose of lamotrigine should be doubled over a 2-week period in equal weekly increments (see Table 6). For patients discontinuing carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin and the protease inhibitors lopinavir/ritonavir and atazanavir/ritonavir that induce lamotrigine glucuronidation, the dose of lamotrigine should remain constant for the first week and then should be decreased by half over a 2-week period in equal weekly decrements (see Table 6). The dose of lamotrigine may then be further adjusted to the target dose (200 mg) as clinically indicated.

        If other drugs are subsequently introduced, the dose of lamotrigine may need to be adjusted. In particular, the introduction of valproate requires reduction in the dose of lamotrigine [see Drug Interactions (7), Clinical Pharmacology (12.3)].

        To avoid an increased risk of rash, the recommended initial dose and subsequent dose escalations of Lamotrigine should not be exceeded [see Boxed Warning].

   

  Table 5. Escalation Regimen for Lamotrigine in Patients With Bipolar Disorder * Valproate has been shown to inhibit glucuronidation and decrease the apparent clearance of lamotrigine [see Drug Interactions (7), Clinical Pharmacology (12.3)]. † Drugs that induce lamotrigine glucuronidation and increase clearance, other than the specified antiepileptic drugs, include estrogen-containing oral contraceptives, rifampin, and the protease inhibitors lopinavir/ritonavir and atazanavir/ritonavir. Dosing recommendations for oral contraceptives and the protease inhibitor atazanavir/ritonavir can be found in General Dosing Considerations [see Dosage and Administration (2.1)]. Patients on rifampin and the protease inhibitor lopinavir/ritonavir should follow the same dosing titration/maintenance regimen used with antiepileptic drugs that induce glucuronidation and increase clearance [see Dosage and Administration (2.1), Drug Interactions (7), and Clinical Pharmacology (12.3)].   In Patients TAKING Valproate* In Patients NOT TAKING Carbamazepine, Phenytoin, Phenobarbital, Primidone†, or Valproate* In Patients TAKING Carbamazepine, Phenytoin, Phenobarbital, or Primidone† and NOT TAKING Valproate* Weeks 1 and 2 25 mg every other day 25 mg daily 50 mg daily Weeks 3 and 4 25 mg daily 50 mg daily 100 mg daily, in divided doses Week 5 50 mg daily 100 mg daily 200 mg daily, in divided doses Week 6 100 mg daily 200 mg daily 300 mg daily, in divided doses Week 7 100 mg daily 200 mg daily up to 400 mg daily, in divided doses Table 6. Dosage Adjustments to Lamotrigine in Patients With Bipolar Disorder Following Discontinuation of Psychotropic Medications * Valproate has been shown to inhibit glucuronidation and decrease the apparent clearance of     lamotrigine [see Drug Interactions (7), Clinical Pharmacology (12.3)]. † Drugs that induce lamotrigine glucuronidation and increase clearance, other than the specified antiepileptic drugs, include estrogen-containing oral contraceptives, rifampin, and the protease inhibitors lopinavir/ritonavir and atazanavir/ritonavir. Dosing recommendations for oral contraceptives and the protease inhibitor atazanavir/ritonavir can be found in General Dosing Considerations [see Dosage and Administration (2.1)]. Patients on rifampin and the protease inhibitor lopinavir/ritonavir should follow the same dosing titration/maintenance regimen used with antiepileptic drugs that induce glucuronidation and increase clearance [see Dosage and Administration (2.1), Drug Interactions (7), and Clinical Pharmacology (12.3)].    

  Discontinuation of Psychotropic Drugs (excluding Valproate*Carbamazepine, Phenytoin, Phenobarbital, Primidone†) After Discontinuation of Valproate* After Discontinuation of Carbamazepine, Phenytoin, Phenobarbital, or Primidone† Current dose of lamotrigine (mg/day) 100

  Current dose of lamotrigine (mg/day) 400

  Week 1 Maintain current dose of Lamotrigine 150 400 Week 2 Maintain current dose of Lamotrigine 200 300 Week 3 onward Maintain current dose of Lamotrigine 200 200

        The benefit of continuing treatment in patients who had been stabilized in an 8- to 16-week open-label phase with Lamotrigine was established in 2 randomized, placebo-controlled clinical maintenance trials [see Clinical Studies (14.2)]. However, the optimal duration of treatment with Lamotrigine has not been established. Thus, patients should be periodically reassessed to determine the need for maintenance treatment.

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  2.1 General Dosing Considerations

  Rash: There are suggestions, yet to be proven, that the risk of severe, potentially life-threatening rash may be increased by (1) coadministration of lamotrigine tablets with valproate, (2) exceeding the recommended initial dose of lamotrigine tablets, or (3) exceeding the recommended dose escalation for lamotrigine tablets. However, cases have occurred in the absence of these factors [see Boxed Warning ]. Therefore, it is important that the dosing recommendations be followed closely.

  The risk of nonserious rash may be increased when the recommended initial dose and/or the rate of dose escalation of lamotrigine tablet is exceeded and in patients with a history of allergy or rash to other AEDs.

  It is recommended that lamotrigine tablets not be restarted in patients who discontinued due to rash associated with prior treatment with lamotrigine, unless the potential benefits clearly outweigh the risks. If the decision is made to restart a patient who has discontinued lamotrigine, the need to restart with the initial dosing recommendations should be assessed. The greater the interval of time since the previous dose, the greater consideration should be given to restarting with the initial dosing recommendations. If a patient has discontinued lamotrigine for a period of more than 5 half-lives, it is recommended that initial dosing recommendations and guidelines be followed. The half-life of lamotrigine is affected by other concomitant medications [see Clinical Pharmacology (12.3) ].

  Lamotrigine Tablets Added to Drugs Known to Induce or Inhibit Glucuronidation: Drugs other than those listed in the Clinical Pharmacology section [see Clinical Pharmacology (12.3) ] have not been systematically evaluated in combination with lamotrigine. Because lamotrigine is metabolized predominantly by glucuronic acid conjugation, drugs that are known to induce or inhibit glucuronidation may affect the apparent clearance of lamotrigine and doses of lamotrigine tablets may require adjustment based on clinical response.

  Target Plasma Levels for Patients With Epilepsy or Bipolar Disorder: A therapeutic plasma concentration range has not been established for lamotrigine. Dosing of lamotrigine tablets should be based on therapeutic response [see Clinical Pharmacology (12.3) ].

  Women Taking Estrogen-Containing Oral Contraceptives: Starting Lamotrigine Tablets  in Women Taking Estrogen-Containing Oral Contraceptives: Although estrogen-containing oral contraceptives have been shown to increase the clearance of lamotrigine [see Clinical Pharmacology (12.3) ], no adjustments to the recommended dose-escalation guidelines for lamotrigine tablets should be necessary solely based on the use of estrogen-containing oral contraceptives. Therefore, dose escalation should follow the recommended guidelines for initiating adjunctive therapy with lamotrigine tablets based on the concomitant AED or other concomitant medications (see Table 1 or Table 5). See below for adjustments to maintenance doses of lamotrigine tablets in women taking estrogen-containing oral contraceptives.

  Adjustments to the Maintenance Dose of Lamotrigine Tablets In Women Taking Estrogen-Containing Oral Contraceptives:

  (1) Taking Estrogen-Containing Oral Contraceptives: For women not taking carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin that induce lamotrigine glucuronidation [see Drug Interactions (7), Clinical Pharmacology (12.3)], the maintenance dose of lamotrigine  tablets will in most cases need to be increased, by as much as 2-fold over the recommended target maintenance dose, in order to maintain a consistent lamotrigine plasma level [see Clinical Pharmacology (12.3) ].

  (2) Starting Estrogen-Containing Oral Contraceptives: In women taking a stable dose of lamotrigine tablets and not taking carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin that induce lamotrigine glucuronidation [see Drug Interactions (7), Clinical Pharmacology (12.3)], the maintenance dose will in most cases need to be increased by as much as 2-fold in order to maintain a consistent lamotrigine plasma level. The dose increases should begin at the same time that the oral contraceptive is introduced and continue, based on clinical response, no more rapidly than 50 to 100 mg/day every week. Dose increases should not exceed the recommended rate (see Table 1 or Table 5) unless lamotrigine plasma levels or clinical response support larger increases. Gradual transient increases in lamotrigine plasma levels may occur during the week of inactive hormonal preparation ("pill-free" week), and these increases will be greater if dose increases are made in the days before or during the week of inactive hormonal preparation. Increased lamotrigine plasma levels could result in additional adverse reactions, such as dizziness, ataxia, and diplopia. If adverse reactions attributable to lamotrigine tablets consistently occur during the "pill-free" week, dose adjustments to the overall maintenance dose may be necessary. Dose adjustments limited to the "pill-free" week are not recommended. For women taking lamotrigine tablets in addition to carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin that induce lamotrigine glucuronidation [see Drug Interactions (7), Clinical Pharmacology (12.3)], no adjustment to the dose of lamotrigine tablets should be necessary.

  (3) Stopping Estrogen-Containing Oral Contraceptives: For women not taking carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin that induce lamotrigine glucuronidation [see Drug Interactions (7), Clinical Pharmacology (12.3)], the maintenance dose of lamotrigine tablets will in most cases need to be decreased by as much as 50% in order to maintain a consistent lamotrigine plasma level. The decrease in dose of lamotrigine tablets should not exceed 25% of the total daily dose per week over a 2-week period, unless clinical response or lamotrigine plasma levels indicate otherwise [see Clinical Pharmacology (12.3) ]. For women taking lamotrigine tablets in addition to carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin that induce lamotrigine glucuronidation [see Drug Interactions (7), Clinical Pharmacology (12.3)], no adjustment to the dose of lamotrigine tablets should be necessary.

  Women and Other Hormonal Contraceptive Preparations or Hormone Replacement Therapy: The effect of other hormonal contraceptive preparations or hormone replacement therapy on the pharmacokinetics of lamotrigine has not been systematically evaluated. It has been reported that ethinylestradiol, not progestogens, increased the clearance of lamotrigine up to 2-fold, and the progestin-only pills had no effect on lamotrigine plasma levels. Therefore, adjustments to the dosage of lamotrigine tablets in the presence of progestogens alone will likely not be needed.

  Patients With Hepatic Impairment: Experience in patients with hepatic impairment is limited. Based on a clinical pharmacology study in 24 patients with mild, moderate, and severe liver impairment [see Use in Specific Populations (8.6) , Clinical Pharmacology (12.3) ], the following general recommendations can be made. No dosage adjustment is needed in patients with mild liver impairment. Initial, escalation, and maintenance doses should generally be reduced by approximately 25% in patients with moderate and severe liver impairment without ascites and 50% in patients with severe liver impairment with ascites. Escalation and maintenance doses may be adjusted according to clinical response.

  Patients With Renal Impairment: Initial doses of lamotrigine tablets should be based on patients' concomitant medications (see Tables 1-3 or Table 5); reduced maintenance doses may be effective for patients with significant renal impairment [see Use in Specific Populations (8.7) , Clinical Pharmacology (12.3) ]. Few patients with severe renal impairment have been evaluated during chronic treatment with lamotrigine tablets. Because there is inadequate experience in this population, lamotrigine tablets should be used with caution in these patients.

  Discontinuation Strategy:

  Epilepsy: For patients receiving lamotrigine tablets in combination with other AEDs, a reevaluation of all AEDs in the regimen should be considered if a change in seizure control or an appearance or worsening of adverse reactions is observed.

  If a decision is made to discontinue therapy with lamotrigine tablets, a step-wise reduction of dose over at least 2 weeks (approximately 50% per week) is recommended unless safety concerns require a more rapid withdrawal [see Warnings and Precautions (5.9) ].

  Discontinuing carbamazepine, phenytoin, phenobarbital, primidone or other drugs such as rifampin that induce lamotrigine glucuronidation should prolong the half-life of lamotrigine; discontinuing valproate should shorten the half-life of lamotrigine.

  Bipolar Disorder: In the controlled clinical trials, there was no increase in the incidence, type, or severity of adverse reactions following abrupt termination of lamotrigine tablets. In clinical trials in patients with Bipolar Disorder, 2 patients experienced seizures shortly after abrupt withdrawal of lamotrigine tablets. However, there were confounding factors that may have contributed to the occurrence of seizures in these bipolar patients. Discontinuation of lamotrigine tablets should involve a step-wise reduction of dose over at least 2 weeks (approximately 50% per week) unless safety concerns require a more rapid withdrawal [see Warnings and Precautions (5.9) ].

  2.2 Epilepsy – Adjunctive Therapy

  This section provides specific dosing recommendations for patients greater than 12 years of age and patients 2 to 12 years of age. Within each of these age-groups, specific dosing recommendations are provided depending upon concomitant AED or other concomitant medications (Table 1 for patients greater than 12 years of age and Table 2 for patients 2 to 12 years of age). A weight-based dosing guide for patients 2 to 12 years of age on concomitant valproate is provided in Table 3.

  Patients Over 12 Years of Age: Recommended dosing guidelines are summarized in Table 1.

  Table 1. Escalation Regimen for Lamotrigine Tablets in Patients Over 12 Years of Age With Epilepsy a Valproate has been shown to inhibit glucuronidation and decrease the apparent clearance of lamotrigine [see Drug Interactions (7), Clinical Pharmacology (12.3)]. b These drugs induce lamotrigine glucuronidation and increase clearance [see Drug Interactions (7), Clinical Pharmacology (12.3)]. Other drugs that have similar effects include estrogen-containing oral contraceptives [see Drug Interactions (7), Clinical Pharmacology (12.3)]. Dosing recommendations for oral contraceptives can be found in General Dosing Considerations [see Dosage and Administration (2.1)]. Patients on rifampin, or other drugs that induce lamotrigine glucuronidation and increase clearance, should follow the same dosing titration/maintenance regimen as that used with anticonvulsants that have this effect.

  For 
  

  For Patients NOT TAKING 
  

  For Patients 
  

  Patients
  

  Carbamazepine, 
  

  TAKING
  

  TAKING
  

  Phenytoin,
  

  Carbamazepine,
  

  Valproatea
  

  Phenobarbital,
  

  Phenytoin, 
  

  or Primidoneb,  
  

  Phenobarbital,
  

  or Valproatea
  

  or Primidoneb
  

  and NOT TAKING
  

  Valproatea
  

  Weeks 1 and 2
  

  25 mg every other day
  

  25 mg every day
  

  50 mg/day
  

  Weeks 3 and 4
  

  25 mg every day
  

  50 mg/day
  

  100 mg/day
  (in 2 divided doses)
  

  Weeks 5 onwards to 
  maintenance
  

  Increase by 25 to 
  50 mg/day every 1 to 2 weeks
  

  Increase by 50
  mg/day every 1
  to 2 weeks
  

  Increase by 
  100 mg/day every 
  1 to 2 weeks.
  

  Usual maintenance 
  dose
  

  100 to 200 mg/day
  with valproate alone
  

  225 to 375 mg/day
  (in 2 divided doses).
  

  300 to 500 mg/day
  (in 2 divided doses).
  

  100 to 400 mg/day
  with valproate
  and other drugs that induce glucuronidation
  

  (in 1 or 2 divided doses)
  

  Patients 2 to 12 Years Of Age: Recommended dosing guidelines are summarized in Table 2.

  Smaller starting doses and slower dose escalations than those used in clinical trials are recommended because of the suggestion that the risk of rash may be decreased by smaller starting doses and slower dose escalations. Therefore, maintenance doses will take longer to reach in clinical practice than in clinical trials. It may take several weeks to months to achieve an individualized maintenance dose. Maintenance doses in patients weighing less than 30 kg, regardless of age or concomitant AED, may need to be increased as much as 50%, based on clinical response.

  Table 2. Escalation Regimen for Lamotrigine Tablets in Patients 2 to 12 Years of Age With Epilepsy Note: Only whole tablets should be used for dosing. a Valproate has been shown to inhibit glucuronidation and decrease the apparent clearance of lamotrigine [see Drug Interactions (7), Clinical Pharmacology (12.3)]. b These drugs induce lamotrigine glucuronidation and increase clearance [see Drug Interactions (7), Clinical Pharmacology (12.3)]. Other drugs which have similar effects include estrogen-containing oral contraceptives [see Drug Interactions (7), Clinical Pharmacology (12.3)]. Dosing recommendations for oral contraceptives can be found in General Dosing Considerations [see Dosage and Administration (2.1)]. Patients on rifampin, or other drugs that induce lamotrigine glucuronidation and increase clearance, should follow the same dosing titration/maintenance regimen as that used with anticonvulsants that have this effect.

  For Patients TAKING 
  Valproatea
  

  For Patients NOT 
  TAKING Carbamazepine, Phenytoin, 
  Phenobarbital, Primidoneb, or 
  Valproatea
  

  For Patients TAKING 
  Carbamazepine, Phenytoin, Phenobarbital, or 
  Primidoneb and NOT 
  TAKING Valproatea
  

  Weeks 1 and 2
  

  0.15 mg/kg/day
  in 1 or 2 divided doses, rounded down to the 
  nearest whole tablet (see Table 3 for weight 
  based dosing guide).
  

  0.3 mg/kg/day
  in 1 or 2 divided doses, rounded down to the 
  nearest whole tablet.
  

  0.6 mg/kg/day
  in 2 divided doses, rounded down to the 
  nearest whole tablet.
  

  Weeks 3 and 4
  

  0.3 mg/kg/day
  in 1 or 2 divided doses,
  rounded down to the 
  nearest whole tablet 
  (see Table 3 for weight 
  based dosing guide).
  

  0.6 mg/kg/day
  in 2 divided doses,
  rounded down to the 
  nearest whole tablet.
  

  1.2 mg/kg/day
  in 2 divided doses, 
  rounded down to the 
  nearest whole tablet.
  

  Weeks 5 
  onwards to 
  maintenance
  

  The dose should be increased every 
  1 to 2 weeks as follows:
  calculate 0.3 mg/kg/day, round this amount 
  down to the nearest whole tablet, and 
  add this amount to the 
  previously administered daily dose.
  

  The dose should be increased every 
  1 to 2 weeks as follows:
  calculate 0.6 mg/kg/day, round this amount 
  down to the nearest whole tablet, and 
  add this amount to the 
  previously administered daily dose
  

  The dose should be increased every 
  1 to 2 weeks as follows:
  calculate 1.2 mg/kg/day, round this amount 
  down to the nearest whole tablet, and 
  add this amount to the 
  previously administered daily dose
  

  Usual 
  Maintenance 
  Dose
  

  1 to 5 mg/kg/day
  (maximum 200 mg/day 
  in 1 or 2 divided doses).
  1 to 3 mg/kg/day with valproate alone
  

  4.5 to 7.5 mg/kg/day
  (maximum 300 mg/day 
  in 2 divided doses)
  

  5 to 15 mg/kg/day
  (maximum 400 mg/day 
  in 2 divided doses)
  

  Maintenance dose in 
  patients 
  less than 30 kg
  

  May need to be increased 
  by as much as 50%, 
  based on clinical response
  

  May need to be increased 
  by as much as 50%, 
  based on clinical response
  

  May need to be increased 
  by as much as 50%, based 
  on clinical response
  

  Table 3. The Initial Weight-Based Dosing Guide for Patients 2 to 12 Years Taking Valproate (Weeks 1 to 4) With Epilepsy If the patient’s weight is
  Give this daily dose, using the most appropriate combination of Lamotrigine 2-mg and 5-mg tablets
  Greater than
  And less than
  Weeks 1 and 2
  Weeks 3 and 4
  

  6.7 kg
  

  14 kg
  

  2 mg every other day
  

  2 mg every day
  

  14.1 kg
  

  27 kg
  

  2 mg every day
  

  4 mg every day
  

  27.1 kg
  

  34 kg
  

  4 mg every day
  

  8 mg every day
  

  34.1 kg
  

  40 kg
  

  5 mg every day
  

  10 mg every day
  

  Usual Adjunctive Maintenance Dose for Epilepsy: The usual maintenance doses identified in Tables 1 and 2 are derived from dosing regimens employed in the placebo-controlled adjunctive studies in which the efficacy of lamotrigine tablets was established. In patients receiving multidrug regimens employing carbamazepine, phenytoin, phenobarbital, or primidone without valproate, maintenance doses of adjunctive lamotrigine tablets as high as 700 mg/day have been used. In patients receiving valproate alone, maintenance doses of adjunctive lamotrigine tablets as high as 200 mg/day have been used. The advantage of using doses above those recommended in Tables 1 through 4 has not been established in controlled trials.

  2.3 Epilepsy – Conversion From Adjunctive Therapy to Monotherapy

  The goal of the transition regimen is to effect the conversion to monotherapy with lamotrigine tablets under conditions that ensure adequate seizure control while mitigating the risk of serious rash associated with the rapid titration of lamotrigine tablets.

  The recommended maintenance dose of lamotrigine tablets as monotherapy is 500 mg/day given in two divided doses.

  To avoid an increased risk of rash, the recommended initial dose and subsequent dose escalations of lamotrigine tablets should not be exceeded [see Boxed Warning].

  Conversion From Adjunctive Therapy With Carbamazepine, Phenytoin, Phenobarbital, or Primidone to Monotherapy With Lamotrigine Tablets: After achieving a dose of 500 mg/day of lamotrigine tablets according to the guidelines in Table 1, the concomitant AED should be withdrawn by 20% decrements each week over a 4-week period. The regimen for the withdrawal of the concomitant AED is based on experience gained in the controlled monotherapy clinical trial.

  Conversion from Adjunctive Therapy With Valproate to Monotherapy With Lamotrigine Tablets:

  The conversion regimen involves 4 steps outlined in Table 4.

  Table 4. Conversion From Adjunctive Therapy With Valproate to Monotherapy With Lamotrigine Tablets in Patients ≥16 Years of Age with Epilepsy

  Lamotrigine Tablets
  

  Valproate
  

  Step 1
  

  Achieve a dose of 200 mg/day according to
  guidelines in Table 1
  (if not already on 200 mg/day).
  

  Maintain previous stable dose.
  

  Step 2
  

  Maintain at 200 mg/day.
  

  Decrease to 500 mg/day by decrements no greater than
  500 mg/day/week and then maintain the dose of
  500 mg/day for 1 week.
  

  Step 3
  

  Increase to 300 mg/day and maintain for 1 week.
  

  Simultaneously decrease to
  250 mg/day and maintain for 1 week.
  

  Step 4
  

  Increase by 100 mg/day every
  week to achieve maintenance dose of 500 mg/day.
  

  Discontinue.
  

  Conversion from Adjunctive Therapy With AEDs Other Than Carbamazepine, Phenytoin, Phenobarbital, Primidone, or Valproate to Monotherapy With Lamotrigine Tablets: No specific dosing guidelines can be provided for conversion to monotherapy with lamotrigine tablets with AEDs other than carbamazepine, phenobarbital, phenytoin, primidone, or valproate.

  2.4 Bipolar Disorder

  The goal of maintenance treatment with lamotrigine tablets is to delay the time to occurrence of mood episodes (depression, mania, hypomania, mixed episodes) in patients treated for acute mood episodes with standard therapy. The target dose of lamotrigine tablets is 200 mg/day (100 mg/day in patients taking valproate, which decreases the apparent clearance of lamotrigine, and 400 mg/day in patients not taking valproate and taking either carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin that increase the apparent clearance of lamotrigine). In the clinical trials, doses up to 400 mg/day as monotherapy were evaluated; however, no additional benefit was seen at 400 mg/day compared with 200 mg/day [see Clinical Studies (14.2) ]. Accordingly, doses above 200 mg/day are not recommended. Treatment with lamotrigine tablets is introduced, based on concurrent medications, according to the regimen outlined in Table 5. If other psychotropic medications are withdrawn following stabilization, the dose of lamotrigine tablets should be adjusted. For patients discontinuing valproate, the dose of lamotrigine tablets should be doubled over a 2-week period in equal weekly increments (see Table 6). For patients discontinuing carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin that induce lamotrigine glucuronidation, the dose of lamotrigine tablets should remain constant for the first week and then should be decreased by half over a 2-week period in equal weekly decrements (see Table 6). The dose of lamotrigine tablets may then be further adjusted to the target dose (200 mg) as clinically indicated.

  If other drugs are subsequently introduced, the dose of lamotrigine tablets may need to be adjusted. In particular, the introduction of valproate requires reduction in the dose of lamotrigine tablets [see Drug Interactions (7) , Clinical Pharmacology (12.3) ].

  To avoid an increased risk of rash, the recommended initial dose and subsequent dose escalations of lamotrigine tablets should not be exceeded [see Boxed Warning ].

  Table 5. Escalation Regimen for Lamotrigine Tablets for Patients With Bipolar Disorder a Valproate has been shown to inhibit glucuronidation and decrease the apparent clearance of lamotrigine [see Drug Interactions (7), Clinical Pharmacology (12.3)]. b These drugs induce lamotrigine glucuronidation and increase clearance [see Drug Interactions (7), Clinical Pharmacology (12.3)]. Other drugs which have similar effects include estrogen-containing oral contraceptives [see Drug Interactions (7), Clinical Pharmacology (12.3)]. Dosing recommendations for oral contraceptives can be found in General Dosing Considerations [see Dosage and Administration (2.1)]. Patients on rifampin, or other drugs that induce lamotrigine glucuronidation and increase clearance, should follow the same dosing titration/maintenance regimen as that used with anticonvulsants that have this effect.

  For Patients TAKING 
  Valproatea
  

  For Patients NOT TAKING 
  Carbamazepine, Phenytoin, Phenobarbital, 
  Primidoneb, or Valproatea
  

  For Patients TAKING 
  Carbamazepine, Phenytoin,
  Phenobarbital, or Primidoneb and NOT TAKING 
  Valproatea
  

  Weeks 1 and 2
  

  25 mg every 
  other day
  

  25 mg daily
  

  50 mg daily
  

  Weeks 3 and 4
  

  25 mg daily
  

  50 mg daily
  

  100 mg daily, in divided doses
  

  Week 5
  

  50 mg daily
  

  100 mg daily
  

  200 mg daily, in divided doses
  

  Week 6
  

  100 mg daily
  

  200 mg daily
  

  300 mg daily, in divided doses
  

  Week 7
  

  100 mg daily
  

  200 mg daily
  

  up to 400 mg daily, in divided doses
  

  Table 6. Dosage Adjustments to Lamotrigine Tablets for Patients With Bipolar Disorder Following Discontinuation of Psychotropic Medications Discontinuation of Psychotropic Drugs 
  (excluding Carbamazepine, Phenytoin, 
  Phenobarbital, Primidoneb, or 
  Valproatea)
  After Discontinuation of 
  Valproatea
  After Discontinuation of 
  Carbamazepine, Phenytoin, 
  Phenobarbital, or Primidoneb
  Current dose of lamotrigine tablets
  (mg/day)
  100
  Current dose of lamotrigine tablets
  (mg/day)
  400
  a Valproate has been shown to inhibit glucuronidation and decrease the apparent clearance of lamotrigine [see Drug Interactions (7), Clinical Pharmacology (12.3)]. b These drugs induce lamotrigine glucuronidation and increase clearance [see Drug Interactions (7), Clinical Pharmacology (12.3)]. Other drugs which have similar effects include estrogen-containing oral contraceptives [see Drug Interactions (7), Clinical Pharmacology (12.3)]. Dosing recommendations for oral contraceptives can be found in General Dosing Considerations [see Dosage and Administration (2.1)]. Patients on rifampin, or other drugs that induce lamotrigine glucuronidation and increase clearance, should follow the same dosing titration/maintenance regimen as that used with anticonvulsants that have this effect.

  Week 1
  

  Maintain current dose of lamotrigine tablets
  

  150
  

  400
  

  Week 2
  

  Maintain current dose of lamotrigine tablets
  

  200
  

  300
  

  Week 3 onward
  

  Maintain current dose of lamotrigine tablets
  

  200
  

  200
  

  The benefit of continuing treatment in patients who had been stabilized in an 8- to 16-week open-label phase with lamotrigine tablets was established in two randomized, placebo-controlled clinical maintenance trials [see Clinical Studies (14.2) ]. However, the optimal duration of treatment with lamotrigine tablets has not been established. Thus, patients should be periodically reassessed to determine the need for maintenance treatment.

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  Dosing is based on concomitant medications, indication, and patient age. ( 2.2 , 2.4 ) To avoid an increased risk of rash, the recommended initial dose and subsequent dose escalations should not be exceeded. ( 2.1 ) Do not restart lamotrigine in patients who discontinued due to rash unless the potential benefits clearly outweigh the risks. ( 2.1 ) Adjustments to maintenance doses will in most cases be required in patients starting or stopping estrogen-containing oral contraceptives. ( 2.1 , 5.8 ) Lamotrigine tablets should be discontinued over a period of at least 2 weeks (approximately 50% reduction per week). ( 2.1 , 5.9 )

  Epilepsy

  Adjunctive therapy—See Table 1 for patients >12 years of age and Tables 2 and 3 for patients 2 to 12 years. ( 2.2 ) Conversion to monotherapy—See Table 4. ( 2.3 )

  Bipolar Disorder: See Tables 5 and 6 ( 2.4 )

   

  Rash: There are suggestions, yet to be proven, that the risk of severe, potentially life-threatening rash may be increased by (1) coadministration of lamotrigine tablets with valproate, (2) exceeding the recommended initial dose of lamotrigine tablets, or (3) exceeding the recommended dose escalation for lamotrigine tablets. However, cases have occurred in the absence of these factors [see Boxed Warning ]. Therefore, it is important that the dosing recommendations be followed closely.

  The risk of nonserious rash may be increased when the recommended initial dose and/or the rate of dose escalation of lamotrigine tablet is exceeded and in patients with a history of allergy or rash to other AEDs.

  It is recommended that lamotrigine tablets not be restarted in patients who discontinued due to rash associated with prior treatment with lamotrigine, unless the potential benefits clearly outweigh the risks. If the decision is made to restart a patient who has discontinued lamotrigine, the need to restart with the initial dosing recommendations should be assessed. The greater the interval of time since the previous dose, the greater consideration should be given to restarting with the initial dosing recommendations. If a patient has discontinued lamotrigine for a period of more than 5 half-lives, it is recommended that initial dosing recommendations and guidelines be followed. The half-life of lamotrigine is affected by other concomitant medications [see Clinical Pharmacology (12.3) ].

  Lamotrigine Tablets Added to Drugs Known to Induce or Inhibit Glucuronidation: Drugs other than those listed in the Clinical Pharmacology section [see Clinical Pharmacology (12.3) ] have not been systematically evaluated in combination with lamotrigine. Because lamotrigine is metabolized predominantly by glucuronic acid conjugation, drugs that are known to induce or inhibit glucuronidation may affect the apparent clearance of lamotrigine and doses of lamotrigine tablets may require adjustment based on clinical response.

  Target Plasma Levels for Patients With Epilepsy or Bipolar Disorder: A therapeutic plasma concentration range has not been established for lamotrigine. Dosing of lamotrigine tablets should be based on therapeutic response [see Clinical Pharmacology (12.3) ].

  Women Taking Estrogen-Containing Oral Contraceptives: Starting Lamotrigine Tablets  in Women Taking Estrogen-Containing Oral Contraceptives: Although estrogen-containing oral contraceptives have been shown to increase the clearance of lamotrigine [see Clinical Pharmacology (12.3) ], no adjustments to the recommended dose-escalation guidelines for lamotrigine tablets should be necessary solely based on the use of estrogen-containing oral contraceptives. Therefore, dose escalation should follow the recommended guidelines for initiating adjunctive therapy with lamotrigine tablets based on the concomitant AED or other concomitant medications (see Table 1 or Table 5). See below for adjustments to maintenance doses of lamotrigine tablets in women taking estrogen-containing oral contraceptives.

  Adjustments to the Maintenance Dose of Lamotrigine Tablets In Women Taking Estrogen-Containing Oral Contraceptives:

  (1) Taking Estrogen-Containing Oral Contraceptives: For women not taking carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin that induce lamotrigine glucuronidation [see Drug Interactions (7), Clinical Pharmacology (12.3)], the maintenance dose of lamotrigine  tablets will in most cases need to be increased, by as much as 2-fold over the recommended target maintenance dose, in order to maintain a consistent lamotrigine plasma level [see Clinical Pharmacology (12.3) ].

  (2) Starting Estrogen-Containing Oral Contraceptives: In women taking a stable dose of lamotrigine tablets and not taking carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin that induce lamotrigine glucuronidation [see Drug Interactions (7), Clinical Pharmacology (12.3)], the maintenance dose will in most cases need to be increased by as much as 2-fold in order to maintain a consistent lamotrigine plasma level. The dose increases should begin at the same time that the oral contraceptive is introduced and continue, based on clinical response, no more rapidly than 50 to 100 mg/day every week. Dose increases should not exceed the recommended rate (see Table 1 or Table 5) unless lamotrigine plasma levels or clinical response support larger increases. Gradual transient increases in lamotrigine plasma levels may occur during the week of inactive hormonal preparation ("pill-free" week), and these increases will be greater if dose increases are made in the days before or during the week of inactive hormonal preparation. Increased lamotrigine plasma levels could result in additional adverse reactions, such as dizziness, ataxia, and diplopia. If adverse reactions attributable to lamotrigine tablets consistently occur during the "pill-free" week, dose adjustments to the overall maintenance dose may be necessary. Dose adjustments limited to the "pill-free" week are not recommended. For women taking lamotrigine tablets in addition to carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin that induce lamotrigine glucuronidation [see Drug Interactions (7), Clinical Pharmacology (12.3)], no adjustment to the dose of lamotrigine tablets should be necessary.

  (3) Stopping Estrogen-Containing Oral Contraceptives: For women not taking carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin that induce lamotrigine glucuronidation [see Drug Interactions (7), Clinical Pharmacology (12.3)], the maintenance dose of lamotrigine tablets will in most cases need to be decreased by as much as 50% in order to maintain a consistent lamotrigine plasma level. The decrease in dose of lamotrigine tablets should not exceed 25% of the total daily dose per week over a 2-week period, unless clinical response or lamotrigine plasma levels indicate otherwise [see Clinical Pharmacology (12.3) ]. For women taking lamotrigine tablets in addition to carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin that induce lamotrigine glucuronidation [see Drug Interactions (7), Clinical Pharmacology (12.3)], no adjustment to the dose of lamotrigine tablets should be necessary.

  Women and Other Hormonal Contraceptive Preparations or Hormone Replacement Therapy: The effect of other hormonal contraceptive preparations or hormone replacement therapy on the pharmacokinetics of lamotrigine has not been systematically evaluated. It has been reported that ethinylestradiol, not progestogens, increased the clearance of lamotrigine up to 2-fold, and the progestin-only pills had no effect on lamotrigine plasma levels. Therefore, adjustments to the dosage of lamotrigine tablets in the presence of progestogens alone will likely not be needed.

  Patients With Hepatic Impairment: Experience in patients with hepatic impairment is limited. Based on a clinical pharmacology study in 24 patients with mild, moderate, and severe liver impairment [see Use in Specific Populations (8.6) , Clinical Pharmacology (12.3) ], the following general recommendations can be made. No dosage adjustment is needed in patients with mild liver impairment. Initial, escalation, and maintenance doses should generally be reduced by approximately 25% in patients with moderate and severe liver impairment without ascites and 50% in patients with severe liver impairment with ascites. Escalation and maintenance doses may be adjusted according to clinical response.

  Patients With Renal Impairment: Initial doses of lamotrigine tablets should be based on patients' concomitant medications (see Tables 1-3 or Table 5); reduced maintenance doses may be effective for patients with significant renal impairment [see Use in Specific Populations (8.7) , Clinical Pharmacology (12.3) ]. Few patients with severe renal impairment have been evaluated during chronic treatment with lamotrigine tablets. Because there is inadequate experience in this population, lamotrigine tablets should be used with caution in these patients.

  Discontinuation Strategy:

  Epilepsy: For patients receiving lamotrigine tablets in combination with other AEDs, a reevaluation of all AEDs in the regimen should be considered if a change in seizure control or an appearance or worsening of adverse reactions is observed.

  If a decision is made to discontinue therapy with lamotrigine tablets, a step-wise reduction of dose over at least 2 weeks (approximately 50% per week) is recommended unless safety concerns require a more rapid withdrawal [see Warnings and Precautions (5.9) ].

  Discontinuing carbamazepine, phenytoin, phenobarbital, primidone or other drugs such as rifampin that induce lamotrigine glucuronidation should prolong the half-life of lamotrigine; discontinuing valproate should shorten the half-life of lamotrigine.

  Bipolar Disorder: In the controlled clinical trials, there was no increase in the incidence, type, or severity of adverse reactions following abrupt termination of lamotrigine tablets. In clinical trials in patients with Bipolar Disorder, 2 patients experienced seizures shortly after abrupt withdrawal of lamotrigine tablets. However, there were confounding factors that may have contributed to the occurrence of seizures in these bipolar patients. Discontinuation of lamotrigine tablets should involve a step-wise reduction of dose over at least 2 weeks (approximately 50% per week) unless safety concerns require a more rapid withdrawal [see Warnings and Precautions (5.9) ].

   

  This section provides specific dosing recommendations for patients greater than 12 years of age and patients 2 to 12 years of age. Within each of these age-groups, specific dosing recommendations are provided depending upon concomitant AED or other concomitant medications (Table 1 for patients greater than 12 years of age and Table 2 for patients 2 to 12 years of age). A weight-based dosing guide for patients 2 to 12 years of age on concomitant valproate is provided in Table 3.

  Patients Over 12 Years of Age: Recommended dosing guidelines are summarized in Table 1.

  Table 1. Escalation Regimen for Lamotrigine Tablets in Patients Over 12 Years of Age With Epilepsy
  For 
  For Patients NOT TAKING 
  For Patients 
  
  Patients
  Carbamazepine, 
  TAKING
  
  TAKING
  Phenytoin,
  Carbamazepine,
  
  Valproatea
  Phenobarbital,
  Phenytoin, 
  
  
  or Primidoneb,  
  Phenobarbital,
  
  
  or Valproatea
  or Primidoneb
  
  
  
  and NOT TAKING
  
  
  
  Valproatea
  Weeks 1 and 2
  25 mg every other day
  25 mg every day
  50 mg/day
  Weeks 3 and 4
  25 mg every day
  50 mg/day
  100 mg/day
  (in 2 divided doses)
  Weeks 5 onwards to 
  maintenance
  Increase by 25 to 
  50 mg/day every 1 to 2 weeks
  Increase by 50
  mg/day every 1
  to 2 weeks
  Increase by 
  100 mg/day every 
  1 to 2 weeks.
  Usual maintenance 
  dose
  100 to 200 mg/day
  with valproate alone
  225 to 375 mg/day
  (in 2 divided doses).
  300 to 500 mg/day
  (in 2 divided doses).
  
  100 to 400 mg/day
  with valproate
  and other drugs that induce glucuronidation
  
  
  
  (in 1 or 2 divided doses)
  
  
  

  a Valproate has been shown to inhibit glucuronidation and decrease the apparent clearance of lamotrigine [see Drug Interactions (7), Clinical Pharmacology (12.3)].

  b These drugs induce lamotrigine glucuronidation and increase clearance [see Drug Interactions (7), Clinical Pharmacology (12.3)]. Other drugs that have similar effects include estrogen-containing oral contraceptives [see Drug Interactions (7), Clinical Pharmacology (12.3)]. Dosing recommendations for oral contraceptives can be found in General Dosing Considerations [see Dosage and Administration (2.1)]. Patients on rifampin, or other drugs that induce lamotrigine glucuronidation and increase clearance, should follow the same dosing titration/maintenance regimen as that used with anticonvulsants that have this effect.

  Patients 2 to 12 Years Of Age: Recommended dosing guidelines are summarized in Table 2.

  Smaller starting doses and slower dose escalations than those used in clinical trials are recommended because of the suggestion that the risk of rash may be decreased by smaller starting doses and slower dose escalations. Therefore, maintenance doses will take longer to reach in clinical practice than in clinical trials. It may take several weeks to months to achieve an individualized maintenance dose. Maintenance doses in patients weighing less than 30 kg, regardless of age or concomitant AED, may need to be increased as much as 50%, based on clinical response.

  Table 2. Escalation Regimen for Lamotrigine Tablets in Patients 2 to 12 Years of Age With Epilepsy
  For Patients TAKING 
  Valproatea
  For Patients NOT 
  TAKING Carbamazepine, Phenytoin, 
  Phenobarbital, Primidoneb, or 
  Valproatea
  For Patients TAKING 
  Carbamazepine, Phenytoin, Phenobarbital, or 
  Primidoneb and NOT 
  TAKING Valproatea
  Weeks 1 and 2
  0.15 mg/kg/day
  in 1 or 2 divided doses, rounded down to the 
  nearest whole tablet (see Table 3 for weight 
  based dosing guide).
  0.3 mg/kg/day
  in 1 or 2 divided doses, rounded down to the 
  nearest whole tablet.
  0.6 mg/kg/day
  in 2 divided doses, rounded down to the 
  nearest whole tablet.
  Weeks 3 and 4
  0.3 mg/kg/day
  in 1 or 2 divided doses,
  rounded down to the 
  nearest whole tablet 
  (see Table 3 for weight 
  based dosing guide).
  0.6 mg/kg/day
  in 2 divided doses,
  rounded down to the 
  nearest whole tablet.
  1.2 mg/kg/day
  in 2 divided doses, 
  rounded down to the 
  nearest whole tablet.
  Weeks 5 
  onwards to 
  maintenance
  The dose should be increased every 
  1 to 2 weeks as follows:
  calculate 0.3 mg/kg/day, round this amount 
  down to the nearest whole tablet, and 
  add this amount to the 
  previously administered daily dose.
  The dose should be increased every 
  1 to 2 weeks as follows:
  calculate 0.6 mg/kg/day, round this amount 
  down to the nearest whole tablet, and 
  add this amount to the 
  previously administered daily dose
  The dose should be increased every 
  1 to 2 weeks as follows:
  calculate 1.2 mg/kg/day, round this amount 
  down to the nearest whole tablet, and 
  add this amount to the 
  previously administered daily dose
  Usual 
  Maintenance 
  Dose
  1 to 5 mg/kg/day
  (maximum 200 mg/day 
  in 1 or 2 divided doses).
  1 to 3 mg/kg/day with valproate alone
  4.5 to 7.5 mg/kg/day
  (maximum 300 mg/day 
  in 2 divided doses)
  5 to 15 mg/kg/day
  (maximum 400 mg/day 
  in 2 divided doses)
  Maintenance dose in 
  patients 
  less than 30 kg
  May need to be increased 
  by as much as 50%, 
  based on clinical response
  May need to be increased 
  by as much as 50%, 
  based on clinical response
  May need to be increased 
  by as much as 50%, based 
  on clinical response
  

  Note: Only whole tablets should be used for dosing.

  a Valproate has been shown to inhibit glucuronidation and decrease the apparent clearance of lamotrigine [see Drug Interactions (7), Clinical Pharmacology (12.3)].

  b These drugs induce lamotrigine glucuronidation and increase clearance [see Drug Interactions (7), Clinical Pharmacology (12.3)]. Other drugs which have similar effects include estrogen-containing oral contraceptives [see Drug Interactions (7), Clinical Pharmacology (12.3)]. Dosing recommendations for oral contraceptives can be found in General Dosing Considerations [see Dosage and Administration (2.1)]. Patients on rifampin, or other drugs that induce lamotrigine glucuronidation and increase clearance, should follow the same dosing titration/maintenance regimen as that used with anticonvulsants that have this effect.

  Table 3. The Initial Weight-Based Dosing Guide for Patients 2 to 12 Years Taking Valproate (Weeks 1 to 4) With Epilepsy If the patient’s weight is
  Give this daily dose, using the most appropriate combination of Lamotrigine 2-mg and 5-mg tablets
  Greater than
  And less than
  Weeks 1 and 2
  Weeks 3 and 4
  6.7 kg
  14 kg
  2 mg every other day
  2 mg every day
  14.1 kg
  27 kg
  2 mg every day
  4 mg every day
  27.1 kg
  34 kg
  4 mg every day
  8 mg every day
  34.1 kg
  40 kg
  5 mg every day
  10 mg every day
  

  Usual Adjunctive Maintenance Dose for Epilepsy: The usual maintenance doses identified in Tables 1 and 2 are derived from dosing regimens employed in the placebo-controlled adjunctive studies in which the efficacy of lamotrigine tablets was established. In patients receiving multidrug regimens employing carbamazepine, phenytoin, phenobarbital, or primidone without valproate, maintenance doses of adjunctive lamotrigine tablets as high as 700 mg/day have been used. In patients receiving valproate alone, maintenance doses of adjunctive lamotrigine tablets as high as 200 mg/day have been used. The advantage of using doses above those recommended in Tables 1 through 4 has not been established in controlled trials.

   

  The goal of the transition regimen is to effect the conversion to monotherapy with lamotrigine tablets under conditions that ensure adequate seizure control while mitigating the risk of serious rash associated with the rapid titration of lamotrigine tablets.

  The recommended maintenance dose of lamotrigine tablets as monotherapy is 500 mg/day given in two divided doses.

  To avoid an increased risk of rash, the recommended initial dose and subsequent dose escalations of lamotrigine tablets should not be exceeded [see Boxed Warning].

  Conversion From Adjunctive Therapy With Carbamazepine, Phenytoin, Phenobarbital, or Primidone to Monotherapy With Lamotrigine Tablets: After achieving a dose of 500 mg/day of lamotrigine tablets according to the guidelines in Table 1, the concomitant AED should be withdrawn by 20% decrements each week over a 4-week period. The regimen for the withdrawal of the concomitant AED is based on experience gained in the controlled monotherapy clinical trial.

  Conversion from Adjunctive Therapy With Valproate to Monotherapy With Lamotrigine Tablets:

  The conversion regimen involves 4 steps outlined in Table 4.

  Table 4. Conversion From Adjunctive Therapy With Valproate to Monotherapy With Lamotrigine Tablets in Patients ≥16 Years of Age with Epilepsy
  Lamotrigine Tablets
  Valproate
  Step 1
  Achieve a dose of 200 mg/day according to
  guidelines in Table 1
  (if not already on 200 mg/day).
  Maintain previous stable dose.
  Step 2
  Maintain at 200 mg/day.
  Decrease to 500 mg/day by decrements no greater than
  500 mg/day/week and then maintain the dose of
  500 mg/day for 1 week.
  Step 3
  Increase to 300 mg/day and maintain for 1 week.
  Simultaneously decrease to
  250 mg/day and maintain for 1 week.
  Step 4
  Increase by 100 mg/day every
  week to achieve maintenance dose of 500 mg/day.
  Discontinue.
  

  Conversion from Adjunctive Therapy With AEDs Other Than Carbamazepine, Phenytoin, Phenobarbital, Primidone, or Valproate to Monotherapy With Lamotrigine Tablets: No specific dosing guidelines can be provided for conversion to monotherapy with lamotrigine tablets with AEDs other than carbamazepine, phenobarbital, phenytoin, primidone, or valproate.

   

  The goal of maintenance treatment with lamotrigine tablets is to delay the time to occurrence of mood episodes (depression, mania, hypomania, mixed episodes) in patients treated for acute mood episodes with standard therapy. The target dose of lamotrigine tablets is 200 mg/day (100 mg/day in patients taking valproate, which decreases the apparent clearance of lamotrigine, and 400 mg/day in patients not taking valproate and taking either carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin that increase the apparent clearance of lamotrigine). In the clinical trials, doses up to 400 mg/day as monotherapy were evaluated; however, no additional benefit was seen at 400 mg/day compared with 200 mg/day [see Clinical Studies (14.2) ]. Accordingly, doses above 200 mg/day are not recommended. Treatment with lamotrigine tablets is introduced, based on concurrent medications, according to the regimen outlined in Table 5. If other psychotropic medications are withdrawn following stabilization, the dose of lamotrigine tablets should be adjusted. For patients discontinuing valproate, the dose of lamotrigine tablets should be doubled over a 2-week period in equal weekly increments (see Table 6). For patients discontinuing carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin that induce lamotrigine glucuronidation, the dose of lamotrigine tablets should remain constant for the first week and then should be decreased by half over a 2-week period in equal weekly decrements (see Table 6). The dose of lamotrigine tablets may then be further adjusted to the target dose (200 mg) as clinically indicated.

  If other drugs are subsequently introduced, the dose of lamotrigine tablets may need to be adjusted. In particular, the introduction of valproate requires reduction in the dose of lamotrigine tablets [see Drug Interactions (7) , Clinical Pharmacology (12.3) ].

  To avoid an increased risk of rash, the recommended initial dose and subsequent dose escalations of lamotrigine tablets should not be exceeded [see Boxed Warning ].

  Table 5. Escalation Regimen for Lamotrigine Tablets for Patients With Bipolar Disorder
  For Patients TAKING 
  Valproatea
  For Patients NOT TAKING 
  Carbamazepine, Phenytoin, Phenobarbital, 
  Primidoneb, or Valproatea
  For Patients TAKING 
  Carbamazepine, Phenytoin,
  Phenobarbital, or Primidoneb and NOT TAKING 
  Valproatea
  Weeks 1 and 2
  25 mg every 
  other day
  25 mg daily
  50 mg daily
  Weeks 3 and 4
  25 mg daily
  50 mg daily
  100 mg daily, in divided doses
  Week 5
  50 mg daily
  100 mg daily
  200 mg daily, in divided doses
  Week 6
  100 mg daily
  200 mg daily
  300 mg daily, in divided doses
  Week 7
  100 mg daily
  200 mg daily
  up to 400 mg daily, in divided doses
  

  a Valproate has been shown to inhibit glucuronidation and decrease the apparent clearance of lamotrigine [see Drug Interactions (7), Clinical Pharmacology (12.3)].

  
  

  b These drugs induce lamotrigine glucuronidation and increase clearance [see Drug Interactions (7), Clinical Pharmacology (12.3)]. Other drugs which have similar effects include estrogen-containing oral contraceptives [see Drug Interactions (7), Clinical Pharmacology (12.3)]. Dosing recommendations for oral contraceptives can be found in General Dosing Considerations [see Dosage and Administration (2.1)]. Patients on rifampin, or other drugs that induce lamotrigine glucuronidation and increase clearance, should follow the same dosing titration/maintenance regimen as that used with anticonvulsants that have this effect.

  Table 6. Dosage Adjustments to Lamotrigine Tablets for Patients With Bipolar Disorder Following Discontinuation of Psychotropic Medications
  Discontinuation of Psychotropic Drugs 
  (excluding Carbamazepine, Phenytoin, 
  Phenobarbital, Primidoneb, or 
  Valproatea)
  After Discontinuation of 
  Valproatea
  After Discontinuation of 
  Carbamazepine, Phenytoin, 
  Phenobarbital, or Primidoneb
  
  
  Current dose of lamotrigine tablets
  (mg/day)
  100
  Current dose of lamotrigine tablets
  (mg/day)
  400
  Week 1
  Maintain current dose of lamotrigine tablets
  150
  400
  Week 2
  Maintain current dose of lamotrigine tablets
  200
  300
  Week 3 onward
  Maintain current dose of lamotrigine tablets
  200
  200
  

  The benefit of continuing treatment in patients who had been stabilized in an 8- to 16-week open-label phase with lamotrigine tablets was established in two randomized, placebo-controlled clinical maintenance trials [see Clinical Studies (14.2) ]. However, the optimal duration of treatment with lamotrigine tablets has not been established. Thus, patients should be periodically reassessed to determine the need for maintenance treatment.

   

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  2.1 General Dosing Considerations

  Rash: There are suggestions, yet to be proven, that the risk of severe, potentially life-threatening rash may be increased by (1) coadministration of lamotrigine with valproate, (2) exceeding the recommended initial dose of lamotrigine, or (3) exceeding the recommended dose escalation for lamotrigine. However, cases have occurred in the absence of these factors [see Boxed Warning]. Therefore, it is important that the dosing recommendations be followed closely.

  The risk of nonserious rash may be increased when the recommended initial dose and/or the rate of dose escalation of lamotrigine is exceeded and in patients with a history of allergy or rash to other AEDs.

  It is recommended that lamotrigine not be restarted in patients who discontinued due to rash associated with prior treatment with lamotrigine, unless the potential benefits clearly outweigh the risks. If the decision is made to restart a patient who has discontinued lamotrigine, the need to restart with the initial dosing recommendations should be assessed. The greater the interval of time since the previous dose, the greater consideration should be given to restarting with the initial dosing recommendations. If a patient has discontinued lamotrigine for a period of more than 5 half-lives, it is recommended that initial dosing recommendations and guidelines be followed. The half-life of lamotrigine is affected by other concomitant medications [see Clinical Pharmacology (12.3)].

  Lamotrigine Added to Drugs Known to Induce or Inhibit Glucuronidation: Drugs other than those listed in the Clinical Pharmacology section [see Clinical Pharmacology (12.3)] have not been systematically evaluated in combination with lamotrigine. Because lamotrigine is metabolized predominantly by glucuronic acid conjugation, drugs that are known to induce or inhibit glucuronidation may affect the apparent clearance of lamotrigine and doses of lamotrigine may require adjustment based on clinical response.

  Target Plasma Levels for Patients With Epilepsy or Bipolar Disorder: A therapeutic plasma concentration range has not been established for lamotrigine. Dosing of lamotrigine should be based on therapeutic response [see Clinical Pharmacology (12.3)].

  Women Taking Estrogen-Containing Oral Contraceptives: Starting Lamotrigine in Women Taking Estrogen-Containing Oral Contraceptives: Although estrogen-containing oral contraceptives have been shown to increase the clearance of lamotrigine [see Clinical Pharmacology (12.3)], no adjustments to the recommended dose-escalation guidelines for lamotrigine should be necessary solely based on the use of estrogen-containing oral contraceptives. Therefore, dose escalation should follow the recommended guidelines for initiating adjunctive therapy with lamotrigine based on the concomitant AED or other concomitant medications (see Table 1 or Table 5). See below for adjustments to maintenance doses of lamotrigine in women taking estrogen-containing oral contraceptives.

  Adjustments to the Maintenance Dose of Lamotrigine In Women Taking Estrogen-Containing Oral Contraceptives:

  (1) Taking Estrogen-Containing Oral Contraceptives: For women not taking carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin that induce lamotrigine glucuronidation [see Drug Interactions (7), Clinical Pharmacology (12.3)], the maintenance dose of lamotrigine will in most cases need to be increased, by as much as 2-fold over the recommended target maintenance dose, in order to maintain a consistent lamotrigine plasma level [see Clinical Pharmacology (12.3)].

  (2) Starting Estrogen-Containing Oral Contraceptives: In women taking a stable dose of lamotrigine and not taking carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin that induce lamotrigine glucuronidation [see Drug Interactions (7), Clinical Pharmacology (12.3)], the maintenance dose will in most cases need to be increased by as much as 2-fold in order to maintain a consistent lamotrigine plasma level. The dose increases should begin at the same time that the oral contraceptive is introduced and continue, based on clinical response, no more rapidly than 50 to 100 mg/day every week. Dose increases should not exceed the recommended rate (see Table 1 or Table 5) unless lamotrigine plasma levels or clinical response support larger increases. Gradual transient increases in lamotrigine plasma levels may occur during the week of inactive hormonal preparation ("pill-free" week), and these increases will be greater if dose increases are made in the days before or during the week of inactive hormonal preparation. Increased lamotrigine plasma levels could result in additional adverse reactions, such as dizziness, ataxia, and diplopia. If adverse reactions attributable to lamotrigine consistently occur during the "pill-free" week, dose adjustments to the overall maintenance dose may be necessary. Dose adjustments limited to the "pill-free" week are not recommended. For women taking lamotrigine in addition to carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin that induce lamotrigine glucuronidation [see Drug Interactions (7), Clinical Pharmacology (12.3)], no adjustment to the dose of lamotrigine should be necessary.

  (3) Stopping Estrogen-Containing Oral Contraceptives: For women not taking carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin that induce lamotrigine glucuronidation [see Drug Interactions (7), Clinical Pharmacology (12.3)], the maintenance dose of lamotrigine will in most cases need to be decreased by as much as 50% in order to maintain a consistent lamotrigine plasma level. The decrease in dose of lamotrigine should not exceed 25% of the total daily dose per week over a 2-week period, unless clinical response or lamotrigine plasma levels indicate otherwise [see Clinical Pharmacology (12.3)]. For women taking lamotrigine in addition to carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin that induce lamotrigine glucuronidation [see Drug Interactions (7), Clinical Pharmacology (12.3)], no adjustment to the dose of lamotrigine should be necessary.

  Women and Other Hormonal Contraceptive Preparations or Hormone Replacement Therapy: The effect of other hormonal contraceptive preparations or hormone replacement therapy on the pharmacokinetics of lamotrigine has not been systematically evaluated. It has been reported that ethinylestradiol, not progestogens, increased the clearance of lamotrigine up to 2-fold, and the progestin-only pills had no effect on lamotrigine plasma levels. Therefore, adjustments to the dosage of lamotrigine in the presence of progestogens alone will likely not be needed.

  Patients With Hepatic Impairment: Experience in patients with hepatic impairment is limited. Based on a clinical pharmacology study in 24 patients with mild, moderate, and severe liver impairment [see Use in Specific Populations (8.6), Clinical Pharmacology (12.3)], the following general recommendations can be made. No dosage adjustment is needed in patients with mild liver impairment. Initial, escalation, and maintenance doses should generally be reduced by approximately 25% in patients with moderate and severe liver impairment without ascites and 50% in patients with severe liver impairment with ascites. Escalation and maintenance doses may be adjusted according to clinical response.

  Patients With Renal Impairment: Initial doses of lamotrigine should be based on patients' concomitant medications (see Tables 1-3 or Table 5); reduced maintenance doses may be effective for patients with significant renal impairment [see Use in Specific Populations (8.7), Clinical Pharmacology (12.3)]. Few patients with severe renal impairment have been evaluated during chronic treatment with lamotrigine. Because there is inadequate experience in this population, lamotrigine should be used with caution in these patients.

  Discontinuation Strategy: Epilepsy: For patients receiving lamotrigine in combination with other AEDs, a reevaluation of all AEDs in the regimen should be considered if a change in seizure control or an appearance or worsening of adverse reactions is observed.

  If a decision is made to discontinue therapy with lamotrigine, a step-wise reduction of dose over at least 2 weeks (approximately 50% per week) is recommended unless safety concerns require a more rapid withdrawal [see Warnings and Precautions (5.9)].

  Discontinuing carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin that induce lamotrigine glucuronidation should prolong the half-life of lamotrigine; discontinuing valproate should shorten the half-life of lamotrigine.

  Bipolar Disorder: In the controlled clinical trials, there was no increase in the incidence, type, or severity of adverse reactions following abrupt termination of lamotrigine. In clinical trials in patients with Bipolar Disorder, 2 patients experienced seizures shortly after abrupt withdrawal of lamotrigine. However, there were confounding factors that may have contributed to the occurrence of seizures in these bipolar patients. Discontinuation of lamotrigine should involve a step-wise reduction of dose over at least 2 weeks (approximately 50% per week) unless safety concerns require a more rapid withdrawal [see Warnings and Precautions (5.9)].

  2.2 Epilepsy – Adjunctive Therapy

  This section provides specific dosing recommendations for patients greater than 12 years of age and patients 2 to 12 years of age. Within each of these age-groups, specific dosing recommendations are provided depending upon concomitant AED or other concomitant medications (Table 1 for patients greater than 12 years of age and Table 2 for patients 2 to 12 years of age). A weight-based dosing guide for patients 2 to 12 years of age on concomitant valproate is provided in Table 3.

  Patients Over 12 Years of Age: Recommended dosing guidelines are summarized in Table 1.

  Table 1. Escalation Regimen for Lamotrigine in Patients Over 12 Years of Age With Epilepsy For Patients TAKING Valproate* For Patients NOT TAKING Carbamazepine, Phenytoin, Phenobarbital, Primidone† or Valproate* For Patients TAKING Carbamazepine, Phenytoin, Phenobarbital, or Primidone† and NOT TAKING Valproate* * Valproate has been shown to inhibit glucuronidation and decrease the apparent clearance of lamotrigine [see Drug Interactions (7), Clinical Pharmacology (12.3)]. † These drugs induce glucuronidation and increase clearance [see Drug Interactions (7) Clinical Pharmacology (12.3)]. Other drugs that have similar effects include estrogen-containing oral contraceptives [See Drug Interactions (7), Clinical Pharmacology (12.3)]. Dosing recommendations for oral contraceptives can be found in General Dosing Considerations [see Dosage and Administration (2.1)]. Patients on rifampin, or other drugs that induce lamotrigine glucuronidation and increase clearance, should follow the same dosing titration/maintenance regimen as that used with anticonvulsants that have this effect. Weeks 1 and 2 25 mg every other day 25 mg every day 50 mg/day Weeks 3 and 4 25 mg every day 50 mg/day 100 mg/day
  (in 2 divided doses) Week 5 onwards to maintenance Increase by 25 to 50 mg/day every 1 to 2 weeks Increase by 50 mg/day every 1 to 2 weeks Increase by 100 mg/day every 1 to 2 weeks Usual maintenance dose 100 to 200 mg/day with valproate alone
  100 to 400 mg/day with valproate and other drugs that induce glucuronidation
  (in 1 or 2 divided doses) 225 to 375 mg/day
  (in 2 divided doses) 300 to 500 mg/day
  (in 2 divided doses)

  Patients 2 to 12 Years of Age: Recommended dosing guidelines are summarized in Table 2.

  Smaller starting doses and slower dose escalations than those used in clinical trials are recommended because of the suggestion that the risk of rash may be decreased by smaller starting doses and slower dose escalations. Therefore, maintenance doses will take longer to reach in clinical practice than in clinical trials. It may take several weeks to months to achieve an individualized maintenance dose. Maintenance doses in patients weighing less than 30 kg, regardless of age or concomitant AED, may need to be increased as much as 50%, based on clinical response.

  Table 2. Escalation Regimen for Lamotrigine in Patients 2 to 12 Years of Age With Epilepsy For Patients TAKING Valproate* For Patients NOT TAKING Carbamazepine, Phenytoin, Phenobarbital, Primidone†, or Valproate* For Patients TAKING Carbamazepine, Phenytoin, Phenobarbital, or Primidone† and NOT TAKING Valproate* Note: Only whole tablets should be used for dosing. * Valproate has been shown to inhibit glucuronidation and decrease the apparent clearance of lamotrigine [see Drug Interactions (7), Clinical Pharmacology (12.3)]. † These drugs induce glucuronidation and increase clearance [see Drug Interactions (7) Clinical Pharmacology (12.3)]. Other drugs that have similar effects include estrogen-containing oral contraceptives [see Drug Interactions (7), Clinical Pharmacology (12.3)]. Dosing recommendations for oral contraceptives can be found in General Dosing Considerations [see Dosage and Administration (2.1)]. Patients on rifampin, or other drugs that induce lamotrigine glucuronidation and increase clearance, should follow the same dosing titration/maintenance regimen as that used with anticonvulsants that have this effect. Weeks 1 and 2 0.15 mg/kg/day
  in 1 or 2 divided doses, rounded down to the nearest whole tablet (see Table 3 for weight-based dosing guide) 0.3 mg/kg/day
  in 1 or 2 divided doses, rounded down to the nearest whole tablet 0.6 mg/kg/day
  in 2 divided doses, rounded down to the nearest whole tablet Weeks 3 and 4 0.3 mg/kg/day
  in 1 or 2 divided doses, rounded down to the nearest whole tablet (see Table 3 for weight-based dosing guide) 0.6 mg/kg/day
  in 2 divided doses, rounded down to the nearest whole tablet 1.2 mg/kg/day
  in 2 divided doses, rounded down to the nearest whole tablet Week 5 onwards to maintenance The dose should be increased every 1 to 2 weeks as follows: calculate 0.3 mg/kg/day, round this amount down to the nearest whole tablet, and add this amount to the previously administered daily dose The dose should be increased every 1 to 2 weeks as follows: calculate 0.6 mg/kg/day, round this amount down to the nearest whole tablet, and add this amount to the previously administered daily dose The dose should be increased every 1 to 2 weeks as follows: calculate 1.2 mg/kg/day, round this amount down to the nearest whole tablet, and add this amount to the previously administered daily dose Usual Maintenance Dose 1 to 5 mg/kg/day
  (maximum 200 mg/day in 1 or 2 divided doses)
  1 to 3 mg/kg/day
  with valproate alone 4.5 to 7.5 mg/kg/day
  (maximum 300 mg/day in 2 divided doses) 5 to 15 mg/kg/day
  (maximum 400 mg/day in 2 divided doses) Maintenance dose in patients less than 30 kg May need to be increased by as much as 50%, based on clinical response May need to be increased by as much as 50%, based on clinical response May need to be increased by as much as 50%, based on clinical response Table 3. The Initial Weight-Based Dosing Guide for Patients 2 to 12 Years of Age Taking Valproate (Weeks 1 to 4) With Epilepsy If the patient's weight is Give this daily dose, using the most appropriate combination of lamotrigine 2-mg and 5-mg tablets Greater than And less than Weeks 1 and 2 Weeks 3 and 4 6.7 kg 14 kg 2 mg every other day 2 mg every day 14.1 kg 27 kg 2 mg every day 4 mg every day 27.1 kg 34 kg 4 mg every day 8 mg every day 34.1 kg 40 kg 5 mg every day 10 mg every day

  Usual Adjunctive Maintenance Dose for Epilepsy: The usual maintenance doses identified in Tables 1 and 2 are derived from dosing regimens employed in the placebo-controlled adjunctive studies in which the efficacy of lamotrigine was established. In patients receiving multidrug regimens employing carbamazepine, phenytoin, phenobarbital, or primidone without valproate, maintenance doses of adjunctive lamotrigine as high as 700 mg/day have been used. In patients receiving valproate alone, maintenance doses of adjunctive lamotrigine as high as 200 mg/day have been used. The advantage of using doses above those recommended in Tables 1 through 4 has not been established in controlled trials.

  2.3 Epilepsy – Conversion From Adjunctive Therapy to Monotherapy

  The goal of the transition regimen is to effect the conversion to monotherapy with lamotrigine under conditions that ensure adequate seizure control while mitigating the risk of serious rash associated with the rapid titration of lamotrigine.

  The recommended maintenance dose of lamotrigine as monotherapy is 500 mg/day given in 2 divided doses.

  To avoid an increased risk of rash, the recommended initial dose and subsequent dose escalations of lamotrigine should not be exceeded [see Boxed Warning].

  Conversion From Adjunctive Therapy With Carbamazepine, Phenytoin, Phenobarbital, or Primidone to Monotherapy With Lamotrigine: After achieving a dose of 500 mg/day of lamotrigine according to the guidelines in Table 1, the concomitant AED should be withdrawn by 20% decrements each week over a 4-week period. The regimen for the withdrawal of the concomitant AED is based on experience gained in the controlled monotherapy clinical trial.

  Conversion From Adjunctive Therapy With Valproate to Monotherapy With Lamotrigine: The conversion regimen involves 4 steps outlined in Table 4.

  Table 4. Conversion From Adjunctive Therapy With Valproate to Monotherapy With Lamotrigine in Patients ≥16 Years of Age with Epilepsy Lamotrigine Valproate Step 1 Achieve a dose of 200 mg/day according to guidelines in Table 1 (if not already on 200 mg/day). Maintain previous stable dose. Step 2 Maintain at 200 mg/day. Decrease to 500 mg/day by decrements no greater than 500 mg/day/week and then maintain the dose of 500 mg/day for 1 week. Step 3 Increase to 300 mg/day and maintain for 1 week. Simultaneously decrease to 250 mg/day and maintain for 1 week. Step 4 Increase by 100 mg/day every week to achieve maintenance dose of 500 mg/day. Discontinue.

  Conversion From Adjunctive Therapy With Antiepileptic Drugs Other Than Carbamazepine, Phenytoin, Phenobarbital, Primidone, or Valproate to Monotherapy With Lamotrigine: No specific dosing guidelines can be provided for conversion to monotherapy with lamotrigine with AEDs other than carbamazepine, phenobarbital, phenytoin, primidone, or valproate.

  2.4 Bipolar Disorder

  The goal of maintenance treatment with lamotrigine is to delay the time to occurrence of mood episodes (depression, mania, hypomania, mixed episodes) in patients treated for acute mood episodes with standard therapy. The target dose of lamotrigine is 200 mg/day (100 mg/day in patients taking valproate, which decreases the apparent clearance of lamotrigine, and 400 mg/day in patients not taking valproate and taking either carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin that increase the apparent clearance of lamotrigine). In the clinical trials, doses up to 400 mg/day as monotherapy were evaluated; however, no additional benefit was seen at 400 mg/day compared with 200 mg/day [see Clinical Studies (14.2)]. Accordingly, doses above 200 mg/day are not recommended. Treatment with lamotrigine is introduced, based on concurrent medications, according to the regimen outlined in Table 5. If other psychotropic medications are withdrawn following stabilization, the dose of lamotrigine should be adjusted. For patients discontinuing valproate, the dose of lamotrigine should be doubled over a 2-week period in equal weekly increments (see Table 6). For patients discontinuing carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin that induce lamotrigine glucuronidation, the dose of lamotrigine should remain constant for the first week and then should be decreased by half over a 2-week period in equal weekly decrements (see Table 6). The dose of lamotrigine may then be further adjusted to the target dose (200 mg) as clinically indicated.

  If other drugs are subsequently introduced, the dose of lamotrigine may need to be adjusted. In particular, the introduction of valproate requires reduction in the dose of lamotrigine [see Drug Interactions (7),Clinical Pharmacology (12.3)].

  To avoid an increased risk of rash, the recommended initial dose and subsequent dose escalations of lamotrigine should not be exceeded [see Boxed Warning].

  Table 5. Escalation Regimen for Lamotrigine for Patients With Bipolar Disorder For Patients TAKING Valproate* For Patients NOT TAKING Carbamazepine, Phenytoin, Phenobarbital, Primidone†, or Valproate* For Patients TAKING Carbamazepine, Phenytoin, Phenobarbital, or Primidone†, and NOT TAKING Valproate* * Valproate has been shown to inhibit glucuronidation and decrease the apparent clearance of lamotrigine [see Drug Interactions (7), Clinical Pharmacology (12.3)]. † These drugs induce lamotrigine glucuronidation and increase clearance [see Drug Interactions (7), Clinical Pharmacology (12.3)]. Other drugs that have similar effects include estrogen-containing oral contraceptives [see Drug Interactions (7), Clinical Pharmacology (12.3)]. Dosing recommendations for oral contraceptives can be found in General Dosing Considerations [see Dosage and Aministration (2.1)]. Patients on rifampin, or other drugs that induce lamotrigine glucuronidation and increase clearance, should follow the same dosing titration/maintenance regimen as that used with anticonvulsants that have this effect. Weeks 1 and 2 25 mg every other day 25 mg daily 50 mg daily Weeks 3 and 4 25 mg daily 50 mg daily 100 mg daily, in divided doses Week 5 50 mg daily 100 mg daily 200 mg daily, in divided doses Week 6 100 mg daily 200 mg daily 300 mg daily, in divided doses Week 7 100 mg daily 200 mg daily up to 400 mg daily, in divided doses Table 6. Dosage Adjustments to Lamotrigine for Patients With Bipolar Disorder Following Discontinuation of Psychotropic Medications* Discontinuation of Psychotropic Drugs (excluding Carbamazepine, Phenytoin, Phenobarbital, Primidone*, or Valproate†) After Discontinuation of Valproate† After Discontinuation of Carbamazepine, Phenytoin, Phenobarbital, or Primidone* Current dose of Lamotrigine
  (mg/day) 100 Current dose of Lamotrigine
  (mg/day) 400 * These drugs induce lamotrigine glucuronidation and increase clearance [see Drug Interactions (7), Clinical Pharmacology (12.3)]. Other drugs that have similar effects include estrogen-containing oral contraceptives [see Drug Interactions (7), Clinical Pharmacology (12.3)]. Dosing recommendations for oral contraceptives can be found in General Dosing Considerations [see Dosage and Aministration (2.1)]. Patients on rifampin, or other drugs that induce lamotrigine glucuronidation and increase clearance, should follow the same dosing titration/maintenance regimen as that used with anticonvulsants that have this effect. † Valproate has been shown to inhibit glucuronidation and decrease the apparent clearance of lamotrigine [see Drug Interactions (7), Clinical Pharmacology (12.3)]. Week 1 Maintain current dose of Lamotrigine 150 400 Week 2 Maintain current dose of Lamotrigine 200 300 Week 3 onward Maintain current dose of Lamotrigine 200 200

  The benefit of continuing treatment in patients who had been stabilized in an 8- to 16-week open-label phase with lamotrigine was established in 2 randomized, placebo-controlled clinical maintenance trials [see Clinical Studies (14.2)]. However, the optimal duration of treatment with lamotrigine has not been established. Thus, patients should be periodically reassessed to determine the need for maintenance treatment.

  2.6 Administration of Lamotrigine Orally Disintegrating Tablets

  Lamotrigine orally disintegrating tablets should be placed onto the tongue and moved around in the mouth. The tablet will disintegrate rapidly, can be swallowed with or without water, and can be taken with or without food.

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  2.1 General Dosing Considerations

  Rash: There are suggestions, yet to be proven, that the risk of severe, potentially life-threatening rash may be increased by (1) coadministration of lamotrigine tablets with valproate, (2) exceeding the recommended initial dose of lamotrigine tablets, or (3) exceeding the recommended dose escalation for lamotrigine tablets. However, cases have occurred in the absence of these factors [see Boxed Warning ]. Therefore, it is important that the dosing recommendations be followed closely.

  The risk of nonserious rash may be increased when the recommended initial dose and/or the rate of dose escalation of lamotrigine tablet is exceeded and in patients with a history of allergy or rash to other AEDs.

  It is recommended that lamotrigine tablets not be restarted in patients who discontinued due to rash associated with prior treatment with lamotrigine, unless the potential benefits clearly outweigh the risks. If the decision is made to restart a patient who has discontinued lamotrigine, the need to restart with the initial dosing recommendations should be assessed. The greater the interval of time since the previous dose, the greater consideration should be given to restarting with the initial dosing recommendations. If a patient has discontinued lamotrigine for a period of more than 5 half-lives, it is recommended that initial dosing recommendations and guidelines be followed. The half-life of lamotrigine is affected by other concomitant medications [see Clinical Pharmacology (12.3) ].

  Lamotrigine Tablets Added to Drugs Known to Induce or Inhibit Glucuronidation: Drugs other than those listed in the Clinical Pharmacology section [see Clinical Pharmacology (12.3) ] have not been systematically evaluated in combination with lamotrigine. Because lamotrigine is metabolized predominantly by glucuronic acid conjugation, drugs that are known to induce or inhibit glucuronidation may affect the apparent clearance of lamotrigine and doses of lamotrigine tablets may require adjustment based on clinical response.

  Target Plasma Levels for Patients With Epilepsy or Bipolar Disorder: A therapeutic plasma concentration range has not been established for lamotrigine. Dosing of lamotrigine tablets should be based on therapeutic response [see Clinical Pharmacology (12.3) ].

  Women Taking Estrogen-Containing Oral Contraceptives: Starting Lamotrigine Tablets  in Women Taking Estrogen-Containing Oral Contraceptives: Although estrogen-containing oral contraceptives have been shown to increase the clearance of lamotrigine [see Clinical Pharmacology (12.3) ], no adjustments to the recommended dose-escalation guidelines for lamotrigine tablets should be necessary solely based on the use of estrogen-containing oral contraceptives. Therefore, dose escalation should follow the recommended guidelines for initiating adjunctive therapy with lamotrigine tablets based on the concomitant AED or other concomitant medications (see Table 1 or Table 5). See below for adjustments to maintenance doses of lamotrigine tablets in women taking estrogen-containing oral contraceptives.

  Adjustments to the Maintenance Dose of Lamotrigine Tablets In Women Taking Estrogen-Containing Oral Contraceptives:

  (1) Taking Estrogen-Containing Oral Contraceptives: For women not taking carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin that induce lamotrigine glucuronidation [see Drug Interactions (7), Clinical Pharmacology (12.3)], the maintenance dose of lamotrigine  tablets will in most cases need to be increased, by as much as 2-fold over the recommended target maintenance dose, in order to maintain a consistent lamotrigine plasma level [see Clinical Pharmacology (12.3) ].

  (2) Starting Estrogen-Containing Oral Contraceptives: In women taking a stable dose of lamotrigine tablets and not taking carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin that induce lamotrigine glucuronidation [see Drug Interactions (7), Clinical Pharmacology (12.3)], the maintenance dose will in most cases need to be increased by as much as 2-fold in order to maintain a consistent lamotrigine plasma level. The dose increases should begin at the same time that the oral contraceptive is introduced and continue, based on clinical response, no more rapidly than 50 to 100 mg/day every week. Dose increases should not exceed the recommended rate (see Table 1 or Table 5) unless lamotrigine plasma levels or clinical response support larger increases. Gradual transient increases in lamotrigine plasma levels may occur during the week of inactive hormonal preparation ("pill-free" week), and these increases will be greater if dose increases are made in the days before or during the week of inactive hormonal preparation. Increased lamotrigine plasma levels could result in additional adverse reactions, such as dizziness, ataxia, and diplopia. If adverse reactions attributable to lamotrigine tablets consistently occur during the "pill-free" week, dose adjustments to the overall maintenance dose may be necessary. Dose adjustments limited to the "pill-free" week are not recommended. For women taking lamotrigine tablets in addition to carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin that induce lamotrigine glucuronidation [see Drug Interactions (7), Clinical Pharmacology (12.3)], no adjustment to the dose of lamotrigine tablets should be necessary.

  (3) Stopping Estrogen-Containing Oral Contraceptives: For women not taking carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin that induce lamotrigine glucuronidation [see Drug Interactions (7), Clinical Pharmacology (12.3)], the maintenance dose of lamotrigine tablets will in most cases need to be decreased by as much as 50% in order to maintain a consistent lamotrigine plasma level. The decrease in dose of lamotrigine tablets should not exceed 25% of the total daily dose per week over a 2-week period, unless clinical response or lamotrigine plasma levels indicate otherwise [see Clinical Pharmacology (12.3) ]. For women taking lamotrigine tablets in addition to carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin that induce lamotrigine glucuronidation [see Drug Interactions (7), Clinical Pharmacology (12.3)], no adjustment to the dose of lamotrigine tablets should be necessary.

  Women and Other Hormonal Contraceptive Preparations or Hormone Replacement Therapy: The effect of other hormonal contraceptive preparations or hormone replacement therapy on the pharmacokinetics of lamotrigine has not been systematically evaluated. It has been reported that ethinylestradiol, not progestogens, increased the clearance of lamotrigine up to 2-fold, and the progestin-only pills had no effect on lamotrigine plasma levels. Therefore, adjustments to the dosage of lamotrigine tablets in the presence of progestogens alone will likely not be needed.

  Patients With Hepatic Impairment: Experience in patients with hepatic impairment is limited. Based on a clinical pharmacology study in 24 patients with mild, moderate, and severe liver impairment [see Use in Specific Populations (8.6) , Clinical Pharmacology (12.3) ], the following general recommendations can be made. No dosage adjustment is needed in patients with mild liver impairment. Initial, escalation, and maintenance doses should generally be reduced by approximately 25% in patients with moderate and severe liver impairment without ascites and 50% in patients with severe liver impairment with ascites. Escalation and maintenance doses may be adjusted according to clinical response.

  Patients With Renal Impairment: Initial doses of lamotrigine tablets should be based on patients' concomitant medications (see Tables 1-3 or Table 5); reduced maintenance doses may be effective for patients with significant renal impairment [see Use in Specific Populations (8.7) , Clinical Pharmacology (12.3) ]. Few patients with severe renal impairment have been evaluated during chronic treatment with lamotrigine tablets. Because there is inadequate experience in this population, lamotrigine tablets should be used with caution in these patients.

  Discontinuation Strategy:

  Epilepsy: For patients receiving lamotrigine tablets in combination with other AEDs, a reevaluation of all AEDs in the regimen should be considered if a change in seizure control or an appearance or worsening of adverse reactions is observed.

  If a decision is made to discontinue therapy with lamotrigine tablets, a step-wise reduction of dose over at least 2 weeks (approximately 50% per week) is recommended unless safety concerns require a more rapid withdrawal [see Warnings and Precautions (5.9) ].

  Discontinuing carbamazepine, phenytoin, phenobarbital, primidone or other drugs such as rifampin that induce lamotrigine glucuronidation should prolong the half-life of lamotrigine; discontinuing valproate should shorten the half-life of lamotrigine.

  Bipolar Disorder: In the controlled clinical trials, there was no increase in the incidence, type, or severity of adverse reactions following abrupt termination of lamotrigine tablets. In clinical trials in patients with Bipolar Disorder, 2 patients experienced seizures shortly after abrupt withdrawal of lamotrigine tablets. However, there were confounding factors that may have contributed to the occurrence of seizures in these bipolar patients. Discontinuation of lamotrigine tablets should involve a step-wise reduction of dose over at least 2 weeks (approximately 50% per week) unless safety concerns require a more rapid withdrawal [see Warnings and Precautions (5.9) ].

  2.2 Epilepsy – Adjunctive Therapy

  This section provides specific dosing recommendations for patients greater than 12 years of age and patients 2 to 12 years of age. Within each of these age-groups, specific dosing recommendations are provided depending upon concomitant AED or other concomitant medications (Table 1 for patients greater than 12 years of age and Table 2 for patients 2 to 12 years of age). A weight-based dosing guide for patients 2 to 12 years of age on concomitant valproate is provided in Table 3.

  Patients Over 12 Years of Age: Recommended dosing guidelines are summarized in Table 1.

  Table 1. Escalation Regimen for Lamotrigine Tablets in Patients Over 12 Years of Age With Epilepsy

  a Valproate has been shown to inhibit glucuronidation and decrease the apparent clearance of lamotrigine [see Drug Interactions (7), Clinical Pharmacology (12.3)].

  b These drugs induce lamotrigine glucuronidation and increase clearance [see Drug Interactions (7), Clinical Pharmacology (12.3)]. Other drugs that have similar effects include estrogen-containing oral contraceptives [see Drug Interactions (7), Clinical Pharmacology (12.3)]. Dosing recommendations for oral contraceptives can be found in General Dosing Considerations [see Dosage and Administration (2.1)]. Patients on rifampin, or other drugs that induce lamotrigine glucuronidation and increase clearance, should follow the same dosing titration/maintenance regimen as that used with anticonvulsants that have this effect.

  For  For Patients NOT TAKING  For Patients  Patients Carbamazepine,  TAKING TAKING Phenytoin, Carbamazepine, Valproatea Phenobarbital, Phenytoin,  or Primidoneb,   Phenobarbital, or Valproatea or Primidoneb and NOT TAKING Valproatea Weeks 1 and 2 25 mg every other day 25 mg every day 50 mg/day Weeks 3 and 4 25 mg every day 50 mg/day 100 mg/day
  (in 2 divided doses) Weeks 5 onwards to 
  maintenance Increase by 25 to 
  50 mg/day every 1 to 2 weeks Increase by 50
  mg/day every 1
  to 2 weeks Increase by 
  100 mg/day every 
  1 to 2 weeks. Usual maintenance 
  dose 100 to 200 mg/day
  with valproate alone 225 to 375 mg/day
  (in 2 divided doses). 300 to 500 mg/day
  (in 2 divided doses). 100 to 400 mg/day
  with valproate
  and other drugs that induce glucuronidation (in 1 or 2 divided doses)

  Patients 2 to 12 Years Of Age: Recommended dosing guidelines are summarized in Table 2.

  Smaller starting doses and slower dose escalations than those used in clinical trials are recommended because of the suggestion that the risk of rash may be decreased by smaller starting doses and slower dose escalations. Therefore, maintenance doses will take longer to reach in clinical practice than in clinical trials. It may take several weeks to months to achieve an individualized maintenance dose. Maintenance doses in patients weighing less than 30 kg, regardless of age or concomitant AED, may need to be increased as much as 50%, based on clinical response.

  Table 2. Escalation Regimen for Lamotrigine Tablets in Patients 2 to 12 Years of Age With Epilepsy

  Note: Only whole tablets should be used for dosing.

  a Valproate has been shown to inhibit glucuronidation and decrease the apparent clearance of lamotrigine [see Drug Interactions (7), Clinical Pharmacology (12.3)].

  b These drugs induce lamotrigine glucuronidation and increase clearance [see Drug Interactions (7), Clinical Pharmacology (12.3)]. Other drugs which have similar effects include estrogen-containing oral contraceptives [see Drug Interactions (7), Clinical Pharmacology (12.3)]. Dosing recommendations for oral contraceptives can be found in General Dosing Considerations [see Dosage and Administration (2.1)]. Patients on rifampin, or other drugs that induce lamotrigine glucuronidation and increase clearance, should follow the same dosing titration/maintenance regimen as that used with anticonvulsants that have this effect.

  For Patients TAKING 
  Valproatea For Patients NOT 
  TAKING Carbamazepine, Phenytoin, 
  Phenobarbital, Primidoneb, or 
  Valproatea For Patients TAKING 
  Carbamazepine, Phenytoin, Phenobarbital, or 
  Primidoneb and NOT 
  TAKING Valproatea Weeks 1 and 2 0.15 mg/kg/day
  in 1 or 2 divided doses, rounded down to the 
  nearest whole tablet (see Table 3 for weight 
  based dosing guide). 0.3 mg/kg/day
  in 1 or 2 divided doses, rounded down to the 
  nearest whole tablet. 0.6 mg/kg/day
  in 2 divided doses, rounded down to the 
  nearest whole tablet. Weeks 3 and 4 0.3 mg/kg/day
  in 1 or 2 divided doses,
  rounded down to the 
  nearest whole tablet 
  (see Table 3 for weight 
  based dosing guide). 0.6 mg/kg/day
  in 2 divided doses,
  rounded down to the 
  nearest whole tablet. 1.2 mg/kg/day
  in 2 divided doses, 
  rounded down to the 
  nearest whole tablet. Weeks 5 
  onwards to 
  maintenance The dose should be increased every 
  1 to 2 weeks as follows:
  calculate 0.3 mg/kg/day, round this amount 
  down to the nearest whole tablet, and 
  add this amount to the 
  previously administered daily dose. The dose should be increased every 
  1 to 2 weeks as follows:
  calculate 0.6 mg/kg/day, round this amount 
  down to the nearest whole tablet, and 
  add this amount to the 
  previously administered daily dose The dose should be increased every 
  1 to 2 weeks as follows:
  calculate 1.2 mg/kg/day, round this amount 
  down to the nearest whole tablet, and 
  add this amount to the 
  previously administered daily dose Usual 
  Maintenance 
  Dose 1 to 5 mg/kg/day
  (maximum 200 mg/day 
  in 1 or 2 divided doses).
  1 to 3 mg/kg/day with valproate alone 4.5 to 7.5 mg/kg/day
  (maximum 300 mg/day 
  in 2 divided doses) 5 to 15 mg/kg/day
  (maximum 400 mg/day 
  in 2 divided doses) Maintenance dose in 
  patients 
  less than 30 kg May need to be increased 
  by as much as 50%, 
  based on clinical response May need to be increased 
  by as much as 50%, 
  based on clinical response May need to be increased 
  by as much as 50%, based 
  on clinical response Table 3. The Initial Weight-Based Dosing Guide for Patients 2 to 12 Years Taking Valproate (Weeks 1 to 4) With Epilepsy If the patient’s weight is Give this daily dose, using the most appropriate combination of Lamotrigine 2-mg and 5-mg tablets Greater than And less than Weeks 1 and 2 Weeks 3 and 4 6.7 kg 14 kg 2 mg every other day 2 mg every day 14.1 kg 27 kg 2 mg every day 4 mg every day 27.1 kg 34 kg 4 mg every day 8 mg every day 34.1 kg 40 kg 5 mg every day 10 mg every day

  Usual Adjunctive Maintenance Dose for Epilepsy: The usual maintenance doses identified in Tables 1 and 2 are derived from dosing regimens employed in the placebo-controlled adjunctive studies in which the efficacy of lamotrigine tablets was established. In patients receiving multidrug regimens employing carbamazepine, phenytoin, phenobarbital, or primidone without valproate, maintenance doses of adjunctive lamotrigine tablets as high as 700 mg/day have been used. In patients receiving valproate alone, maintenance doses of adjunctive lamotrigine tablets as high as 200 mg/day have been used. The advantage of using doses above those recommended in Tables 1 through 4 has not been established in controlled trials.

  2.3 Epilepsy – Conversion From Adjunctive Therapy to Monotherapy

  The goal of the transition regimen is to effect the conversion to monotherapy with lamotrigine tablets under conditions that ensure adequate seizure control while mitigating the risk of serious rash associated with the rapid titration of lamotrigine tablets.

  The recommended maintenance dose of lamotrigine tablets as monotherapy is 500 mg/day given in two divided doses.

  To avoid an increased risk of rash, the recommended initial dose and subsequent dose escalations of lamotrigine tablets should not be exceeded [see Boxed Warning].

  Conversion From Adjunctive Therapy With Carbamazepine, Phenytoin, Phenobarbital, or Primidone to Monotherapy With Lamotrigine Tablets: After achieving a dose of 500 mg/day of lamotrigine tablets according to the guidelines in Table 1, the concomitant AED should be withdrawn by 20% decrements each week over a 4-week period. The regimen for the withdrawal of the concomitant AED is based on experience gained in the controlled monotherapy clinical trial.

  Conversion from Adjunctive Therapy With Valproate to Monotherapy With Lamotrigine Tablets:

  The conversion regimen involves 4 steps outlined in Table 4.

  Table 4. Conversion From Adjunctive Therapy With Valproate to Monotherapy With Lamotrigine Tablets in Patients ≥16 Years of Age with Epilepsy Lamotrigine Tablets Valproate Step 1 Achieve a dose of 200 mg/day according to
  guidelines in Table 1
  (if not already on 200 mg/day). Maintain previous stable dose. Step 2 Maintain at 200 mg/day. Decrease to 500 mg/day by decrements no greater than
  500 mg/day/week and then maintain the dose of
  500 mg/day for 1 week. Step 3 Increase to 300 mg/day and maintain for 1 week. Simultaneously decrease to
  250 mg/day and maintain for 1 week. Step 4 Increase by 100 mg/day every
  week to achieve maintenance dose of 500 mg/day. Discontinue.

  Conversion from Adjunctive Therapy With AEDs Other Than Carbamazepine, Phenytoin, Phenobarbital, Primidone, or Valproate to Monotherapy With Lamotrigine Tablets: No specific dosing guidelines can be provided for conversion to monotherapy with lamotrigine tablets with AEDs other than carbamazepine, phenobarbital, phenytoin, primidone, or valproate.

  2.4 Bipolar Disorder

  The goal of maintenance treatment with lamotrigine tablets is to delay the time to occurrence of mood episodes (depression, mania, hypomania, mixed episodes) in patients treated for acute mood episodes with standard therapy. The target dose of lamotrigine tablets is 200 mg/day (100 mg/day in patients taking valproate, which decreases the apparent clearance of lamotrigine, and 400 mg/day in patients not taking valproate and taking either carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin that increase the apparent clearance of lamotrigine). In the clinical trials, doses up to 400 mg/day as monotherapy were evaluated; however, no additional benefit was seen at 400 mg/day compared with 200 mg/day [see Clinical Studies (14.2) ]. Accordingly, doses above 200 mg/day are not recommended. Treatment with lamotrigine tablets is introduced, based on concurrent medications, according to the regimen outlined in Table 5. If other psychotropic medications are withdrawn following stabilization, the dose of lamotrigine tablets should be adjusted. For patients discontinuing valproate, the dose of lamotrigine tablets should be doubled over a 2-week period in equal weekly increments (see Table 6). For patients discontinuing carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin that induce lamotrigine glucuronidation, the dose of lamotrigine tablets should remain constant for the first week and then should be decreased by half over a 2-week period in equal weekly decrements (see Table 6). The dose of lamotrigine tablets may then be further adjusted to the target dose (200 mg) as clinically indicated.

  If other drugs are subsequently introduced, the dose of lamotrigine tablets may need to be adjusted. In particular, the introduction of valproate requires reduction in the dose of lamotrigine tablets [see Drug Interactions (7) , Clinical Pharmacology (12.3) ].

  To avoid an increased risk of rash, the recommended initial dose and subsequent dose escalations of lamotrigine tablets should not be exceeded [see Boxed Warning ].

  Table 5. Escalation Regimen for Lamotrigine Tablets for Patients With Bipolar Disorder

  a Valproate has been shown to inhibit glucuronidation and decrease the apparent clearance of lamotrigine [see Drug Interactions (7), Clinical Pharmacology (12.3)].

  b These drugs induce lamotrigine glucuronidation and increase clearance [see Drug Interactions (7), Clinical Pharmacology (12.3)]. Other drugs which have similar effects include estrogen-containing oral contraceptives [see Drug Interactions (7), Clinical Pharmacology (12.3)]. Dosing recommendations for oral contraceptives can be found in General Dosing Considerations [see Dosage and Administration (2.1)]. Patients on rifampin, or other drugs that induce lamotrigine glucuronidation and increase clearance, should follow the same dosing titration/maintenance regimen as that used with anticonvulsants that have this effect.

  For Patients TAKING 
  Valproatea For Patients NOT TAKING 
  Carbamazepine, Phenytoin, Phenobarbital, 
  Primidoneb, or Valproatea For Patients TAKING 
  Carbamazepine, Phenytoin,
  Phenobarbital, or Primidoneb and NOT TAKING 
  Valproatea Weeks 1 and 2 25 mg every 
  other day 25 mg daily 50 mg daily Weeks 3 and 4 25 mg daily 50 mg daily 100 mg daily, in divided doses Week 5 50 mg daily 100 mg daily 200 mg daily, in divided doses Week 6 100 mg daily 200 mg daily 300 mg daily, in divided doses Week 7 100 mg daily 200 mg daily up to 400 mg daily, in divided doses Table 6. Dosage Adjustments to Lamotrigine Tablets for Patients With Bipolar Disorder Following Discontinuation of Psychotropic Medications Discontinuation of Psychotropic Drugs 
  (excluding Carbamazepine, Phenytoin, 
  Phenobarbital, Primidoneb, or 
  Valproatea) After Discontinuation of 
  Valproatea After Discontinuation of 
  Carbamazepine, Phenytoin, 
  Phenobarbital, or Primidoneb Current dose of lamotrigine tablets
  (mg/day)
  100 Current dose of lamotrigine tablets
  (mg/day)
  400

  a Valproate has been shown to inhibit glucuronidation and decrease the apparent clearance of lamotrigine [see Drug Interactions (7), Clinical Pharmacology (12.3)].

  b These drugs induce lamotrigine glucuronidation and increase clearance [see Drug Interactions (7), Clinical Pharmacology (12.3)]. Other drugs which have similar effects include estrogen-containing oral contraceptives [see Drug Interactions (7), Clinical Pharmacology (12.3)]. Dosing recommendations for oral contraceptives can be found in General Dosing Considerations [see Dosage and Administration (2.1)]. Patients on rifampin, or other drugs that induce lamotrigine glucuronidation and increase clearance, should follow the same dosing titration/maintenance regimen as that used with anticonvulsants that have this effect.

  Week 1 Maintain current dose of lamotrigine tablets 150 400 Week 2 Maintain current dose of lamotrigine tablets 200 300 Week 3 onward Maintain current dose of lamotrigine tablets 200 200

  The benefit of continuing treatment in patients who had been stabilized in an 8- to 16-week open-label phase with lamotrigine tablets was established in two randomized, placebo-controlled clinical maintenance trials [see Clinical Studies (14.2) ]. However, the optimal duration of treatment with lamotrigine tablets has not been established. Thus, patients should be periodically reassessed to determine the need for maintenance treatment.

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  2.1 General Dosing Considerations

  Rash: There are suggestions, yet to be proven, that the risk of severe, potentially life-threatening rash may be increased by (1) coadministration of lamotrigine tablets with valproate, (2) exceeding the recommended initial dose of lamotrigine tablets, or (3) exceeding the recommended dose escalation for lamotrigine tablets. However, cases have occurred in the absence of these factors [see Boxed Warning ]. Therefore, it is important that the dosing recommendations be followed closely.

  The risk of nonserious rash may be increased when the recommended initial dose and/or the rate of dose escalation of lamotrigine tablet is exceeded and in patients with a history of allergy or rash to other AEDs.

  It is recommended that lamotrigine tablets not be restarted in patients who discontinued due to rash associated with prior treatment with lamotrigine, unless the potential benefits clearly outweigh the risks. If the decision is made to restart a patient who has discontinued lamotrigine, the need to restart with the initial dosing recommendations should be assessed. The greater the interval of time since the previous dose, the greater consideration should be given to restarting with the initial dosing recommendations. If a patient has discontinued lamotrigine for a period of more than 5 half-lives, it is recommended that initial dosing recommendations and guidelines be followed. The half-life of lamotrigine is affected by other concomitant medications [see Clinical Pharmacology (12.3) ].

  Lamotrigine Tablets Added to Drugs Known to Induce or Inhibit Glucuronidation: Drugs other than those listed in the Clinical Pharmacology section [see Clinical Pharmacology (12.3) ] have not been systematically evaluated in combination with lamotrigine. Because lamotrigine is metabolized predominantly by glucuronic acid conjugation, drugs that are known to induce or inhibit glucuronidation may affect the apparent clearance of lamotrigine and doses of lamotrigine tablets may require adjustment based on clinical response.

  Target Plasma Levels for Patients With Epilepsy or Bipolar Disorder: A therapeutic plasma concentration range has not been established for lamotrigine. Dosing of lamotrigine tablets should be based on therapeutic response [see Clinical Pharmacology (12.3) ].

  Women Taking Estrogen-Containing Oral Contraceptives: Starting Lamotrigine Tablets  in Women Taking Estrogen-Containing Oral Contraceptives: Although estrogen-containing oral contraceptives have been shown to increase the clearance of lamotrigine [see Clinical Pharmacology (12.3) ], no adjustments to the recommended dose-escalation guidelines for lamotrigine tablets should be necessary solely based on the use of estrogen-containing oral contraceptives. Therefore, dose escalation should follow the recommended guidelines for initiating adjunctive therapy with lamotrigine tablets based on the concomitant AED or other concomitant medications (see Table 1 or Table 5). See below for adjustments to maintenance doses of lamotrigine tablets in women taking estrogen-containing oral contraceptives.

  Adjustments to the Maintenance Dose of Lamotrigine Tablets In Women Taking Estrogen-Containing Oral Contraceptives:

  (1) Taking Estrogen-Containing Oral Contraceptives: For women not taking carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin that induce lamotrigine glucuronidation [see Drug Interactions (7), Clinical Pharmacology (12.3)], the maintenance dose of lamotrigine  tablets will in most cases need to be increased, by as much as 2-fold over the recommended target maintenance dose, in order to maintain a consistent lamotrigine plasma level [see Clinical Pharmacology (12.3) ].

  (2) Starting Estrogen-Containing Oral Contraceptives: In women taking a stable dose of lamotrigine tablets and not taking carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin that induce lamotrigine glucuronidation [see Drug Interactions (7), Clinical Pharmacology (12.3)], the maintenance dose will in most cases need to be increased by as much as 2-fold in order to maintain a consistent lamotrigine plasma level. The dose increases should begin at the same time that the oral contraceptive is introduced and continue, based on clinical response, no more rapidly than 50 to 100 mg/day every week. Dose increases should not exceed the recommended rate (see Table 1 or Table 5) unless lamotrigine plasma levels or clinical response support larger increases. Gradual transient increases in lamotrigine plasma levels may occur during the week of inactive hormonal preparation ("pill-free" week), and these increases will be greater if dose increases are made in the days before or during the week of inactive hormonal preparation. Increased lamotrigine plasma levels could result in additional adverse reactions, such as dizziness, ataxia, and diplopia. If adverse reactions attributable to lamotrigine tablets consistently occur during the "pill-free" week, dose adjustments to the overall maintenance dose may be necessary. Dose adjustments limited to the "pill-free" week are not recommended. For women taking lamotrigine tablets in addition to carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin that induce lamotrigine glucuronidation [see Drug Interactions (7), Clinical Pharmacology (12.3)], no adjustment to the dose of lamotrigine tablets should be necessary.

  (3) Stopping Estrogen-Containing Oral Contraceptives: For women not taking carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin that induce lamotrigine glucuronidation [see Drug Interactions (7), Clinical Pharmacology (12.3)], the maintenance dose of lamotrigine tablets will in most cases need to be decreased by as much as 50% in order to maintain a consistent lamotrigine plasma level. The decrease in dose of lamotrigine tablets should not exceed 25% of the total daily dose per week over a 2-week period, unless clinical response or lamotrigine plasma levels indicate otherwise [see Clinical Pharmacology (12.3) ]. For women taking lamotrigine tablets in addition to carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin that induce lamotrigine glucuronidation [see Drug Interactions (7), Clinical Pharmacology (12.3)], no adjustment to the dose of lamotrigine tablets should be necessary.

  Women and Other Hormonal Contraceptive Preparations or Hormone Replacement Therapy: The effect of other hormonal contraceptive preparations or hormone replacement therapy on the pharmacokinetics of lamotrigine has not been systematically evaluated. It has been reported that ethinylestradiol, not progestogens, increased the clearance of lamotrigine up to 2-fold, and the progestin-only pills had no effect on lamotrigine plasma levels. Therefore, adjustments to the dosage of lamotrigine tablets in the presence of progestogens alone will likely not be needed.

  Patients With Hepatic Impairment: Experience in patients with hepatic impairment is limited. Based on a clinical pharmacology study in 24 patients with mild, moderate, and severe liver impairment [see Use in Specific Populations (8.6) , Clinical Pharmacology (12.3) ], the following general recommendations can be made. No dosage adjustment is needed in patients with mild liver impairment. Initial, escalation, and maintenance doses should generally be reduced by approximately 25% in patients with moderate and severe liver impairment without ascites and 50% in patients with severe liver impairment with ascites. Escalation and maintenance doses may be adjusted according to clinical response.

  Patients With Renal Impairment: Initial doses of lamotrigine tablets should be based on patients' concomitant medications (see Tables 1-3 or Table 5); reduced maintenance doses may be effective for patients with significant renal impairment [see Use in Specific Populations (8.7) , Clinical Pharmacology (12.3) ]. Few patients with severe renal impairment have been evaluated during chronic treatment with lamotrigine tablets. Because there is inadequate experience in this population, lamotrigine tablets should be used with caution in these patients.

  Discontinuation Strategy:

  Epilepsy: For patients receiving lamotrigine tablets in combination with other AEDs, a reevaluation of all AEDs in the regimen should be considered if a change in seizure control or an appearance or worsening of adverse reactions is observed.

  If a decision is made to discontinue therapy with lamotrigine tablets, a step-wise reduction of dose over at least 2 weeks (approximately 50% per week) is recommended unless safety concerns require a more rapid withdrawal [see Warnings and Precautions (5.9) ].

  Discontinuing carbamazepine, phenytoin, phenobarbital, primidone or other drugs such as rifampin that induce lamotrigine glucuronidation should prolong the half-life of lamotrigine; discontinuing valproate should shorten the half-life of lamotrigine.

  Bipolar Disorder: In the controlled clinical trials, there was no increase in the incidence, type, or severity of adverse reactions following abrupt termination of lamotrigine tablets. In clinical trials in patients with Bipolar Disorder, 2 patients experienced seizures shortly after abrupt withdrawal of lamotrigine tablets. However, there were confounding factors that may have contributed to the occurrence of seizures in these bipolar patients. Discontinuation of lamotrigine tablets should involve a step-wise reduction of dose over at least 2 weeks (approximately 50% per week) unless safety concerns require a more rapid withdrawal [see Warnings and Precautions (5.9) ].

  2.2 Epilepsy – Adjunctive Therapy

  This section provides specific dosing recommendations for patients greater than 12 years of age and patients 2 to 12 years of age. Within each of these age-groups, specific dosing recommendations are provided depending upon concomitant AED or other concomitant medications (Table 1 for patients greater than 12 years of age and Table 2 for patients 2 to 12 years of age). A weight-based dosing guide for patients 2 to 12 years of age on concomitant valproate is provided in Table 3.

  Patients Over 12 Years of Age: Recommended dosing guidelines are summarized in Table 1.

  Table 1. Escalation Regimen for Lamotrigine Tablets in Patients Over 12 Years of Age With Epilepsy

  a Valproate has been shown to inhibit glucuronidation and decrease the apparent clearance of lamotrigine [see Drug Interactions (7), Clinical Pharmacology (12.3)].

  b These drugs induce lamotrigine glucuronidation and increase clearance [see Drug Interactions (7), Clinical Pharmacology (12.3)]. Other drugs that have similar effects include estrogen-containing oral contraceptives [see Drug Interactions (7), Clinical Pharmacology (12.3)]. Dosing recommendations for oral contraceptives can be found in General Dosing Considerations [see Dosage and Administration (2.1)]. Patients on rifampin, or other drugs that induce lamotrigine glucuronidation and increase clearance, should follow the same dosing titration/maintenance regimen as that used with anticonvulsants that have this effect.

  
  For 
  For Patients NOT TAKING 
  For Patients 
  
  Patients
  Carbamazepine, 
  TAKING
  
  TAKING
  Phenytoin,
  Carbamazepine,
  
  Valproatea
  Phenobarbital,
  Phenytoin, 
  
  
  or Primidoneb,  
  Phenobarbital,
  
  
  or Valproatea
  or Primidoneb
  
  
  
  and NOT TAKING
  
  
  
  Valproatea
  Weeks 1 and 2
  25 mg every other day
  25 mg every day
  50 mg/day
  Weeks 3 and 4
  25 mg every day
  50 mg/day
  100 mg/day
  (in 2 divided doses)
  Weeks 5 onwards to 
  maintenance
  Increase by 25 to 
  50 mg/day every 1 to 2 weeks
  Increase by 50
  mg/day every 1
  to 2 weeks
  Increase by 
  100 mg/day every 
  1 to 2 weeks.
  Usual maintenance 
  dose
  100 to 200 mg/day
  with valproate alone
  225 to 375 mg/day
  (in 2 divided doses).
  300 to 500 mg/day
  (in 2 divided doses).
  
  100 to 400 mg/day
  with valproate
  and other drugs that induce glucuronidation
  
  
  
  (in 1 or 2 divided doses)
  
  
  

  Patients 2 to 12 Years Of Age: Recommended dosing guidelines are summarized in Table 2.

  Smaller starting doses and slower dose escalations than those used in clinical trials are recommended because of the suggestion that the risk of rash may be decreased by smaller starting doses and slower dose escalations. Therefore, maintenance doses will take longer to reach in clinical practice than in clinical trials. It may take several weeks to months to achieve an individualized maintenance dose. Maintenance doses in patients weighing less than 30 kg, regardless of age or concomitant AED, may need to be increased as much as 50%, based on clinical response.

  Table 2. Escalation Regimen for Lamotrigine Tablets in Patients 2 to 12 Years of Age With Epilepsy

  Note: Only whole tablets should be used for dosing.

  a Valproate has been shown to inhibit glucuronidation and decrease the apparent clearance of lamotrigine [see Drug Interactions (7), Clinical Pharmacology (12.3)].

  b These drugs induce lamotrigine glucuronidation and increase clearance [see Drug Interactions (7), Clinical Pharmacology (12.3)]. Other drugs which have similar effects include estrogen-containing oral contraceptives [see Drug Interactions (7), Clinical Pharmacology (12.3)]. Dosing recommendations for oral contraceptives can be found in General Dosing Considerations [see Dosage and Administration (2.1)]. Patients on rifampin, or other drugs that induce lamotrigine glucuronidation and increase clearance, should follow the same dosing titration/maintenance regimen as that used with anticonvulsants that have this effect.

  
  For Patients TAKING 
  Valproatea
  For Patients NOT 
  TAKING Carbamazepine, Phenytoin, 
  Phenobarbital, Primidoneb, or 
  Valproatea
  For Patients TAKING 
  Carbamazepine, Phenytoin, Phenobarbital, or 
  Primidoneb and NOT 
  TAKING Valproatea
  Weeks 1 and 2
  0.15 mg/kg/day
  in 1 or 2 divided doses, rounded down to the 
  nearest whole tablet (see Table 3 for weight 
  based dosing guide).
  0.3 mg/kg/day
  in 1 or 2 divided doses, rounded down to the 
  nearest whole tablet.
  0.6 mg/kg/day
  in 2 divided doses, rounded down to the 
  nearest whole tablet.
  Weeks 3 and 4
  0.3 mg/kg/day
  in 1 or 2 divided doses,
  rounded down to the 
  nearest whole tablet 
  (see Table 3 for weight 
  based dosing guide).
  0.6 mg/kg/day
  in 2 divided doses,
  rounded down to the 
  nearest whole tablet.
  1.2 mg/kg/day
  in 2 divided doses, 
  rounded down to the 
  nearest whole tablet.
  Weeks 5 
  onwards to 
  maintenance
  The dose should be increased every 
  1 to 2 weeks as follows:
  calculate 0.3 mg/kg/day, round this amount 
  down to the nearest whole tablet, and 
  add this amount to the 
  previously administered daily dose.
  The dose should be increased every 
  1 to 2 weeks as follows:
  calculate 0.6 mg/kg/day, round this amount 
  down to the nearest whole tablet, and 
  add this amount to the 
  previously administered daily dose
  The dose should be increased every 
  1 to 2 weeks as follows:
  calculate 1.2 mg/kg/day, round this amount 
  down to the nearest whole tablet, and 
  add this amount to the 
  previously administered daily dose
  Usual 
  Maintenance 
  Dose
  1 to 5 mg/kg/day
  (maximum 200 mg/day 
  in 1 or 2 divided doses).
  1 to 3 mg/kg/day with valproate alone
  4.5 to 7.5 mg/kg/day
  (maximum 300 mg/day 
  in 2 divided doses)
  5 to 15 mg/kg/day
  (maximum 400 mg/day 
  in 2 divided doses)
  Maintenance dose in 
  patients 
  less than 30 kg
  May need to be increased 
  by as much as 50%, 
  based on clinical response
  May need to be increased 
  by as much as 50%, 
  based on clinical response
  May need to be increased 
  by as much as 50%, based 
  on clinical response
  Table 3. The Initial Weight-Based Dosing Guide for Patients 2 to 12 Years Taking Valproate (Weeks 1 to 4) With Epilepsy If the patient’s weight is
  Give this daily dose, using the most appropriate combination of Lamotrigine 2-mg and 5-mg tablets
  Greater than
  And less than
  Weeks 1 and 2
  Weeks 3 and 4
  6.7 kg
  14 kg
  2 mg every other day
  2 mg every day
  14.1 kg
  27 kg
  2 mg every day
  4 mg every day
  27.1 kg
  34 kg
  4 mg every day
  8 mg every day
  34.1 kg
  40 kg
  5 mg every day
  10 mg every day
  

  Usual Adjunctive Maintenance Dose for Epilepsy: The usual maintenance doses identified in Tables 1 and 2 are derived from dosing regimens employed in the placebo-controlled adjunctive studies in which the efficacy of lamotrigine tablets was established. In patients receiving multidrug regimens employing carbamazepine, phenytoin, phenobarbital, or primidone without valproate, maintenance doses of adjunctive lamotrigine tablets as high as 700 mg/day have been used. In patients receiving valproate alone, maintenance doses of adjunctive lamotrigine tablets as high as 200 mg/day have been used. The advantage of using doses above those recommended in Tables 1 through 4 has not been established in controlled trials.

  2.3 Epilepsy – Conversion From Adjunctive Therapy to Monotherapy

  The goal of the transition regimen is to effect the conversion to monotherapy with lamotrigine tablets under conditions that ensure adequate seizure control while mitigating the risk of serious rash associated with the rapid titration of lamotrigine tablets.

  The recommended maintenance dose of lamotrigine tablets as monotherapy is 500 mg/day given in two divided doses.

  To avoid an increased risk of rash, the recommended initial dose and subsequent dose escalations of lamotrigine tablets should not be exceeded [see Boxed Warning].

  Conversion From Adjunctive Therapy With Carbamazepine, Phenytoin, Phenobarbital, or Primidone to Monotherapy With Lamotrigine Tablets: After achieving a dose of 500 mg/day of lamotrigine tablets according to the guidelines in Table 1, the concomitant AED should be withdrawn by 20% decrements each week over a 4-week period. The regimen for the withdrawal of the concomitant AED is based on experience gained in the controlled monotherapy clinical trial.

  Conversion from Adjunctive Therapy With Valproate to Monotherapy With Lamotrigine Tablets:

  The conversion regimen involves 4 steps outlined in Table 4.

  Table 4. Conversion From Adjunctive Therapy With Valproate to Monotherapy With Lamotrigine Tablets in Patients ≥16 Years of Age with Epilepsy
  Lamotrigine Tablets
  Valproate
  Step 1
  Achieve a dose of 200 mg/day according to
  guidelines in Table 1
  (if not already on 200 mg/day).
  Maintain previous stable dose.
  Step 2
  Maintain at 200 mg/day.
  Decrease to 500 mg/day by decrements no greater than
  500 mg/day/week and then maintain the dose of
  500 mg/day for 1 week.
  Step 3
  Increase to 300 mg/day and maintain for 1 week.
  Simultaneously decrease to
  250 mg/day and maintain for 1 week.
  Step 4
  Increase by 100 mg/day every
  week to achieve maintenance dose of 500 mg/day.
  Discontinue.
  

  Conversion from Adjunctive Therapy With AEDs Other Than Carbamazepine, Phenytoin, Phenobarbital, Primidone, or Valproate to Monotherapy With Lamotrigine Tablets: No specific dosing guidelines can be provided for conversion to monotherapy with lamotrigine tablets with AEDs other than carbamazepine, phenobarbital, phenytoin, primidone, or valproate.

  2.4 Bipolar Disorder

  The goal of maintenance treatment with lamotrigine tablets is to delay the time to occurrence of mood episodes (depression, mania, hypomania, mixed episodes) in patients treated for acute mood episodes with standard therapy. The target dose of lamotrigine tablets is 200 mg/day (100 mg/day in patients taking valproate, which decreases the apparent clearance of lamotrigine, and 400 mg/day in patients not taking valproate and taking either carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin that increase the apparent clearance of lamotrigine). In the clinical trials, doses up to 400 mg/day as monotherapy were evaluated; however, no additional benefit was seen at 400 mg/day compared with 200 mg/day [see Clinical Studies (14.2) ]. Accordingly, doses above 200 mg/day are not recommended. Treatment with lamotrigine tablets is introduced, based on concurrent medications, according to the regimen outlined in Table 5. If other psychotropic medications are withdrawn following stabilization, the dose of lamotrigine tablets should be adjusted. For patients discontinuing valproate, the dose of lamotrigine tablets should be doubled over a 2-week period in equal weekly increments (see Table 6). For patients discontinuing carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin that induce lamotrigine glucuronidation, the dose of lamotrigine tablets should remain constant for the first week and then should be decreased by half over a 2-week period in equal weekly decrements (see Table 6). The dose of lamotrigine tablets may then be further adjusted to the target dose (200 mg) as clinically indicated.

  If other drugs are subsequently introduced, the dose of lamotrigine tablets may need to be adjusted. In particular, the introduction of valproate requires reduction in the dose of lamotrigine tablets [see Drug Interactions (7) , Clinical Pharmacology (12.3) ].

  To avoid an increased risk of rash, the recommended initial dose and subsequent dose escalations of lamotrigine tablets should not be exceeded [see Boxed Warning ].

  Table 5. Escalation Regimen for Lamotrigine Tablets for Patients With Bipolar Disorder

  a Valproate has been shown to inhibit glucuronidation and decrease the apparent clearance of lamotrigine [see Drug Interactions (7), Clinical Pharmacology (12.3)].

  
  

  b These drugs induce lamotrigine glucuronidation and increase clearance [see Drug Interactions (7), Clinical Pharmacology (12.3)]. Other drugs which have similar effects include estrogen-containing oral contraceptives [see Drug Interactions (7), Clinical Pharmacology (12.3)]. Dosing recommendations for oral contraceptives can be found in General Dosing Considerations [see Dosage and Administration (2.1)]. Patients on rifampin, or other drugs that induce lamotrigine glucuronidation and increase clearance, should follow the same dosing titration/maintenance regimen as that used with anticonvulsants that have this effect.

  
  For Patients TAKING 
  Valproatea
  For Patients NOT TAKING 
  Carbamazepine, Phenytoin, Phenobarbital, 
  Primidoneb, or Valproatea
  For Patients TAKING 
  Carbamazepine, Phenytoin,
  Phenobarbital, or Primidoneb and NOT TAKING 
  Valproatea
  Weeks 1 and 2
  25 mg every 
  other day
  25 mg daily
  50 mg daily
  Weeks 3 and 4
  25 mg daily
  50 mg daily
  100 mg daily, in divided doses
  Week 5
  50 mg daily
  100 mg daily
  200 mg daily, in divided doses
  Week 6
  100 mg daily
  200 mg daily
  300 mg daily, in divided doses
  Week 7
  100 mg daily
  200 mg daily
  up to 400 mg daily, in divided doses
  Table 6. Dosage Adjustments to Lamotrigine Tablets for Patients With Bipolar Disorder Following Discontinuation of Psychotropic Medications
  Discontinuation of Psychotropic Drugs 
  (excluding Carbamazepine, Phenytoin, 
  Phenobarbital, Primidoneb, or 
  Valproatea)
  After Discontinuation of 
  Valproatea
  After Discontinuation of 
  Carbamazepine, Phenytoin, 
  Phenobarbital, or Primidoneb
  
  
  Current dose of lamotrigine tablets
  (mg/day)
  100
  Current dose of lamotrigine tablets
  (mg/day)
  400
  

  a Valproate has been shown to inhibit glucuronidation and decrease the apparent clearance of lamotrigine [see Drug Interactions (7), Clinical Pharmacology (12.3)].

  
  

  b These drugs induce lamotrigine glucuronidation and increase clearance [see Drug Interactions (7), Clinical Pharmacology (12.3)]. Other drugs which have similar effects include estrogen-containing oral contraceptives [see Drug Interactions (7), Clinical Pharmacology (12.3)]. Dosing recommendations for oral contraceptives can be found in General Dosing Considerations [see Dosage and Administration (2.1)]. Patients on rifampin, or other drugs that induce lamotrigine glucuronidation and increase clearance, should follow the same dosing titration/maintenance regimen as that used with anticonvulsants that have this effect.

  Week 1
  Maintain current dose of lamotrigine tablets
  150
  400
  Week 2
  Maintain current dose of lamotrigine tablets
  200
  300
  Week 3 onward
  Maintain current dose of lamotrigine tablets
  200
  200
  

  The benefit of continuing treatment in patients who had been stabilized in an 8- to 16-week open-label phase with lamotrigine tablets was established in two randomized, placebo-controlled clinical maintenance trials [see Clinical Studies (14.2) ]. However, the optimal duration of treatment with lamotrigine tablets has not been established. Thus, patients should be periodically reassessed to determine the need for maintenance treatment.

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  2.1 General Dosing Considerations

  Rash: There are suggestions, yet to be proven, that the risk of severe, potentially life-threatening rash may be increased by (1) coadministration of lamotrigine with valproate, (2) exceeding the recommended initial dose of lamotrigine, or (3) exceeding the recommended dose escalation for lamotrigine. However, cases have occurred in the absence of these factors [see Boxed Warning]. Therefore, it is important that the dosing recommendations be followed closely.

  The risk of nonserious rash may be increased when the recommended initial dose and/or the rate of dose escalation of lamotrigine is exceeded and in patients with a history of allergy or rash to other AEDs.

  Lamotrigine Starter Kits provide lamotrigine at doses consistent with the recommended titration schedule for the first 5 weeks of treatment, based upon concomitant medications for patients with epilepsy (>12 years of age) and Bipolar I Disorder (≥18 years of age) and are intended to help reduce the potential for rash. The use of lamotrigine Starter Kits is recommended for appropriate patients who are starting or restarting lamotrigine [see How Supplied/Storage and Handling (16)].

  It is recommended that lamotrigine tablets, USP not be restarted in patients who discontinued due to rash associated with prior treatment with lamotrigine, unless the potential benefits clearly outweigh the risks. If the decision is made to restart a patient who has discontinued lamotrigine, the need to restart with the initial dosing recommendations should be assessed. The greater the interval of time since the previous dose, the greater consideration should be given to restarting with the initial dosing recommendations. If a patient has discontinued lamotrigine for a period of more than 5 half-lives, it is recommended that initial dosing recommendations and guidelines be followed. The half-life of lamotrigine is affected by other concomitant medications [see Clinical Pharmacology (12.3)].

  Lamotrigine Added to Drugs Known to Induce or Inhibit Glucuronidation: Drugs other than those listed in the Clinical Pharmacology section [see Clinical Pharmacology (12.3)] have not been systematically evaluated in combination with lamotrigine. Because lamotrigine is metabolized predominantly by glucuronic acid conjugation, drugs that are known to induce or inhibit glucuronidation may affect the apparent clearance of lamotrigine and doses of lamotrigine may require adjustment based on clinical response.

  Target Plasma Levels for Patients With Epilepsy or Bipolar Disorder: A therapeutic plasma concentration range has not been established for lamotrigine. Dosing of lamotrigine should be based on therapeutic response [see Clinical Pharmacology (12.3)].

  Women Taking Estrogen-Containing Oral Contraceptives: Starting Lamotrigine in Women Taking Estrogen-Containing Oral Contraceptives: Although estrogen-containing oral contraceptives have been shown to increase the clearance of lamotrigine [see Clinical Pharmacology (12.3)], no adjustments to the recommended dose-escalation guidelines for lamotrigine should be necessary solely based on the use of estrogen-containing oral contraceptives. Therefore, dose escalation should follow the recommended guidelines for initiating adjunctive therapy with lamotrigine based on the concomitant AED or other concomitant medications (see Table 1 or Table 5). See below for adjustments to maintenance doses of lamotrigine in women taking estrogen-containing oral contraceptives.

  Adjustments to the Maintenance Dose of Lamotrigine in Women Taking Estrogen-Containing Oral Contraceptives:

  (1) Taking Estrogen-Containing Oral Contraceptives: For women not taking carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin that induce lamotrigine glucuronidation [see Drug Interactions (7), Clinical Pharmacology (12.3)], the maintenance dose of lamotrigine will in most cases need to be increased, by as much as 2-fold over the recommended target maintenance dose, in order to maintain a consistent lamotrigine plasma level [see Clinical Pharmacology (12.3)].

  (2) Starting Estrogen-Containing Oral Contraceptives: In women taking a stable dose of lamotrigine and not taking carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin that induce lamotrigine glucuronidation [see Drug Interactions (7), Clinical Pharmacology (12.3)], the maintenance dose will in most cases need to be increased by as much as 2-fold in order to maintain a consistent lamotrigine plasma level. The dose increases should begin at the same time that the oral contraceptive is introduced and continue, based on clinical response, no more rapidly than 50 to 100 mg/day every week. Dose increases should not exceed the recommended rate (see Table 1 or Table 5) unless lamotrigine plasma levels or clinical response support larger increases. Gradual transient increases in lamotrigine plasma levels may occur during the week of inactive hormonal preparation ("pill-free" week), and these increases will be greater if dose increases are made in the days before or during the week of inactive hormonal preparation. Increased lamotrigine plasma levels could result in additional adverse reactions, such as dizziness, ataxia, and diplopia. If adverse reactions attributable to lamotrigine consistently occur during the "pill-free" week, dose adjustments to the overall maintenance dose may be necessary. Dose adjustments limited to the "pill-free" week are not recommended. For women taking lamotrigine in addition to carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin that induce lamotrigine glucuronidation [see Drug Interactions (7), Clinical Pharmacology (12.3)], no adjustment to the dose of lamotrigine should be necessary.  

  (3) Stopping Estrogen-Containing Oral Contraceptives: For women not taking carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin that induce lamotrigine glucuronidation [see Drug Interactions (7), Clinical Pharmacology (12.3)], the maintenance dose of lamotrigine will in most cases need to be decreased by as much as 50% in order to maintain a consistent lamotrigine plasma level. The decrease in dose of lamotrigine should not exceed 25% of the total daily dose per week over a 2-week period, unless clinical response or lamotrigine plasma levels indicate otherwise [see Clinical Pharmacology (12.3)]. For women taking lamotrigine in addition to carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin that induce lamotrigine glucuronidation [see Drug Interactions (7), Clinical Pharmacology (12.3)], no adjustment to the dose of lamotrigine should be necessary.

  Women and Other Hormonal Contraceptive Preparations or Hormone Replacement Therapy: The effect of other hormonal contraceptive preparations or hormone replacement therapy on the pharmacokinetics of lamotrigine has not been systematically evaluated. It has been reported that ethinylestradiol, not progestogens, increased the clearance of lamotrigine up to 2-fold, and the progestin-only pills had no effect on lamotrigine plasma levels. Therefore, adjustments to the dosage of lamotrigine in the presence of progestogens alone will likely not be needed.

  Patients With Hepatic Impairment: Experience in patients with hepatic impairment is limited. Based on a clinical pharmacology study in 24 patients with mild, moderate, and severe liver impairment [see Use in Specific Populations (8.6), Clinical Pharmacology (12.3)], the following general recommendations can be made. No dosage adjustment is needed in patients with mild liver impairment. Initial, escalation, and maintenance doses should generally be reduced by approximately 25% in patients with moderate and severe liver impairment without ascites and 50% in patients with severe liver impairment with ascites. Escalation and maintenance doses may be adjusted according to clinical response.

  Patients With Renal Impairment: Initial doses of lamotrigine should be based on patients' concomitant medications (see Tables 1-3 or Table 5); reduced maintenance doses may be effective for patients with significant renal impairment [see Use in Specific Populations (8.7), Clinical Pharmacology (12.3)]. Few patients with severe renal impairment have been evaluated during chronic treatment with lamotrigine. Because there is inadequate experience in this population, lamotrigine should be used with caution in these patients.

  Discontinuation Strategy: Epilepsy: For patients receiving lamotrigine in combination with other AEDs, a reevaluation of all AEDs in the regimen should be considered if a change in seizure control or an appearance or worsening of adverse reactions is observed.

  If a decision is made to discontinue therapy with lamotrigine, a step-wise reduction of dose over at least 2 weeks (approximately 50% per week) is recommended unless safety concerns require a more rapid withdrawal [see Warnings and Precautions (5.9)].

  Discontinuing carbamazepine, phenytoin, phenobarbital, primidone or other drugs such as rifampin that induce lamotrigine glucuronidation should prolong the half-life of lamotrigine; discontinuing valproate should shorten the half-life of lamotrigine.

  Bipolar Disorder: In the controlled clinical trials, there was no increase in the incidence, type, or severity of adverse reactions following abrupt termination of lamotrigine. In clinical trials in patients with Bipolar Disorder, 2 patients experienced seizures shortly after abrupt withdrawal of lamotrigine. However, there were confounding factors that may have contributed to the occurrence of seizures in these bipolar patients. Discontinuation of lamotrigine should involve a step-wise reduction of dose over at least 2 weeks (approximately 50% per week) unless safety concerns require a more rapid withdrawal [see Warnings and Precautions (5.9)].

  2.2 Epilepsy – Adjunctive Therapy

  This section provides specific dosing recommendations for patients greater than 12 years of age and patients 2 to 12 years of age. Within each of these age-groups, specific dosing recommendations are provided depending upon concomitant AED or other concomitant medications (Table 1 for patients greater than 12 years of age and Table 2 for patients 2 to 12 years of age). A weight-based dosing guide for patients 2 to 12 years of age on concomitant valproate is provided in Table 3.

  Patients Over 12 Years of Age: Recommended dosing guidelines are summarized in Table 1.

  Table 1. Escalation Regimen for Lamotrigine in Patients Over 12 Years of Age With Epilepsy

  a Valproate has been shown to inhibit glucuronidation and decrease the apparent clearance of lamotrigine [see Drug Interactions (7), Clinical Pharmacology (12.3)].

  b These drugs induce lamotrigine glucuronidation and increase clearance [see Drug Interactions (7), Clinical Pharmacology (12.3)]. Other drugs that have similar effects include estrogen-containing oral contraceptives [see Drug Interactions (7), Clinical Pharmacology (12.3)]. Dosing recommendations for oral contraceptives can be found in General Dosing Considerations [see Dosage and Administration (2.1)]. Patients on rifampin, or other drugs that induce lamotrigine glucuronidation and increase clearance, should follow the same dosing titration/maintenance regimen as that used with anticonvulsants that have this effect.

  
  For Patients TAKING
   Valproatea
  For Patients NOT 
  TAKING 
  Carbamazepine, 
  Phenytoin, 
  Phenobarbital,
   Primidoneb, or 
  Valproatea
  For Patients 
  TAKING 
  Carbamazepine, 
  Phenytoin, 
  Phenobarbital, or 
  Primidoneb and 
  NOT TAKING Valproatea
  Weeks 1 and 2
  25 mg every other day
  25 mg every day
  50 mg/day
  Weeks 3 and 4
  25 mg every day
  50 mg/day
  100 mg/day 
  (in 2 divided doses)
  Week 5
  onwards to
  maintenance
  Increase by 25 to 50
  mg/day every 1 to
  2 weeks
  Increase by 50
  mg/day every 1 to
  2 weeks
  Increase by 100
  mg/day every 1 to
  2 weeks.
  Usual
  Maintenance
  Dose
  100 to 200 mg/day
  with valproate 
  alone 
  100 to 400 mg/day 
  with valproate and 
  other drugs that 
  induce 
  glucuronidation 
  (in 1 or 2 divided 
  doses)
  225 to 375 mg/day 
  (in 2 divided doses)
  300 to 500 mg/day 
  (in 2 divided doses)
  

  Patients 2 to 12 Years of Age: Recommended dosing guidelines are summarized in Table 2.

  Smaller starting doses and slower dose escalations than those used in clinical trials are recommended because of the suggestion that the risk of rash may be decreased by smaller starting doses and slower dose escalations. Therefore, maintenance doses will take longer to reach in clinical practice than in clinical trials. It may take several weeks to months to achieve an individualized maintenance dose. Maintenance doses in patients weighing less than 30 kg, regardless of age or concomitant AED, may need to be increased as much as 50%, based on clinical response.

  The smallest available strength of lamotrigine tablets is 25 mg, and only whole tablets should be administered. If the calculated dose cannot be achieved using whole tablets, the dose should be rounded down to the nearest whole tablet [see How Supplied/Storage and Handling (16) and Medication Guide].

  Table 2. Escalation Regimen for Lamotrigine in Patients 2 to 12 Years of Age With Epilepsy

  Note: Only whole tablets should be used for dosing.
  

  aValproate has been shown to inhibit glucuronidation and decrease the apparent clearance of lamotrigine [see Drug Interactions (7),
  Clinical Pharmacology (12.3)].
  

  bThese drugs induce lamotrigine glucuronidation and increase clearance [see Drug Interactions (7), Clinical Pharmacology (12.3)].
  Other drugs that have similar effects include estrogen-containing oral contraceptives [see Drug Interactions (7), Clinical Pharmacology (12.3)]. Dosing recommendations for oral contraceptives can be found in General Dosing Considerations [see 
  Dosage and Administration (2.1)]. Patients on rifampin, or other drugs that induce lamotrigine glucuronidation and increase clearance, should follow the same dosing titration/maintenance regimen as that used with anticonvulsants that have this effect.
  

  
  For Patients 
  TAKING Valproatea
  For Patients NOT
   TAKING 
  Carbamazepine, 
  Phenytoin, 
  Phenobarbital, 
  Primidoneb, or 
  Valproatea
  For Patients TAKING
   Carbamazepine, 
  Phenytoin, 
  Phenobarbital, or 
  Primidoneb and NOT
  TAKING Valproatea
  Weeks 1 
  and 2 
  0.15 mg/kg/day 
  in 1 or 2 divided 
  doses, rounded 
  down to the nearest
  whole tablet (see 
  Table 3 for weight-based dosing guide)
  0.3 mg/kg/day 
  in 1 or 2 divided 
  doses, rounded down 
  to the nearest whole 
  tablet
  0.6 mg/kg/day 
  in 2 divided doses,
   rounded down to the
   nearest whole tablet
  Weeks 3 
  and 4 
  0.3 mg/kg/day 
  in 1 or 2 divided 
  doses, rounded 
  down to the nearest
  whole tablet (see
  Table 3 for weight-based dosing guide)
  0.6 mg/kg/day 
  in 2 divided doses, 
  rounded down to the 
  nearest whole tablet
  1.2 mg/kg/day 
  in 2 divided doses,
   rounded down to the
   nearest whole tablet
  Week 5 
  onwards to 
  maintenance
  The dose should be 
  increased every 1 to 
  2 weeks as follows:
  calculate 0.3 mg/kg/day, 
  round this amount
  down to the nearest
  whole tablet, and
  add this amount to
  the previously 
  administered daily
  dose
  The dose should be increased every 1 to 
  2 weeks as follows: calculate 
  0.6 mg/kg/day, round 
  this amount down to 
  the nearest whole 
  tablet, and add this 
  amount to the 
  previously 
  administered daily
   dose
  The dose should be increased every 1 to 
  2 weeks as follows: calculate 
  1.2 mg/kg/day, round
   this amount down to
   the nearest whole
   tablet, and add this
   amount to the
   previously
   administered daily
   dose
  Usual 
  Maintenance 
  Dose 
  1 to 5 mg/kg/day
   (maximum 
  200 mg/day in 1 or 2
   divided doses). 
  1 to 3 mg/kg/day 
  with valproate alone
  4.5 to 7.5 mg/kg/day
   (maximum 300 
  mg/day in 2 divided
  doses)
  5 to 15 mg/kg/day
   (maximum 400 
  mg/day in 2 divided
   doses)
  Maintenance 
  dose in 
  patients less 
  than 30 kg 
  May need to be 
  increased by as 
  much as 50%, based 
  on clinical response
  May need to be
   increased by as much
   as 50%, based on 
  clinical response
  May need to be 
  increased by as much
   as 50%, based on 
  clinical response
  Table 3. The Initial Weight-Based Dosing Guide for Patients 2 to 12 Years of Age Taking Valproate (Weeks 1 to 4) With Epilepsy If the patient’s weight is
  Give this daily dose, using the most appropriate combination of lamotrigine
  2-mg and 5-mg tablets 
  Greater than 
  And less than 
  Weeks 1 and 2
  Weeks 3 and 4
  6.7 kg 
  14 kg 
  2 mg every other day
  2 mg every day
  14.1 kg 
  27 kg 
  2 mg every day
  4 mg every day
  27.1 kg 
  34 kg 
  4 mg every day
  8 mg every day
  34.1 kg 
  40 kg 
  5 mg every day
  10 mg every day
  

  Usual Adjunctive Maintenance Dose for Epilepsy: The usual maintenance doses identified in Tables 1 and 2 are derived from dosing regimens employed in the placebo-controlled adjunctive studies in which the efficacy of lamotrigine was established. In patients receiving multidrug regimens employing carbamazepine, phenytoin, phenobarbital, or primidone without valproate, maintenance doses of adjunctive lamotrigine as high as 700 mg/day have been used. In patients receiving valproate alone, maintenance doses of adjunctive lamotrigine as high as 200 mg/day have been used. The advantage of using doses above those recommended in Tables 1 through 4 has not been established in controlled trials.

  2.3 Epilepsy – Conversion From Adjunctive Therapy to Monotherapy

  The goal of the transition regimen is to effect the conversion to monotherapy with lamotrigine under conditions that ensure adequate seizure control while mitigating the risk of serious rash associated with the rapid titration of lamotrigine.

  The recommended maintenance dose of lamotrigine as monotherapy is 500 mg/day given in 2 divided doses.

  To avoid an increased risk of rash, the recommended initial dose and subsequent dose escalations of lamotrigine should not be exceeded [see Boxed Warning].

  Conversion From Adjunctive Therapy With Carbamazepine, Phenytoin, Phenobarbital, or Primidone to Monotherapy With Lamotrigine: After achieving a dose of 500 mg/day of lamotrigine according to the guidelines in Table 1, the concomitant AED should be withdrawn by 20% decrements each week over a 4-week period. The regimen for the withdrawal of the concomitant AED is based on experience gained in the controlled monotherapy clinical trial.

  Conversion From Adjunctive Therapy With Valproate to Monotherapy With Lamotrigine: The conversion regimen involves 4 steps outlined in Table 4.

  Table 4. Conversion From Adjunctive Therapy With Valproate to Monotherapy With Lamotrigine in Patients ≥16 Years of Age With Epilepsy
  Lamotrigine
  Valproate
  Step 1 
  Achieve a dose of 200 mg/day according to 
  guidelines in Table 1 (if not already on 
  200 mg/day).
  Maintain previous stable dose.
  Step 2 
  Maintain at 200 mg/day.
  Decrease to 500 mg/day by 
  decrements no greater than 
  500 mg/day/week and then 
  maintain the dose of 
  500 mg/day for 1 week.
  Step 3 
  Increase to 300 mg/day and maintain for 1 
  week.
  Simultaneously decrease to 
  250 mg/day and maintain for 1 week.
  Step 4 
  Increase by 100 mg/day every week to achieve 
  maintenance dose of 500 mg/day.
  Discontinue.
  

  Conversion From Adjunctive Therapy With Antiepileptic Drugs Other Than Carbamazepine, Phenytoin, Phenobarbital, Primidone, or Valproate to Monotherapy With Lamotrigine: No specific dosing guidelines can be provided for conversion to monotherapy with lamotrigine with AEDs other than carbamazepine, phenobarbital, phenytoin, primidone, or valproate.

  2.4 Bipolar Disorder

  The goal of maintenance treatment with lamotrigine is to delay the time to occurrence of mood episodes (depression, mania, hypomania, mixed episodes) in patients treated for acute mood episodes with standard therapy. The target dose of lamotrigine is 200 mg/day (100 mg/day in patients taking valproate, which decreases the apparent clearance of lamotrigine, and 400 mg/day in patients not taking valproate and taking either carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin that increase the apparent clearance of lamotrigine). In the clinical trials, doses up to 400 mg/day as monotherapy were evaluated; however, no additional benefit was seen at 400 mg/day compared with 200 mg/day [see Clinical Studies (14.2)]. Accordingly, doses above 200 mg/day are not recommended. Treatment with lamotrigine is introduced, based on concurrent medications, according to the regimen outlined in Table 5. If other psychotropic medications are withdrawn following stabilization, the dose of lamotrigine should be adjusted. For patients discontinuing valproate, the dose of lamotrigine should be doubled over a 2-week period in equal weekly increments (see Table 6). For patients discontinuing carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin that induce lamotrigine glucuronidation, the dose of lamotrigine should remain constant for the first week and then should be decreased by half over a 2-week period in equal weekly decrements (see Table 6). The dose of lamotrigine may then be further adjusted to the target dose (200 mg) as clinically indicated.

  If other drugs are subsequently introduced, the dose of lamotrigine may need to be adjusted. In particular, the introduction of valproate requires reduction in the dose of lamotrigine [see Drug Interactions (7), Clinical Pharmacology (12.3)].

  To avoid an increased risk of rash, the recommended initial dose and subsequent dose escalations of lamotrigine should not be exceeded [see Boxed Warning].

  Table 5. Escalation Regimen for Lamotrigine for Patients With Bipolar Disorder

  a Valproate has been shown to inhibit glucuronidation and decrease the apparent clearance of lamotrigine [see Drug Interactions (7), Clinical Pharmacology (12.3)].

  b These drugs induce lamotrigine glucuronidation and increase clearance [see Drug Interactions (7), Clinical Pharmacology (12.3)]. Other drugs that have similar effects include estrogen-containing oral contraceptives [see Drug Interactions (7), Clinical Pharmacology (12.3)]. Dosing recommendations for oral contraceptives can be found in General Dosing Considerations [see Dosage and Administration (2.1)]. Patients on rifampin, or other drugs that induce lamotrigine glucuronidation and increase clearance, should follow the same dosing titration/maintenance regimen as that used with anticonvulsants that have this effect.

  
  For Patients TAKING Valproatea
  For Patients NOT TAKING
  Carbamazepine, Phenytoin, 
  Phenobarbital, Primidoneb, or
   Valproatea
  For Patients TAKING
   Carbamazepine, Phenytoin, Phenobarbital,
  or Primidoneb and 
  NOT TAKING Valproatea
  Weeks 1 and 2 
  25 mg every other day
  25 mg daily
  50 mg daily
  Weeks 3 and 4 
  25 mg daily
  50 mg daily
  100 mg daily, in divided doses
  Week 5 
  50 mg daily
  100 mg daily
  200 mg daily, in divided doses
  Week 6 
  100 mg daily
  200 mg daily
  300 mg daily, in divided doses
  Week 7 
  100 mg daily
  200 mg daily
  up to 400 mg daily, in
  divided doses
  Table 6. Dosage Adjustments to Lamotrigine for Patients With Bipolar Disorder Following Discontinuation of Psychotropic Medications

  a Valproate has been shown to inhibit glucuronidation and decrease the apparent clearance of lamotrigine [see Drug Interactions (7), Clinical Pharmacology (12.3)].

  b These drugs induce lamotrigine glucuronidation and increase clearance [see Drug Interactions (7), Clinical Pharmacology (12.3)]. Other drugs that have similar effects include estrogen-containing oral contraceptives [see Drug Interactions (7), Clinical Pharmacology (12.3)]. Dosing recommendations for oral contraceptives can be found in General Dosing Considerations [see Dosage and Administration (2.1)]. Patients on rifampin, or other drugs that induce lamotrigine glucuronidation and increase clearance, should follow the same dosing titration/maintenance regimen as that used with anticonvulsants that have this effect.

  
  Discontinuation of Psychotropic Drugs 
  (excluding Carbamazepine, Phenytoin, 
  After Discontinuation of Valproatea
  After Discontinuation of Carbamazepine, 
  Phenytoin, Phenobarbital,or
   Primidoneb
  
  Phenobarbital, Primidoneb, or Valproatea)
  Current dose of Lamotrigine (mg/day) 
  100
  Current dose of Lamotrigine (mg/day) 
  400
  Week 1 
  Maintain current dose of Lamotrigine
  150
  400
  Week 2 
  Maintain current dose of Lamotrigine
  200
  300
  Week 3 onward 
  Maintain current dose of Lamotrigine
  200
  200
  

  The benefit of continuing treatment in patients who had been stabilized in an 8- to 16-week open-label phase with lamotrigine was established in 2 randomized, placebo-controlled clinical maintenance trials [see Clinical Studies (14.2)]. However, the optimal duration of treatment with lamotrigine has not been established. Thus, patients should be periodically reassessed to determine the need for maintenance treatment.

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  2.1 General Dosing Considerations

  Rash: There are suggestions, yet to be proven, that the risk of severe, potentially life-threatening rash may be increased by (1) coadministration of lamotrigine with valproate, (2) exceeding the recommended initial dose of lamotrigine, or (3) exceeding the recommended dose escalation for lamotrigine. However, cases have occurred in the absence of these factors [see Boxed Warning]. Therefore, it is important that the dosing recommendations be followed closely.

  The risk of nonserious rash may be increased when the recommended initial dose and/or the rate of dose escalation of lamotrigine is exceeded and in patients with a history of allergy or rash to other AEDs.

  Lamotrigine Starter Kits provide lamotrigine at doses consistent with the recommended titration schedule for the first 5 weeks of treatment, based upon concomitant medications for patients with epilepsy (>12 years of age) and Bipolar I Disorder (≥18 years of age) and are intended to help reduce the potential for rash. The use of Lamotrigine Starter Kits is recommended for appropriate patients who are starting or restarting lamotrigine [see How Supplied/Storage and Handling (16)].

  It is recommended that lamotrigine not be restarted in patients who discontinued due to rash associated with prior treatment with lamotrigine, unless the potential benefits clearly outweigh the risks. If the decision is made to restart a patient who has discontinued lamotrigine, the need to restart with the initial dosing recommendations should be assessed. The greater the interval of time since the previous dose, the greater consideration should be given to restarting with the initial dosing recommendations. If a patient has discontinued lamotrigine for a period of more than 5 half-lives, it is recommended that initial dosing recommendations and guidelines be followed. The half-life of lamotrigine is affected by other concomitant medications [see Clinical Pharmacology (12.3)].

  Lamotrigine Added to Drugs Known to Induce or Inhibit Glucuronidation: Drugs other than those listed in the Clinical Pharmacology section [see Clinical Pharmacology (12.3)] have not been systematically evaluated in combination with lamotrigine. Because lamotrigine is metabolized predominantly by glucuronic acid conjugation, drugs that are known to induce or inhibit glucuronidation may affect the apparent clearance of lamotrigine and doses of lamotrigine may require adjustment based on clinical response.

  Target Plasma Levels for Patients With Epilepsy or Bipolar Disorder: A therapeutic plasma concentration range has not been established for lamotrigine. Dosing of lamotrigine should be based on therapeutic response [see Clinical Pharmacology (12.3)].

  Women Taking Estrogen-Containing Oral Contraceptives: Starting Lamotrigine in Women Taking Estrogen-Containing Oral Contraceptives: Although estrogen-containing oral contraceptives have been shown to increase the clearance of lamotrigine [see Clinical Pharmacology (12.3)], no adjustments to the recommended dose-escalation guidelines for lamotrigine should be necessary solely based on the use of estrogen-containing oral contraceptives. Therefore, dose escalation should follow the recommended guidelines for initiating adjunctive therapy with lamotrigine based on the concomitant AED or other concomitant medications (see Table 1 or Table 5). See below for adjustments to maintenance doses of lamotrigine in women taking estrogen-containing oral contraceptives.

  Adjustments to the Maintenance Dose of Lamotrigine In Women Taking Estrogen-Containing Oral Contraceptives:

  (1) Taking Estrogen-Containing Oral Contraceptives: For women not taking carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin that induce lamotrigine glucuronidation [see Drug Interactions (7), Clinical Pharmacology (12.3)], the maintenance dose of lamotrigine will in most cases need to be increased, by as much as 2-fold over the recommended target maintenance dose, in order to maintain a consistent lamotrigine plasma level [see Clinical Pharmacology (12.3)].

  (2) Starting Estrogen-Containing Oral Contraceptives: In women taking a stable dose of lamotrigine and not taking carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin that induce lamotrigine glucuronidation [see Drug Interactions (7), Clinical Pharmacology (12.3)], the maintenance dose will in most cases need to be increased by as much as 2-fold in order to maintain a consistent lamotrigine plasma level. The dose increases should begin at the same time that the oral contraceptive is introduced and continue, based on clinical response, no more rapidly than 50 to 100 mg/day every week. Dose increases should not exceed the recommended rate (see Table 1 or Table 5) unless lamotrigine plasma levels or clinical response support larger increases. Gradual transient increases in lamotrigine plasma levels may occur during the week of inactive hormonal preparation ("pill-free" week), and these increases will be greater if dose increases are made in the days before or during the week of inactive hormonal preparation. Increased lamotrigine plasma levels could result in additional adverse reactions, such as dizziness, ataxia, and diplopia. If adverse reactions attributable to lamotrigine consistently occur during the "pill-free" week, dose adjustments to the overall maintenance dose may be necessary. Dose adjustments limited to the "pill-free" week are not recommended. For women taking lamotrigine in addition to carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin that induce lamotrigine glucuronidation [see Drug Interactions (7), Clinical Pharmacology (12.3)], no adjustment to the dose of lamotrigine should be necessary.

  (3) Stopping Estrogen-Containing Oral Contraceptives: For women not taking carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin that induce lamotrigine glucuronidation [see Drug Interactions (7), Clinical Pharmacology (12.3)], the maintenance dose of lamotrigine will in most cases need to be decreased by as much as 50% in order to maintain a consistent lamotrigine plasma level. The decrease in dose of lamotrigine should not exceed 25% of the total daily dose per week over a 2-week period, unless clinical response or lamotrigine plasma levels indicate otherwise [see Clinical Pharmacology (12.3)]. For women taking lamotrigine in addition to carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin that induce lamotrigine glucuronidation [see Drug Interactions (7), Clinical Pharmacology (12.3)], no adjustment to the dose of lamotrigine should be necessary.

  Women and Other Hormonal Contraceptive Preparations or Hormone Replacement Therapy: The effect of other hormonal contraceptive preparations or hormone replacement therapy on the pharmacokinetics of lamotrigine has not been systematically evaluated. It has been reported that ethinylestradiol, not progestogens, increased the clearance of lamotrigine up to 2-fold, and the progestin-only pills had no effect on lamotrigine plasma levels. Therefore, adjustments to the dosage of lamotrigine in the presence of progestogens alone will likely not be needed.

  Patients With Hepatic Impairment: Experience in patients with hepatic impairment is limited. Based on a clinical pharmacology study in 24 patients with mild, moderate, and severe liver impairment [see Use in Specific Populations (8.6), Clinical Pharmacology (12.3)], the following general recommendations can be made. No dosage adjustment is needed in patients with mild liver impairment. Initial, escalation, and maintenance doses should generally be reduced by approximately 25% in patients with moderate and severe liver impairment without ascites and 50% in patients with severe liver impairment with ascites. Escalation and maintenance doses may be adjusted according to clinical response.

  Patients With Renal Impairment: Initial doses of lamotrigine should be based on patients' concomitant medications (see Tables 1-3 or Table 5); reduced maintenance doses may be effective for patients with significant renal impairment [see Use in Specific Populations (8.7), Clinical Pharmacology (12.3)]. Few patients with severe renal impairment have been evaluated during chronic treatment with lamotrigine. Because there is inadequate experience in this population, lamotrigine should be used with caution in these patients.

  Discontinuation Strategy: Epilepsy: For patients receiving lamotrigine in combination with other AEDs, a reevaluation of all AEDs in the regimen should be considered if a change in seizure control or an appearance or worsening of adverse reactions is observed.

  If a decision is made to discontinue therapy with lamotrigine, a step-wise reduction of dose over at least 2 weeks (approximately 50% per week) is recommended unless safety concerns require a more rapid withdrawal [see Warnings and Precautions (5.9)].

  Discontinuing carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin that induce lamotrigine glucuronidation should prolong the half-life of lamotrigine; discontinuing valproate should shorten the half-life of lamotrigine.

  Bipolar Disorder: In the controlled clinical trials, there was no increase in the incidence, type, or severity of adverse reactions following abrupt termination of lamotrigine. In clinical trials in patients with Bipolar Disorder, 2 patients experienced seizures shortly after abrupt withdrawal of lamotrigine. However, there were confounding factors that may have contributed to the occurrence of seizures in these bipolar patients. Discontinuation of lamotrigine should involve a step-wise reduction of dose over at least 2 weeks (approximately 50% per week) unless safety concerns require a more rapid withdrawal [see Warnings and Precautions (5.9)].

  2.2 Epilepsy – Adjunctive Therapy

  This section provides specific dosing recommendations for patients greater than 12 years of age and patients 2 to 12 years of age. Within each of these age-groups, specific dosing recommendations are provided depending upon concomitant AED or other concomitant medications (Table 1 for patients greater than 12 years of age and Table 2 for patients 2 to 12 years of age). A weight-based dosing guide for patients 2 to 12 years of age on concomitant valproate is provided in Table 3.

  Patients Over 12 Years of Age: Recommended dosing guidelines are summarized in Table 1.

  Table 1. Escalation Regimen for Lamotrigine in Patients Over 12 Years of Age With Epilepsy For Patients TAKING Valproate * For Patients NOT TAKING Carbamazepine, Phenytoin, Phenobarbital, Primidone†, or Valproate* For Patients TAKING Carbamazepine, Phenytoin, Phenobarbital, or Primidone† and NOT TAKING Valproate* * Valproate has been shown to inhibit glucuronidation and decrease the apparent clearance of lamotrigine [see Drug Interactions (7), Clinical Pharmacology (12.3)]. † These drugs induce lamotrigine glucuronidation and increase clearance [see Drug Interactions (7), Clinical Pharmacology (12.3)]. Other drugs that have similar effects include estrogen-containing oral contraceptives [see Drug Interactions (7), Clinical Pharmacology (12.3)]. Weeks 1 and 2 25 mg every other day 25 mg every day 50 mg/day Weeks 3 and 4 25 mg every day 50 mg/day 100 mg/day
  (in 2 divided doses) Week 5 onwards to maintenance Increase by 25 to 50 mg/day every 1 to 2 weeks Increase by 50 mg/day every 1 to 2 weeks Increase by 100 mg/day every 1 to 2 weeks Usual maintenance dose 100 to 200 mg/day with valproate alone
  100 to 400 mg/day with valproate and other drugs that induce glucuronidation
  (in 1 or 2 divided doses) 225 to 375 mg/day
  (in 2 divided doses) 300 to 500 mg/day
  (in 2 divided doses)

  Dosing recommendations for oral contraceptives can be found in General Dosing Considerations [see Dosage and Administration (2.1)]. Patients on rifampin, or other drugs that induce lamotrigine glucuronidation and increase clearance, should follow the same dosing titration/maintenance regimen as that used with anticonvulsants that have this effect.

  Patients 2 to 12 Years of Age: Recommended dosing guidelines are summarized in Table 2.

  Smaller starting doses and slower dose escalations than those used in clinical trials are recommended because of the suggestion that the risk of rash may be decreased by smaller starting doses and slower dose escalations. Therefore, maintenance doses will take longer to reach in clinical practice than in clinical trials. It may take several weeks to months to achieve an individualized maintenance dose. Maintenance doses in patients weighing less than 30 kg, regardless of age or concomitant AED, may need to be increased as much as 50%, based on clinical response.

  Table 2. Escalation Regimen for Lamotrigine in Patients 2 to 12 Years of Age With Epilepsy For Patients TAKING Valproate * For Patients NOT TAKING Carbamazepine, Phenytoin, Phenobarbital, Primidone†, or Valproate* For Patients TAKING Carbamazepine, Phenytoin, Phenobarbital, or Primidone† and NOT TAKING Valproate* Note: Only whole tablets should be used for dosing. * Valproate has been shown to inhibit glucuronidation and decrease the apparent clearance of lamotrigine [see Drug Interactions (7), Clinical Pharmacology (12.3)]. † These drugs induce lamotrigine glucuronidation and increase clearance [see Drug Interactions (7), Clinical Pharmacology (12.3)]. Other drugs that have similar effects include estrogen-containing oral contraceptives [see Drug Interactions (7), Clinical Pharmacology (12.3)]. Weeks 1 and 2 0.15 mg/kg/day
  in 1 or 2 divided doses, rounded down to the nearest whole tablet (see Table 3 for weight based dosing guide) 0.3 mg/kg/day
  in 1 or 2 divided doses, rounded down to the nearest whole tablet 0.6 mg/kg/day
  in 2 divided doses, rounded down to the nearest whole tablet Weeks 3 and 4 0.3 mg/kg/day
  in 1 or 2 divided doses, rounded down to the nearest whole tablet (see Table 3 for weight based dosing guide) 0.6 mg/kg/day
  in 2 divided doses, rounded down to the nearest whole tablet 1.2 mg/kg/day
  in 2 divided doses, rounded down to the nearest whole tablet Week 5 onwards to maintenance The dose should be increased every 1 to 2 weeks as follows: calculate 0.3 mg/kg/day, round this amount down to the nearest whole tablet, and add this amount to the previously administered daily dose The dose should be increased every 1 to 2 weeks as follows: calculate 0.6 mg/kg/day, round this amount down to the nearest whole tablet, and add this amount to the previously administered daily dose The dose should be increased every 1 to 2 weeks as follows: calculate 1.2 mg/kg/day, round this amount down to the nearest whole tablet, and add this amount to the previously administered daily dose Usual maintenance dose 1 to 5 mg/kg/day
  (maximum 200 mg/day in 1 or 2 divided doses)
  1 to 3 mg/kg/day with valproate alone 4.5 to 7.5 mg/kg/day
  (maximum 300 mg/day in 2 divided doses) 5 to 15 mg/kg/day
  (maximum 400 mg/day in 2 divided doses) Maintenance dose in patients less than 30 kg May need to be increased by as much as 50%, based on clinical response May need to be increased by as much as 50%, based on clinical response May need to be increased by as much as 50%, based on clinical response

  Dosing recommendations for oral contraceptives can be found in General Dosing Considerations [see Dosage and Administration (2.1)]. Patients on rifampin, or other drugs that induce lamotrigine glucuronidation and increase clearance, should follow the same dosing titration/maintenance regimen as that used with anticonvulsants that have this effect.

  Table 3. The Initial Weight-Based Dosing Guide for Patients 2 to 12 Years of Age Taking Valproate (Weeks 1 to 4) With Epilepsy If the patient's weight is Give this daily dose, using the most appropriate combination of Lamotrigine 2-mg and 5-mg tablets Greater than And less than Weeks 1 and 2 Weeks 3 and 4 6.7 kg 14 kg 2 mg every other day 2 mg every day 14.1 kg 27 kg 2 mg every day 4 mg every day 27.1 kg 34 kg 4 mg every day 8 mg every day 34.1 kg 40 kg 5 mg every day 10 mg every day

  Usual Adjunctive Maintenance Dose for Epilepsy: The usual maintenance doses identified in Tables 1 and 2 are derived from dosing regimens employed in the placebo-controlled adjunctive studies in which the efficacy of lamotrigine was established. In patients receiving multidrug regimens employing carbamazepine, phenytoin, phenobarbital, or primidone without valproate, maintenance doses of adjunctive lamotrigine as high as 700 mg/day have been used. In patients receiving valproate alone, maintenance doses of adjunctive lamotrigine as high as 200 mg/day have been used. The advantage of using doses above those recommended in Tables 1 through 4 has not been established in controlled trials.

  2.3 Epilepsy – Conversion From Adjunctive Therapy to Monotherapy

  The goal of the transition regimen is to effect the conversion to monotherapy with lamotrigine under conditions that ensure adequate seizure control while mitigating the risk of serious rash associated with the rapid titration of lamotrigine.

  The recommended maintenance dose of lamotrigine as monotherapy is 500 mg/day given in 2 divided doses.

  To avoid an increased risk of rash, the recommended initial dose and subsequent dose escalations of lamotrigine should not be exceeded [see Boxed Warning].

  Conversion From Adjunctive Therapy With Carbamazepine, Phenytoin, Phenobarbital, or Primidone to Monotherapy With Lamotrigine: After achieving a dose of 500 mg/day of lamotrigine according to the guidelines in Table 1, the concomitant AED should be withdrawn by 20% decrements each week over a 4-week period. The regimen for the withdrawal of the concomitant AED is based on experience gained in the controlled monotherapy clinical trial.

  Conversion From Adjunctive Therapy With Valproate to Monotherapy With Lamotrigine: The conversion regimen involves 4 steps outlined in Table 4.

  Table 4. Conversion From Adjunctive Therapy With Valproate to Monotherapy With Lamotrigine in Patients ≥16 Years of Age With Epilepsy Lamotrigine Valproate Step 1 Achieve a dose of 200 mg/day according to guidelines in Table 1 (if not already on 200 mg/day). Maintain previous stable dose. Step 2 Maintain at 200 mg/day. Decrease to 500 mg/day by decrements no greater than 500 mg/day/week and then maintain the dose of 500 mg/day for 1 week. Step 3 Increase to 300 mg/day and maintain for 1 week. Simultaneously decrease to 250 mg/day and maintain for 1 week. Step 4 Increase by 100 mg/day every week to achieve maintenance dose of 500 mg/day. Discontinue.

  Conversion From Adjunctive Therapy With Antiepileptic Drugs Other Than Carbamazepine, Phenytoin, Phenobarbital, Primidone, or Valproate to Monotherapy With Lamotrigine: No specific dosing guidelines can be provided for conversion to monotherapy with lamotrigine with AEDs other than carbamazepine, phenobarbital, phenytoin, primidone, or valproate.

  2.4 Bipolar Disorder

  The goal of maintenance treatment with lamotrigine is to delay the time to occurrence of mood episodes (depression, mania, hypomania, mixed episodes) in patients treated for acute mood episodes with standard therapy. The target dose of lamotrigine is 200 mg/day (100 mg/day in patients taking valproate, which decreases the apparent clearance of lamotrigine, and 400 mg/day in patients not taking valproate and taking either carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin that increase the apparent clearance of lamotrigine). In the clinical trials, doses up to 400 mg/day as monotherapy were evaluated; however, no additional benefit was seen at 400 mg/day compared with 200 mg/day [see Clinical Studies (14.2)]. Accordingly, doses above 200 mg/day are not recommended. Treatment with lamotrigine is introduced, based on concurrent medications, according to the regimen outlined in Table 5. If other psychotropic medications are withdrawn following stabilization, the dose of lamotrigine should be adjusted. For patients discontinuing valproate, the dose of lamotrigine should be doubled over a 2-week period in equal weekly increments (see Table 6). For patients discontinuing carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin that induce lamotrigine glucuronidation, the dose of lamotrigine should remain constant for the first week and then should be decreased by half over a 2-week period in equal weekly decrements (see Table 6). The dose of lamotrigine may then be further adjusted to the target dose (200 mg) as clinically indicated.

  If other drugs are subsequently introduced, the dose of lamotrigine may need to be adjusted. In particular, the introduction of valproate requires reduction in the dose of lamotrigine [see Drug Interactions (7), Clinical Pharmacology (12.3)].

  To avoid an increased risk of rash, the recommended initial dose and subsequent dose escalations of lamotrigine should not be exceeded [see Boxed Warning].

  Table 5. Escalation Regimen for Lamotrigine for Patients With Bipolar Disorder For Patients TAKING Valproate* For Patients NOT TAKING Carbamazepine, Phenytoin, Phenobarbital, Primidone†, or Valproate* For Patients TAKING Carbamazepine, Phenytoin, Phenobarbital, or Primidone†, and NOT TAKING Valproate* * Valproate has been shown to inhibit glucuronidation and decrease the apparent clearance of lamotrigine [see Drug Interactions (7), Clinical Pharmacology (12.3)]. † These drugs induce lamotrigine glucuronidation and increase clearance [see Drug Interactions (7), Clinical Pharmacology (12.3)]. Other drugs which have similar effects include estrogen-containing oral contraceptives [see Drug Interactions (7), Clinical Pharmacology (12.3)]. Dosing recommendations for oral contraceptives can be found in General Dosing Considerations [see Dosage and Administration (2.1)]. Patients on rifampin, or other drugs that induce lamotrigine glucuronidation and increase clearance, should follow the same dosing titration/maintenance regimen as that used with anticonvulsants that have this effect. Weeks 1 and 2 25 mg every other day 25 mg daily 50 mg daily Weeks 3 and 4 25 mg daily 50 mg daily 100 mg daily, in divided doses Week 5 50 mg daily 100 mg daily 200 mg daily, in divided doses Week 6 100 mg daily 200 mg daily 300 mg daily, in divided doses Week 7 100 mg daily 200 mg daily up to 400 mg daily, in divided doses Table 6. Dosage Adjustments to Lamotrigine for Patients With Bipolar Disorder Following Discontinuation of Psychotropic Medications Discontinuation of Psychotropic Drugs (excluding Carbamazepine, Phenytoin, Phenobarbital, Primidone*, or Valproate†) After Discontinuation of Valproate† After Discontinuation of Carbamazepine, Phenytoin, Phenobarbital or Primidone* Current dose of Lamotrigine (mg/day) 100 Current dose of Lamotrigine (mg/day) 400 * These drugs induce lamotrigine glucuronidation and increase clearance [see Drug Interactions (7), Clinical Pharmacology (12.3)]. Other drugs which have similar effects include estrogen-containing oral contraceptives [see Drug Interactions (7), Clinical Pharmacology (12.3)]. Dosing recommendations for oral contraceptives can be found in General Dosing Considerations [see Dosage and Administration (2.1)]. Patients on rifampin, or other drugs that induce lamotrigine glucuronidation and increase clearance, should follow the same dosing titration/maintenance regimen as that used with anticonvulsants that have this effect. † Valproate has been shown to inhibit glucuronidation and decrease the apparent clearance of lamotrigine [see Drug Interactions (7), Clinical Pharmacology (12.3)]. Week 1 Maintain current dose of Lamotrigine 150 400 Week 2 Maintain current dose of Lamotrigine 200 300 Week 3 onward Maintain current dose of Lamotrigine 200 200

  The benefit of continuing treatment in patients who had been stabilized in an 8- to 16-week open-label phase with lamotrigine was established in 2 randomized, placebo-controlled clinical maintenance trials [see Clinical Studies (14.2)]. However, the optimal duration of treatment with lamotrigine has not been established. Thus, patients should be periodically reassessed to determine the need for maintenance treatment.

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  2.1 General Dosing Considerations

  Rash:  There are suggestions, yet to be proven, that the risk of severe, potentially life-threatening rash may be increased by (1) coadministration of lamotrigine with valproate, (2) exceeding the recommended initial dose of lamotrigine, or (3) exceeding the recommended dose escalation for lamotrigine. However, cases have occurred in the absence of these factors [see Boxed Warning]. Therefore, it is important that the dosing recommendations be followed closely.

  The risk of nonserious rash may be increased when the recommended initial dose and/or the rate of dose escalation of lamotrigine is exceeded and in patients with a history of allergy or rash to other AEDs.

  Lamotrigine Tablet Starter Kits provide lamotrigine at doses consistent with the recommended titration schedule for the first 5 weeks of treatment, based upon concomitant medications for patients with epilepsy (>12 years of age) and Bipolar I Disorder (≥18 years of age) and are intended to help reduce the potential for rash. The use of lamotrigine Starter Kits is recommended for appropriate patients who are starting or restarting lamotrigine [see How Supplied/Storage and Handling (16 ).

  It is recommended that lamotrigine not be restarted in patients who discontinued due to rash associated with prior treatment with lamotrigine, unless the potential benefits clearly outweigh the risks. If the decision is made to restart a patient who has discontinued lamotrigine, the need to restart with the initial dosing recommendations should be assessed. The greater the interval of time since the previous dose, the greater consideration should be given to restarting with the initial dosing recommendations. If a patient has discontinued lamotrigine for a period of more than 5 half-lives, it is recommended that initial dosing recommendations and guidelines be followed. The half-life of lamotrigine is affected by other concomitant medications [see Clinical Pharmacology (12.3)].

  Lamotrigine Added to Drugs Known to Induce or Inhibit Glucuronidation: Drugs other than those listed in the Clinical Pharmacology section [see Clinical Pharmacology (12.3)] have not been systematically evaluated in combination with lamotrigine. Because lamotrigine is metabolized predominantly by glucuronic acid conjugation, drugs that are known to induce or inhibit glucuronidation may affect the apparent clearance of lamotrigine and doses of lamotrigine may require adjustment based on clinical response.

  Target Plasma Levels for Patients With Epilepsy or Bipolar Disorder: A therapeutic plasma concentration range has not been established for lamotrigine. Dosing of lamotrigine should be based on therapeutic response [see Clinical Pharmacology (12.3)].

  Women Taking Estrogen-Containing Oral Contraceptives:Starting Lamotrigine in Women Taking Estrogen-Containing Oral Contraceptives: Although estrogen-containing oral contraceptives have been shown to increase the clearance of lamotrigine [see Clinical Pharmacology (12.3)], no adjustments to the recommended dose-escalation guidelines for lamotrigine should be necessary solely based on the use of estrogen-containing oral contraceptives. Therefore, dose escalation should follow the recommended guidelines for initiating adjunctive therapy with lamotrigine based on the concomitant AED or other concomitant medications (see Table 1 or Table 5). See below for adjustments to maintenance doses of lamotrigine in women taking estrogen-containing oral contraceptives.

  Adjustments to the Maintenance Dose of Lamotrigine In Women Taking Estrogen-Containing Oral Contraceptives: 

  Taking Estrogen-Containing Oral Contraceptives: For women not taking carbamazepine, phenytoin, phenobarbital, primidone, or rifampin, the maintenance dose of lamotrigine will in most cases need to be increased, by as much as 2-fold over the recommended target maintenance dose, in order to maintain a consistent lamotrigine plasma level [see Clinical Pharmacology (12.3)]. Starting Estrogen-Containing Oral Contraceptives: In women taking a stable dose of lamotrigine and not taking carbamazepine, phenytoin, phenobarbital, primidone, or rifampin, the maintenance dose will in most cases need to be increased by as much as 2-fold in order to maintain a consistent lamotrigine plasma level. The dose increases should begin at the same time that the oral contraceptive is introduced and continue, based on clinical response, no more rapidly than 50 to 100 mg/day every week. Dose increases should not exceed the recommended rate (see Table 1 or Table 5) unless lamotrigine plasma levels or clinical response support larger increases. Gradual transient increases in lamotrigine plasma levels may occur during the week of inactive hormonal preparation ("pill-free" week), and these increases will be greater if dose increases are made in the days before or during the week of inactive hormonal preparation. Increased lamotrigine plasma levels could result in additional adverse reactions, such as dizziness, ataxia, and diplopia. If adverse reactions attributable to lamotrigine consistently occur during the "pill-free" week, dose adjustments to the overall maintenance dose may be necessary. Dose adjustments limited to the "pill-free" week are not recommended. For women taking lamotrigine in addition to carbamazepine, phenytoin, phenobarbital, primidone, or rifampin, no adjustment should be necessary to the dose of lamotrigine. Stopping Estrogen-Containing Oral Contraceptives: For women not taking carbamazepine, phenytoin, phenobarbital, primidone, or rifampin, the maintenance dose of lamotrigine will in most cases need to be decreased by as much as 50% in order to maintain a consistent lamotrigine plasma level. The decrease in dose of lamotrigine should not exceed 25% of the total daily dose per week over a 2-week period, unless clinical response or lamotrigine plasma levels indicate otherwise [see Clinical Pharmacology (12.3)]. For women taking lamotrigine in addition to carbamazepine, phenytoin, phenobarbital, primidone, or rifampin, no adjustment to the dose of lamotrigine should be necessary.

  Women and Other Hormonal Contraceptive Preparations or Hormone Replacement Therapy: The effect of other hormonal contraceptive preparations or hormone replacement therapy on the pharmacokinetics of lamotrigine has not been systematically evaluated. It has been reported that ethinylestradiol, not progestogens, increased the clearance of lamotrigine up to 2-fold, and the progestin-only pills had no effect on lamotrigine plasma levels. Therefore, adjustments to the dosage of lamotrigine in the presence of progestogens alone will likely not be needed.

  Patients With Hepatic Impairment: Experience in patients with hepatic impairment is limited. Based on a clinical pharmacology study in 24 patients with mild, moderate, and severe liver impairment [see Use in Specific Populations (8.6), Clinical Pharmacology (12.3)], the following general recommendations can be made. No dosage adjustment is needed in patients with mild liver impairment. Initial, escalation, and maintenance doses should generally be reduced by approximately 25% in patients with moderate and severe liver impairment without ascites and 50% in patients with severe liver impairment with ascites. Escalation and maintenance doses may be adjusted according to clinical response. 

  Patients With Renal Impairment: Initial doses of lamotrigine should be based on patients' concomitant medications (see Tables 1-3 or Table 5); reduced maintenance doses may be effective for patients with significant renal impairment [see Use in Specific Populations ( 8.7), Clinical Pharmacology (12.3 )]. Few patients with severe renal impairment have been evaluated during chronic treatment with lamotrigine. Because there is inadequate experience in this population, lamotrigine should be used with caution in these patients.

  Discontinuation Strategy:Epilepsy: For patients receiving lamotrigine in combination with other AEDs, a re-evaluation of all AEDs in the regimen should be considered if a change in seizure control or an appearance or worsening of adverse reactions is observed.

  If a decision is made to discontinue therapy with lamotrigine, a step-wise reduction of dose over at least 2 weeks (approximately 50% per week) is recommended unless safety concerns require a more rapid withdrawal [see Warnings and Precautions (5.9)].

  Discontinuing carbamazepine, phenytoin, phenobarbital, or primidone should prolong the half-life of lamotrigine; discontinuing valproate should shorten the half-life of lamotrigine.

  Bipolar Disorder: In the controlled clinical trials, there was no increase in the incidence, type, or severity of adverse reactions following abrupt termination of lamotrigine. In clinical trials in patients with Bipolar Disorder, 2 patients experienced seizures shortly after abrupt withdrawal of lamotrigine. However, there were confounding factors that may have contributed to the occurrence of seizures in these bipolar patients. Discontinuation of lamotrigine should involve a step-wise reduction of dose over at least 2 weeks (approximately 50% per week) unless safety concerns require a more rapid withdrawal [see Warnings and Precautions (5.9)].

  2.2 Epilepsy - Adjunctive Therapy

  This section provides specific dosing recommendations for patients greater than 12 years of age and patients 2 to 12 years of age. Within each of these age-groups, specific dosing recommendations are provided depending upon concomitant AED or other concomitant medications (Table 1 for patients greater than 12 years of age and Table 2 for patients 2 to 12 years of age). A weight-based dosing guide for patients 2 to 12 years of age on concomitant valproate is provided in Table 3.

  Patients Over 12 Years of Age: Recommended dosing guidelines are summarized in Table 1.

  
  Table 1. Escalation Epilepsy Regimen for Lamotrigine in Patients Over 12 Years of Age With

  For Patients Taking

  Valproate *

  For Patients Taking

  AEDs Other Than

  Carbamazepine,

  Phenytoin,

  Phenobarbital, or

  Primidone†, and Not

  Taking Valproate

  For Patients Taking

  Carbamazepine,

  Phenytoin,

  Phenobarbital, or

  Primidone† and Not

  Taking Valproate Weeks 1 and 2 25 mg every other day 25 mg every day 50 mg/day Weeks 3 and 4 25 mg every day 50 mg/day

  100 mg/day

  (in 2 divided doses)

  Weeks 5 onwards

  to maintenance

  Increase by 25 to

  50 mg/day every 1 to

  2 weeks

  Increase by 50 mg/day

  every 1 to 2 weeks

  Increase by

  100 mg/day every 1 to

  2 weeks.

  Usual

  Maintenance

  Dose

  100 to 200 mg/day

  with valproate alone

  100 to 400 mg/day with

  valproate and other

  drugs that induce

  glucuronication

  (in 1 or 2 divided doses)

  225 to 375 mg/day

  (in 2 divided doses)

  300 to 500 mg/day

  (in 2 divided doses)

  * Valproate has been shown to inhibit glucuronidation and decrease the apparent clearance of lamotrigine [see Drug Interactions (7), Pharmacokinetics (12.3)].

  †  These drugs induce glucuronidation and increase clearance [see Drug Interactions (7), 

  Pharmacokinetics (12.3)]. Other drugs which have similar effects include estrogen-containing oral contraceptives and rifampin [see Drug Interactions (7), Pharmacokinetics 12.3)]. Dosing recommendations for oral contraceptives can be found in General Dosing Considerations [see Dosage and Administration (2.1)]. Patients on rifampin should follow the same dosing titration/maintenance regimen used with drugs that induce glucuronidation and increase clearance.

  Patients 2 to 12 Years of Age:Recommended dosing guidelines are summarized in Table 2.

  Smaller starting doses and slower dose escalations than those used in clinical trials are recommended because of the suggestion that the risk of rash may be decreased by smaller starting doses and slower dose escalations. Therefore, maintenance doses will take longer to reach in clinical practice than in clinical trials. It may take several weeks to months to achieve an individualized maintenance dose. Maintenance doses in patients weighing less than 30 kg, regardless of age or concomitant AED, may need to be increased as much as 50%, based on clinical response.

  Table 2. Escalation Regimen for LAMOTRIGINE in Patients 2 to 12 Years of Age With Epilepsy

  For Patients Taking

  Valproate *

  For Patients Taking

  AEDs Other Than

  Carbamazepine,

  Phenytoin,

  Phenobarbital, or

  Primidone†, and Not

  Taking Valproate

  For Patients Taking

  Carbamazepine,

  Phenytoin,

  Phenobarbital, or

  Primidone† and Not

  Taking Valproate Weeks 1 and 2

  0.15 mg/kg/day

  in 1 or 2 divided doses,

  rounded down to the

  nearest whole tablet

  (see Table 3 for weight

  based dosing guide)

  0.3mg/kg/day

  in 1 or 2 divided doses,

  rounded down to the

  nearest whole tablet

  0.6mg/kg/day

  in 2 divided doses,

  rounded down to the

  nearest whole tablet Weeks 3 and 4

  0.3mg/kg/day

  in 1 or 2 divided doses,

  rounded down to the

  nearest whole tablet

  (see Table 3 for weight

  based dosing guide)

  0.6mg/kg/day

  in 2 divided doses,

  rounded down to the

  nearest whole tablet

  1.2mg/kg/day

  in 2 divided doses,

  rounded down to the

  nearest whole tablet

  Weeks 5

  onwards to

  maintenance

  The dose should be

  increased every 1 to

  2 weeks as follows:

  calculate

  0.3 mg/kg/day, round

  this amount down to

  the nearest whole

  tablet, and add this

  amount to the

  previously

  administered daily dose

  The dose should be

  increased every 1 to

  2 weeks as follows:

  calculate 0.6 mg/kg/day,

  round this amount down

  to the nearest whole

  tablet, and add this

  amount to the previously

  administered daily dose

  The dose should be

  increased every 1 to

  2 weeks as follows:

  calculate 1.2 mg/kg/day,

  round this amount down

  to the nearest whole

  tablet, and add this

  amount to the previously

  administered daily dose

  Usual

  Maintenance

  Dose

  1 to 5mg/kg/day

  (maximum

  200 mg/day in 1 or

  2 divided doses).

  1 to 3mg/kg/day with

  valproate alone

  4.5 to 7.5mg/kg/day

  (maximum 300 mg/day

  in 2 divided doses)

  5 to 15mg/kg/day

  (maximum 400 mg/day

  in 2 divided doses)

  Maintenance

  dose in

  patients less

  than 30 kg

  May need to be

  increased by as much

  as 50%, based on

  clinical response

  May need to be increased

  by as much as 50%,

  based on clinical

  response

  May need to be

  increased by as much as

  50%, based on clinical

  response
  

  Note: Only whole tablets should be used for dosing.

  * Valproate has been shown to inhibit glucuronidation and decrease the apparent clearance of lamotrigine [see Drug Interactions (7), Pharmacokinetics (12.3)].

  † These drugs induce glucuronidation and increase clearance [see Drug Interactions (7),
  Pharmacokinetics (12.3)]. Other drugs which have similar effects include estrogen-containing
  oral contraceptives and rifampin [see Drug Interactions (7), Pharmacokinetics (12.3)].
  Dosing recommendations for oral contraceptives can be found in General Dosing
  Considerations [see Dosage and Administration (2.1)]. Patients on rifampin should follow the
  same dosing titration/maintenance regimen used with drugs that induce glucuronidation and
  increase clearance.

  Table 3. The Initial Weight-Based Dosing Guide for Patients 2 to 12 Years Taking Valproate (Weeks 1 to 4) With Epilepsy

  If the patient's weight is Give this daily dose, using the most appropriate combination of LAMOTRIGINE 2-mg and 5-mg tablets Greater than And less than Weeks 1 and 2 Weeks 3 and 4 6.7 kg 14 kg 2 mg every other day 2 mg every day 14.1 kg 27 kg 2 mg every day 4 mg every day 27.1 kg 34 kg 4 mg every day 8 mg every day 34.1 kg 40 kg 5 mg every day 10 mg every day

  Usual Adjunctive Maintenance Dose for Epilepsy: The usual maintenance doses identified in Tables 1 and 2 are derived from dosing regimens employed in the placebo-controlled adjunctive studies in which the efficacy of lamotrigine was established. In patients receiving multidrug regimens employing carbamazepine, phenytoin, phenobarbital, or primidone without valproate, maintenance doses of adjunctive lamotrigine as high as 700 mg/day have been used. In patients receiving valproate alone, maintenance doses of adjunctive lamotrigine as high as 200 mg/day have been used. The advantage of using doses above those recommended in Tables 1 through 4 has not been established in controlled trials.

  2.3 Epilepsy - Conversion From Adjunctive Therapy to Monotherapy

  The goal of the transition regimen is to effect the conversion to monotherapy with lamotrigine under conditions that ensure adequate seizure control while mitigating the risk of serious rash associated with the rapid titration of lamotrigine.

  The recommended maintenance dose of lamotrigine as monotherapy is 500 mg/day given in 2 divided doses.

  To avoid an increased risk of rash, the recommended initial dose and subsequent dose escalations of lamotrigine should not be exceeded [see Boxed Warning].

  Conversion From Adjunctive Therapy With Carbamazepine, Phenytoin, Phenobarbital, or Primidone to Monotherapy With Lamotrigine:After achieving a dose of 500 mg/day of lamotrigine according to the guidelines in Table 1, the concomitant AED should be withdrawn by 20% decrements each week over a 4-week period. The regimen for the withdrawal of the concomitant AED is based on experience gained in the controlled monotherapy clinical trial.

  Conversion from Adjunctive Therapy With Valproate to Monotherapy With Lamotrigine:The conversion regimen involves 4 steps outlined in Table 4.

  Table 4. Conversion From Adjunctive Therapy With Valproate to Monotherapy With Lamotrigine in Patients ≥16 Years of Age with Epilepsy

  Lamotrigine Valproate Step 1 Achieve a dose of 200 mg/day according to guidelines in Table 1 (if not already on 200 mg/day). Maintain previous stable dose. Step 2 Maintain at 200 mg/day. Decrease to 500 mg/day by decrements no greater than 500 mg/day/week and then maintain the dose of 500 mg/day for 1 week. Step 3 Increase to 300 mg/day and maintain for 1 week.

  Simultaneously decrease to 250 mg/day and maintain for

  1 week. Step 4 Increase by 100 mg/day every week to achieve maintenance dose of 500 mg/day. Discontinue.

  Conversion from Adjunctive Therapy With AEDs Other Than Carbamazepine, Phenytoin, Phenobarbital, Primidone, or Valproate to Monotherapy With Lamotrigine:No specific dosing guidelines can be provided for conversion to monotherapy with lamotrigine with AEDs other than carbamazepine, phenobarbital, phenytoin, primidone, or valproate.

  2.4 Bipolar Disorder

  The goal of maintenance treatment with lamotrigine is to delay the time to occurrence of mood episodes (depression, mania, hypomania, mixed episodes) in patients treated for acute mood episodes with standard therapy. The target dose of lamotrigine is 200 mg/day (100 mg/day in patients taking valproate, which decreases the apparent clearance of lamotrigine, and 400 mg/day in patients not taking valproate and taking either carbamazepine, phenytoin, phenobarbital, primidone, or rifampin, which increase the apparent clearance of lamotrigine). In the clinical trials, doses up to 400 mg/day as monotherapy were evaluated; however, no additional benefit was seen at 400 mg/day compared with 200 mg/day [see Clinical Studies (14.2)]. Accordingly, doses above 200 mg/day are not recommended. Treatment with lamotrigine is introduced, based on concurrent medications, according to the regimen outlined in Table 5. If other psychotropic medications are withdrawn following stabilization, the dose of lamotrigine should be adjusted. For patients discontinuing valproate, the dose of lamotrigine should be doubled over a 2-week period in equal weekly increments (see Table 6). For patients discontinuing carbamazepine, phenytoin, phenobarbital, primidone, or rifampin, the dose of lamotrigine should remain constant for the first week and then should be decreased by half over a 2-week period in equal weekly decrements (see Table 6). The dose of lamotrigine may then be further adjusted to the target dose (200 mg) as clinically indicated.

  If other drugs are subsequently introduced, the dose of lamotrigine may need to be adjusted. In particular, the introduction of valproate requires reduction in the dose of lamotrigine [see Drug Interactions (7), Clinical Pharmacology (12.3)].

  To avoid an increased risk of rash, the recommended initial dose and subsequent dose escalations of lamotrigine should not be exceeded [see Boxed Warning].

  Table 5. Escalation Regimen for Lamotrigine for Patients With Bipolar Disorder*

  For Patients Taking Valproate‡ For Patients Not Taking Carbamazepine, Phenytoin, Phenobarbital, Primidone, or Rifampin† and Not Taking Valproate‡ For Patients Taking Carbamazepine, Phenytoin, Phenobarbital, Primidone, or Rifampin† and Not Taking Valproate‡ Weeks 1 and 2 25 mg every other day 25 mg daily 50 mg daily Weeks 3 and 4 25 mg daily 50 mg daily 100 mg daily, in divided doses Week 5 50 mg daily 100 mg daily 200 mg daily, in divided doses Week 6 100 mg daily 200 mg daily 300 mg daily, in divided doses Week 7 100 mg daily 200 mg daily up to 400 mg daily, in divided doses

  * See Drug Interactions (7) and Clinical Pharmacology (12.3) for a description of known drug interactions.

  † Carbamazepine, phenytoin, phenobarbital, primidone, and rifampin have been shown to increase the apparent clearance of lamotrigine.

  ‡  Valproate has been shown to decrease the apparent clearance of lamotrigine.

  Table 6. Dosage Adjustments to Lamotrigine for Patients With Bipolar Disorder Following Discontinuation of Psychotropic Medications*

  Discontinuation of

  Psychotropic Drugs

  (excluding

  Carbamazepine,

  Phenytoin,

  Phenobarbital,

  Primidone, Rifampin†, or

  Valproate‡)

  After Discontinuation

  of Valproate‡

  After Discontinuation of

  Carbamazepine,

  Phenytoin,

  Phenobarbital,

  Primidone, or Rifampin†

  Current dose of

  lamotrigine (mg/day)

  100

  Current dose of

  lamotrigine (mg/day)

  400 Week1

  Maintain current dose of

  lamotrigine 150 400 Week 2

  Maintain current dose of

  lamotrigine 200 300

  Week 3

  onward

  Maintain current dose of

  lamotrigine 200 200

  * See Drug Interactions (7) and Clinical Pharmacology (12.3) for a description of known dru interactions.

  † Carbamazepine, phenytoin, phenobarbital, primidone, and rifampin have been shown to
  increase the apparent clearance of lamotrigine.

  ‡  Valproate has been shown to decrease the apparent clearance of lamotrigine.

  The benefit of continuing treatment in patients who had been stabilized in an 8- to 16-week open-label phase with lamotrigine was established in 2 randomized, placebo-controlled clinical maintenance trials [see Clinical Studies (14.2)]. However, the optimal duration of treatment with lamotrigine has not been established. Thus, patients should be periodically reassessed to determine the need for maintenance treatment.

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  Epilepsy: Adjunctive Use:

  Lamotrigine tablets are indicated as adjunctive therapy for partial seizures and the generalized seizures of Lennox-Gastaut syndrome in adult and pediatric patients (≥ 2 years of age).

  Monotherapy Use:

  Lamotrigine tablets are indicated for conversion to monotherapy in adults with partial seizures who are receiving treatment with carbamazepine, phenytoin, phenobarbital, primidone, or valproate as the single AED.

  Safety and effectiveness of lamotrigine tablets have not been established (1) as initial monotherapy, (2) for conversion to monotherapy from AEDs other than carbamazepine, phenytoin, phenobarbital, primidone, or valproate, or (3) for simultaneous conversion to monotherapy from 2 or more concomitant AEDs.

  Bipolar Disorder:

  Lamotrigine tablets are indicated for the maintenance treatment of Bipolar I Disorder to delay the time to occurrence of mood episodes (depression, mania, hypomania, mixed episodes) in patients treated for acute mood episodes with standard therapy. The effectiveness of lamotrigine tablets in the acute treatment of mood episodes has not been established.

  General Dosing Considerations for Epilepsy and Bipolar Disorder Patients:

  The risk of nonserious rash is increased when the recommended initial dose and/or the rate of dose escalation of lamotrigine tablets is exceeded. There are suggestions, yet to be proven, that the risk of severe, potentially life-threatening rash may be increased by (1) coadministration of lamotrigine tablets with valproate, (2) exceeding the recommended initial dose of lamotrigine tablets, or (3) exceeding the recommended dose escalation for lamotrigine tablets. However, cases have been reported in the absence of these factors (see BOX WARNING). Therefore, it is important that the dosing recommendations be followed closely.

  It is recommended that lamotrigine not be restarted in patients who discontinued due to rash associated with prior treatment with lamotrigine, unless the potential benefits clearly outweigh the risks. If the decision is made to restart a patient who has discontinued lamotrigine, the need to restart with the initial dosing recommendations should be assessed. The greater the interval of time since the previous dose, the greater consideration should be given to restarting with the initial dosing recommendations. If a patient has discontinued lamotrigine for a period of more than 5 halflives, it is recommended that initial dosing recommendations and guidelines be followed.

  Lamotrigine Added to Drugs Known to Induce or Inhibit Glucuronidation:

  Drugs other than those listed in PRECAUTIONS: Drug Interactionshave not been systematically evaluated in combination with lamotrigine. Since lamotrigine is metabolized predominantly by glucuronic acid conjugation, drugs that are known to induce or inhibit glucuronidation may affect the apparent clearance of lamotrigine, and doses of lamotrigine may require adjustment based on clinical response.

  Target Plasma Levels for Patients With Epilepsy or Bipolar Disorder:

  A therapeutic plasma concentration range has not been established for lamotrigine. Dosing of lamotrigine should be based on therapeutic response.

  The half-life of lamotrigine is affected by other concomitant medications (see CLINICAL PHARMACOLOGY: Pharmacokinetics and Drug Metabolism).

  See also DOSAGE AND ADMINISTRATION: Special Populations.

  Special Populations: Women and Oral Contraceptives:   Starting Lamotrigine in Women Taking Oral Contraceptives:

  Although estrogen-containing oral contraceptives have been shown to increase the clearance of lamotrigine (see PRECAUTIONS: Drug Interactions), no adjustments to the recommended dose escalation guidelines for lamotrigine should be necessary solely based on the use of estrogen-containing oral contraceptives. Therefore, dose escalation should follow the recommended guidelines for initiating adjunctive therapy with lamotrigine based on the concomitant AED (see Table 11). See below for adjustments to maintenance doses of lamotrigine in women taking estrogen-containing oral contraceptives.

  Adjustments to the Maintenance Dose of Lamotrigine:

   (1) Taking Estrogen-Containing Oral Contraceptives:  For women not taking carbamazepine, phenytoin, phenobarbital, primidone, or rifampin, the maintenance dose of lamotrigine will in most cases need to be increased, by as much as 2-fold over the recommended target maintenance dosein order to maintain a consistent lamotrigine plasma level (see PRECAUTIONS: Drug Interactions). (2) Starting Estrogen-Containing Oral Contraceptives: In women taking a stable dose of lamotrigine and not taking carbamazepine, phenytoin, phenobarbital, primidone, or rifampin, the maintenance dose will in most cases need to be increased by as much as 2-fold, in order to maintain a consistent lamotrigine plasma level. The dose increases should begin at the same time that the oral contraceptive is introduced and continue, based on clinical response, no more rapidly than 50 to 100 mg/day every week. Dose increases should not exceed the recommended rate unless lamotrigineplasma levels or clinical response support larger increases (see Table 11, column 2).Gradual transient increases in lamotrigine plasma levels may occur during the week of inactive hormonal preparation (“pill-free” week), and these increases will be greater if dose increases are made in the days before or during the week of inactive hormonal preparation. Increased lamotrigine plasma levels could result in additional adverse events, such as dizziness, ataxia, and diplopia (see PRECAUTIONS: Drug Interactions). If adverse events attributable to lamotrigine consistently occur during the “pill-free” week, dose adjustments to the overall maintenance dose may be necessary. Dose adjustments limited to the “pill-free” week are not recommended. For women taking lamotrigine in addition to carbamazepine, phenytoin, phenobarbital, primidone, or rifampin, no adjustment should be necessary to the dose of lamotrigine.  (3) Stopping Estrogen-Containing Oral Contraceptives: For women not taking carbamazepine, phenytoin, phenobarbital, primidone, or rifampin, the maintenance dose of lamotrigine will in most cases need to be decreased by as much as 50%, in order to maintain a consistent lamotrigine plasma level. The decrease in dose of lamotrigine should not exceed 25% of the total daily dose per week over a 2-week period, unless clinical response or lamotrigine plasma levels indicate otherwise (see PRECAUTIONS: Drug Interactions). For women taking lamotrigine in addition to carbamazepine, phenytoin, phenobarbital, primidone, or rifampin, no adjustment to the dose of lamotrigine should be necessary.

  Women and Other Hormonal Contraceptive Preparations or Hormone Replacement Therapy:

  The effect of other hormonal contraceptive preparations or hormone replacement therapy on the pharmacokinetics of lamotrigine has not been systematically evaluated. It has been reported that ethinylestradiol, not progestogens, increased the clearance of lamotrigine up to 2-fold, and the progestin only pills had no effect on lamotrigine plasma levels. Therefore, adjustments to the dosage of lamotrigine in the presence of progestogens alone will likely not be needed.

  Patients With Hepatic Impairment:

  Experience in patients with hepatic impairment is limited. Based on a clinical pharmacology study in 24 patients with mild, moderate, and severe liver dysfunction (see CLINICAL PHARMACOLOGY), the following general recommendations can be made. No dosage adjustment is needed in patients with mild liver impairment. Initial, escalation, and maintenance doses should generally be reduced by approximately 25% in patients with moderate and severe liver impairment without ascites and 50% in patients with severe liver impairment with ascites. Escalation and maintenance doses may be adjusted according to clinical response.

  Patients With Renal Functional Impairment:

  Initial doses of lamotrigine should be based on patients’ AED regimen (see above); reduced maintenance doses may be effective for patients with significant renal functional impairment (see CLINICAL PHARMACOLOGY). Few patients with severe renal impairment have been evaluated during chronic treatment with lamotrigine. Because there is inadequate experience in this population, lamotrigine should be used with caution in these patients.

  Epilepsy: Adjunctive Therapy With Lamotrigine for Epilepsy:

  This section provides specific dosing recommendations for patients 2 to 12 years of age and patients greater than 12 years of age. Within each of these age groups, specific dosing recommendations are provided depending upon concomitant AED (Table 9 for patients 2 to 12 years of age and Table 11 for patients greater than 12 years of age). A weight based dosing guide for pediatric patients on concomitant valproate is provided in Table 10.

  Patients 2 to 12 Years of Age:

  Recommended dosing guidelines are summarized in Table 9. Note that some of the starting doses and dose escalations listed in Table 9 are different than those used in clinical trials; however, the maintenance doses are the same as in clinical trials. Smaller starting doses and slower dose escalations than those used in clinical trials are recommended because of the suggestions that the risk of rash may be decreased by smaller starting doses and slower dose escalations. Therefore, maintenance doses will take longer to reach in clinical practice than in clinical trials. It may take several weeks to months to achieve an individualized maintenance dose. Maintenance doses in patients weighing less than 30 kg, regardless of age or concomitant AED, may need to be increased as much as 50%, based on clinical response.

  Table 9. Escalation Regimen for Lamotrigine in Patients 2 to 12 Years of Age With Epilepsy Note: Only whole tablets should be used for dosing * Rifampin and estrogen-containing contraceptives have also been shown to increase the apparent clearance of lamotrigine (see PRECAUTIONS: Drug Interactions).

  For Patients Taking
  Valproate (see Table 10 for
  weight-based dosing guide)

  For Patients Taking AEDs
  Other Than Carbamazepine,
  Phenytoin, Phenobarbital,
  Primidone or Valproate*

  For Patients Taking
  Carbamazepine, Phenytoin,
  Phenobarbital, Primidone*
  and Not Taking Valproate

  Weeks 1 and 2

  0.15 mg/kg/day in 1 or 2
  divided doses, rounded
  down to the nearest whole
  tablet (see Table 10 for
  weight-based dosing guide).

  0.3 mg/kg/day in 1 or
  2 divided doses, rounded down to the nearest
  whole tablet.

  0.6 mg/kg/day in 2 divided
  doses, rounded down to the
  nearest whole tablet.

  Weeks 3 and 4

  0.3 mg/kg/day in 1 or
  2 divided doses, rounded
  down to the nearest whole
  tablet (see Table 10 for
  weight-based dosing guide).

  0.6 mg/kg/day in 2 divided
  doses, rounded down to the
  nearest whole tablet.

  1.2 mg/kg/day in 2 divided doses,
  rounded down to the
  nearest whole tablet.

  Weeks 5 onwards to 
  maintenance

  The dose should be increased
  every 1 to 2 weeks as follows:
  calculate 0.3 mg/kg/day,
  round this amount down to the nearest whole tablet, and add
  this amount to the previously
  administered daily dose.

  The dose should be increased
  every 1 to 2 weeks as follows:
  calculate 0.6 mg/kg/day,
  round this amount down to the nearest whole tablet,
  and add this amount to the
  previously administered daily dose

  The dose should be increased
  every 1 to 2 weeks as follows:
  calculate 1.2 mg/kg/day,
  round this amount down to
  the nearest whole tablet, and
  add this amount to the previously administered daily
  dose

  Usual Maintenance
  Dose

  1 to 5 mg/kg/day (maximum 200 mg/day in 1 or 2 divided doses).
  1 to 3 mg/kg/day with valproate alone

  4.5 to 7.5 mg/kg/day 
  (maximum 300 mg/day in
  2 divided doses)

  5 to 15 mg/kg/day
  (maximum 400 mg/day in
  2 divided doses)

  Maintenance dose in patients less than
  30 kg

  May need to be increased by as 
  much as 50%, based on clinical
  response

  May need to be increased by as 
  much as 50%, based on
  clinical response

  May need to be increased by as 
  much as 50%, based on
  clinical response

  Table 10. The Initial Weight-Based Dosing Guide for Patients 2 to 12 Years Taking Valproate (Weeks 1 to 4) With Epilepsy

  If the patient’s weight is

  Give this daily dose, using the most appropriate 
  combination of lamotrigine 2-mg and 5-mg tablets

  Greater than

  And less than

  Weeks 1 and 2

  Weeks 3 and 4

  6.7 kg

  14 kg

  2 mg every other day

  2 mg every day

  14.1 kg

  27 kg

  2 mg every day

  4 mg every day

  27.1 kg

  34 kg

  4 mg every day

  8 mg every day

  34.1 kg

  40 kg

  5 mg every day

  10 mg every day

   

  Patients Over 12 Years of Age:

  Recommended dosing guidelines are summarized in Table 11

  Table 11. Escalation Regimen for Lamotrigine in Patients Over 12 Years of Age With Epilepsy * Rifampin and estrogen-containing oral contraceptives have also been shown to increase the apparent clearance of lamotrigine (see PRECAUTIONS: Drug Interactions)

  For Patients Taking Valproate

  For Patients Taking AEDs
  Other Than Carbamazepine,
  Phenytoin, Phenobarbital,
  Primidone or Valproate*

  For Patients Taking
  Carbamazepine, Phenytoin,
  Phenobarbital, Primidone*
  and Not Taking Valproate

  Weeks 1 and 2

  25 mg every other day

  25 mg every day

  50 mg/day

  Weeks 3 and 4

  25 mg every day

  50 mg/day

  100 mg/day

  (in 2 divided doses)

  Weeks 5 onwards to 
  maintenance

  Increase by 25 to 50 mg/day every
  1 to 2 weeks

  Increase by 50 mg/day
  every 1 to 2 weeks

  Increase by 100 mg/day
  every 1 to 2 weeks.

  Usual Maintenance 
  Dose

  100 to 400 mg/day 
  (1 or 2 divided doses) 100 to
  200 mg/daywith valproate alone

  225 to 375 mg/day
  (in 2 divided doses).

  300 to 500 mg/day 
  (in 2 divided doses).

  Conversion From Adjunctive Therapy With Carbamazepine, Phenytoin, Phenobarbital, Primidone, or Valproate as the Single AED to Monotherapy With Lamotrigine in Patients ≥ 16 Years of Age With Epilepsy:

  The goal of the transition regimen is to effect the conversion to monotherapy with lamotrigine under conditions that ensure adequate seizure control while mitigating the risk of serious rash associated with the rapid titration of lamotrigine.

  The recommended maintenance dose of lamotrigine as monotherapy is 500 mg/day given in 2 divided doses.

  To avoid an increased risk of rash, the recommended initial dose and subsequent dose escalations of lamotrigine should not be exceeded (see BOX WARNING).

  Conversion From Adjunctive Therapy With Carbamazepine, Phenytoin, Phenobarbital, or Primidone to Monotherapy With Lamotrigine:  

  After achieving a dose of 500 mg/day  of lamotrigine according to Table 11, the concomitant AED should be withdrawn by 20% decrements each week over a 4-week period. The regimen for the withdrawal of the concomitant AED is based on experience gained in the controlled monotherapy clinical trial.

  Conversion From Adjunctive Therapy With Valproate to Monotherapy With Lamotrigine:

  The conversion regimen involves 4 steps. (see Table 12).

  Table 12. Conversion From Adjunctive Therapy With Valproate to Monotherapy With Lamotrigine in Patients ≥16 Years of Age With Epilepsy

  Lamotrigine

  Valproate

  Step 1

  Achieve a dose of 200 mg/day according to 
  guidelines in Table 11 (if not already on
  200 mg/day).

  Maintain previous stable dose.

  Step 2

  Maintain at 200 mg/day.

  Decrease to 500 mg/day by decrements
  no greater than 500 mg/day per week
  and then maintain the dose of
  500 mg/day for 1 week.

  Step 3

  Increase to 300 mg/day and maintain for 1 week.

  Simultaneously decrease to 250 mg/day
  and maintain for 1 week.

  Step 4

  Increase by 100 mg/day every week to achieve
  maintenance dose of 500 mg/day.

  Discontinue.

  Conversion From Adjunctive Therapy With Antiepileptic Drugs Other Than Carbamazepine, Phenytoin, Phenobarbital, Primidone, or Valproate to Monotherapy With Lamotrigine:

  No specific dosing guidelines can be provided for conversion to monotherapy with lamotrigine with AEDs other than carbamazepine, phenobarbital, phenytoin, primidone, or valproate.

  Usual Maintenance Dose for Epilepsy:

  The usual maintenance doses identified in Tables 9 -11 are derived from dosing regimens employed in the placebo-controlled adjunctive studies in which the efficacy of lamotrigine was established. In patients receiving multidrug regimens employing carbamazepine, phenytoin, phenobarbital, or primidone without valproate, maintenance doses of adjunctive lamotrigine as high as 700 mg/day have been used. In patients receiving valproate alone, maintenance doses of adjunctive lamotrigine as high as 200 mg/ day have been used. The advantage of using doses above those recommended in the Tables 9 -12 has not been established in controlled trials.

  Discontinuation Strategy for Patients With Epilepsy:

  For patients receiving lamotrigine in combination with other AEDs, a reevaluation of all AEDs in the regimen should be considered if a change in seizure control or an appearance or worsening of adverse experiences is observed.

  If a decision is made to discontinue therapy with lamotrigine, a step-wise reduction of dose over at least 2 weeks (approximately 50% per week) is recommended unless safety concerns require a more rapid withdrawal (see PRECAUTIONS).

  Discontinuing carbamazepine, phenytoin, phenobarbital, or primidone should prolong the half-life of lamotrigine; discontinuing valproate should shorten the half-life of lamotrigine.

  Bipolar Disorder:

  The goal of maintenance treatment with lamotrigine tablets is to delay the time to occurrence of mood episodes (depression, mania, hypomania, mixed episodes) in patients treated for acute mood episodes with standard therapy. The target dose of lamotrigine tablets is 200 mg/day (100 mg/day in patients taking valproate, which decreases the apparent clearance of lamotrigine, and 400 mg/day in patients not taking valproate and taking either carbamazepine, phenytoin, phenobarbital, primidone, or rifampin, which increase the apparent clearance of lamotrigine). In the clinical trials, doses up to 400 mg/day as monotherapy were evaluated, however, no additional benefit was seen at 400 mg/day compared to 200 mg/day (see CLINICAL STUDIES: Bipolar Disorder). Accordingly, doses above 200 mg/day are not recommended. Treatment with lamotrigine tablets is introduced, based on concurrent medications, according to the regimen outlined in Table 13. If other psychotropic medications are withdrawn following stabilization, the dose of lamotrigine tablets should be adjusted. For patients discontinuing valproate, the dose of lamotrigine tablets should be doubled over a 2 week period in equal weekly increments (see Table 14). For patients discontinuing carbamazepine, phenytoin, phenobarbital, primidone, or rifampin, the dose of lamotrigine tablets should remain constant for the first week and then should be decreased by half over a 2 week period in equal weekly decrements (see Table 14). The dose of lamotrigine tablets may then be further adjusted to the target dose (200 mg) as clinically indicated.

  Dosage adjustments will be necessary in most patients who start or stop estrogen-containing oral contraceptives while taking lamotrigine (see DOSAGE AND ADMINISTRATION, Special Populations, Women and oral contraceptives, Adjustments to the maintenance dose of lamotrigine).

  If other drugs are subsequently introduced, the dose of lamotrigine tablets may need to be adjusted. In particular, the introduction of valproate requires reduction in the dose of lamotrigine tablets (see CLINICAL PHARMACOLOGY: Drug Interactions).

  To avoid an increased risk of rash, the recommended initial dose and subsequent dose escalations of lamotrigine tablets should not be exceeded (see BOX WARNING).

  Table 13. Escalation Regimen for Lamotrigine for Patients With Bipolar Disorder* * See  CLINICAL PHARMACOLOGY, Drug Interactions and PRECAUTIONS, Drug Interactions for a description of known drug interactions. † Carbamazepine, phenytoin, phenobarbital, primidone, and rifampin have been shown to increase the apparent clearance of lamotrigine. ‡ Valproate has been shown to decrease the apparent clearance of lamotrigine. For Patients Not Taking
  Carbamazepine, (or Other Enzyme-
  Inducing Drugs†) or Valproate‡

  For Patients Taking
  Valproate‡

  For Patients Taking Carbamazepine
  (or Other Enzyme-Inducing Drugs)
  and Not Taking Valproate‡

  Weeks 1 and 2

  25 mg daily

  25 mg every other day

  50 mg daily

  Weeks 3 and 4

  50 mg daily

  25 mg daily

  100 mg daily, in divided doses

  Week 5

  100 mg daily

  50 mg daily

  200 mg daily, in divided doses

  Week 6

  200 mg daily

  100 mg daily

  300 mg daily, in divided doses

  Week 7

  200 mg daily

  100 mg daily

  up to 400 mg daily, in divided doses

  Table 14. Adjustments to Lamotrigine Dosing for Patients With Bipolar Disorder Following Discontinuation of Psychotropic Medications* * See CLINICAL PHARMACOLOGY, Drug Interactionsand PRECAUTIONS, Drug Interactions for a description of known drug interactions † Carbamazepine, phenytoin, phenobarbital, primidone, and rifampin have been shown to increase the apparent clearance of lamotrigine. ‡ Valproate has been shown to decrease the apparent clearance of lamotrigine.

  Discontinuation of
  Psychotropic Drugs
  (excluding Carbamazepine, or Other Enzyme-Inducing Drugs)†

  After Discontinuation of
  Valproate‡

  After Discontinuation of
  Carbamazepine, or Other
  Enzyme-Inducing Drugs†

  Current lamotrigine dose (mg/day) 100

  Current lamotrigine dose
  (mg/day) 400

  Week 1

  Maintain current
  Lamotrigine dose

  150

  400

  Week 2

  Maintain current
  Lamotrigine dose

  200

  300

  Week 3 onward

  Maintain current
  Lamotrigine dose

  200

  200

  There is no body of evidence available to answer the question of how long the patient should remain on lamotrigine tablet therapy. Systematic evaluation of the efficacy of lamotrigine in patients with either depression or mania who responded to standard therapy during an acute 8 to 16 week treatment phase and were then randomized to lamotrigine or placebo for up to 76 weeks of observation for affective relapse demonstrated a benefit of such maintenance treatment (see CLINICAL STUDIES: Bipolar Disorder). Nevertheless, patients should be periodically reassessed to determine the need for maintenance treatment.

  Discontinuation Strategy in Bipolar Disorder:

  As with other AEDs, lamotrigine tablets should not be abruptly discontinued. In the controlled clinical trials, there was no increase in the incidence, type, or severity of adverse experiences following abrupt termination of lamotrigine. In clinical trials in patients with bipolar disorder, 2 patients experienced seizures shortly after abrupt withdrawal of lamotrigine. However, there were confounding factors that may have contributed to the occurrence of seizures in these bipolar patients. Discontinuation of lamotrigine tablets should involve a step-wise reduction of dose over at least 2 weeks (approximately 50% per week) unless safety concerns require a more rapid withdrawal.

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  2.1. General Dosing Considerations

  Rash: There are suggestions, yet to be proven, that the risk of severe, potentially life-threatening rash may be increased by (1) coadministration of lamotrigine tablets with valproate, (2) exceeding the recommended initial dose of lamotrigine tablets, or (3) exceeding the recommended dose escalation for lamotrigine tablets. However, cases have occurred in the absence of these factors [see Boxed Warning]. Therefore, it is important that the dosing recommendations be followed closely.

  The risk of nonserious rash may be increased when the recommended initial dose and/or the rate of dose escalation of lamotrigine tablets is exceeded and in patients with a history of allergy or rash to other AEDs.

  It is recommended that lamotrigine tablets not be restarted in patients who discontinued due to rash associated with prior treatment with lamotrigine, unless the potential benefits clearly outweigh the risks. If the decision is made to restart a patient who has discontinued lamotrigine, the need to restart with the initial dosing recommendations should be assessed. The greater the interval of time since the previous dose, the greater consideration should be given to restarting with the initial dosing recommendations. If a patient has discontinued lamotrigine for a period of more than 5 half-lives, it is recommended that initial dosing recommendations and guidelines be followed. The half-life of lamotrigine is affected by other concomitant medications [see Clinical Pharmacology (12.3)].

  Lamotrigine tablets Added to Drugs Known to Induce or Inhibit Glucuronidation: Drugs other than those listed in the Clinical Pharmacology section [see Clinical Pharmacology (12.3)] have not been systematically evaluated in combination with lamotrigine. Because lamotrigine is metabolized predominantly by glucuronic acid conjugation, drugs that are known to induce or inhibit glucuronidation may affect the apparent clearance of lamotrigine and doses of lamotrigine tablets may require adjustment based on clinical response.

  Target Plasma Levels for Patients With Epilepsy or Bipolar Disorder: A therapeutic plasma concentration range has not been established for lamotrigine. Dosing of lamotrigine tablets should be based on therapeutic response [see Clinical Pharmacology (12.3)].

  Women Taking Estrogen-Containing Oral Contraceptives: Starting Lamotrigine Tablets in Women Taking Estrogen-Containing Oral Contraceptives: Although estrogen-containing oral contraceptives have been shown to increase the clearance of lamotrigine [see Clinical Pharmacology (12.3)], no adjustments to the recommended dose-escalation guidelines for lamotrigine tablets should be necessary solely based on the use of estrogen-containing oral contraceptives. Therefore, dose escalation should follow the recommended guidelines for initiating adjunctive therapy with lamotrigine tablets based on the concomitant AED or other concomitant medications (see Table 1 or Table 5). See below for adjustments to maintenance doses of lamotrigine tablets in women taking estrogen-containing oral contraceptives.

  Adjustments to the Maintenance Dose of Lamotrigine Tablets In Women Taking Estrogen-Containing Oral Contraceptives:

  Taking Estrogen-Containing Oral Contraceptives: For women not taking carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin that induce lamotrigine glucuronidation [see Drug Interactions (7), Clinical Pharmacology (12.3)], the maintenance dose of lamotrigine tablets will in most cases need to be increased, by as much as 2-fold over the recommended target maintenance dose, in order to maintain a consistent lamotrigine plasma level [see Clinical Pharmacology (12.3)]. Starting Estrogen-Containing Oral Contraceptives: In women taking a stable dose of lamotrigine tablets and not taking carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin that induce lamotrigine glucuronidation [see Drug Interactions (7), Clinical Pharmacology (12.3)], the maintenance dose will in most cases need to be increased by as much as 2-fold, in order to maintain a consistent lamotrigine plasma level. The dose increases should begin at the same time that the oral contraceptive is introduced and continue, based on clinical response, no more rapidly than 50 to 100 mg/day every week. Dose increases should not exceed the recommended rate (see Table 1 or Table 5) unless lamotrigine plasma levels or clinical response support larger increases. Gradual transient increases in lamotrigine plasma levels may occur during the week of inactive hormonal preparation (“pill-free” week), and these increases will be greater if dose increases are made in the days before or during the week of inactive hormonal preparation. Increased lamotrigine plasma levels could result in additional adverse reactions, such as dizziness, ataxia, and diplopia. If adverse reactions attributable to lamotrigine tablets consistently occur during the “pill-free” week, dose adjustments to the overall maintenance dose may be necessary. Dose adjustments limited to the “pill-free” week are not recommended. For women taking lamotrigine tablets in addition to carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin that induce lamotrigine glucuronidation [see Drug Interactions (7), Clinical Pharmacology (12.3)], no adjustment to the dose of lamotrigine should be necessary. Stopping Estrogen-Containing Oral Contraceptives: For women not taking carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin that induce lamotrigine glucuronidation [see Drug Interactions (7), Clinical Pharmacology (12.3)], the maintenance dose of lamotrigine tablets will in most cases need to be decreased by as much as 50%, in order to maintain a consistent lamotrigine plasma level. The decrease in dose of lamotrigine tablets should not exceed 25% of the total daily dose per week over a 2-week period, unless clinical response or lamotrigine plasma levels indicate otherwise [see Clinical Pharmacology (12.3)]. For women taking lamotrigine tablets in addition to carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin that induce lamotrigine glucuronidation [see Drug Interactions (7), Clinical Pharmacology (12.3)], no adjustment to the dose of lamotrigine tablets should be necessary.

  Women and Other Hormonal Contraceptive Preparations or Hormone Replacement Therapy: The effect of other hormonal contraceptive preparations or hormone replacement therapy on the pharmacokinetics of lamotrigine has not been systematically evaluated. It has been reported that ethinylestradiol, not progestogens, increased the clearance of lamotrigine up to 2-fold, and the progestin only pills had no effect on lamotrigine plasma levels. Therefore, adjustments to the dosage of lamotrigine tablets in the presence of progestogens alone will likely not be needed.

  Patients With Hepatic Impairment:  Experience in patients with hepatic impairment is limited. Based on a clinical pharmacology study in 24 patients with mild, moderate, and severe liver impairment [see Use in Specific Populations (8.6), Clinical Pharmacology (12.3)],

  the following general recommendations can be made. No dosage adjustment is needed in patients with mild liver impairment. Initial, escalation, and maintenance doses should generally be reduced by approximately 25% in patients with moderate and severe liver impairment without ascites and 50% in patients with severe liver impairment with ascites. Escalation and maintenance doses may be adjusted according to clinical response. 

  Patients With Renal Impairment:  Initial doses of lamotrigine tablets should be based on patients' concomitant medications (see Tables 1-3 or Table 5); reduced maintenance doses may be effective for patients with significant renal impairment [see Use in Specific Populations (8.7), Clinical Pharmacology (12.3)]. Few patients with severe renal impairment have been evaluated during chronic treatment with lamotrigine tablets. Because there is inadequate experience in this population, lamotrigine tablets should be used with caution in these patients.

  Discontinuation Strategy:Epilepsy: For patients receiving lamotrigine tablets in combination with other AEDs, a re-evaluation of all AEDs in the regimen should be considered if a change in seizure control or an appearance or worsening of adverse reactions is observed.

  If a decision is made to discontinue therapy with lamotrigine tablets, a step-wise reduction of dose over at least 2 weeks (approximately 50% per week) is recommended unless safety concerns require a more rapid withdrawal [see Warnings and Precautions (5.10)].

  Discontinuing carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin that induce lamotrigine glucuronidation should prolong the half-life of lamotrigine; discontinuing valproate should shorten the half-life of lamotrigine. 

  Bipolar Disorder:

  In the controlled clinical trials, there was no increase in the incidence, type, or severity of adverse reactions following abrupt termination of lamotrigine tablets. In clinical trials in patients with Bipolar Disorder, 2 patients experienced seizures shortly after abrupt withdrawal of lamotrigine tablets. However, there were confounding factors that may have contributed to the occurrence of seizures in these bipolar patients. Discontinuation of lamotrigine tablets should involve a step-wise reduction of dose over at least 2 weeks (approximately 50% per week) unless safety concerns require a more rapid withdrawal [see Warnings and Precautions (5.10)].

  2.2. Epilepsy - Adjunctive Therapy

  This section provides specific dosing recommendations for patients greater than 12 years of age and patients 2 to 12 years of age. Within each of these age-groups, specific dosing recommendations are provided depending upon concomitant AED or other concomitant medications (Table 1 for patients greater than 12 years of age and Table 2 for patients 2 to 12 years of age). A weight-based dosing guide for patients 2 to 12 years of age on concomitant valproate is provided in Table 3.

  Patients Over 12 Years of Age:

  Recommended dosing guidelines are summarized in Table 1.

  Table 1Escalation Regimen for Lamotrigine Tablets in Patients Over 12 Years of Age With Epilepsy

   
  For Patients TAKING Valproatea
  For Patients NOT TAKING Carbamazepine, Phenytoin, Phenobarbital, Primidoneb, or Valproatea
  For Patients TAKING Carbamazepine, Phenytoin, Phenobarbital, or Primidoneb and NOT TAKING Valproatea
  Weeks 1 and 2
  25 mg every other day 
  25 mg every day 
  50 mg/day  
  Weeks 3 and 4
  25 mg every day 
  50 mg/day  
  100 mg/day  
  (in 2 divided doses)
  Week 5 onwards to maintenance
  Increase by 25 to 50 mg/day every 1 to 2 weeks
  Increase by 50 mg/day every 1 to 2 weeks
  Increase by 100 mg/day every 1 to 2 weeks.
  Usual Maintenance Dose
  100 to 200 mg/day with valproate alone
   
  100 to 400 mg/day 
  with valproate and other drugs that induce glucuronication 
  ( in 1 or 2 divided doses)
  225 to 375 mg/day 
  (in 2 divided doses).
  300 to 500 mg/day 
  (in 2 divided doses).
  

  a Valproate has been shown to inhibit glucuronidation and decrease the apparent clearance of lamotrigine [see Drug Interactions (7), Clinical Pharmacology (12.3)].

  b These drugs induce lamotrigine glucuronidation and increase clearance [see Drug Interactions (7) Clinical Pharmacology (12.3)]. Other drugs which have similar effects include estrogen-containing oral contraceptives [see Drug Interactions (7), Clinical Pharmacology (12.3)]. Dosing recommendations for oral contraceptives can be found in General Dosing Considerations [see Dosage and Administration (2.1)]. Patients on rifampin, or other drugs that induce lamotrigine glucuronidation and increase clearance, should follow the same dosing titration/maintenance regimen as that used with anticonvulsants that have this effect.

  Patients 2 to 12 Years of Age: Recommended dosing guidelines are summarized in Table 2.

  Smaller starting doses and slower dose escalations than those used in clinical trials are recommended because of the suggestions that the risk of rash may be decreased by smaller starting doses and slower dose escalations. Therefore, maintenance doses will take longer to reach in clinical practice than in clinical trials. It may take several weeks to months to achieve an individualized maintenance dose. Maintenance doses in patients weighing less than 30 kg, regardless of age or concomitant AED, may need to be increased as much as 50%, based on clinical response. 

  Table 2Escalation Regimen for Lamotrigine Tablets in Patients 2 to 12 Years of Age With Epilepsy  

   
  For Patients TAKING Valproatea
  For Patients
  NOT TAKING Carbamazepine,
  Phenytoin,
  Phenobarbital,
  Primidoneb, or  Valproatea
  For Patients TAKING Carbamazepine, Phenytoin, Phenobarbital, or Primidoneb and NOT TAKING Valproatea
  Weeks 1 and 2
  0.15 mg/kg/day  
  in 1 or 2 divided doses, rounded down to the nearest whole tablet (see Table 3 for weight based dosing guide).
  0.3 mg/kg/day  
  in 1 or 2 divided doses, rounded down to the nearest whole tablet.
  0.6 mg/kg/day  
  in 2 divided doses, rounded down to the nearest whole tablet.
  Weeks 3 and 4
  0.3 mg/kg/day  
  in 1 or 2 divided doses, rounded down to the nearest whole tablet (see Table 3 for weight based dosing guide).
  0.6 mg/kg/day  
  in 2 divided doses, rounded down to the nearest whole tablet.
  1.2 mg/kg/day  
  in 2 divided doses, rounded down to the nearest whole tablet.
  Week 5 onwards to maintenance
  The dose should be increased every 1 to 2 weeks as follows: calculate 0.3 mg/kg/day, round this amount down to the nearest whole tablet, and add this amount to the previously administered daily dose.
  The dose should be increased every 1 to 2 weeks as follows: calculate 0.6 mg/kg/day, round this amount down to the nearest whole tablet, and add this amount to the previously administered daily dose
  The dose should be increased every 1 to 2 weeks as follows: calculate 1.2 mg/kg/day, round this amount down to the nearest whole tablet, and add this amount to the previously administered daily dose
  Usual Maintenance Dose
  1 to 5 mg/kg/day(maximum 200 mg/day in 1 or 2 divided doses).
  1 to 3 mg/kg/day with valproate alone
  4.5 to 7.5 mg/kg/day 
  (maximum 300 mg/day in 2 divided doses)
  5 to 15 mg/kg/day (maximum 400 mg/day in 2 divided doses)
  Maintenance dose in patients less than 30 kg
  May need to be increased by as much as 50%, based on clinical response
  May need to be increased by as much as 50%, based on clinical response
  May need to be increased by as much as 50%, based on clinical response
  

  Note: Only whole tablets should be used for dosing

  a Valproate has been shown to inhibit glucuronidation and decrease the apparent clearance of lamotrigine [see Drug Interactions (7), Clinical Pharmacology (12.3)].

  b These drugs induce lamotrigine glucuronidation and increase clearance [see Drug Interactions (7) Clinical Pharmacology (12.3)]. Other drugs which have similar effects include estrogen-containing oral contraceptives [see Drug Interactions (7), Clinical Pharmacology (12.3)].

  Dosing recommendations for oral contraceptives can be found in General Dosing Considerations [see Dosage and Administration (2.1)].

  Patients on rifampin, or other drugs that induce lamotrigine glucuronidation and increase clearance, should follow the same dosing titration/maintenance regimen as that used with anticonvulsants that have this effect.

  Table 3The Initial Weight-Based Dosing Guide for Patients 2 to 12 Years Taking Valproate (Weeks 1 to 4) With Epilepsy 

  If the patient’s weight is
  Give this daily dose, using the most appropriate combination of lamotrigine tablets 2-mg and 5-mg tablets
  Greater than
  And less than
  Weeks 1 and 2
  Weeks 3 and 4
  6.7 kg
  14 kg
  2 mg every other day
  2 mg every day
  14.1 kg
  27 kg
  2 mg every day
  4 mg every day
  27.1 kg
  34 kg
  4 mg every day
  8 mg every day
  34.1 kg
  40 kg
  5 mg every day
  10 mg every day
  

  Usual Maintenance Dose for Epilepsy:

  The usual maintenance doses identified in Tables 1 and 2 are derived from dosing regimens employed in the placebo-controlled adjunctive studies in which the efficacy of lamotrigine tablets was established. In patients receiving multidrug regimens employing carbamazepine, phenytoin, phenobarbital, or primidone without valproate, maintenance doses of adjunctive lamotrigine tablets as high as 700 mg/day have been used. In patients receiving valproate alone, maintenance doses of adjunctive lamotrigine tablets as high as 200 mg/day have been used. The advantage of using doses above those recommended in Tables 1 through 4 has not been established in controlled trials.

  2.3. Epilepsy - Conversion From Adjunctive Therapy to Monotherapy

  The goal of the transition regimen is to effect the conversion to monotherapy with lamotrigine tablet under conditions that ensure adequate seizure control while mitigating the risk of serious rash associated with the rapid titration of lamotrigine tablet.

  The recommended maintenance dose of lamotrigine tablet as monotherapy is 500 mg/day given in 2 divided doses.

  To avoid an increased risk of rash, the recommended initial dose and subsequent dose escalations of lamotrigine tablets should not be exceeded [see Boxed Warning].

  Conversion From Adjunctive Therapy With Carbamazepine, Phenytoin, Phenobarbital, or Primidone to Monotherapy with Lamotrigine Tablets: After achieving a dose of 500 mg/day of lamotrigine tablets according to the guidelines in Table 1, the concomitant AED should be withdrawn by 20% decrements each week over a 4-week period. The regimen for the withdrawal of the concomitant AED is based on experience gained in the controlled monotherapy clinical trial.

  Conversion from Adjunctive Therapy with Valproate to Monotherapy with Lamotrigine Tablets: The conversion regimen involves 4 steps outline in Table 4.

  
  Table 4Conversion From Adjunctive Therapy with Valproate to Monotherapy with Lamotrigine Tablets in Patients ≥16 Years of Age with Epilepsy

   
  Lamotrigine Tablets
  Valproate
  Step 1
  Achieve a dose of 200 mg/day according to guidelines in Table 1 (if not already on 200 mg/day).
  Maintain previous stable dose.
  Step 2
  Maintain at 200 mg/day.
  Decrease to 500 mg/day by decrements no greater than 500 mg/day per week and then maintain the dose of 500 mg/day for 1 week.
  Step 3
  Increase to 300 mg/day and maintain for 1 week.
  Simultaneously decrease to 250 mg/day and maintain for 1 week.
  Step 4
  Increase by 100 mg/day every week to achieve maintenance dose of 500 mg/day.
  Discontinue.
  

  Conversion from Adjunctive Therapy With AEDs Other Than Carbamazepine, Phenytoin, Phenobarbital, Primidone, or Valproate to Monotherapy With Lamotrigine Tablets: No specific dosing guidelines can be provided for conversion to monotherapy with lamotrigine tablets with AEDs other than carbamazepine, phenobarbital, phenytoin, primidone, or valproate.

  2.4. Bipolar Disorder

  The goal of maintenance treatment with lamotrigine tablet is to delay the time to occurrence of mood episodes (depression, mania, hypomania, mixed episodes) in patients treated for acute mood episodes with standard therapy. The target dose of lamotrigine tablets is 200 mg/day (100 mg/day in patients taking valproate, which decreases the apparent clearance of lamotrigine, and 400 mg/day in patients not taking valproate and taking either carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin that increase the apparent clearance of lamotrigine). In the clinical trials, doses up to 400 mg/day as monotherapy were evaluated; however, no additional benefit was seen at 400 mg/day compared with 200 mg/day [see Clinical Studies (14.2)]. Accordingly, doses above 200 mg/day are not recommended. Treatment with lamotrigine tablets is introduced, based on concurrent medications, according to the regimen outlined in Table 5. If other psychotropic medications are withdrawn following stabilization, the dose of lamotrigine tablets should be adjusted. For patients discontinuing valproate, the dose of lamotrigine tablets should be doubled over a 2-week period in equal weekly increments (see Table 6). For patients discontinuing carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin that induce lamotrigine glucoronidation, the dose of lamotrigine tablets should remain constant for the first week and then should be decreased by half over a 2-week period in equal weekly decrements (see Table 6). The dose of lamotrigine tablets may then be further adjusted to the target dose (200 mg) as clinically indicated.

  If other drugs are subsequently introduced, the dose of lamotrigine tablet may need to be adjusted. In particular, the introduction of valproate requires reduction in the dose of lamotrigine tablet [see Drug Interactions (7), Clinical Pharmacology (12.3)].

  To avoid an increased risk of rash, the recommended initial dose and subsequent dose escalations of lamotrigine tablets should not be exceeded [see Boxed Warning].

  Table 5 Escalation Regimen for Lamotrigine Tablets for Patients with Bipolar Disorder

   
  For Patients TAKING Valproatea
  For Patients NOT TAKING Carbamazepine, Phenytoin, Phenobarbital, Primidoneb, or Valproatea
  For Patients TAKING Carbamazepine, Phenytoin, Phenobarbital, or Primidoneb and NOT TAKING Valproatea
  Weeks 1 and 2
  25 mg every other day
  25 mg daily
  50 mg daily
  Weeks 3 and 4
  25 mg daily
  50 mg daily
  100 mg daily, in divided doses
  Week 5
  50 mg daily
  100 mg daily
  200 mg daily, in divided doses
  Week 6
  100 mg daily
  200 mg daily
  300 mg daily, in divided doses
  Week 7
  100 mg daily
  200 mg daily
  up to 400 mg daily, in divided doses
  

  a Valproate has been shown to inhibit glucuronidation and decrease the apparent clearance of lamotrigine [see Drug Interactions (7), Clinical Pharmacology (12.3)].

  b These drugs induce lamotrigine glucuronidation and increase clearance [see Drug Interactions (7), Clinical Pharmacology (12.3)]. Other drugs which have similar effects include estrogen-containing oral contraceptives [see Drug Interactions (7), Clinical Pharmacology (12.3)]. Dosing recommendations for oral contraceptives can be found in General Dosing Considerations [see Dosage and Administration (2.1)]. Patients on rifampin, or other drugs that induce lamotrigine glucuronidation and increase clearance, should follow the same dosing titration/maintenance regimen as that used with anticonvulsants that have this effect.

  
  
  Table 6Dosage Adjustments to Lamotrigine Tablets for Patients with Bipolar Disorder Following Discontinuation of Psychotropic Medications

   
  Discontinuation of Psychotropic Drugs (excluding Carbamazepine, Phenytoin, Phenobarbital, Primidoneb, or Valproatea)
  After Discontinuation of Valproatea
  After Discontinuation of Carbamazepine, Phenytoin, Phenobarbital, or Primidoneb
  Current dose of Lamotrigine Tablets (mg/day) 100
  Current dose of Lamotrigine Tablets (mg/day) 400
  Week 1
  Maintain current dose of Lamotrigine Tablets
  150
  400
  Week 2
  Maintain current dose of Lamotrigine Tablets
  200
  300
  Week 3 onward
  Maintain current dose of Lamotrigine Tablets
  200
  200
  

  a Valproate has been shown to inhibit glucuronidation and decrease the apparent clearance of lamotrigine [see Drug Interactions (7), Clinical Pharmacology (12.3)].

  b These drugs induce lamotrigine glucuronidation and increase clearance [see Drug Interactions (7), Clinical Pharmacology (12.3)]. Other drugs which have similar effects include estrogen-containing oral contraceptives [see Drug Interactions (7), Clinical Pharmacology (12.3)]. Dosing recommendations for oral contraceptives can be found in General Dosing Considerations [see Dosage and Administration (2.1)]. Patients on rifampin, or other drugs that induce lamotrigine glucuronidation and increase clearance, should follow the same dosing titration/maintenance regimen as that used with anticonvulsants that have this effect.

  The benefit of continuing treatment in patients who had been stabilized in an 8- to 16-week open-label phase with lamotrigine tablets was established in 2 randomized, placebo-controlled clinical maintenance trials [see Clinical Studies (14.2)]. However, the optimal duration of treatment with lamotrigine tablets has not been established. Thus, patients should be periodically reassessed to determine the need for maintenance treatment.

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  2.1 General Dosing Considerations 

  Rash: There are suggestions, yet to be proven, that the risk of severe, potentially life-threatening rash may be increased by (1) coadministration of lamotrigine tablets with valproate, (2) exceeding the recommended initial dose of lamotrigine tablets, or (3) exceeding the recommended dose escalation for lamotrigine tablets. However, cases have occurred in the absence of these factors [see Boxed Warning]. Therefore, it is important that the dosing recommendations be followed closely.

  The risk of nonserious rash may be increased when the recommended initial dose and/or the rate of dose escalation of lamotrigine tablets is exceeded and in patients with a history of allergy or rash to other AEDs.

  It is recommended that lamotrigine tablets not be restarted in patients who discontinued due to rash associated with prior treatment with lamotrigine, unless the potential benefits clearly outweigh the risks. If the decision is made to restart a patient who has discontinued lamotrigine, the need to restart with the initial dosing recommendations should be assessed. The greater the interval of time since the previous dose, the greater consideration should be given to restarting with the initial dosing recommendations. If a patient has discontinued lamotrigine for a period of more than 5 half-lives, it is recommended that initial dosing recommendations and guidelines be followed. The half-life of lamotrigine is affected by other concomitant medications [see Clinical Pharmacology (12.3)].

  Lamotrigine Added to Drugs Known to Induce or Inhibit Glucuronidation: Drugs other than those listed in the Clinical Pharmacology section [see Clinical Pharmacology (12.3)] have not been systematically evaluated in combination with lamotrigine. Because lamotrigine is metabolized predominantly by glucuronic acid conjugation, drugs that are known to induce or inhibit glucuronidation may affect the apparent clearance of lamotrigine and doses of lamotrigine tablets may require adjustment based on clinical response.

  Target Plasma Levels for Patients With Epilepsy or Bipolar Disorder: A therapeutic plasma concentration range has not been established for lamotrigine. Dosing of lamotrigine tablets should be based on therapeutic response [see Clinical Pharmacology (12.3)].

  Women Taking Estrogen-Containing Oral Contraceptives:  Starting Lamotrigine Tablets in Women Taking Estrogen-Containing Oral Contraceptives: Although estrogen-containing oral contraceptives have been shown to increase the clearance of lamotrigine [see Clinical Pharmacology (12.3)], no adjustments to the recommended dose-escalation guidelines for lamotrigine tablets should be necessary solely based on the use of estrogen-containing oral contraceptives. Therefore, dose escalation should follow the recommended guidelines for initiating adjunctive therapy with lamotrigine tablets based on the concomitant AED or other concomitant medications (see Table 1 or Table 5). See below for adjustments to maintenance doses of lamotrigine tablets in women taking estrogen-containing oral contraceptives.

  Adjustments to the Maintenance Dose of Lamotrigine Tablets in Women Taking Estrogen-Containing Oral Contraceptives:

  (1) Taking Estrogen-Containing Oral Contraceptives: For women not taking carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin that induce lamotrigine glucuronidation [see Drug Interactions (7), Clinical Pharmacology (12.3)], the maintenance dose of lamotrigine tablets will in most cases need to be increased, by as much as 2 fold over the recommended target maintenance dose, in order to maintain a consistent lamotrigine plasma level [see Clinical Pharmacology (12.3)].

  (2) Starting Estrogen-Containing Oral Contraceptives: In women taking a stable dose of lamotrigine tablets and not taking carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin that induce lamotrigine glucuronidation [see Drug Interactions (7), Clinical Pharmacology (12.3)], the maintenance dose will in most cases need to be increased by as much as 2 fold in order to maintain a consistent lamotrigine plasma level. The dose increases should begin at the same time that the oral contraceptive is introduced and continue, based on clinical response, no more rapidly than 50 to 100 mg/day every week. Dose increases should not exceed the recommended rate (seeTable 1 orTable 5) unless lamotrigine plasma levels or clinical response support larger increases. Gradual transient increases in lamotrigine plasma levels may occur during the week of inactive hormonal preparation (“pill-free” week), and these increases will be greater if dose increases are made in the days before or during the week of inactive hormonal preparation. Increased lamotrigine plasma levels could result in additional adverse reactions, such as dizziness, ataxia, and diplopia. If adverse reactions attributable to lamotrigine tablets consistently occur during the “pill-free” week, dose adjustments to the overall maintenance dose may be necessary. Dose adjustments limited to the “pill-free” week are not recommended. For women taking lamotrigine tablets in addition to carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin that induce lamotrigine glucuronidation [see Drug Interactions (7), Clinical Pharmacology (12.3)], no adjustment to the dose of lamotrigine tablets should be necessary.

  (3) Stopping Estrogen-Containing Oral Contraceptives: For women not taking carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin that induce lamotrigine glucuronidation [see Drug Interactions (7), Clinical Pharmacology (12.3)], the maintenance dose of lamotrigine tablets will in most cases need to be decreased by as much as 50% in order to maintain a consistent lamotrigine plasma level. The decrease in dose of lamotrigine tablets should not exceed 25% of the total daily dose per week over a 2 week period, unless clinical response or lamotrigine plasma levels indicate otherwise [see Clinical Pharmacology (12.3)]. For women taking lamotrigine tablets in addition to carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin that induce lamotrigine glucuronidation [see Drug Interactions (7), Clinical Pharmacology (12.3)], no adjustment to the dose of lamotrigine tablets should be necessary.

  Women and Other Hormonal Contraceptive Preparations or Hormone Replacement Therapy: The effect of other hormonal contraceptive preparations or hormone replacement therapy on the pharmacokinetics of lamotrigine has not been systematically evaluated. It has been reported that ethinylestradiol, not progestogens, increased the clearance of lamotrigine up to 2 fold, and the progestin-only pills had no effect on lamotrigine plasma levels. Therefore, adjustments to the dosage of lamotrigine tablets in the presence of progestogens alone will likely not be needed.

  Patients With Hepatic Impairment: Experience in patients with hepatic impairment is limited. Based on a clinical pharmacology study in 24 patients with mild, moderate, and severe liver impairment [see Use in Specific Populations (8.6), Clinical Pharmacology (12.3)], the following general recommendations can be made. No dosage adjustment is needed in patients with mild liver impairment. Initial, escalation, and maintenance doses should generally be reduced by approximately 25% in patients with moderate and severe liver impairment without ascites and 50% in patients with severe liver impairment with ascites. Escalation and maintenance doses may be adjusted according to clinical response.

  Patients With Renal Impairment: Initial doses of lamotrigine tablets should be based on patients' concomitant medications (see Tables 1to3 or Table 5); reduced maintenance doses may be effective for patients with significant renal impairment [see Use in Specific Populations (8.7), Clinical Pharmacology (12.3)]. Few patients with severe renal impairment have been evaluated during chronic treatment with lamotrigine tablets. Because there is inadequate experience in this population, lamotrigine tablets should be used with caution in these patients.

  Discontinuation Strategy:  Epilepsy: For patients receiving lamotrigine tablets in combination with other AEDs, a reevaluation of all AEDs in the regimen should be considered if a change in seizure control or an appearance or worsening of adverse reactions is observed.

  If a decision is made to discontinue therapy with lamotrigine tablets, a step-wise reduction of dose over at least 2 weeks (approximately 50% per week) is recommended unless safety concerns require a more rapid withdrawal [see Warnings and Precautions (5.10)].

  Discontinuing carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin that induce lamotrigine glucuronidation should prolong the half-life of lamotrigine; discontinuing valproate should shorten the half-life of lamotrigine.

  Bipolar Disorder: In the controlled clinical trials, there was no increase in the incidence, type, or severity of adverse reactions following abrupt termination of lamotrigine tablets. In clinical trials in patients with Bipolar Disorder, 2 patients experienced seizures shortly after abrupt withdrawal of lamotrigine tablets. However, there were confounding factors that may have contributed to the occurrence of seizures in these bipolar patients. Discontinuation of lamotrigine tablets should involve a step-wise reduction of dose over at least 2 weeks (approximately 50% per week) unless safety concerns require a more rapid withdrawal [see Warnings and Precautions (5.10)].

  2.2 Epilepsy – Adjunctive Therapy

  This section provides specific dosing recommendations for patients greater than 12 years of age and patients 2 to 12 years of age. Within each of these age-groups, specific dosing recommendations are provided depending upon concomitant AED or other concomitant medications (Table 1 for patients greater than 12 years of age and Table 2 for patients 2 to 12 years of age). A weight-based dosing guide for patients 2 to 12 years of age on concomitant valproate is provided in Table 3.

  Patients Over 12 Years of Age: Recommended dosing guidelines are summarized in Table 1.

  Table 1. Escalation Regimen for Lamotrigine in Patients Over 12 Years of Age With Epilepsy  * Valproate has been shown to inhibit glucuronidation and decrease the apparent clearance of lamotrigine [ see Drug Interactions (7), Clinical Pharmacology (12.3)] . † These drugs induce lamotrigine glucuronidation and increase clearance [ see Drug Interactions (7) Clinical Pharmacology (12.3)]. Other drugs which have similar effects include estrogen-containing oral contraceptives [ see Drug Interactions (7), Clinical Pharmacology (12.3)] . Dosing recommendations for oral contraceptives can be found in General Dosing Considerations [ see Dosage and Administration (2.1)] . Patients on rifampin, or other drugs that induce lamotrigine glucuronidation and increase clearance, should follow the same dosing titration/maintenance regimen as that used with anticonvulsants that have this effect. For Patients TAKING Valproate* For Patients NOT TAKING Carbamazepine, Phenytoin, Phenobarbital, Primidone,† or Valproate* For Patients TAKING Carbamazepine, Phenytoin, Phenobarbital, or Primidone† and NOT TAKING Valproate* Weeks 1 and 2 25 mg every other day 25 mg every day 50 mg/day Weeks 3 and 4 25 mg every day 50 mg/day 100 mg/day (in 2 divided doses) Week 5 onwards to maintenance Increase by 25 to 50 mg/day every 1 to 2 weeks Increase by 50 mg/day every 1 to 2 weeks Increase by 100 mg/day every 1 to 2 weeks Usual Maintenance Dose

  100 to 200 mg/day with valproate alone

  100 to 400 mg/day with valproate and other drugs that induce glucuronidation

  (in 1 or 2 divided doses)

  225 to 375 mg/day (in 2 divided doses)

  300 to 500 mg/day

   (in 2 divided doses)

  Patients 2 to 12 Years of Age: Recommended dosing guidelines are summarized in Table 2.

  Smaller starting doses and slower dose escalations than those used in clinical trials are recommended because of the suggestion that the risk of rash may be decreased by smaller starting doses and slower dose escalations. Therefore, maintenance doses will take longer to reach in clinical practice than in clinical trials. It may take several weeks to months to achieve an individualized maintenance dose. Maintenance doses in patients weighing less than 30 kg, regardless of age or concomitant AED, may need to be increased as much as 50%, based on clinical response.

  Table 2. Escalation Regimen for Lamotrigine in Patients 2 to 12 Years of Age With Epilepsy * Valproate has been shown to inhibit glucuronidation and decrease the apparent clearance of lamotrigine [ see Drug Interactions (7), Clinical Pharmacology (12.3)] . † These drugs induce lamotrigine glucuronidation and increase clearance [ see Drug Interactions (7), Clinical Pharmacology (12.3)]. Other drugs which have similar effects include estrogen-containing oral contraceptives [ see Drug Interactions (7), Clinical Pharmacology (12.3)] . Dosing recommendations for oral contraceptives can be found in General Dosing Considerations  [ see Dosage and Administration (2.1)] . Patients on rifampin, or other drugs that induce lamotrigine glucuronidation and increase clearance, should follow the same dosing titration/maintenance regimen as that used with anticonvulsants that have this effect. For Patients TAKING Valproate* For Patients NOT TAKING Carbamazepine, Phenytoin, Phenobarbital, Primidone,† or Valproate* For Patients TAKING Carbamazepine, Phenytoin, Phenobarbital, or Primidone† and NOT TAKING Valproate* Weeks 1 and 2 0.15 mg/kg/day in 1 or 2 divided doses, rounded down to the nearest whole tablet (see Table 3 for weight based dosing guide) 0.3 mg/kg/day in 1 or 2 divided doses, rounded down to the nearest whole tablet 0.6 mg/kg/day in 2 divided doses, rounded down to the nearest whole tablet Weeks 3 and 4 0.3 mg/kg/day in 1 or 2 divided doses, rounded down to the nearest whole tablet (see Table 3 for weight based dosing guide) 0.6 mg/kg/day in 2 divided doses, rounded down to the nearest whole tablet 1.2 mg/kg/day in 2 divided doses, rounded down to the nearest whole tablet Week 5 onwards to maintenance The dose should be increased every 1 to 2 weeks as follows: calculate 0.3 mg/kg/day, round this amount down to the nearest whole tablet, and add this amount to the previously administered daily dose The dose should be increased every 1 to 2 weeks as follows: calculate 0.6 mg/kg/day, round this amount down to the nearest whole tablet, and add this amount to the previously administered daily dose The dose should be increased every 1 to 2 weeks as follows: calculate 1.2 mg/kg/day, round this amount down to the nearest whole tablet, and add this amount to the previously administered daily dose Usual Maintenance Dose 1 to 5 mg/kg/day (maximum 200 mg/day in 1 or 2 divided doses).
  1 to 3 mg/kg/day with valproate alone 4.5 to 7.5 mg/kg/day (maximum 300 mg/day in 2 divided doses) 5 to 15 mg/kg/day (maximum 400 mg/day in 2 divided doses) Maintenance dose in patients less than 30 kg May need to be increased by as much as 50%, based on clinical response May need to be increased by as much as 50%, based on clinical response May need to be increased by as much as 50%, based on clinical response

  Note: Only whole tablets should be used for dosing.

  Table 3. The Initial Weight-Based Dosing Guide for Patients 2 to 12 Years Taking Valproate (Weeks 1 to 4) With Epilepsy If the patient’s weight is Give this daily dose, using the most appropriate combination of lamotrigine tablets, 2 mg and 5 mg Greater than And less than Weeks 1 and 2 Weeks 3 and 4 6.7 kg 14 kg 2 mg every other day 2 mg every day 14.1 kg 27 kg 2 mg every day 4 mg every day 27.1 kg 34 kg 4 mg every day 8 mg every day 34.1 kg 40 kg 5 mg every day 10 mg every day

  Usual Adjunctive Maintenance Dose for Epilepsy: The usual maintenance doses identified in Tables 1 and 2 are derived from dosing regimens employed in the placebo-controlled adjunctive studies in which the efficacy of lamotrigine tablets was established. In patients receiving multidrug regimens employing carbamazepine, phenytoin, phenobarbital, or primidone without valproate, maintenance doses of adjunctive lamotrigine tablets as high as 700 mg/day have been used. In patients receiving valproate alone, maintenance doses of adjunctive lamotrigine tablets as high as 200 mg/day have been used. The advantage of using doses above those recommended in Tables 1 through 4 has not been established in controlled trials.

  2.3 Epilepsy – Conversion From Adjunctive Therapy to Monotherapy

  The goal of the transition regimen is to effect the conversion to monotherapy with lamotrigine tablets under conditions that ensure adequate seizure control while mitigating the risk of serious rash associated with the rapid titration of lamotrigine tablets.

  The recommended maintenance dose of lamotrigine tablets as monotherapy is 500 mg/day given in 2 divided doses.

  To avoid an increased risk of rash, the recommended initial dose and subsequent dose escalations of lamotrigine tablets should not be exceeded [see Boxed Warning].

  Conversion From Adjunctive Therapy With Carbamazepine, Phenytoin, Phenobarbital, or Primidone to Monotherapy With Lamotrigine Tablets: After achieving a dose of 500 mg/day of lamotrigine tablets according to the guidelines in Table 1, the concomitant AED should be withdrawn by 20% decrements each week over a 4 week period. The regimen for the withdrawal of the concomitant AED is based on experience gained in the controlled monotherapy clinical trial.

  Conversion From Adjunctive Therapy With Valproate to Monotherapy With Lamotrigine Tablets: The conversion regimen involves 4 steps outlined in Table 4.

  Table 4. Conversion From Adjunctive Therapy With Valproate to Monotherapy With Lamotrigine in Patients ≥ 16 Years of Age With Epilepsy   Lamotrigine Valproate Step 1 Achieve a dose of 200 mg/day according to guidelines in Table 1 (if not already on 200 mg/day). Maintain previous stable dose. Step 2 Maintain at 200 mg/day. Decrease to 500 mg/day by decrements no greater than 500 mg/day/week and then maintain the dose of 500 mg/day for 1 week. Step 3 Increase to 300 mg/day and maintain for 1 week. Simultaneously decrease to 250 mg/day and maintain for 1 week. Step 4 Increase by 100 mg/day every week to achieve maintenance dose of 500 mg/day. Discontinue.

  Conversion From Adjunctive Therapy With AEDs Other Than Carbamazepine, Phenytoin, Phenobarbital, Primidone, or Valproate to Monotherapy With Lamotrigine Tablets: No specific dosing guidelines can be provided for conversion to monotherapy with lamotrigine tablets with AEDs other than carbamazepine, phenobarbital, phenytoin, primidone, or valproate.

  2.4 Bipolar Disorder

  The goal of maintenance treatment with lamotrigine tablets is to delay the time to occurrence of mood episodes (depression, mania, hypomania, mixed episodes) in patients treated for acute mood episodes with standard therapy. The target dose of lamotrigine tablets is 200 mg/day (100 mg/day in patients taking valproate, which decreases the apparent clearance of lamotrigine, and 400 mg/day in patients not taking valproate and taking either carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin that increase the apparent clearance of lamotrigine). In the clinical trials, doses up to 400 mg/day as monotherapy were evaluated; however, no additional benefit was seen at 400 mg/day compared with 200 mg/day [see Clinical Studies (14.2)]. Accordingly, doses above 200 mg/day are not recommended. Treatment with lamotrigine tablets is introduced, based on concurrent medications, according to the regimen outlined in Table 5. If other psychotropic medications are withdrawn following stabilization, the dose of lamotrigine tablets should be adjusted. For patients discontinuing valproate, the dose of lamotrigine tablets should be doubled over a 2 week period in equal weekly increments (see Table 6). For patients discontinuing carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin that induce lamotrigine glucuronidation, the dose of lamotrigine tablets should remain constant for the first week and then should be decreased by half over a 2 week period in equal weekly decrements (see Table 6). The dose of lamotrigine tablets may then be further adjusted to the target dose (200 mg) as clinically indicated.

  If other drugs are subsequently introduced, the dose of lamotrigine tablets may need to be adjusted. In particular, the introduction of valproate requires reduction in the dose of lamotrigine tablets [see Drug Interactions (7), Clinical Pharmacology (12.3)].

  To avoid an increased risk of rash, the recommended initial dose and subsequent dose escalations of lamotrigine tablets should not be exceeded [see Boxed Warning].

   

  Table 5. Escalation Regimen for Lamotrigine for Patients With Bipolar Disorder * Valproate has been shown to inhibit glucuronidation and decrease the apparent clearance of lamotrigine [ see Drug Interactions (7), Clinical Pharmacology (12.3)]. † These drugs induce lamotrigine glucuronidation and increase clearance [ see Drug Interactions (7), Clinical Pharmacology (12.3)]. Other drugs which have similar effects include estrogen-containing oral contraceptives [ see Drug Interactions (7), Clinical Pharmacology (12.3)]. Dosing recommendations for oral contraceptives can be found in General Dosing Considerations [ see Dosage and Administration (2.1)]. Patients on rifampin, or other drugs that induce lamotrigine glucuronidation and increase clearance, should follow the same dosing titration/maintenance regimen as that used with anticonvulsants that have this effect. For Patients TAKING Valproate* For Patients NOT TAKING Carbamazepine, Phenytoin, Phenobarbital, Primidone,† or Valproate* For Patients TAKING Carbamazepine, Phenytoin, Phenobarbital, or Primidone† and NOT TAKING Valproate* Weeks 1 and 2 25 mg every other day 25 mg daily 50 mg daily Weeks 3 and 4 25 mg daily 50 mg daily 100 mg daily, in divided doses Week 5 50 mg daily 100 mg daily 200 mg daily, in divided doses Week 6 100 mg daily 200 mg daily 300 mg daily, in divided doses Week 7 100 mg daily 200 mg daily up to 400 mg daily, in divided doses Table 6. Dosage Adjustments to Lamotrigine for Patients With Bipolar Disorder Following Discontinuation of Psychotropic Medications * These drugs induce lamotrigine glucuronidation and increase clearance [ see Drug Interactions (7), Clinical Pharmacology (12.3)]. Other drugs which have similar effects include estrogen-containing oral contraceptives [ see Drug Interactions (7), Clinical Pharmacology (12.3)]. Dosing recommendations for oral contraceptives can be found in General Dosing Considerations [ see Dosage and Administration (2.1)]. Patients on rifampin, or other drugs that induce lamotrigine glucuronidation and increase clearance, should follow the same dosing titration/maintenance regimen as that used with anticonvulsants that have this effect. † Valproate has been shown to inhibit glucuronidation and decrease the apparent clearance of lamotrigine [ see Drug Interactions (7), Clinical Pharmacology (12.3)].   Discontinuation of Psychotropic Drugs (excluding Carbamazepine, Phenytoin, Phenobarbital, Primidone,* or Valproate†) After Discontinuation of Valproate† After Discontinuation of Carbamazepine, Phenytoin, Phenobarbital, or Primidone* Current dose of Lamotrigine (mg/day) 100

  Current dose of Lamotrigine (mg/day)

  400

  Week 1 Maintain current dose of lamotrigine 150 400 Week 2 Maintain current dose of lamotrigine 200 300 Week 3 onward Maintain current dose of lamotrigine 200 200

  The benefit of continuing treatment in patients who had been stabilized in an 8 to 16 week open-label phase with lamotrigine tablets was established in 2 randomized, placebo-controlled clinical maintenance trials [see Clinical Studies (14.2)]. However, the optimal duration of treatment with lamotrigine tablets has not been established. Thus, patients should be periodically reassessed to determine the need for maintenance treatment.

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  2.1 General Dosing Considerations

  Rash: There are suggestions, yet to be proven, that the risk of severe, potentially life-threatening rash may be increased by (1) coadministration of lamotrigine with valproate, (2) exceeding the recommended initial dose of lamotrigine, or (3) exceeding the recommended dose escalation for lamotrigine. However, cases have occurred in the absence of these factors [see Boxed Warning]. Therefore, it is important that the dosing recommendations be followed closely.

  The risk of nonserious rash may be increased when the recommended initial dose and/or the rate of dose escalation of lamotrigine is exceeded and in patients with a history of allergy or rash to other AEDs.

  Lamotrigine Starter Kits provide lamotrigine at doses consistent with the recommended titration schedule for the first 5 weeks of treatment, based upon concomitant medications for patients with epilepsy (>12 years of age) and Bipolar I Disorder (≥18 years of age) and are intended to help reduce the potential for rash. The use of lamotrigine Starter Kits is recommended for appropriate patients who are starting or restarting lamotrigine [see How Supplied/Storage and Handling (16)].

  It is recommended that lamotrigine not be restarted in patients who discontinued due to rash associated with prior treatment with lamotrigine, unless the potential benefits clearly outweigh the risks. If the decision is made to restart a patient who has discontinued lamotrigine, the need to restart with the initial dosing recommendations should be assessed. The greater the interval of time since the previous dose, the greater consideration should be given to restarting with the initial dosing recommendations. If a patient has discontinued lamotrigine for a period of more than 5 half-lives, it is recommended that initial dosing recommendations and guidelines be followed. The half-life of lamotrigine is affected by other concomitant medications [see Clinical Pharmacology (12.3)].

  Lamotrigine Added to Drugs Known to Induce or Inhibit Glucuronidation: Drugs other than those listed in the Clinical Pharmacology section [see Clinical Pharmacology (12.3)] have not been systematically evaluated in combination with lamotrigine. Because lamotrigine is metabolized predominantly by glucuronic acid conjugation, drugs that are known to induce or inhibit glucuronidation may affect the apparent clearance of lamotrigine and doses of lamotrigine may require adjustment based on clinical response.

  Target Plasma Levels for Patients With Epilepsy or Bipolar Disorder: A therapeutic plasma concentration range has not been established for lamotrigine. Dosing of lamotrigine should be based on therapeutic response [see Clinical Pharmacology (12.3)].

  Women Taking Estrogen-Containing Oral Contraceptives: Starting Lamotrigine in Women Taking Estrogen-Containing Oral Contraceptives: Although estrogen-containing oral contraceptives have been shown to increase the clearance of lamotrigine [see Clinical Pharmacology (12.3)], no adjustments to the recommended dose-escalation guidelines for lamotrigine should be necessary solely based on the use of estrogen-containing oral contraceptives. Therefore, dose escalation should follow the recommended guidelines for initiating adjunctive therapy with lamotrigine based on the concomitant AED or other concomitant medications (see Table 1 or Table 5). See below for adjustments to maintenance doses of lamotrigine in women taking estrogen-containing oral contraceptives.

  Adjustments to the Maintenance Dose of Lamotrigine In Women Taking Estrogen-Containing Oral Contraceptives:

  (1) Taking Estrogen-Containing Oral Contraceptives: For women not taking carbamazepine, phenytoin, phenobarbital, primidone, or rifampin, the maintenance dose of lamotrigine will in most cases need to be increased, by as much as 2-fold over the recommended target maintenance dose, in order to maintain a consistent lamotrigine plasma level [see Clinical Pharmacology (12.3)].

  (2) Starting Estrogen-Containing Oral Contraceptives: In women taking a stable dose of lamotrigine and not taking carbamazepine, phenytoin, phenobarbital, primidone, or rifampin, the maintenance dose will in most cases need to be increased by as much as 2-fold in order to maintain a consistent lamotrigine plasma level. The dose increases should begin at the same time that the oral contraceptive is introduced and continue, based on clinical response, no more rapidly than 50 to 100 mg/day every week. Dose increases should not exceed the recommended rate (see Table 1 or Table 5) unless lamotrigine plasma levels or clinical response support larger increases. Gradual transient increases in lamotrigine plasma levels may occur during the week of inactive hormonal preparation ("pill-free" week), and these increases will be greater if dose increases are made in the days before or during the week of inactive hormonal preparation. Increased lamotrigine plasma levels could result in additional adverse reactions, such as dizziness, ataxia, and diplopia. If adverse reactions attributable to lamotrigine consistently occur during the "pill-free" week, dose adjustments to the overall maintenance dose may be necessary. Dose adjustments limited to the "pill-free" week are not recommended. For women taking lamotrigine in addition to carbamazepine, phenytoin, phenobarbital, primidone, or rifampin, no adjustment should be necessary to the dose of lamotrigine.

  (3) Stopping Estrogen-Containing Oral Contraceptives: For women not taking carbamazepine, phenytoin, phenobarbital, primidone, or rifampin, the maintenance dose of lamotrigine will in most cases need to be decreased by as much as 50% in order to maintain a consistent lamotrigine plasma level. The decrease in dose of lamotrigine should not exceed 25% of the total daily dose per week over a 2-week period, unless clinical response or lamotrigine plasma levels indicate otherwise [see Clinical Pharmacology (12.3)]. For women taking lamotrigine in addition to carbamazepine, phenytoin, phenobarbital, primidone, or rifampin, no adjustment to the dose of lamotrigine should be necessary.

  Women and Other Hormonal Contraceptive Preparations or Hormone Replacement Therapy: The effect of other hormonal contraceptive preparations or hormone replacement therapy on the pharmacokinetics of lamotrigine has not been systematically evaluated. It has been reported that ethinylestradiol, not progestogens, increased the clearance of lamotrigine up to 2-fold, and the progestin-only pills had no effect on lamotrigine plasma levels. Therefore, adjustments to the dosage of lamotrigine in the presence of progestogens alone will likely not be needed.

  Patients With Hepatic Impairment: Experience in patients with hepatic impairment is limited. Based on a clinical pharmacology study in 24 patients with mild, moderate, and severe liver impairment [see Use in Specific Populations (8.6), Clinical Pharmacology (12.3)], the following general recommendations can be made. No dosage adjustment is needed in patients with mild liver impairment. Initial, escalation, and maintenance doses should generally be reduced by approximately 25% in patients with moderate and severe liver impairment without ascites and 50% in patients with severe liver impairment with ascites. Escalation and maintenance doses may be adjusted according to clinical response.

  Patients With Renal Impairment: Initial doses of lamotrigine should be based on patients' concomitant medications (see Tables 1-3 or Table 5); reduced maintenance doses may be effective for patients with significant renal impairment [see Use in Specific Populations (8.7), Clinical Pharmacology (12.3)]. Few patients with severe renal impairment have been evaluated during chronic treatment with lamotrigine. Because there is inadequate experience in this population, lamotrigine should be used with caution in these patients.

  Discontinuation Strategy: Epilepsy: For patients receiving lamotrigine in combination with other AEDs, a re-evaluation of all AEDs in the regimen should be considered if a change in seizure control or an appearance or worsening of adverse reactions is observed.

  If a decision is made to discontinue therapy with lamotrigine, a step-wise reduction of dose over at least 2 weeks (approximately 50% per week) is recommended unless safety concerns require a more rapid withdrawal [see Warnings and Precautions (5.9)].

  Discontinuing carbamazepine, phenytoin, phenobarbital, or primidone should prolong the half-life of lamotrigine; discontinuing valproate should shorten the half-life of lamotrigine.

  Bipolar Disorder: In the controlled clinical trials, there was no increase in the incidence, type, or severity of adverse reactions following abrupt termination of lamotrigine. In clinical trials in patients with Bipolar Disorder, 2 patients experienced seizures shortly after abrupt withdrawal of lamotrigine. However, there were confounding factors that may have contributed to the occurrence of seizures in these bipolar patients. Discontinuation of lamotrigine should involve a step-wise reduction of dose over at least 2 weeks (approximately 50% per week) unless safety concerns require a more rapid withdrawal [see Warnings and Precautions (5.9)].

  2.2 Epilepsy – Adjunctive Therapy

  This section provides specific dosing recommendations for patients greater than 12 years of age and patients 2 to 12 years of age. Within each of these age-groups, specific dosing recommendations are provided depending upon concomitant AED or other concomitant medications (Table 1 for patients greater than 12 years of age and Table 2 for patients 2 to 12 years of age). A weight-based dosing guide for patients 2 to 12 years of age on concomitant valproate is provided in Table 3.

  Patients Over 12 Years of Age: Recommended dosing guidelines are summarized in Table 1.

  Table 1. Escalation Regimen for Lamotrigine in Patients Over 12 Years of Age With Epilepsy *  These drugs induce glucuronidation and increase clearance  [see Drug Interactions (7) Pharmacokinetics (12.3)]. Other drugs, which have similar effects include estrogen-containing oral contraceptives and rifampin [see Drug Interactions (7), Pharmacokinetics (12.3)]. Dosing recommendations for oral contraceptives can be found in General Dosing Considerations [see Dosage and Administration (2.1)]. Patients on rifampin should follow the same dosing titration/maintenance regimen used with drugs that induce glucuronidation and increase clearance.
  For Patients Taking
   Valproate 
  For Patients Taking AEDs Other Than 
  Carbamazepine, Phenytoin, Phenobarbital, or 
  Primidone*, and Not Taking Valproate
  For Patients Taking Carbamazepine, 
  Phenytoin, Phenobarbital, or 
  Primidone* and Not Taking Valproate
  Weeks 1 and 2 
  25 mg every other day
  25 mg every day
  50 mg/day
  Weeks 3 and 4 
  25 mg every day
  50 mg/day
  100 mg/day 
  (in 2 divided doses)
  Weeks 5 onwards
  to maintenance  
  Increase by 25 to 
  50 mg/day every 1 to 
  2 weeks
  Increase by 50 mg/day
   every 1 to 2 weeks
  Increase by 
  100 mg/day every 1 to
   2 weeks.
  Usual Maintenance
  Dose 
  100 to 200 mg/day with
  valproate alone 
  
  100 to 400 mg/day with
  valproate and other
  drugs that induce
  glucuronication 
  
  (in 1 or 2 divided doses)
  225 to 375 mg/day 
  (in 2 divided doses)
  300 to 500 mg/day 
  (in 2 divided doses)
  

  Patients 2 to 12 Years of Age: Recommended dosing guidelines are summarized in Table 2.

  Smaller starting doses and slower dose escalations than those used in clinical trials are recommended because of the suggestion that the risk of rash may be decreased by smaller starting doses and slower dose escalations. Therefore, maintenance doses will take longer to reach in clinical practice than in clinical trials. It may take several weeks to months to achieve an individualized maintenance dose. Maintenance doses in patients weighing less than 30 kg, regardless of age or concomitant AED, may need to be increased as much as 50%, based on clinical response.

  The smallest available strength of lamotrigine tablets is 25 mg, and only whole tablets should be administered. If the calculated dose cannot be achieved using whole tablets, the dose should be rounded down to the nearest whole tablet [see How Supplied/Storage and Handling (16) and Medication Guide].

  Table 2. Escalation Regimen for Lamotrigine in Patients 2 to 12 Years of Age With Epilepsy

  Note: Only whole tablets should be used for dosing.

  *  These drugs induce glucuronidation and increase clearance  [see Drug Interactions (7) Pharmacokinetics (12.3)]. Other drugs, which have similar effects include estrogen-containing oral contraceptives and rifampin [see Drug Interactions (7), Pharmacokinetics (12.3)]. Dosing recommendations for oral contraceptives can be found in General Dosing Considerations [see Dosage and Administration (2.1)]. Patients on rifampin should follow the same dosing titration/maintenance regimen used with drugs that induce glucuronidation.
  For Patients Taking
   Valproate 
  For Patients Taking 
  AEDs Other Than 
  Carbamazepine, 
  Phenytoin, 
  Phenobarbital, or 
  Primidone*, and Not 
  Taking Valproate
  For Patients Taking 
  Carbamazepine, 
  Phenytoin, 
  Phenobarbital, or 
  Primidone* and Not 
  Taking Valproate
  Weeks 1 and 2 
  0.15 mg/kg/day 
  in 1 or 2 divided doses,
   rounded down to the 
  nearest whole tablet 
  (see Table 3 for weight
   based dosing guide)
  0.3 mg/kg/day 
  in 1 or 2 divided doses, 
  rounded down to the 
  nearest whole tablet
  0.6 mg/kg/day 
  in 2 divided doses, 
  rounded down to the 
  nearest whole tablet
  Weeks 3 and 4 
  0.3 mg/kg/day 
  in 1 or 2 divided doses,
   rounded down to the 
  nearest whole tablet 
  (see Table 3 for weight
   based dosing guide)
  0.6 mg/kg/day 
  in 2 divided doses, 
  rounded down to the 
  nearest whole tablet
  1.2 mg/kg/day 
  in 2 divided doses, 
  rounded down to the 
  nearest whole tablet
  Weeks 5 onwards to 
  maintenance
  The dose should be 
  increased every 1 to 
  2 weeks as follows: 
  calculate 
  0.3 mg/kg/day, round 
  this amount down to 
  the nearest whole 
  tablet, and add this 
  amount to the 
  previously administered
  daily dose
  The dose should be 
  increased every 1 to 
  2 weeks as follows: 
  calculate 
  0.6 mg/kg/day, round this
   amount down to the 
  nearest whole tablet, and 
  add this amount to the 
  previously administered 
  daily dose
  The dose should be 
  increased every 1 to 
  2 weeks as follows: 
  calculate 
  1.2 mg/kg/day, round 
  this amount down to the 
  nearest whole tablet, and
   add this amount to the 
  previously administered 
  daily dose
  Usual Maintenance 
  Dose 
  1 to 5 mg/kg/day (maximum 
  200 mg/day in 1 or 2 
  divided doses). 
  1 to 3 mg/kg/day with 
  valproate alone
  4.5 to 7.5 mg/kg/day 
  (maximum 300 mg/day 
  in 2 divided doses)
  5 to 15 mg/kg/day 
  (maximum 400 mg/day 
  in 2 divided doses)
  Maintenance dose in 
  patients less than 30 kg 
  May need to be 
  increased by as much 
  as 50%, based on 
  clinical response
  May need to be increased
   by as much as 50%, 
  based on clinical 
  response
  May need to be 
  increased by as much as
   50%, based on clinical 
  response
  Table 3. The Initial Weight-Based Dosing Guide for Patients 2 to 12 Years Taking Valproate (Weeks 1 to 4) With Epilepsy If the patient’s weight is
  Give this daily dose, using the most appropriate combination of lamotrigine
  2-mg and 5-mg tablets 
  Greater than 
  And less than 
  Weeks 1 and 2
  Weeks 3 and 4
  6.7 kg 
  14 kg 
  2 mg every other day
  2 mg every day
  14.1 kg 
  27 kg 
  2 mg every day
  4 mg every day
  27.1 kg 
  34 kg 
  4 mg every day
  8 mg every day
  34.1 kg 
  40 kg 
  5 mg every day
  10 mg every day
  

  Usual Adjunctive Maintenance Dose for Epilepsy: The usual maintenance doses identified in Tables 1 and 2 are derived from dosing regimens employed in the placebo-controlled adjunctive studies in which the efficacy of lamotrigine was established. In patients receiving multidrug regimens employing carbamazepine, phenytoin, phenobarbital, or primidone without valproate, maintenance doses of adjunctive lamotrigine as high as 700 mg/day have been used. In patients receiving valproate alone, maintenance doses of adjunctive lamotrigine as high as 200 mg/day have been used. The advantage of using doses above those recommended in Tables 1 through 4 has not been established in controlled trials.

  2.3 Epilepsy – Conversion From Adjunctive Therapy to Monotherapy

  The goal of the transition regimen is to effect the conversion to monotherapy with lamotrigine under conditions that ensure adequate seizure control while mitigating the risk of serious rash associated with the rapid titration of lamotrigine.

  The recommended maintenance dose of lamotrigine as monotherapy is 500 mg/day given in 2 divided doses.

  To avoid an increased risk of rash, the recommended initial dose and subsequent dose escalations of lamotrigine should not be exceeded [see Boxed Warning].

  Conversion From Adjunctive Therapy With Carbamazepine, Phenytoin, Phenobarbital, or Primidone to Monotherapy With Lamotrigine: After achieving a dose of 500 mg/day of lamotrigine according to the guidelines in Table 1, the concomitant AED should be withdrawn by 20% decrements each week over a 4-week period. The regimen for the withdrawal of the concomitant AED is based on experience gained in the controlled monotherapy clinical trial.

  Conversion from Adjunctive Therapy With Valproate to Monotherapy With Lamotrigine: The conversion regimen involves 4 steps outlined in Table 4.

  Table 4. Conversion From Adjunctive Therapy With Valproate to Monotherapy With Lamotrigine in Patients ≥16 Years of Age with Epilepsy
  Lamotrigine
  Valproate
  Step 1 
  Achieve a dose of 200 mg/day according to 
  guidelines in Table 1 (if not already on 
  200 mg/day).
  Maintain previous stable dose.
  Step 2 
  Maintain at 200 mg/day.
  Decrease to 500 mg/day by 
  decrements no greater than 
  500 mg/day/week and then 
  maintain the dose of 
  500 mg/day for 1 week.
  Step 3 
  Increase to 300 mg/day and maintain for 1 
  week.
  Simultaneously decrease to 
  250 mg/day and maintain for 1 week.
  Step 4 
  Increase by 100 mg/day every week to achieve 
  maintenance dose of 500 mg/day.
  Discontinue.
  

  Conversion from Adjunctive Therapy With AEDs Other Than Carbamazepine, Phenytoin, Phenobarbital, Primidone, or Valproate to Monotherapy With Lamotrigine: No specific dosing guidelines can be provided for conversion to monotherapy with lamotrigine with AEDs other than carbamazepine, phenobarbital, phenytoin, primidone, or valproate.

  2.4 Bipolar Disorder

  The goal of maintenance treatment with lamotrigine is to delay the time to occurrence of mood episodes (depression, mania, hypomania, mixed episodes) in patients treated for acute mood episodes with standard therapy. The target dose of lamotrigine is 200 mg/day (100 mg/day in patients taking valproate, which decreases the apparent clearance of lamotrigine, and 400 mg/day in patients not taking valproate and taking either carbamazepine, phenytoin, phenobarbital, primidone, or rifampin, which increase the apparent clearance of lamotrigine). In the clinical trials, doses up to 400 mg/day as monotherapy were evaluated; however, no additional benefit was seen at 400 mg/day compared with 200 mg/day [see Clinical Studies (14.2)]. Accordingly, doses above 200 mg/day are not recommended. Treatment with lamotrigine is introduced, based on concurrent medications, according to the regimen outlined in Table 5. If other psychotropic medications are withdrawn following stabilization, the dose of lamotrigine should be adjusted. For patients discontinuing valproate, the dose of lamotrigine should be doubled over a 2-week period in equal weekly increments (see Table 6). For patients discontinuing carbamazepine, phenytoin, phenobarbital, primidone, or rifampin, the dose of lamotrigine should remain constant for the first week and then should be decreased by half over a 2-week period in equal weekly decrements (see Table 6). The dose of lamotrigine may then be further adjusted to the target dose (200 mg) as clinically indicated.

  If other drugs are subsequently introduced, the dose of lamotrigine may need to be adjusted. In particular, the introduction of valproate requires reduction in the dose of lamotrigine [see Drug Interactions (7), Clinical Pharmacology (12.3)].

  To avoid an increased risk of rash, the recommended initial dose and subsequent dose escalations of lamotrigine should not be exceeded [see Boxed Warning].

  Table 5. Escalation Regimen for Lamotrigine for Patients With Bipolar Disorder*

  * See Drug Interactions (7) and Clinical Pharmacology (12.3) for a description of known drug interactions.

  † Carbamazepine, phenytoin, phenobarbital, primidone, and rifampin have been shown to increase the apparent clearance of lamotrigine.

  ‡ Valproate has been shown to decrease the apparent clearance of lamotrigine.

  
  For Patients Taking
  Valproate‡
  For Patients Not Taking Carbamazepine, 
  Phenytoin, Phenobarbital, Primidone, or 
  Rifampin†  and Not Taking Valproate‡
  For Patients Taking Carbamazepine, Phenytoin, 
  Phenobarbital, Primidone, or Rifampin† and Not 
  Taking Valproate‡
  Weeks 1 and 2 
  25 mg every other day
  25 mg daily
  50 mg daily
  Weeks 3 and 4 
  25 mg daily
  50 mg daily
  100 mg daily, in divided doses
  Week 5 
  50 mg daily
  100 mg daily
  200 mg daily, in divided doses
  Week 6 
  100 mg daily
  200 mg daily
  300 mg daily, in divided doses
  Week 7 
  100 mg daily
  200 mg daily
  up to 400 mg daily, in
  divided doses
  Table 6. Dosage Adjustments to Lamotrigine for Patients With Bipolar Disorder Following Discontinuation of Psychotropic Medications * Carbamazepine, phenytoin, phenobarbital, primidone, and rifampin have been shown to increase the apparent clearance of lamotrigine. † Valproate has been shown to decrease the apparent clearance of lamotrigine.
  Discontinuation of Psychotropic Drugs 
  (excluding Carbamazepine,
  After Discontinuation of Valproate†
  After Discontinuation of Carbamazepine,
  Phenytoin, Phenobarbital, Primidone,
  or Rifampin*
  
  Phenytoin, Phenobarbital, Primidone, 
  Rifampin*, or Valproate†)
  Current dose of Lamotrigine
  (mg/day) 
  100
  Current dose of Lamotrigine 
  (mg/day) 
  400
  Week 1 
  Maintain current dose of Lamotrigine
  150
  400
  Week 2 
  Maintain current dose of Lamotrigine
  200
  300
  Week 3 onward 
  Maintain current dose of Lamotrigine
  200
  200
  

  The benefit of continuing treatment in patients who had been stabilized in an 8- to 16-week open-label phase with lamotrigine was established in 2 randomized, placebo-controlled clinical maintenance trials [see Clinical Studies (14.2)]. However, the optimal duration of treatment with lamotrigine has not been established. Thus, patients should be periodically reassessed to determine the need for maintenance treatment.

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  2.1 General Dosing Considerations

  Rash: There are suggestions, yet to be proven, that the risk of severe, potentially life-threatening rash may be increased by (1) coadministration of lamotrigine with valproate, (2) exceeding the recommended initial dose of lamotrigine, or (3) exceeding the recommended dose escalation for lamotrigine. However, cases have occurred in the absence of these factors [see Boxed Warning]. Therefore, it is important that the dosing recommendations be followed closely.

  The risk of nonserious rash may be increased when the recommended initial dose and/or the rate of dose escalation of lamotrigine is exceeded and in patients with a history of allergy or rash to other AEDs.

  Lamotrigine Starter Kits provide lamotrigine at doses consistent with the recommended titration schedule for the first 5 weeks of treatment, based upon concomitant medications for patients with epilepsy (>12 years of age) and Bipolar I Disorder (≥18 years of age) and are intended to help reduce the potential for rash. The use of lamotrigine Starter Kits is recommended for appropriate patients who are starting or restarting lamotrigine [see How Supplied/Storage and Handling (16)].

  It is recommended that lamotrigine not be restarted in patients who discontinued due to rash associated with prior treatment with lamotrigine, unless the potential benefits clearly outweigh the risks. If the decision is made to restart a patient who has discontinued lamotrigine, the need to restart with the initial dosing recommendations should be assessed. The greater the interval of time since the previous dose, the greater consideration should be given to restarting with the initial dosing recommendations. If a patient has discontinued lamotrigine for a period of more than 5 half-lives, it is recommended that initial dosing recommendations and guidelines be followed. The half-life of lamotrigine is affected by other concomitant medications [see Clinical Pharmacology (12.3)].

  Lamotrigine Added to Drugs Known to Induce or Inhibit Glucuronidation: Drugs other than those listed in the Clinical Pharmacology section [see Clinical Pharmacology (12.3)] have not been systematically evaluated in combination with lamotrigine. Because lamotrigine is metabolized predominantly by glucuronic acid conjugation, drugs that are known to induce or inhibit glucuronidation may affect the apparent clearance of lamotrigine and doses of lamotrigine may require adjustment based on clinical response.

  Target Plasma Levels for Patients With Epilepsy or Bipolar Disorder: A therapeutic plasma concentration range has not been established for lamotrigine. Dosing of lamotrigine should be based on therapeutic response [see Clinical Pharmacology (12.3)].

  Women Taking Estrogen-Containing Oral Contraceptives: Starting Lamotrigine in Women Taking Estrogen-Containing Oral Contraceptives: Although estrogen-containing oral contraceptives have been shown to increase the clearance of lamotrigine [see Clinical Pharmacology (12.3)], no adjustments to the recommended dose-escalation guidelines for lamotrigine should be necessary solely based on the use of estrogen-containing oral contraceptives. Therefore, dose escalation should follow the recommended guidelines for initiating adjunctive therapy with lamotrigine based on the concomitant AED or other concomitant medications (see Table 1 or Table 5). See below for adjustments to maintenance doses of lamotrigine in women taking estrogen-containing oral contraceptives.

  Adjustments to the Maintenance Dose of Lamotrigine In Women Taking Estrogen-Containing Oral Contraceptives:

  (1) Taking Estrogen-Containing Oral Contraceptives: For women not taking carbamazepine, phenytoin, phenobarbital, primidone, or rifampin, the maintenance dose of lamotrigine will in most cases need to be increased, by as much as 2-fold over the recommended target maintenance dose, in order to maintain a consistent lamotrigine plasma level [see Clinical Pharmacology (12.3)].

  (2) Starting Estrogen-Containing Oral Contraceptives: In women taking a stable dose of lamotrigine and not taking carbamazepine, phenytoin, phenobarbital, primidone, or rifampin, the maintenance dose will in most cases need to be increased by as much as 2-fold in order to maintain a consistent lamotrigine plasma level. The dose increases should begin at the same time that the oral contraceptive is introduced and continue, based on clinical response, no more rapidly than 50 to 100 mg/day every week. Dose increases should not exceed the recommended rate (see Table 1 or Table 5) unless lamotrigine plasma levels or clinical response support larger increases. Gradual transient increases in lamotrigine plasma levels may occur during the week of inactive hormonal preparation ("pill-free" week), and these increases will be greater if dose increases are made in the days before or during the week of inactive hormonal preparation. Increased lamotrigine plasma levels could result in additional adverse reactions, such as dizziness, ataxia, and diplopia. If adverse reactions attributable to lamotrigine consistently occur during the "pill-free" week, dose adjustments to the overall maintenance dose may be necessary. Dose adjustments limited to the "pill-free" week are not recommended. For women taking lamotrigine in addition to carbamazepine, phenytoin, phenobarbital, primidone, or rifampin, no adjustment should be necessary to the dose of lamotrigine.

  (3) Stopping Estrogen-Containing Oral Contraceptives: For women not taking carbamazepine, phenytoin, phenobarbital, primidone, or rifampin, the maintenance dose of lamotrigine will in most cases need to be decreased by as much as 50% in order to maintain a consistent lamotrigine plasma level. The decrease in dose of lamotrigine should not exceed 25% of the total daily dose per week over a 2-week period, unless clinical response or lamotrigine plasma levels indicate otherwise [see Clinical Pharmacology (12.3)]. For women taking lamotrigine in addition to carbamazepine, phenytoin, phenobarbital, primidone, or rifampin, no adjustment to the dose of lamotrigine should be necessary.

  Women and Other Hormonal Contraceptive Preparations or Hormone Replacement Therapy: The effect of other hormonal contraceptive preparations or hormone replacement therapy on the pharmacokinetics of lamotrigine has not been systematically evaluated. It has been reported that ethinylestradiol, not progestogens, increased the clearance of lamotrigine up to 2-fold, and the progestin-only pills had no effect on lamotrigine plasma levels. Therefore, adjustments to the dosage of lamotrigine in the presence of progestogens alone will likely not be needed.

  Patients With Hepatic Impairment: Experience in patients with hepatic impairment is limited. Based on a clinical pharmacology study in 24 patients with mild, moderate, and severe liver impairment [see Use in Specific Populations (8.6), Clinical Pharmacology (12.3)], the following general recommendations can be made. No dosage adjustment is needed in patients with mild liver impairment. Initial, escalation, and maintenance doses should generally be reduced by approximately 25% in patients with moderate and severe liver impairment without ascites and 50% in patients with severe liver impairment with ascites. Escalation and maintenance doses may be adjusted according to clinical response.

  Patients With Renal Impairment: Initial doses of lamotrigine should be based on patients' concomitant medications (see Tables 1-3 or Table 5); reduced maintenance doses may be effective for patients with significant renal impairment [see Use in Specific Populations (8.7), Clinical Pharmacology (12.3)]. Few patients with severe renal impairment have been evaluated during chronic treatment with lamotrigine. Because there is inadequate experience in this population, lamotrigine should be used with caution in these patients.

  Discontinuation Strategy: Epilepsy: For patients receiving lamotrigine in combination with other AEDs, a re-evaluation of all AEDs in the regimen should be considered if a change in seizure control or an appearance or worsening of adverse reactions is observed.

  If a decision is made to discontinue therapy with lamotrigine, a step-wise reduction of dose over at least 2 weeks (approximately 50% per week) is recommended unless safety concerns require a more rapid withdrawal [see Warnings and Precautions (5.9)].

  Discontinuing carbamazepine, phenytoin, phenobarbital, or primidone should prolong the half-life of lamotrigine; discontinuing valproate should shorten the half-life of lamotrigine.

  Bipolar Disorder: In the controlled clinical trials, there was no increase in the incidence, type, or severity of adverse reactions following abrupt termination of lamotrigine. In clinical trials in patients with Bipolar Disorder, 2 patients experienced seizures shortly after abrupt withdrawal of lamotrigine. However, there were confounding factors that may have contributed to the occurrence of seizures in these bipolar patients. Discontinuation of lamotrigine should involve a step-wise reduction of dose over at least 2 weeks (approximately 50% per week) unless safety concerns require a more rapid withdrawal [see Warnings and Precautions (5.9)].

  2.2 Epilepsy – Adjunctive Therapy

  This section provides specific dosing recommendations for patients greater than 12 years of age and patients 2 to 12 years of age. Within each of these age-groups, specific dosing recommendations are provided depending upon concomitant AED or other concomitant medications (Table 1 for patients greater than 12 years of age and Table 2 for patients 2 to 12 years of age). A weight-based dosing guide for patients 2 to 12 years of age on concomitant valproate is provided in Table 3.

  Patients Over 12 Years of Age: Recommended dosing guidelines are summarized in Table 1.

  Table 1. Escalation Regimen for Lamotrigine in Patients Over 12 Years of Age With Epilepsy *  These drugs induce glucuronidation and increase clearance  [see Drug Interactions (7) Pharmacokinetics (12.3)]. Other drugs, which have similar effects include estrogen-containing oral contraceptives and rifampin [see Drug Interactions (7), Pharmacokinetics (12.3)]. Dosing recommendations for oral contraceptives can be found in General Dosing Considerations [see Dosage and Administration (2.1)]. Patients on rifampin should follow the same dosing titration/maintenance regimen used with drugs that induce glucuronidation and increase clearance.
  For Patients Taking
   Valproate 
  For Patients Taking AEDs Other Than 
  Carbamazepine, Phenytoin, Phenobarbital, or 
  Primidone*, and Not Taking Valproate
  For Patients Taking Carbamazepine, 
  Phenytoin, Phenobarbital, or 
  Primidone* and Not Taking Valproate
  Weeks 1 and 2 
  25 mg every other day
  25 mg every day
  50 mg/day
  Weeks 3 and 4 
  25 mg every day
  50 mg/day
  100 mg/day 
  (in 2 divided doses)
  Weeks 5 onwards
  to maintenance  
  Increase by 25 to 
  50 mg/day every 1 to 
  2 weeks
  Increase by 50 mg/day
   every 1 to 2 weeks
  Increase by 
  100 mg/day every 1 to
   2 weeks.
  Usual Maintenance
  Dose 
  100 to 200 mg/day with
  valproate alone 
  
  100 to 400 mg/day with
  valproate and other
  drugs that induce
  glucuronication 
  
  (in 1 or 2 divided doses)
  225 to 375 mg/day 
  (in 2 divided doses)
  300 to 500 mg/day 
  (in 2 divided doses)
  

  Patients 2 to 12 Years of Age: Recommended dosing guidelines are summarized in Table 2.

  Smaller starting doses and slower dose escalations than those used in clinical trials are recommended because of the suggestion that the risk of rash may be decreased by smaller starting doses and slower dose escalations. Therefore, maintenance doses will take longer to reach in clinical practice than in clinical trials. It may take several weeks to months to achieve an individualized maintenance dose. Maintenance doses in patients weighing less than 30 kg, regardless of age or concomitant AED, may need to be increased as much as 50%, based on clinical response.

  The smallest available strength of lamotrigine tablets is 25 mg, and only whole tablets should be administered. If the calculated dose cannot be achieved using whole tablets, the dose should be rounded down to the nearest whole tablet [see How Supplied/Storage and Handling (16) and Medication Guide].

  Table 2. Escalation Regimen for Lamotrigine in Patients 2 to 12 Years of Age With Epilepsy

  Note: Only whole tablets should be used for dosing.

  *  These drugs induce glucuronidation and increase clearance  [see Drug Interactions (7) Pharmacokinetics (12.3)]. Other drugs, which have similar effects include estrogen-containing oral contraceptives and rifampin [see Drug Interactions (7), Pharmacokinetics (12.3)]. Dosing recommendations for oral contraceptives can be found in General Dosing Considerations [see Dosage and Administration (2.1)]. Patients on rifampin should follow the same dosing titration/maintenance regimen used with drugs that induce glucuronidation.
  For Patients Taking
   Valproate 
  For Patients Taking 
  AEDs Other Than 
  Carbamazepine, 
  Phenytoin, 
  Phenobarbital, or 
  Primidone*, and Not 
  Taking Valproate
  For Patients Taking 
  Carbamazepine, 
  Phenytoin, 
  Phenobarbital, or 
  Primidone* and Not 
  Taking Valproate
  Weeks 1 and 2 
  0.15 mg/kg/day 
  in 1 or 2 divided doses,
   rounded down to the 
  nearest whole tablet 
  (see Table 3 for weight
   based dosing guide)
  0.3 mg/kg/day 
  in 1 or 2 divided doses, 
  rounded down to the 
  nearest whole tablet
  0.6 mg/kg/day 
  in 2 divided doses, 
  rounded down to the 
  nearest whole tablet
  Weeks 3 and 4 
  0.3 mg/kg/day 
  in 1 or 2 divided doses,
   rounded down to the 
  nearest whole tablet 
  (see Table 3 for weight
   based dosing guide)
  0.6 mg/kg/day 
  in 2 divided doses, 
  rounded down to the 
  nearest whole tablet
  1.2 mg/kg/day 
  in 2 divided doses, 
  rounded down to the 
  nearest whole tablet
  Weeks 5 onwards to 
  maintenance
  The dose should be 
  increased every 1 to 
  2 weeks as follows: 
  calculate 
  0.3 mg/kg/day, round 
  this amount down to 
  the nearest whole 
  tablet, and add this 
  amount to the 
  previously administered
  daily dose
  The dose should be 
  increased every 1 to 
  2 weeks as follows: 
  calculate 
  0.6 mg/kg/day, round this
   amount down to the 
  nearest whole tablet, and 
  add this amount to the 
  previously administered 
  daily dose
  The dose should be 
  increased every 1 to 
  2 weeks as follows: 
  calculate 
  1.2 mg/kg/day, round 
  this amount down to the 
  nearest whole tablet, and
   add this amount to the 
  previously administered 
  daily dose
  Usual Maintenance 
  Dose 
  1 to 5 mg/kg/day (maximum 
  200 mg/day in 1 or 2 
  divided doses). 
  1 to 3 mg/kg/day with 
  valproate alone
  4.5 to 7.5 mg/kg/day 
  (maximum 300 mg/day 
  in 2 divided doses)
  5 to 15 mg/kg/day 
  (maximum 400 mg/day 
  in 2 divided doses)
  Maintenance dose in 
  patients less than 30 kg 
  May need to be 
  increased by as much 
  as 50%, based on 
  clinical response
  May need to be increased
   by as much as 50%, 
  based on clinical 
  response
  May need to be 
  increased by as much as
   50%, based on clinical 
  response
  Table 3. The Initial Weight-Based Dosing Guide for Patients 2 to 12 Years Taking Valproate (Weeks 1 to 4) With Epilepsy If the patient’s weight is
  Give this daily dose, using the most appropriate combination of lamotrigine
  2-mg and 5-mg tablets 
  Greater than 
  And less than 
  Weeks 1 and 2
  Weeks 3 and 4
  6.7 kg 
  14 kg 
  2 mg every other day
  2 mg every day
  14.1 kg 
  27 kg 
  2 mg every day
  4 mg every day
  27.1 kg 
  34 kg 
  4 mg every day
  8 mg every day
  34.1 kg 
  40 kg 
  5 mg every day
  10 mg every day
  

  Usual Adjunctive Maintenance Dose for Epilepsy: The usual maintenance doses identified in Tables 1 and 2 are derived from dosing regimens employed in the placebo-controlled adjunctive studies in which the efficacy of lamotrigine was established. In patients receiving multidrug regimens employing carbamazepine, phenytoin, phenobarbital, or primidone without valproate, maintenance doses of adjunctive lamotrigine as high as 700 mg/day have been used. In patients receiving valproate alone, maintenance doses of adjunctive lamotrigine as high as 200 mg/day have been used. The advantage of using doses above those recommended in Tables 1 through 4 has not been established in controlled trials.

  2.3 Epilepsy – Conversion From Adjunctive Therapy to Monotherapy

  The goal of the transition regimen is to effect the conversion to monotherapy with lamotrigine under conditions that ensure adequate seizure control while mitigating the risk of serious rash associated with the rapid titration of lamotrigine.

  The recommended maintenance dose of lamotrigine as monotherapy is 500 mg/day given in 2 divided doses.

  To avoid an increased risk of rash, the recommended initial dose and subsequent dose escalations of lamotrigine should not be exceeded [see Boxed Warning].

  Conversion From Adjunctive Therapy With Carbamazepine, Phenytoin, Phenobarbital, or Primidone to Monotherapy With Lamotrigine: After achieving a dose of 500 mg/day of lamotrigine according to the guidelines in Table 1, the concomitant AED should be withdrawn by 20% decrements each week over a 4-week period. The regimen for the withdrawal of the concomitant AED is based on experience gained in the controlled monotherapy clinical trial.

  Conversion from Adjunctive Therapy With Valproate to Monotherapy With Lamotrigine: The conversion regimen involves 4 steps outlined in Table 4.

  Table 4. Conversion From Adjunctive Therapy With Valproate to Monotherapy With Lamotrigine in Patients ≥16 Years of Age with Epilepsy
  Lamotrigine
  Valproate
  Step 1 
  Achieve a dose of 200 mg/day according to 
  guidelines in Table 1 (if not already on 
  200 mg/day).
  Maintain previous stable dose.
  Step 2 
  Maintain at 200 mg/day.
  Decrease to 500 mg/day by 
  decrements no greater than 
  500 mg/day/week and then 
  maintain the dose of 
  500 mg/day for 1 week.
  Step 3 
  Increase to 300 mg/day and maintain for 1 
  week.
  Simultaneously decrease to 
  250 mg/day and maintain for 1 week.
  Step 4 
  Increase by 100 mg/day every week to achieve 
  maintenance dose of 500 mg/day.
  Discontinue.
  

  Conversion from Adjunctive Therapy With AEDs Other Than Carbamazepine, Phenytoin, Phenobarbital, Primidone, or Valproate to Monotherapy With Lamotrigine: No specific dosing guidelines can be provided for conversion to monotherapy with lamotrigine with AEDs other than carbamazepine, phenobarbital, phenytoin, primidone, or valproate.

  2.4 Bipolar Disorder

  The goal of maintenance treatment with lamotrigine is to delay the time to occurrence of mood episodes (depression, mania, hypomania, mixed episodes) in patients treated for acute mood episodes with standard therapy. The target dose of lamotrigine is 200 mg/day (100 mg/day in patients taking valproate, which decreases the apparent clearance of lamotrigine, and 400 mg/day in patients not taking valproate and taking either carbamazepine, phenytoin, phenobarbital, primidone, or rifampin, which increase the apparent clearance of lamotrigine). In the clinical trials, doses up to 400 mg/day as monotherapy were evaluated; however, no additional benefit was seen at 400 mg/day compared with 200 mg/day [see Clinical Studies (14.2)]. Accordingly, doses above 200 mg/day are not recommended. Treatment with lamotrigine is introduced, based on concurrent medications, according to the regimen outlined in Table 5. If other psychotropic medications are withdrawn following stabilization, the dose of lamotrigine should be adjusted. For patients discontinuing valproate, the dose of lamotrigine should be doubled over a 2-week period in equal weekly increments (see Table 6). For patients discontinuing carbamazepine, phenytoin, phenobarbital, primidone, or rifampin, the dose of lamotrigine should remain constant for the first week and then should be decreased by half over a 2-week period in equal weekly decrements (see Table 6). The dose of lamotrigine may then be further adjusted to the target dose (200 mg) as clinically indicated.

  If other drugs are subsequently introduced, the dose of lamotrigine may need to be adjusted. In particular, the introduction of valproate requires reduction in the dose of lamotrigine [see Drug Interactions (7), Clinical Pharmacology (12.3)].

  To avoid an increased risk of rash, the recommended initial dose and subsequent dose escalations of lamotrigine should not be exceeded [see Boxed Warning].

  Table 5. Escalation Regimen for Lamotrigine for Patients With Bipolar Disorder*

  * See Drug Interactions (7) and Clinical Pharmacology (12.3) for a description of known drug interactions.

  † Carbamazepine, phenytoin, phenobarbital, primidone, and rifampin have been shown to increase the apparent clearance of lamotrigine.

  ‡ Valproate has been shown to decrease the apparent clearance of lamotrigine.

  
  For Patients Taking
  Valproate‡
  For Patients Not Taking Carbamazepine, 
  Phenytoin, Phenobarbital, Primidone, or 
  Rifampin†  and Not Taking Valproate‡
  For Patients Taking Carbamazepine, Phenytoin, 
  Phenobarbital, Primidone, or Rifampin† and Not 
  Taking Valproate‡
  Weeks 1 and 2 
  25 mg every other day
  25 mg daily
  50 mg daily
  Weeks 3 and 4 
  25 mg daily
  50 mg daily
  100 mg daily, in divided doses
  Week 5 
  50 mg daily
  100 mg daily
  200 mg daily, in divided doses
  Week 6 
  100 mg daily
  200 mg daily
  300 mg daily, in divided doses
  Week 7 
  100 mg daily
  200 mg daily
  up to 400 mg daily, in
  divided doses
  Table 6. Dosage Adjustments to Lamotrigine for Patients With Bipolar Disorder Following Discontinuation of Psychotropic Medications * Carbamazepine, phenytoin, phenobarbital, primidone, and rifampin have been shown to increase the apparent clearance of lamotrigine. † Valproate has been shown to decrease the apparent clearance of lamotrigine.
  Discontinuation of Psychotropic Drugs 
  (excluding Carbamazepine,
  After Discontinuation of Valproate†
  After Discontinuation of Carbamazepine,
  Phenytoin, Phenobarbital, Primidone,
  or Rifampin*
  
  Phenytoin, Phenobarbital, Primidone, 
  Rifampin*, or Valproate†)
  Current dose of Lamotrigine
  (mg/day) 
  100
  Current dose of Lamotrigine 
  (mg/day) 
  400
  Week 1 
  Maintain current dose of Lamotrigine
  150
  400
  Week 2 
  Maintain current dose of Lamotrigine
  200
  300
  Week 3 onward 
  Maintain current dose of Lamotrigine
  200
  200
  

  The benefit of continuing treatment in patients who had been stabilized in an 8- to 16-week open-label phase with lamotrigine was established in 2 randomized, placebo-controlled clinical maintenance trials [see Clinical Studies (14.2)]. However, the optimal duration of treatment with lamotrigine has not been established. Thus, patients should be periodically reassessed to determine the need for maintenance treatment.

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  2.1 General Dosing Considerations

  Rash: There are suggestions, yet to be proven, that the risk of severe, potentially life-threatening rash may be increased by (1) coadministration of lamotrigine with valproate, (2) exceeding the recommended initial dose of lamotrigine, or (3) exceeding the recommended dose escalation for lamotrigine. However, cases have occurred in the absence of these factors [see Boxed Warning]. Therefore, it is important that the dosing recommendations be followed closely.

  The risk of nonserious rash may be increased when the recommended initial dose and/or the rate of dose escalation of lamotrigine is exceeded and in patients with a history of allergy or rash to other AEDs.

  Lamotrigine Starter Kits provide lamotrigine at doses consistent with the recommended titration schedule for the first 5 weeks of treatment, based upon concomitant medications for patients with epilepsy (>12 years of age) and Bipolar I Disorder (≥18 years of age) and are intended to help reduce the potential for rash. The use of lamotrigine Starter Kits is recommended for appropriate patients who are starting or restarting lamotrigine [see How Supplied/Storage and Handling (16)].

  It is recommended that lamotrigine not be restarted in patients who discontinued due to rash associated with prior treatment with lamotrigine, unless the potential benefits clearly outweigh the risks. If the decision is made to restart a patient who has discontinued lamotrigine, the need to restart with the initial dosing recommendations should be assessed. The greater the interval of time since the previous dose, the greater consideration should be given to restarting with the initial dosing recommendations. If a patient has discontinued lamotrigine for a period of more than 5 half-lives, it is recommended that initial dosing recommendations and guidelines be followed. The half-life of lamotrigine is affected by other concomitant medications [see Clinical Pharmacology (12.3)].

  Lamotrigine Added to Drugs Known to Induce or Inhibit Glucuronidation: Drugs other than those listed in the Clinical Pharmacology section [see Clinical Pharmacology (12.3)] have not been systematically evaluated in combination with lamotrigine. Because lamotrigine is metabolized predominantly by glucuronic acid conjugation, drugs that are known to induce or inhibit glucuronidation may affect the apparent clearance of lamotrigine and doses of lamotrigine may require adjustment based on clinical response.

  Target Plasma Levels for Patients With Epilepsy or Bipolar Disorder: A therapeutic plasma concentration range has not been established for lamotrigine. Dosing of lamotrigine should be based on therapeutic response [see Clinical Pharmacology (12.3)].

  Women Taking Estrogen-Containing Oral Contraceptives: Starting Lamotrigine in Women Taking Estrogen-Containing Oral Contraceptives: Although estrogen-containing oral contraceptives have been shown to increase the clearance of lamotrigine [see Clinical Pharmacology (12.3)], no adjustments to the recommended dose-escalation guidelines for lamotrigine should be necessary solely based on the use of estrogen-containing oral contraceptives. Therefore, dose escalation should follow the recommended guidelines for initiating adjunctive therapy with lamotrigine based on the concomitant AED or other concomitant medications (see Table 1 or Table 5). See below for adjustments to maintenance doses of lamotrigine in women taking estrogen-containing oral contraceptives.

  Adjustments to the Maintenance Dose of Lamotrigine In Women Taking Estrogen-Containing Oral Contraceptives:

  (1) Taking Estrogen-Containing Oral Contraceptives: For women not taking carbamazepine, phenytoin, phenobarbital, primidone, or rifampin, the maintenance dose of lamotrigine will in most cases need to be increased, by as much as 2-fold over the recommended target maintenance dose, in order to maintain a consistent lamotrigine plasma level [see Clinical Pharmacology (12.3)].

  (2) Starting Estrogen-Containing Oral Contraceptives: In women taking a stable dose of lamotrigine and not taking carbamazepine, phenytoin, phenobarbital, primidone, or rifampin, the maintenance dose will in most cases need to be increased by as much as 2-fold in order to maintain a consistent lamotrigine plasma level. The dose increases should begin at the same time that the oral contraceptive is introduced and continue, based on clinical response, no more rapidly than 50 to 100 mg/day every week. Dose increases should not exceed the recommended rate (see Table 1 or Table 5) unless lamotrigine plasma levels or clinical response support larger increases. Gradual transient increases in lamotrigine plasma levels may occur during the week of inactive hormonal preparation ("pill-free" week), and these increases will be greater if dose increases are made in the days before or during the week of inactive hormonal preparation. Increased lamotrigine plasma levels could result in additional adverse reactions, such as dizziness, ataxia, and diplopia. If adverse reactions attributable to lamotrigine consistently occur during the "pill-free" week, dose adjustments to the overall maintenance dose may be necessary. Dose adjustments limited to the "pill-free" week are not recommended. For women taking lamotrigine in addition to carbamazepine, phenytoin, phenobarbital, primidone, or rifampin, no adjustment should be necessary to the dose of lamotrigine.

  (3) Stopping Estrogen-Containing Oral Contraceptives: For women not taking carbamazepine, phenytoin, phenobarbital, primidone, or rifampin, the maintenance dose of lamotrigine will in most cases need to be decreased by as much as 50% in order to maintain a consistent lamotrigine plasma level. The decrease in dose of lamotrigine should not exceed 25% of the total daily dose per week over a 2-week period, unless clinical response or lamotrigine plasma levels indicate otherwise [see Clinical Pharmacology (12.3)]. For women taking lamotrigine in addition to carbamazepine, phenytoin, phenobarbital, primidone, or rifampin, no adjustment to the dose of lamotrigine should be necessary.

  Women and Other Hormonal Contraceptive Preparations or Hormone Replacement Therapy: The effect of other hormonal contraceptive preparations or hormone replacement therapy on the pharmacokinetics of lamotrigine has not been systematically evaluated. It has been reported that ethinylestradiol, not progestogens, increased the clearance of lamotrigine up to 2-fold, and the progestin-only pills had no effect on lamotrigine plasma levels. Therefore, adjustments to the dosage of lamotrigine in the presence of progestogens alone will likely not be needed.

  Patients With Hepatic Impairment: Experience in patients with hepatic impairment is limited. Based on a clinical pharmacology study in 24 patients with mild, moderate, and severe liver impairment [see Use in Specific Populations (8.6), Clinical Pharmacology (12.3)], the following general recommendations can be made. No dosage adjustment is needed in patients with mild liver impairment. Initial, escalation, and maintenance doses should generally be reduced by approximately 25% in patients with moderate and severe liver impairment without ascites and 50% in patients with severe liver impairment with ascites. Escalation and maintenance doses may be adjusted according to clinical response.

  Patients With Renal Impairment: Initial doses of lamotrigine should be based on patients' concomitant medications (see Tables 1-3 or Table 5); reduced maintenance doses may be effective for patients with significant renal impairment [see Use in Specific Populations (8.7), Clinical Pharmacology (12.3)]. Few patients with severe renal impairment have been evaluated during chronic treatment with lamotrigine. Because there is inadequate experience in this population, lamotrigine should be used with caution in these patients.

  Discontinuation Strategy: Epilepsy: For patients receiving lamotrigine in combination with other AEDs, a re-evaluation of all AEDs in the regimen should be considered if a change in seizure control or an appearance or worsening of adverse reactions is observed.

  If a decision is made to discontinue therapy with lamotrigine, a step-wise reduction of dose over at least 2 weeks (approximately 50% per week) is recommended unless safety concerns require a more rapid withdrawal [see Warnings and Precautions (5.9)].

  Discontinuing carbamazepine, phenytoin, phenobarbital, or primidone should prolong the half-life of lamotrigine; discontinuing valproate should shorten the half-life of lamotrigine.

  Bipolar Disorder: In the controlled clinical trials, there was no increase in the incidence, type, or severity of adverse reactions following abrupt termination of lamotrigine. In clinical trials in patients with Bipolar Disorder, 2 patients experienced seizures shortly after abrupt withdrawal of lamotrigine. However, there were confounding factors that may have contributed to the occurrence of seizures in these bipolar patients. Discontinuation of lamotrigine should involve a step-wise reduction of dose over at least 2 weeks (approximately 50% per week) unless safety concerns require a more rapid withdrawal [see Warnings and Precautions (5.9)].

  2.2 Epilepsy – Adjunctive Therapy

  This section provides specific dosing recommendations for patients greater than 12 years of age and patients 2 to 12 years of age. Within each of these age-groups, specific dosing recommendations are provided depending upon concomitant AED or other concomitant medications (Table 1 for patients greater than 12 years of age and Table 2 for patients 2 to 12 years of age). A weight-based dosing guide for patients 2 to 12 years of age on concomitant valproate is provided in Table 3.

  Patients Over 12 Years of Age: Recommended dosing guidelines are summarized in Table 1.

  Table 1. Escalation Regimen for Lamotrigine in Patients Over 12 Years of Age With Epilepsy *  These drugs induce glucuronidation and increase clearance  [see Drug Interactions (7) Pharmacokinetics (12.3)]. Other drugs, which have similar effects include estrogen-containing oral contraceptives and rifampin [see Drug Interactions (7), Pharmacokinetics (12.3)]. Dosing recommendations for oral contraceptives can be found in General Dosing Considerations [see Dosage and Administration (2.1)]. Patients on rifampin should follow the same dosing titration/maintenance regimen used with drugs that induce glucuronidation and increase clearance.
  For Patients Taking
   Valproate 
  For Patients Taking AEDs Other Than 
  Carbamazepine, Phenytoin, Phenobarbital, or 
  Primidone*, and Not Taking Valproate
  For Patients Taking Carbamazepine, 
  Phenytoin, Phenobarbital, or 
  Primidone* and Not Taking Valproate
  Weeks 1 and 2 
  25 mg every other day
  25 mg every day
  50 mg/day
  Weeks 3 and 4 
  25 mg every day
  50 mg/day
  100 mg/day 
  (in 2 divided doses)
  Weeks 5 onwards
  to maintenance  
  Increase by 25 to 
  50 mg/day every 1 to 
  2 weeks
  Increase by 50 mg/day
   every 1 to 2 weeks
  Increase by 
  100 mg/day every 1 to
   2 weeks.
  Usual Maintenance
  Dose 
  100 to 200 mg/day with
  valproate alone 
  
  100 to 400 mg/day with
  valproate and other
  drugs that induce
  glucuronication 
  
  (in 1 or 2 divided doses)
  225 to 375 mg/day 
  (in 2 divided doses)
  300 to 500 mg/day 
  (in 2 divided doses)
  

  Patients 2 to 12 Years of Age: Recommended dosing guidelines are summarized in Table 2.

  Smaller starting doses and slower dose escalations than those used in clinical trials are recommended because of the suggestion that the risk of rash may be decreased by smaller starting doses and slower dose escalations. Therefore, maintenance doses will take longer to reach in clinical practice than in clinical trials. It may take several weeks to months to achieve an individualized maintenance dose. Maintenance doses in patients weighing less than 30 kg, regardless of age or concomitant AED, may need to be increased as much as 50%, based on clinical response.

  The smallest available strength of lamotrigine tablets is 25 mg, and only whole tablets should be administered. If the calculated dose cannot be achieved using whole tablets, the dose should be rounded down to the nearest whole tablet [see How Supplied/Storage and Handling (16) and Medication Guide].

  Table 2. Escalation Regimen for Lamotrigine in Patients 2 to 12 Years of Age With Epilepsy

  Note: Only whole tablets should be used for dosing.

  *  These drugs induce glucuronidation and increase clearance  [see Drug Interactions (7) Pharmacokinetics (12.3)]. Other drugs, which have similar effects include estrogen-containing oral contraceptives and rifampin [see Drug Interactions (7), Pharmacokinetics (12.3)]. Dosing recommendations for oral contraceptives can be found in General Dosing Considerations [see Dosage and Administration (2.1)]. Patients on rifampin should follow the same dosing titration/maintenance regimen used with drugs that induce glucuronidation.
  For Patients Taking
   Valproate 
  For Patients Taking 
  AEDs Other Than 
  Carbamazepine, 
  Phenytoin, 
  Phenobarbital, or 
  Primidone*, and Not 
  Taking Valproate
  For Patients Taking 
  Carbamazepine, 
  Phenytoin, 
  Phenobarbital, or 
  Primidone* and Not 
  Taking Valproate
  Weeks 1 and 2 
  0.15 mg/kg/day 
  in 1 or 2 divided doses,
   rounded down to the 
  nearest whole tablet 
  (see Table 3 for weight
   based dosing guide)
  0.3 mg/kg/day 
  in 1 or 2 divided doses, 
  rounded down to the 
  nearest whole tablet
  0.6 mg/kg/day 
  in 2 divided doses, 
  rounded down to the 
  nearest whole tablet
  Weeks 3 and 4 
  0.3 mg/kg/day 
  in 1 or 2 divided doses,
   rounded down to the 
  nearest whole tablet 
  (see Table 3 for weight
   based dosing guide)
  0.6 mg/kg/day 
  in 2 divided doses, 
  rounded down to the 
  nearest whole tablet
  1.2 mg/kg/day 
  in 2 divided doses, 
  rounded down to the 
  nearest whole tablet
  Weeks 5 onwards to 
  maintenance
  The dose should be 
  increased every 1 to 
  2 weeks as follows: 
  calculate 
  0.3 mg/kg/day, round 
  this amount down to 
  the nearest whole 
  tablet, and add this 
  amount to the 
  previously administered
  daily dose
  The dose should be 
  increased every 1 to 
  2 weeks as follows: 
  calculate 
  0.6 mg/kg/day, round this
   amount down to the 
  nearest whole tablet, and 
  add this amount to the 
  previously administered 
  daily dose
  The dose should be 
  increased every 1 to 
  2 weeks as follows: 
  calculate 
  1.2 mg/kg/day, round 
  this amount down to the 
  nearest whole tablet, and
   add this amount to the 
  previously administered 
  daily dose
  Usual Maintenance 
  Dose 
  1 to 5 mg/kg/day (maximum 
  200 mg/day in 1 or 2 
  divided doses). 
  1 to 3 mg/kg/day with 
  valproate alone
  4.5 to 7.5 mg/kg/day 
  (maximum 300 mg/day 
  in 2 divided doses)
  5 to 15 mg/kg/day 
  (maximum 400 mg/day 
  in 2 divided doses)
  Maintenance dose in 
  patients less than 30 kg 
  May need to be 
  increased by as much 
  as 50%, based on 
  clinical response
  May need to be increased
   by as much as 50%, 
  based on clinical 
  response
  May need to be 
  increased by as much as
   50%, based on clinical 
  response
  Table 3. The Initial Weight-Based Dosing Guide for Patients 2 to 12 Years Taking Valproate (Weeks 1 to 4) With Epilepsy If the patient’s weight is
  Give this daily dose, using the most appropriate combination of lamotrigine
  2-mg and 5-mg tablets 
  Greater than 
  And less than 
  Weeks 1 and 2
  Weeks 3 and 4
  6.7 kg 
  14 kg 
  2 mg every other day
  2 mg every day
  14.1 kg 
  27 kg 
  2 mg every day
  4 mg every day
  27.1 kg 
  34 kg 
  4 mg every day
  8 mg every day
  34.1 kg 
  40 kg 
  5 mg every day
  10 mg every day
  

  Usual Adjunctive Maintenance Dose for Epilepsy: The usual maintenance doses identified in Tables 1 and 2 are derived from dosing regimens employed in the placebo-controlled adjunctive studies in which the efficacy of lamotrigine was established. In patients receiving multidrug regimens employing carbamazepine, phenytoin, phenobarbital, or primidone without valproate, maintenance doses of adjunctive lamotrigine as high as 700 mg/day have been used. In patients receiving valproate alone, maintenance doses of adjunctive lamotrigine as high as 200 mg/day have been used. The advantage of using doses above those recommended in Tables 1 through 4 has not been established in controlled trials.

  2.3 Epilepsy – Conversion From Adjunctive Therapy to Monotherapy

  The goal of the transition regimen is to effect the conversion to monotherapy with lamotrigine under conditions that ensure adequate seizure control while mitigating the risk of serious rash associated with the rapid titration of lamotrigine.

  The recommended maintenance dose of lamotrigine as monotherapy is 500 mg/day given in 2 divided doses.

  To avoid an increased risk of rash, the recommended initial dose and subsequent dose escalations of lamotrigine should not be exceeded [see Boxed Warning].

  Conversion From Adjunctive Therapy With Carbamazepine, Phenytoin, Phenobarbital, or Primidone to Monotherapy With Lamotrigine: After achieving a dose of 500 mg/day of lamotrigine according to the guidelines in Table 1, the concomitant AED should be withdrawn by 20% decrements each week over a 4-week period. The regimen for the withdrawal of the concomitant AED is based on experience gained in the controlled monotherapy clinical trial.

  Conversion from Adjunctive Therapy With Valproate to Monotherapy With Lamotrigine: The conversion regimen involves 4 steps outlined in Table 4.

  Table 4. Conversion From Adjunctive Therapy With Valproate to Monotherapy With Lamotrigine in Patients ≥16 Years of Age with Epilepsy
  Lamotrigine
  Valproate
  Step 1 
  Achieve a dose of 200 mg/day according to 
  guidelines in Table 1 (if not already on 
  200 mg/day).
  Maintain previous stable dose.
  Step 2 
  Maintain at 200 mg/day.
  Decrease to 500 mg/day by 
  decrements no greater than 
  500 mg/day/week and then 
  maintain the dose of 
  500 mg/day for 1 week.
  Step 3 
  Increase to 300 mg/day and maintain for 1 
  week.
  Simultaneously decrease to 
  250 mg/day and maintain for 1 week.
  Step 4 
  Increase by 100 mg/day every week to achieve 
  maintenance dose of 500 mg/day.
  Discontinue.
  

  Conversion from Adjunctive Therapy With AEDs Other Than Carbamazepine, Phenytoin, Phenobarbital, Primidone, or Valproate to Monotherapy With Lamotrigine: No specific dosing guidelines can be provided for conversion to monotherapy with lamotrigine with AEDs other than carbamazepine, phenobarbital, phenytoin, primidone, or valproate.

  2.4 Bipolar Disorder

  The goal of maintenance treatment with lamotrigine is to delay the time to occurrence of mood episodes (depression, mania, hypomania, mixed episodes) in patients treated for acute mood episodes with standard therapy. The target dose of lamotrigine is 200 mg/day (100 mg/day in patients taking valproate, which decreases the apparent clearance of lamotrigine, and 400 mg/day in patients not taking valproate and taking either carbamazepine, phenytoin, phenobarbital, primidone, or rifampin, which increase the apparent clearance of lamotrigine). In the clinical trials, doses up to 400 mg/day as monotherapy were evaluated; however, no additional benefit was seen at 400 mg/day compared with 200 mg/day [see Clinical Studies (14.2)]. Accordingly, doses above 200 mg/day are not recommended. Treatment with lamotrigine is introduced, based on concurrent medications, according to the regimen outlined in Table 5. If other psychotropic medications are withdrawn following stabilization, the dose of lamotrigine should be adjusted. For patients discontinuing valproate, the dose of lamotrigine should be doubled over a 2-week period in equal weekly increments (see Table 6). For patients discontinuing carbamazepine, phenytoin, phenobarbital, primidone, or rifampin, the dose of lamotrigine should remain constant for the first week and then should be decreased by half over a 2-week period in equal weekly decrements (see Table 6). The dose of lamotrigine may then be further adjusted to the target dose (200 mg) as clinically indicated.

  If other drugs are subsequently introduced, the dose of lamotrigine may need to be adjusted. In particular, the introduction of valproate requires reduction in the dose of lamotrigine [see Drug Interactions (7), Clinical Pharmacology (12.3)].

  To avoid an increased risk of rash, the recommended initial dose and subsequent dose escalations of lamotrigine should not be exceeded [see Boxed Warning].

  Table 5. Escalation Regimen for Lamotrigine for Patients With Bipolar Disorder*

  * See Drug Interactions (7) and Clinical Pharmacology (12.3) for a description of known drug interactions.

  † Carbamazepine, phenytoin, phenobarbital, primidone, and rifampin have been shown to increase the apparent clearance of lamotrigine.

  ‡ Valproate has been shown to decrease the apparent clearance of lamotrigine.

  
  For Patients Taking
  Valproate‡
  For Patients Not Taking Carbamazepine, 
  Phenytoin, Phenobarbital, Primidone, or 
  Rifampin†  and Not Taking Valproate‡
  For Patients Taking Carbamazepine, Phenytoin, 
  Phenobarbital, Primidone, or Rifampin† and Not 
  Taking Valproate‡
  Weeks 1 and 2 
  25 mg every other day
  25 mg daily
  50 mg daily
  Weeks 3 and 4 
  25 mg daily
  50 mg daily
  100 mg daily, in divided doses
  Week 5 
  50 mg daily
  100 mg daily
  200 mg daily, in divided doses
  Week 6 
  100 mg daily
  200 mg daily
  300 mg daily, in divided doses
  Week 7 
  100 mg daily
  200 mg daily
  up to 400 mg daily, in
  divided doses
  Table 6. Dosage Adjustments to Lamotrigine for Patients With Bipolar Disorder Following Discontinuation of Psychotropic Medications * Carbamazepine, phenytoin, phenobarbital, primidone, and rifampin have been shown to increase the apparent clearance of lamotrigine. † Valproate has been shown to decrease the apparent clearance of lamotrigine.
  Discontinuation of Psychotropic Drugs 
  (excluding Carbamazepine,
  After Discontinuation of Valproate†
  After Discontinuation of Carbamazepine,
  Phenytoin, Phenobarbital, Primidone,
  or Rifampin*
  
  Phenytoin, Phenobarbital, Primidone, 
  Rifampin*, or Valproate†)
  Current dose of Lamotrigine
  (mg/day) 
  100
  Current dose of Lamotrigine 
  (mg/day) 
  400
  Week 1 
  Maintain current dose of Lamotrigine
  150
  400
  Week 2 
  Maintain current dose of Lamotrigine
  200
  300
  Week 3 onward 
  Maintain current dose of Lamotrigine
  200
  200
  

  The benefit of continuing treatment in patients who had been stabilized in an 8- to 16-week open-label phase with lamotrigine was established in 2 randomized, placebo-controlled clinical maintenance trials [see Clinical Studies (14.2)]. However, the optimal duration of treatment with lamotrigine has not been established. Thus, patients should be periodically reassessed to determine the need for maintenance treatment.

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  2.1 General Dosing Considerations

  Rash: There are suggestions, yet to be proven, that the risk of severe, potentially life-threatening rash may be increased by (1) coadministration of lamotrigine with valproate, (2) exceeding the recommended initial dose of lamotrigine, or (3) exceeding the recommended dose escalation for lamotrigine. However, cases have occurred in the absence of these factors [see Boxed Warning]. Therefore, it is important that the dosing recommendations be followed closely.

  The risk of nonserious rash may be increased when the recommended initial dose and/or the rate of dose escalation of lamotrigine is exceeded and in patients with a history of allergy or rash to other AEDs.

  Lamotrigine Starter Kits provide lamotrigine at doses consistent with the recommended titration schedule for the first 5 weeks of treatment, based upon concomitant medications for patients with epilepsy (>12 years of age) and Bipolar I Disorder (≥18 years of age) and are intended to help reduce the potential for rash. The use of lamotrigine Starter Kits is recommended for appropriate patients who are starting or restarting lamotrigine [see How Supplied/Storage and Handling (16)].

  It is recommended that lamotrigine not be restarted in patients who discontinued due to rash associated with prior treatment with lamotrigine, unless the potential benefits clearly outweigh the risks. If the decision is made to restart a patient who has discontinued lamotrigine, the need to restart with the initial dosing recommendations should be assessed. The greater the interval of time since the previous dose, the greater consideration should be given to restarting with the initial dosing recommendations. If a patient has discontinued lamotrigine for a period of more than 5 half-lives, it is recommended that initial dosing recommendations and guidelines be followed. The half-life of lamotrigine is affected by other concomitant medications [see Clinical Pharmacology (12.3)].

  Lamotrigine Added to Drugs Known to Induce or Inhibit Glucuronidation: Drugs other than those listed in the Clinical Pharmacology section [see Clinical Pharmacology (12.3)] have not been systematically evaluated in combination with lamotrigine. Because lamotrigine is metabolized predominantly by glucuronic acid conjugation, drugs that are known to induce or inhibit glucuronidation may affect the apparent clearance of lamotrigine and doses of lamotrigine may require adjustment based on clinical response.

  Target Plasma Levels for Patients With Epilepsy or Bipolar Disorder: A therapeutic plasma concentration range has not been established for lamotrigine. Dosing of lamotrigine should be based on therapeutic response [see Clinical Pharmacology (12.3)].

  Women Taking Estrogen-Containing Oral Contraceptives: Starting Lamotrigine in Women Taking Estrogen-Containing Oral Contraceptives: Although estrogen-containing oral contraceptives have been shown to increase the clearance of lamotrigine [see Clinical Pharmacology (12.3)], no adjustments to the recommended dose-escalation guidelines for lamotrigine should be necessary solely based on the use of estrogen-containing oral contraceptives. Therefore, dose escalation should follow the recommended guidelines for initiating adjunctive therapy with lamotrigine based on the concomitant AED or other concomitant medications (see Table 1 or Table 5). See below for adjustments to maintenance doses of lamotrigine in women taking estrogen-containing oral contraceptives.

  Adjustments to the Maintenance Dose of Lamotrigine In Women Taking Estrogen-Containing Oral Contraceptives:

  (1) Taking Estrogen-Containing Oral Contraceptives: For women not taking carbamazepine, phenytoin, phenobarbital, primidone, or rifampin, the maintenance dose of lamotrigine will in most cases need to be increased, by as much as 2-fold over the recommended target maintenance dose, in order to maintain a consistent lamotrigine plasma level [see Clinical Pharmacology (12.3)].

  (2) Starting Estrogen-Containing Oral Contraceptives: In women taking a stable dose of lamotrigine and not taking carbamazepine, phenytoin, phenobarbital, primidone, or rifampin, the maintenance dose will in most cases need to be increased by as much as 2-fold in order to maintain a consistent lamotrigine plasma level. The dose increases should begin at the same time that the oral contraceptive is introduced and continue, based on clinical response, no more rapidly than 50 to 100 mg/day every week. Dose increases should not exceed the recommended rate (see Table 1 or Table 5) unless lamotrigine plasma levels or clinical response support larger increases. Gradual transient increases in lamotrigine plasma levels may occur during the week of inactive hormonal preparation ("pill-free" week), and these increases will be greater if dose increases are made in the days before or during the week of inactive hormonal preparation. Increased lamotrigine plasma levels could result in additional adverse reactions, such as dizziness, ataxia, and diplopia. If adverse reactions attributable to lamotrigine consistently occur during the "pill-free" week, dose adjustments to the overall maintenance dose may be necessary. Dose adjustments limited to the "pill-free" week are not recommended. For women taking lamotrigine in addition to carbamazepine, phenytoin, phenobarbital, primidone, or rifampin, no adjustment should be necessary to the dose of lamotrigine.

  (3) Stopping Estrogen-Containing Oral Contraceptives: For women not taking carbamazepine, phenytoin, phenobarbital, primidone, or rifampin, the maintenance dose of lamotrigine will in most cases need to be decreased by as much as 50% in order to maintain a consistent lamotrigine plasma level. The decrease in dose of lamotrigine should not exceed 25% of the total daily dose per week over a 2-week period, unless clinical response or lamotrigine plasma levels indicate otherwise [see Clinical Pharmacology (12.3)]. For women taking lamotrigine in addition to carbamazepine, phenytoin, phenobarbital, primidone, or rifampin, no adjustment to the dose of lamotrigine should be necessary.

  Women and Other Hormonal Contraceptive Preparations or Hormone Replacement Therapy: The effect of other hormonal contraceptive preparations or hormone replacement therapy on the pharmacokinetics of lamotrigine has not been systematically evaluated. It has been reported that ethinylestradiol, not progestogens, increased the clearance of lamotrigine up to 2-fold, and the progestin-only pills had no effect on lamotrigine plasma levels. Therefore, adjustments to the dosage of lamotrigine in the presence of progestogens alone will likely not be needed.

  Patients With Hepatic Impairment: Experience in patients with hepatic impairment is limited. Based on a clinical pharmacology study in 24 patients with mild, moderate, and severe liver impairment [see Use in Specific Populations (8.6), Clinical Pharmacology (12.3)], the following general recommendations can be made. No dosage adjustment is needed in patients with mild liver impairment. Initial, escalation, and maintenance doses should generally be reduced by approximately 25% in patients with moderate and severe liver impairment without ascites and 50% in patients with severe liver impairment with ascites. Escalation and maintenance doses may be adjusted according to clinical response.

  Patients With Renal Impairment: Initial doses of lamotrigine should be based on patients' concomitant medications (see Tables 1-3 or Table 5); reduced maintenance doses may be effective for patients with significant renal impairment [see Use in Specific Populations (8.7), Clinical Pharmacology (12.3)]. Few patients with severe renal impairment have been evaluated during chronic treatment with lamotrigine. Because there is inadequate experience in this population, lamotrigine should be used with caution in these patients.

  Discontinuation Strategy: Epilepsy: For patients receiving lamotrigine in combination with other AEDs, a re-evaluation of all AEDs in the regimen should be considered if a change in seizure control or an appearance or worsening of adverse reactions is observed.

  If a decision is made to discontinue therapy with lamotrigine, a step-wise reduction of dose over at least 2 weeks (approximately 50% per week) is recommended unless safety concerns require a more rapid withdrawal [see Warnings and Precautions (5.9)].

  Discontinuing carbamazepine, phenytoin, phenobarbital, or primidone should prolong the half-life of lamotrigine; discontinuing valproate should shorten the half-life of lamotrigine.

  Bipolar Disorder: In the controlled clinical trials, there was no increase in the incidence, type, or severity of adverse reactions following abrupt termination of lamotrigine. In clinical trials in patients with Bipolar Disorder, 2 patients experienced seizures shortly after abrupt withdrawal of lamotrigine. However, there were confounding factors that may have contributed to the occurrence of seizures in these bipolar patients. Discontinuation of lamotrigine should involve a step-wise reduction of dose over at least 2 weeks (approximately 50% per week) unless safety concerns require a more rapid withdrawal [see Warnings and Precautions (5.9)].

  2.2 Epilepsy – Adjunctive Therapy

  This section provides specific dosing recommendations for patients greater than 12 years of age and patients 2 to 12 years of age. Within each of these age-groups, specific dosing recommendations are provided depending upon concomitant AED or other concomitant medications (Table 1 for patients greater than 12 years of age and Table 2 for patients 2 to 12 years of age). A weight-based dosing guide for patients 2 to 12 years of age on concomitant valproate is provided in Table 3.

  Patients Over 12 Years of Age: Recommended dosing guidelines are summarized in Table 1.

  Table 1. Escalation Regimen for Lamotrigine in Patients Over 12 Years of Age With Epilepsy *  These drugs induce glucuronidation and increase clearance  [see Drug Interactions (7) Pharmacokinetics (12.3)]. Other drugs, which have similar effects include estrogen-containing oral contraceptives and rifampin [see Drug Interactions (7), Pharmacokinetics (12.3)]. Dosing recommendations for oral contraceptives can be found in General Dosing Considerations [see Dosage and Administration (2.1)]. Patients on rifampin should follow the same dosing titration/maintenance regimen used with drugs that induce glucuronidation and increase clearance.
  For Patients Taking
   Valproate 
  For Patients Taking AEDs Other Than 
  Carbamazepine, Phenytoin, Phenobarbital, or 
  Primidone*, and Not Taking Valproate
  For Patients Taking Carbamazepine, 
  Phenytoin, Phenobarbital, or 
  Primidone* and Not Taking Valproate
  Weeks 1 and 2 
  25 mg every other day
  25 mg every day
  50 mg/day
  Weeks 3 and 4 
  25 mg every day
  50 mg/day
  100 mg/day 
  (in 2 divided doses)
  Weeks 5 onwards
  to maintenance  
  Increase by 25 to 
  50 mg/day every 1 to 
  2 weeks
  Increase by 50 mg/day
   every 1 to 2 weeks
  Increase by 
  100 mg/day every 1 to
   2 weeks.
  Usual Maintenance
  Dose 
  100 to 200 mg/day with
  valproate alone 
  
  100 to 400 mg/day with
  valproate and other
  drugs that induce
  glucuronication 
  
  (in 1 or 2 divided doses)
  225 to 375 mg/day 
  (in 2 divided doses)
  300 to 500 mg/day 
  (in 2 divided doses)
  

  Patients 2 to 12 Years of Age: Recommended dosing guidelines are summarized in Table 2.

  Smaller starting doses and slower dose escalations than those used in clinical trials are recommended because of the suggestion that the risk of rash may be decreased by smaller starting doses and slower dose escalations. Therefore, maintenance doses will take longer to reach in clinical practice than in clinical trials. It may take several weeks to months to achieve an individualized maintenance dose. Maintenance doses in patients weighing less than 30 kg, regardless of age or concomitant AED, may need to be increased as much as 50%, based on clinical response.

  The smallest available strength of lamotrigine tablets is 25 mg, and only whole tablets should be administered. If the calculated dose cannot be achieved using whole tablets, the dose should be rounded down to the nearest whole tablet [see How Supplied/Storage and Handling (16) and Medication Guide].

  Table 2. Escalation Regimen for Lamotrigine in Patients 2 to 12 Years of Age With Epilepsy

  Note: Only whole tablets should be used for dosing.

  *  These drugs induce glucuronidation and increase clearance  [see Drug Interactions (7) Pharmacokinetics (12.3)]. Other drugs, which have similar effects include estrogen-containing oral contraceptives and rifampin [see Drug Interactions (7), Pharmacokinetics (12.3)]. Dosing recommendations for oral contraceptives can be found in General Dosing Considerations [see Dosage and Administration (2.1)]. Patients on rifampin should follow the same dosing titration/maintenance regimen used with drugs that induce glucuronidation.
  For Patients Taking
   Valproate 
  For Patients Taking 
  AEDs Other Than 
  Carbamazepine, 
  Phenytoin, 
  Phenobarbital, or 
  Primidone*, and Not 
  Taking Valproate
  For Patients Taking 
  Carbamazepine, 
  Phenytoin, 
  Phenobarbital, or 
  Primidone* and Not 
  Taking Valproate
  Weeks 1 and 2 
  0.15 mg/kg/day 
  in 1 or 2 divided doses,
   rounded down to the 
  nearest whole tablet 
  (see Table 3 for weight
   based dosing guide)
  0.3 mg/kg/day 
  in 1 or 2 divided doses, 
  rounded down to the 
  nearest whole tablet
  0.6 mg/kg/day 
  in 2 divided doses, 
  rounded down to the 
  nearest whole tablet
  Weeks 3 and 4 
  0.3 mg/kg/day 
  in 1 or 2 divided doses,
   rounded down to the 
  nearest whole tablet 
  (see Table 3 for weight
   based dosing guide)
  0.6 mg/kg/day 
  in 2 divided doses, 
  rounded down to the 
  nearest whole tablet
  1.2 mg/kg/day 
  in 2 divided doses, 
  rounded down to the 
  nearest whole tablet
  Weeks 5 onwards to 
  maintenance
  The dose should be 
  increased every 1 to 
  2 weeks as follows: 
  calculate 
  0.3 mg/kg/day, round 
  this amount down to 
  the nearest whole 
  tablet, and add this 
  amount to the 
  previously administered
  daily dose
  The dose should be 
  increased every 1 to 
  2 weeks as follows: 
  calculate 
  0.6 mg/kg/day, round this
   amount down to the 
  nearest whole tablet, and 
  add this amount to the 
  previously administered 
  daily dose
  The dose should be 
  increased every 1 to 
  2 weeks as follows: 
  calculate 
  1.2 mg/kg/day, round 
  this amount down to the 
  nearest whole tablet, and
   add this amount to the 
  previously administered 
  daily dose
  Usual Maintenance 
  Dose 
  1 to 5 mg/kg/day (maximum 
  200 mg/day in 1 or 2 
  divided doses). 
  1 to 3 mg/kg/day with 
  valproate alone
  4.5 to 7.5 mg/kg/day 
  (maximum 300 mg/day 
  in 2 divided doses)
  5 to 15 mg/kg/day 
  (maximum 400 mg/day 
  in 2 divided doses)
  Maintenance dose in 
  patients less than 30 kg 
  May need to be 
  increased by as much 
  as 50%, based on 
  clinical response
  May need to be increased
   by as much as 50%, 
  based on clinical 
  response
  May need to be 
  increased by as much as
   50%, based on clinical 
  response
  Table 3. The Initial Weight-Based Dosing Guide for Patients 2 to 12 Years Taking Valproate (Weeks 1 to 4) With Epilepsy If the patient’s weight is
  Give this daily dose, using the most appropriate combination of lamotrigine
  2-mg and 5-mg tablets 
  Greater than 
  And less than 
  Weeks 1 and 2
  Weeks 3 and 4
  6.7 kg 
  14 kg 
  2 mg every other day
  2 mg every day
  14.1 kg 
  27 kg 
  2 mg every day
  4 mg every day
  27.1 kg 
  34 kg 
  4 mg every day
  8 mg every day
  34.1 kg 
  40 kg 
  5 mg every day
  10 mg every day
  

  Usual Adjunctive Maintenance Dose for Epilepsy: The usual maintenance doses identified in Tables 1 and 2 are derived from dosing regimens employed in the placebo-controlled adjunctive studies in which the efficacy of lamotrigine was established. In patients receiving multidrug regimens employing carbamazepine, phenytoin, phenobarbital, or primidone without valproate, maintenance doses of adjunctive lamotrigine as high as 700 mg/day have been used. In patients receiving valproate alone, maintenance doses of adjunctive lamotrigine as high as 200 mg/day have been used. The advantage of using doses above those recommended in Tables 1 through 4 has not been established in controlled trials.

  2.3 Epilepsy – Conversion From Adjunctive Therapy to Monotherapy

  The goal of the transition regimen is to effect the conversion to monotherapy with lamotrigine under conditions that ensure adequate seizure control while mitigating the risk of serious rash associated with the rapid titration of lamotrigine.

  The recommended maintenance dose of lamotrigine as monotherapy is 500 mg/day given in 2 divided doses.

  To avoid an increased risk of rash, the recommended initial dose and subsequent dose escalations of lamotrigine should not be exceeded [see Boxed Warning].

  Conversion From Adjunctive Therapy With Carbamazepine, Phenytoin, Phenobarbital, or Primidone to Monotherapy With Lamotrigine: After achieving a dose of 500 mg/day of lamotrigine according to the guidelines in Table 1, the concomitant AED should be withdrawn by 20% decrements each week over a 4-week period. The regimen for the withdrawal of the concomitant AED is based on experience gained in the controlled monotherapy clinical trial.

  Conversion from Adjunctive Therapy With Valproate to Monotherapy With Lamotrigine: The conversion regimen involves 4 steps outlined in Table 4.

  Table 4. Conversion From Adjunctive Therapy With Valproate to Monotherapy With Lamotrigine in Patients ≥16 Years of Age with Epilepsy
  Lamotrigine
  Valproate
  Step 1 
  Achieve a dose of 200 mg/day according to 
  guidelines in Table 1 (if not already on 
  200 mg/day).
  Maintain previous stable dose.
  Step 2 
  Maintain at 200 mg/day.
  Decrease to 500 mg/day by 
  decrements no greater than 
  500 mg/day/week and then 
  maintain the dose of 
  500 mg/day for 1 week.
  Step 3 
  Increase to 300 mg/day and maintain for 1 
  week.
  Simultaneously decrease to 
  250 mg/day and maintain for 1 week.
  Step 4 
  Increase by 100 mg/day every week to achieve 
  maintenance dose of 500 mg/day.
  Discontinue.
  

  Conversion from Adjunctive Therapy With AEDs Other Than Carbamazepine, Phenytoin, Phenobarbital, Primidone, or Valproate to Monotherapy With Lamotrigine: No specific dosing guidelines can be provided for conversion to monotherapy with lamotrigine with AEDs other than carbamazepine, phenobarbital, phenytoin, primidone, or valproate.

  2.4 Bipolar Disorder

  The goal of maintenance treatment with lamotrigine is to delay the time to occurrence of mood episodes (depression, mania, hypomania, mixed episodes) in patients treated for acute mood episodes with standard therapy. The target dose of lamotrigine is 200 mg/day (100 mg/day in patients taking valproate, which decreases the apparent clearance of lamotrigine, and 400 mg/day in patients not taking valproate and taking either carbamazepine, phenytoin, phenobarbital, primidone, or rifampin, which increase the apparent clearance of lamotrigine). In the clinical trials, doses up to 400 mg/day as monotherapy were evaluated; however, no additional benefit was seen at 400 mg/day compared with 200 mg/day [see Clinical Studies (14.2)]. Accordingly, doses above 200 mg/day are not recommended. Treatment with lamotrigine is introduced, based on concurrent medications, according to the regimen outlined in Table 5. If other psychotropic medications are withdrawn following stabilization, the dose of lamotrigine should be adjusted. For patients discontinuing valproate, the dose of lamotrigine should be doubled over a 2-week period in equal weekly increments (see Table 6). For patients discontinuing carbamazepine, phenytoin, phenobarbital, primidone, or rifampin, the dose of lamotrigine should remain constant for the first week and then should be decreased by half over a 2-week period in equal weekly decrements (see Table 6). The dose of lamotrigine may then be further adjusted to the target dose (200 mg) as clinically indicated.

  If other drugs are subsequently introduced, the dose of lamotrigine may need to be adjusted. In particular, the introduction of valproate requires reduction in the dose of lamotrigine [see Drug Interactions (7), Clinical Pharmacology (12.3)].

  To avoid an increased risk of rash, the recommended initial dose and subsequent dose escalations of lamotrigine should not be exceeded [see Boxed Warning].

  Table 5. Escalation Regimen for Lamotrigine for Patients With Bipolar Disorder*

  * See Drug Interactions (7) and Clinical Pharmacology (12.3) for a description of known drug interactions.

  † Carbamazepine, phenytoin, phenobarbital, primidone, and rifampin have been shown to increase the apparent clearance of lamotrigine.

  ‡ Valproate has been shown to decrease the apparent clearance of lamotrigine.

  
  For Patients Taking
  Valproate‡
  For Patients Not Taking Carbamazepine, 
  Phenytoin, Phenobarbital, Primidone, or 
  Rifampin†  and Not Taking Valproate‡
  For Patients Taking Carbamazepine, Phenytoin, 
  Phenobarbital, Primidone, or Rifampin† and Not 
  Taking Valproate‡
  Weeks 1 and 2 
  25 mg every other day
  25 mg daily
  50 mg daily
  Weeks 3 and 4 
  25 mg daily
  50 mg daily
  100 mg daily, in divided doses
  Week 5 
  50 mg daily
  100 mg daily
  200 mg daily, in divided doses
  Week 6 
  100 mg daily
  200 mg daily
  300 mg daily, in divided doses
  Week 7 
  100 mg daily
  200 mg daily
  up to 400 mg daily, in
  divided doses
  Table 6. Dosage Adjustments to Lamotrigine for Patients With Bipolar Disorder Following Discontinuation of Psychotropic Medications * Carbamazepine, phenytoin, phenobarbital, primidone, and rifampin have been shown to increase the apparent clearance of lamotrigine. † Valproate has been shown to decrease the apparent clearance of lamotrigine.
  Discontinuation of Psychotropic Drugs 
  (excluding Carbamazepine,
  After Discontinuation of Valproate†
  After Discontinuation of Carbamazepine,
  Phenytoin, Phenobarbital, Primidone,
  or Rifampin*
  
  Phenytoin, Phenobarbital, Primidone, 
  Rifampin*, or Valproate†)
  Current dose of Lamotrigine
  (mg/day) 
  100
  Current dose of Lamotrigine 
  (mg/day) 
  400
  Week 1 
  Maintain current dose of Lamotrigine
  150
  400
  Week 2 
  Maintain current dose of Lamotrigine
  200
  300
  Week 3 onward 
  Maintain current dose of Lamotrigine
  200
  200
  

  The benefit of continuing treatment in patients who had been stabilized in an 8- to 16-week open-label phase with lamotrigine was established in 2 randomized, placebo-controlled clinical maintenance trials [see Clinical Studies (14.2)]. However, the optimal duration of treatment with lamotrigine has not been established. Thus, patients should be periodically reassessed to determine the need for maintenance treatment.

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  Epilepsy
  Adjunctive Use:
  Lamotrigine is indicated as adjunctive therapy for partial seizures and the generalized seizures of Lennox-Gastaut syndrome in adult and pediatric patients (years of age).
  Monotherapy Use:
  Lamotrigine tablets and lamotrigine tablets (chewable, dispersible) are indicated for conversion to monotherapy in adults with partial seizures who are receiving treatment with carbamazepine, phenytoin, phenobarbital, primidone, or valproate as the single AED.
  Safety and effectiveness of lamotrigine tablets and lamotrigine tablets (chewable, dispersible)have not been established. (1) as initial monotherapy, (2) for conversion to monotherapy from AEDs other than carbamazepine, phenytoin, phenobarbital, primidone, or valproate, or (3) for simultaneous conversion to monotherapy from 2 or more concomitant AEDs.
  Bipolar Disorder
  Lamotrigine tablets and lamotrigine tablets (chewable, dispersible) are indicated for the maintenance treatment of Bipolar I Disorder to delay the time to occurrence of mood episodes (depression, mania, hypomania, mixed episodes) in patients treated for acute mood episodes with standard therapy. The effectiveness of lamotrigine in the acute treatment of mood episodes has not been established.
  General Dosing Considerations for Epilepsy and Bipolar Disorder Patients:
  The risk of nonserious rash is increased when the recommended initial dose and/or the rate of dose escalation of Lamotrigine is exceeded. There are suggestions, yet to be proven, that the risk of severe, potentially life-threatening rash may be increased by (1) coadministration of lamotrigine with valproate, (2) exceeding the recommended initial dose of lamotrigine, or (3) exceeding the recommended dose escalation for lamotrigine. However, cases have been reported in the absence of these factors (see BOX WARNING). Therefore, it is important that the dosing recommendations be followed closely.
  It is recommended that lamotrigine not be restarted in patients who discontinued due to rash associated with prior treatment with lamotrigine, unless the potential benefits clearly outweigh the risks. If the decision is made to restart a patient who has discontinued lamotrigine, the need to restart with the initial dosing recommendations should be assessed. The greater the interval of time since the previous dose, the greater consideration should be given to restarting with the initial dosing recommendations. If a patient has discontinued lamotrigine for a period of more than 5 half-lives, it is recommended that initial dosing recommendations and guidelines be followed.
  Lamotrigine Tablets and Lamotrigine Tablets (Chewable, Dispersible)Added to Drugs Known to Induce or Inhibit Glucuronidation:
  Drugs other than those listed in PRECAUTIONS: Drug Interactionshave not been systematically evaluated in
  combination with Lamotrigine. Since lamotrigine is metabolized predominantly by glucuronic acid conjugation, drugs that are known to induce or inhibit glucuronidation may affect the apparent clearance of lamotrigine, and doses of Lamotrigine may require adjustment based on clinical response.
  Target Plasma Levels for Patients With Epilepsy or Bipolar Disorder:
  A therapeutic plasma concentration range has not been established for lamotrigine. Dosing of lamotrigine should be based on therapeutic response.
  The half-life of lamotrigine is affected by other concomitant medications (see CLINICAL PHARMACOLOGY: Pharmacokinetics and Drug Metabolism).
  See also DOSAGE AND ADMINISTRATION: Special Populations.
  Special Populations: Women and Oral Contraceptives: Starting Lamotrigine Tablets and LamotrigineTablets (Chewable, Dispersible)in Women Taking Oral Contraceptives
  Although estrogen-containing oral contraceptives have been shown to increase the clearance of lamotrigine (see PRECAUTIONS: Drug Interactions), no adjustments to the recommended dose escalation guidelines for lamotrigine should be necessary solely based on the use of estrogen-containing oral contraceptives. Therefore, dose escalation should follow the recommended guidelines for initiating adjunctive therapy with lamotrigine based on the concomitant AED (see Table 11). See below for adjustments to maintenance doses of lamotrigine in women taking estrogen-containing oral contraceptives.
  Adjustments to the Maintenance Dose of Lamotrigine Tablets and Lamotrigine Tablets (Chewable, Dispersible)
       Taking Estrogen-Containing Oral Contraceptives:
  For women not taking carbamazepine, phenytoin, phenobarbital, primidone,
  or rifampin, the maintenance dose of Lamotrigine will in most cases need to be increased, by as much as 2-fold over the recommended target maintenance dose, in order to maintain a consistent lamotrigine plasma level (see PRECAUTIONS: Drug Interactions). (2) Starting Estrogen-Containing Oral Contraceptives: In women taking a stable dose of Lamotrigine and not taking carbamazepine, phenytoin, phenobarbital, primidone, or rifampin, the maintenance dose will in most cases need to be increased by as much as 2-fold, in order to maintain a consistent lamotrigine plasma level. The dose increases should begin at the same time that the oral contraceptive is introduced and continue, based on clinical response, no more rapidly than 50 to 100 mg/day every week. Dose increases should not exceed the recommended rate unless lamotrigine plasma levels or clinical response support larger increases (see Table 11, column 2,). Gradual transient increases in lamotrigine plasma levels may occur during the week of inactive hormonal preparation ("pill-free" week), and these increases will be greater if dose increases are made in the days before or during the week of inactive hormonal preparation. Increased lamotrigine plasma levels could result in additional adverse events, such as dizziness, ataxia, and diplopia (see PRECAUTIONS: Drug Interactions). If adverse events attributable to lamotrigine consistently occur during the "pill-free" week, dose adjustments to the overall maintenance dose may be necessary. Dose adjustments limited to the "pill-free" week are not recommended. For women taking Lamotrigine in addition to carbamazepine, phenytoin, phenobarbital, primidone, or rifampin, no adjustment should be necessary to the dose of Lamotrigine. (3) Stopping Estrogen-Containing Oral Contraceptives: For women not taking carbamazepine, phenytoin, phenobarbital, primidone, or rifampin, the maintenance dose of lamotrigine will in most cases need to be decreased by as much as 50%, in order to maintain a consistent lamotrigine plasma level. The decrease in dose of Lamotrigine should not exceed 25% of the total daily dose per week over a 2-week period, unless clinical response or lamotrigine plasma levels indicate otherwise (see PRECAUTIONS: Drug Interactions). For women taking lamotrigine in addition to carbamazepine, phenytoin, phenobarbital, primidone, or rifampin, no adjustment to the dose of lamotrigine should be necessary.
  Women and Other Hormonal Contraceptive Preparations or Hormone Replacement Therapy:
  The effect of other hormonal contraceptive preparations or hormone replacement therapy on the pharmacokinetics of lamotrigine has not been systematically evaluated. It has been reported that ethinylestradiol, not progestogens, increased the clearance of lamotrigine up to 2-fold, and the progestin only pills had no effect on lamotrigine plasma levels. Therefore, adjustments to the dosage of lamotrigine in the presence of progestogens alone will likely not be needed.
  Patients With Hepatic Impairment:
  Experience in patients with hepatic impairment is limited. Based on a clinical pharmacology study in 24 patients with mild, moderate, and severe liver dysfunction (see CLINICAL PHARMACOLOGY), the following general recommendations can be made. No dosage adjustment is needed in patients with mild liver impairment. Initial, escalation, and maintenance doses should generally be reduced by approximately 25% in patients with moderate and severe liver impairment without
  ascites and 50% in patients with severe liver impairment with ascites. Escalation and maintenance doses may be adjusted according to clinical response.
  Patients With Renal Functional Impairment:
  Initial doses of lamotrigine tablets and lamotrigine tablets (chewable, dispersible) should be based on patients' AED regimen (see above); reduced maintenance doses may be effective for patients with significant renal functional impairment (see CLINICAL PHARMACOLOGY). Few patients with severe renal impairment have been evaluated during chronic treatment with lamotrigine. Because there is inadequate experience in this population, lamotrigine should be used with caution in these patients.
  Epilepsy:
  Adjunctive Therapy With Lamotrigine Tablets and Lamotrigine Tablets (Chewable, Dispersible) for Epilepsy:
  This section provides specific dosing recommendations for patients 2 to 12 years of age and patients greater than 12 years of age. Within each of these age-groups, specific dosing recommendations are provided depending upon concomitant AED (Table 9 for patients 2 to 12 years of age and Table 11 for patients greater than 12 years of age). A weight based dosing guide for pediatric patients on concomitant valproate is provided in Table 10.
  Patients 2 to 12 Years of Age:
  Recommended dosing guidelines are summarized in Table 9.
  Note that some of the starting doses and dose escalations listed in Table 9 are different than those used in clinical trials; however, the maintenance doses are the same as in clinical trials. Smaller starting doses and slower dose escalations than those used in clinical trials are recommended because of the suggestions that the risk of rash may be decreased by smaller starting doses and slower dose escalations. Therefore, maintenance doses will take longer to reach in clinical practice than in clinical trials. It may take several weeks to months to achieve an individualized maintenance dose. Maintenance doses in patients weighing less than 30 kg, regardless of age or concomitant AED, may need to be increased as much as 50%, based on clinical response.
  
  Table 9. Escalation Regimen for Lamotrigine in Patients 2 to 12 Years of Age With Epilepsy
  *Rifampin and estrogen-containing oral contraceptives have also been shown to increase the apparent clearance of lamotrigine (see PRECAUTIONS: Drug Interactions).For Patients Taking Valproate (see Table 10 for weight- based dosing guide)For Patients Taking AEDs Other Than Carbamazepine, Phenytoi n, Phenobarbital, Primidone *, or ValproateFor Patients Taking Carbamazepine, Phenytoin, Phenobarbital, Primidone *and Not Taking ValproateWeeks 1 and 20.15 mg/kg/day in 1 or 2 divided doses, rounded down to the nearest whole tablet (see Table 10 for weight-based dosing guide).0.3 mg/kg/day in 1 or 2 divided doses, rounded down to the nearest whole tablet.0.6 mg/kg/day in 2 divided doses, rounded down to the nearest whole tablet.Weeks 3 and 40.3 mg/kg/day in 1 or 2 divided doses, rounded down to the nearest whole tablet (see Table 10 for weight-based dosing guide).0.6 mg/kg/day in 2 divided doses, rounded down to the nearest whole tablet.1.2 mg/kg/day in 2 divided doses, rounded down to the nearest whole tablet.Weeks 5 onwards to maintenanceThe dose should be increased every 1 to 2 weeks as follows: calculate 0.3 mg/kg/day, round this amount down to the nearest whole tablet, and add this amount to the previously administered daily dose.The dose should be increased every 1 to 2 weeks as follows: calculate 0.6 mg/kg/day, round this amount down to the nearest whole tablet, and add this amount to the previously administered daily doseThe dose should be increased every 1 to 2 weeks as follows: calculate 1.2 mg/kg/day, round this amount down to the nearest whole tablet, and add this amount to the previously administered daily doseUsual Maintenance Dose1 to 5 mg/kg/day (maximum 200 mg/day in 1 or 2 divided doses). 1 to 3 mg/kg/day with valproate alone4.5 to 7.5 mg/kg/day (maximum 300 mg/day in 2 divided doses)5 to 15 mg/kg/day (maximum 400 mg/day in 2 divided doses)Maintenance dose in patients less than 30 kgMay need to be increased by as much as 50%, based on clinical responseMay need to be increased by as much as 50%, based on clinical responseMay need to be increased by as much as 50%, based on clinical responseNote: Only whole tablets should be used for dosing
  
  Table 10. The Initial Weight-Based Dosing Guide for Patients 2 to 12 Years Taking Valproate (Weeks 1 to 4) With Epilepsy
  If the patient's weight isGive this daily dose, using the most appropriate combination of lamotrigine tablets (chewable, dispersible), 5 mgGreater thanAnd less thanWeeks 1 and 2Weeks 3 and 434.1 kg40 kg5 mg every day10 mg every dayPatients Over 12 Years of Age:
  Recommended dosing guidelines are summarized in Table 11.
  
  Table 11. Escalation Regimen for Lamotrigine in Patients Over 12 Years of Age With Epilepsy
  *Rifampin and estrogen-containing oral contraceptives have also been shown to increase the apparent clearance of lamotrigine (see PRECAUTIONS: Drug Interactions).For Patients Taking ValproateFor Patients Taking AEDs Other Than Carbamazepine, Phenytoin, Phenobarbital, Primidone, or Valproate *For Patients Taking Carbamazepine, Phenytoin, PhenobarbitaL, Primidone *and Not Taking ValproateWeeks 1 and 225 mg every other day25 mg every day50 mg/dayWeeks 3 and 425 mg every day50 mg/day100 mg/day (in 2 divided doses)Weeks 5 onwards to maintenanceIncrease by 25 to 50 mg/ day every 1 to 2 weeksIncrease by 50 mg/ day every 1 to 2 weeksIncrease by 100 mg/ day every 1 to 2 weeks.Usual Maintenance Dose100 to 400 mg/day (1 or 2 divided doses) 100 to 200 mg/day with Valproate alone225 to 375 mg/day (in 2 divided doses).300 to 500 mg/day (in 2 divided doses).Conversion from Adjunctive Therapy With Carbamazepine, Phenytoin, Phenobarbital, Primidone, or Valproate as the Single AED to Monotherapy With Lamotrigine in PatientsYears of Age With Epilepsy:
  The goal of the transition regimen is to effect the conversion to monotherapy with Lamotrigine under conditions that ensure adequate seizure control while mitigating the risk of serious rash associated with the rapid titration of lamotrigine.
  The recommended maintenance dose of lamotrigine as monotherapy is 500 mg/day given in 2 divided doses.
  To avoid an increased risk of rash, the recommended initial dose and subsequent dose escalations of lamotrigine should not be exceeded (see BOX WARNING).
  Conversion From Adjunctive Therapy With Carbamazepine, Phenytoin, Phenobarbital, or Primidone to Monotherapy With Lamotrigine:
  After achieving a dose of 500 mg/day of lamotrigine according to the guidelines in Table 11, the concomitant AED should be withdrawn by 20% decrements each week over a 4-week period. The regimen for the withdrawal of the concomitant AED is based on experience gained in the controlled monotherapy clinical trial.
  Conversion from Adjunctive Therapy With Valproate to Monotherapy With Lamotrigine The conversion regimen involves 4 steps (see Table 12).
  
  Table 12. Conversion From Adjunctive Therapy With Valproate to Monotherapy With Lamotrigine in PatientsYears of Age With Epilepsy
  LamotrigineValproateStep 1Achieve a dose of 200 mg/day according to guidelines in Table 11 (if not already on 200 mg/ day).Maintain previous stable dose.Step 2Maintain at 200 mg/day.Decrease to 500 mg/day by decrements no greater than 500 mg/day per week and then maintain the dose of 500 mg/day for 1 week.Step 3Increase to 300 mg/day and maintain for 1 week.Simultaneously decrease to 250 mg/day and maintain for 1 week.Step 4Increase by 100 mg/day every week to achieve maintenance dose of 500 mg/day.Discontinue.Conversion from Adjunctive Therapy With Antiepileptic Drugs Other Than Carbamazepine, Phenytoin, Phenobarbital, Primidone, or Valproate to Monotherapy With Lamotrigine:
  No specific dosing guidelines can be provided for conversion to monotherapy with lamotrigine with AEDs other than carbamazepine, phenobarbital, phenytoin, primidone, or valproate.
  Usual Maintenance Dose for Epilepsy
  The usual maintenance doses identified in Tables 9-11 are derived from dosing regimens employed in the placebo-controlled adjunctive studies in which the efficacy of lamotrigine was established. In patients receiving multidrug regimens employing carbamazepine, phenytoin, phenobarbital, or primidone without valproate, maintenance doses of adjunctive Lamotrigine as high as 700 mg/day have been used. In patients receiving valproate alone, maintenance doses of adjunctive Lamotrigine as high as 200 mg/ day have been used. The advantage of using doses above those recommended in Tables 9-12 has not been established in controlled trials.
  Discontinuation Strategy for Patients With Epilepsy:
  For patients receiving lamotrigine in combination with other AEDs, a reevaluation of all AEDs in the regimen should be considered if a change in seizure control or an appearance or worsening of adverse experiences is observed.
  If a decision is made to discontinue therapy with Lamotrigine, a step-wise reduction of dose over at least 2 weeks (approximately 50% per week) is recommended unless safety concerns require a more rapid withdrawal (see PRECAUTIONS).
  Discontinuing carbamazepine, phenytoin, phenobarbital, or primidone should prolong the half-life of lamotrigine; discontinuing valproate should shorten the half-life of lamotrigine.
  Bipolar Disorder
  The goal of maintenance treatment with lamotrigine is to delay the time to occurrence of mood episodes (depression, mania, hypomania, mixed episodes) in patients treated for acute mood episodes with standard therapy. The target dose of lamotrigine is 200 mg/day (100 mg/day in patients taking valproate,which decreases the apparent clearance of lamotrigine, and 400 mg/day in patients not taking valproate and taking either carbamazepine, phenytoin, phenobarbital, primidone, or rifampin, which increase the apparent clearance of lamotrigine). In the clinical trials, doses up to 400 mg/day as monotherapy were evaluated, however, no additional benefit was seen at 400 mg/day compared to 200 mg/day (see CLINICAL STUDIES: Bipolar Disorder). Accordingly, doses above 200 mg/ day are not recommended. Treatment with lamotrigine is introduced, based on concurrent medications, according to the regimen outlined in Table 13. If other psychotropic medications are withdrawn following stabilization, the dose of lamotrigine should be adjusted. For patients discontinuing valproate, the dose of lamotrigine should be doubled over a 2-week period in equal weekly increments (see Table 14). For patients discontinuing carbamazepine, phenytoin, phenobarbital, primidone, or rifampin, the dose of lamotrigine should remain constant for the first week and then should be decreased by half over a 2-week period in equal weekly decrements (see Table 14). The dose of lamotrigine may then be further adjusted to the target dose (200 mg) as clinically indicated.
  Dosage adjustments will be necessary in most patients who start or stop estrogen-containing oral contraceptives while taking lamotrigine (see DOSAGE AND ADMINISTRATION: Special Populations: Women and Oral Contraceptives: Adjustments to the Maintenace Dose of Lamotrigine).
  If other drugs are subsequently introduced, the dose of Lamotrigine may need to be adjusted.
  In particular, the introduction of valproate requires reduction in the dose of Lamotrigine (see CLINICAL PHARMACOLOGY: Drug Interactions). To avoid an increased risk of rash, the recommended initial dose and subsequent dose escalations of Lamotrigine should not be exceeded (see BOX WARNING).
  
  Table 13. Escalation Regimen for Lamotrigine for Patients With Bipolar Disorder *
  *See CLINICAL PHARMACOLOGY: Drug Interactions:and PRECAUTIONS: Drug Interactionsfor a description of known drug interactions. Carbamazepine, phenytoin, phenobarbital, primidone, rifampin, have been shown to increase the apparent clearance of lamotrigine. Valproate has been shown to decrease the apparent clearance of lamotrigine.For Patients Not Taking Carbamazepine, Phenytoin, Phenobarbital, Primidone or Rifampin and Not Taking Valproate For Patients Taking Valproate For Patients Taking Carbamazepine (or Other Enzyme-Inducing Drugs) and Not Taking Valproate Weeks 1 and 225 mg daily25 mg every other day50 mg dailyWeeks 3 and 450 mg daily25 mg daily100 mg daily, in divided dosesWeek 5100 mg daily50 mg daily200 mg daily, in divided dosesWeek 6200 mg daily100 mg daily300 mg daily, in divided dosesWeek 7200 mg daily100 mg dailyup to 400 mg daily, in divided doses
  Table 14. Adjustments to Lamotrigine Dosing for Patients With Bipolar Disorder Following Discontinuation of Psychotropic Medications *
  *See CLINICAL PHARMACOLOGY: Drug Interactions:and PRECAUTIONS: Drug Interactionsfor a description of known drug interactions. Carbamazepine, phenytoin, phenobarbital, primidone, and rifampin have been shown to increase the apparent clearance of lamotrigine. Valproate has been shown to decrease the apparent clearance of lamotrigine.Discontinuation of Psychotropic Drugs (excluding Valproate , Carbamazepine, or Other Enzyme-Inducing Drugs )After Discontinuation of Valproate After Discontinuation of Carbamazepine or Other Enzyme-Inducing Drugs Current Lamotrigine dose (mg/day) 100Current Lamotrigine dose (mg/day) 400Week 1Maintain current lamotrigine dose150400Week 2Maintain current lamotrigine dose200300Week 3 onwardMaintain current lamotrigine dose200200There is no body of evidence available to answer the question of how long the patient should remain on lamotrigine therapy. Systematic evaluation of the efficacy of lamotrigine in patients with either depression or mania who responded to standard therapy during an acute 8 to 16 week treatment phase and were then randomized to lamotrigine or placebo for up to 76 weeks of observation for affective relapse demonstrated a benefit of such maintenance treatment (see CLINICAL STUDIES: Bipolar Disorder). Nevertheless, patients should be periodically reassessed to determine the need for maintenance treatment.
  Discontinuation Strategy in Bipolar Disorder:
  As with other AEDs, lamotrigine should not be abruptly discontinued. In the controlled clinical trials, there was no increase in the incidence, type, or severity of adverse experiences following abrupt termination of lamotrigine. In clinical trials in patients with bipolar disorder, 2 patients experienced seizures shortly after abrupt withdrawal of lamotrigine. However, there were confounding factors that may have contributed to the occurrence of seizures in these bipolar patients. Discontinuation of lamotrigine should involve a step-wise reduction of dose over at least 2 weeks (approximately 50% per week) unless safety concerns require a more rapid withdrawal.
  Administration of Lamotrigine Tablets (Chewable, Dispersible)
  Lamotrigine tablets (Chewable, Dispersible) may be swallowed whole, chewed, or dispersed in water or diluted fruit juice. If the tablets are chewed, consume a small amount of water or diluted fruit juice to aid in swallowing.
  To disperse lamotrigine tablets (chewable, dispersible), add the tablets to a small amount of liquid (1 teaspoon, or enough to cover the medication). Approximately 1 minute later, when the tablets are completely dispersed, swirl the solution and consume the entire quantity immediately.
  No attempt should be made to administer partial quantities of the dispersed tablets.
  
  

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  Epilepsy
  Adjunctive Use:
  Lamotrigine is indicated as adjunctive therapy for partial seizures and the generalized seizures of Lennox-Gastaut syndrome in adult and pediatric patients (years of age).
  Monotherapy Use:
  Lamotrigine tablets and lamotrigine tablets (chewable, dispersible) are indicated for conversion to monotherapy in adults with partial seizures who are receiving treatment with carbamazepine, phenytoin, phenobarbital, primidone, or valproate as the single AED.
  Safety and effectiveness of lamotrigine tablets and lamotrigine tablets (chewable, dispersible)have not been established. (1) as initial monotherapy, (2) for conversion to monotherapy from AEDs other than carbamazepine, phenytoin, phenobarbital, primidone, or valproate, or (3) for simultaneous conversion to monotherapy from 2 or more concomitant AEDs.
  Bipolar Disorder
  Lamotrigine tablets and lamotrigine tablets (chewable, dispersible) are indicated for the maintenance treatment of Bipolar I Disorder to delay the time to occurrence of mood episodes (depression, mania, hypomania, mixed episodes) in patients treated for acute mood episodes with standard therapy. The effectiveness of lamotrigine in the acute treatment of mood episodes has not been established.
  General Dosing Considerations for Epilepsy and Bipolar Disorder Patients:
  The risk of nonserious rash is increased when the recommended initial dose and/or the rate of dose escalation of Lamotrigine is exceeded. There are suggestions, yet to be proven, that the risk of severe, potentially life-threatening rash may be increased by (1) coadministration of lamotrigine with valproate, (2) exceeding the recommended initial dose of lamotrigine, or (3) exceeding the recommended dose escalation for lamotrigine. However, cases have been reported in the absence of these factors (see BOX WARNING). Therefore, it is important that the dosing recommendations be followed closely.
  It is recommended that lamotrigine not be restarted in patients who discontinued due to rash associated with prior treatment with lamotrigine, unless the potential benefits clearly outweigh the risks. If the decision is made to restart a patient who has discontinued lamotrigine, the need to restart with the initial dosing recommendations should be assessed. The greater the interval of time since the previous dose, the greater consideration should be given to restarting with the initial dosing recommendations. If a patient has discontinued lamotrigine for a period of more than 5 half-lives, it is recommended that initial dosing recommendations and guidelines be followed.
  Lamotrigine Tablets and Lamotrigine Tablets (Chewable, Dispersible)Added to Drugs Known to Induce or Inhibit Glucuronidation:
  Drugs other than those listed in PRECAUTIONS: Drug Interactionshave not been systematically evaluated in
  combination with Lamotrigine. Since lamotrigine is metabolized predominantly by glucuronic acid conjugation, drugs that are known to induce or inhibit glucuronidation may affect the apparent clearance of lamotrigine, and doses of Lamotrigine may require adjustment based on clinical response.
  Target Plasma Levels for Patients With Epilepsy or Bipolar Disorder:
  A therapeutic plasma concentration range has not been established for lamotrigine. Dosing of lamotrigine should be based on therapeutic response.
  The half-life of lamotrigine is affected by other concomitant medications (see CLINICAL PHARMACOLOGY: Pharmacokinetics and Drug Metabolism).
  See also DOSAGE AND ADMINISTRATION: Special Populations.
  Special Populations: Women and Oral Contraceptives: Starting Lamotrigine Tablets and LamotrigineTablets (Chewable, Dispersible)in Women Taking Oral Contraceptives
  Although estrogen-containing oral contraceptives have been shown to increase the clearance of lamotrigine (see PRECAUTIONS: Drug Interactions), no adjustments to the recommended dose escalation guidelines for lamotrigine should be necessary solely based on the use of estrogen-containing oral contraceptives. Therefore, dose escalation should follow the recommended guidelines for initiating adjunctive therapy with lamotrigine based on the concomitant AED (see Table 11). See below for adjustments to maintenance doses of lamotrigine in women taking estrogen-containing oral contraceptives.
  Adjustments to the Maintenance Dose of Lamotrigine Tablets and Lamotrigine Tablets (Chewable, Dispersible)
       1. Taking Estrogen-Containing Oral Contraceptives:
  For women not taking carbamazepine, phenytoin, phenobarbital, primidone,
  or rifampin, the maintenance dose of Lamotrigine will in most cases need to be increased, by as much as 2-fold over the recommended target maintenance dose, in order to maintain a consistent lamotrigine plasma level (see PRECAUTIONS: Drug Interactions). (2) Starting Estrogen-Containing Oral Contraceptives:In women taking a stable dose of Lamotrigine and not taking carbamazepine, phenytoin, phenobarbital, primidone, or rifampin, the maintenance dose will in most cases need to be increased by as much as 2-fold, in order to maintain a consistent lamotrigine plasma level. The dose increases should begin at the same time that the oral contraceptive is introduced and continue, based on clinical response, no more rapidly than 50 to 100 mg/day every week. Dose increases should not exceed the recommended rate unless lamotrigine plasma levels or clinical response support larger increases (see Table 11, column 2,). Gradual transient increases in lamotrigine plasma levels may occur during the week of inactive hormonal preparation ("pill-free" week), and these increases will be greater if dose increases are made in the days before or during the week of inactive hormonal preparation. Increased lamotrigine plasma levels could result in additional adverse events, such as dizziness, ataxia, and diplopia (see PRECAUTIONS: Drug Interactions). If adverse events attributable to lamotrigine consistently occur during the "pill-free" week, dose adjustments to the overall maintenance dose may be necessary. Dose adjustments limited to the "pill-free" week are not recommended. For women taking Lamotrigine in addition to carbamazepine, phenytoin, phenobarbital, primidone, or rifampin, no adjustment should be necessary to the dose of Lamotrigine. ( 3) Stopping Estrogen-Containing Oral Contraceptives:For women not taking carbamazepine, phenytoin, phenobarbital, primidone, or rifampin, the maintenance dose of lamotrigine will in most cases need to be decreased by as much as 50%, in order to maintain a consistent lamotrigine plasma level. The decrease in dose of Lamotrigine should not exceed 25% of the total daily dose per week over a 2-week period, unless clinical response or lamotrigine plasma levels indicate otherwise (see PRECAUTIONS: Drug Interactions). For women taking lamotrigine in addition to carbamazepine, phenytoin, phenobarbital, primidone, or rifampin, no adjustment to the dose of lamotrigine should be necessary.
  Women and Other Hormonal Contraceptive Preparations or Hormone Replacement Therapy:
  The effect of other hormonal contraceptive preparations or hormone replacement therapy on the pharmacokinetics of lamotrigine has not been systematically evaluated. It has been reported that ethinylestradiol, not progestogens, increased the clearance of lamotrigine up to 2-fold, and the progestin only pills had no effect on lamotrigine plasma levels. Therefore, adjustments to the dosage of lamotrigine in the presence of progestogens alone will likely not be needed.
  Patients With Hepatic Impairment:
  Experience in patients with hepatic impairment is limited. Based on a clinical pharmacology study in 24 patients with mild, moderate, and severe liver dysfunction (see CLINICAL PHARMACOLOGY), the following general recommendations can be made. No dosage adjustment is needed in patients with mild liver impairment. Initial, escalation, and maintenance doses should generally be reduced by approximately 25% in patients with moderate and severe liver impairment without
  ascites and 50% in patients with severe liver impairment with ascites. Escalation and maintenance doses may be adjusted according to clinical response.
  Patients With Renal Functional Impairment:
  Initial doses of lamotrigine tablets and lamotrigine tablets (chewable, dispersible) should be based on patients' AED regimen (see above); reduced maintenance doses may be effective for patients with significant renal functional impairment (see CLINICAL PHARMACOLOGY). Few patients with severe renal impairment have been evaluated during chronic treatment with lamotrigine. Because there is inadequate experience in this population, lamotrigine should be used with caution in these patients.
  Epilepsy:
  Adjunctive Therapy With Lamotrigine Tablets and Lamotrigine Tablets (Chewable, Dispersible) for Epilepsy:
  This section provides specific dosing recommendations for patients 2 to 12 years of age and patients greater than 12 years of age. Within each of these age-groups, specific dosing recommendations are provided depending upon concomitant AED (Table 9 for patients 2 to 12 years of age and Table 11 for patients greater than 12 years of age). A weight based dosing guide for pediatric patients on concomitant valproate is provided in Table 10.
  Patients 2 to 12 Years of Age:
  Recommended dosing guidelines are summarized in Table 9.
  Note that some of the starting doses and dose escalations listed in Table 9 are different than those used in clinical trials; however, the maintenance doses are the same as in clinical trials. Smaller starting doses and slower dose escalations than those used in clinical trials are recommended because of the suggestions that the risk of rash may be decreased by smaller starting doses and slower dose escalations. Therefore, maintenance doses will take longer to reach in clinical practice than in clinical trials. It may take several weeks to months to achieve an individualized maintenance dose. Maintenance doses in patients weighing less than 30 kg, regardless of age or concomitant AED, may need to be increased as much as 50%, based on clinical response.
  
  Table 9. Escalation Regimen for Lamotrigine in Patients 2 to 12 Years of Age With Epilepsy
  *Rifampin and estrogen-containing oral contraceptives have also been shown to increase the apparent clearance of lamotrigine (see PRECAUTIONS: Drug Interactions).For Patients Taking Valproate (see Table 10 for weight- based dosing guide)For Patients Taking AEDs Other Than Carbamazepine, Phenytoi n, Phenobarbital, Primidone *, or ValproateFor Patients Taking Carbamazepine, Phenytoin, Phenobarbital, Primidone *and Not Taking ValproateWeeks 1 and 20.15 mg/kg/day in 1 or 2 divided doses, rounded down to the nearest whole tablet (see Table 10 for weight-based dosing guide).0.3 mg/kg/day in 1 or 2 divided doses, rounded down to the nearest whole tablet.0.6 mg/kg/day in 2 divided doses, rounded down to the nearest whole tablet.Weeks 3 and 40.3 mg/kg/day in 1 or 2 divided doses, rounded down to the nearest whole tablet (see Table 10 for weight-based dosing guide).0.6 mg/kg/day in 2 divided doses, rounded down to the nearest whole tablet.1.2 mg/kg/day in 2 divided doses, rounded down to the nearest whole tablet.Weeks 5 onwards to maintenanceThe dose should be increased every 1 to 2 weeks as follows: calculate 0.3 mg/kg/day, round this amount down to the nearest whole tablet, and add this amount to the previously administered daily dose.The dose should be increased every 1 to 2 weeks as follows: calculate 0.6 mg/kg/day, round this amount down to the nearest whole tablet, and add this amount to the previously administered daily doseThe dose should be increased every 1 to 2 weeks as follows: calculate 1.2 mg/kg/day, round this amount down to the nearest whole tablet, and add this amount to the previously administered daily doseUsual Maintenance Dose1 to 5 mg/kg/day (maximum 200 mg/day in 1 or 2 divided doses). 1 to 3 mg/kg/day with valproate alone4.5 to 7.5 mg/kg/day (maximum 300 mg/day in 2 divided doses)5 to 15 mg/kg/day (maximum 400 mg/day in 2 divided doses)Maintenance dose in patients less than 30 kgMay need to be increased by as much as 50%, based on clinical responseMay need to be increased by as much as 50%, based on clinical responseMay need to be increased by as much as 50%, based on clinical responseNote: Only whole tablets should be used for dosing
  
  Table 10. The Initial Weight-Based Dosing Guide for Patients 2 to 12 Years Taking Valproate (Weeks 1 to 4) With Epilepsy
  If the patient's weight isGive this daily dose, using the most appropriate combination of lamotrigine tablets (chewable, dispersible), 5 mgGreater thanAnd less thanWeeks 1 and 2Weeks 3 and 434.1 kg40 kg5 mg every day10 mg every dayPatients Over 12 Years of Age:
  Recommended dosing guidelines are summarized in Table 11.
  
  Table 11. Escalation Regimen for Lamotrigine in Patients Over 12 Years of Age With Epilepsy
  *Rifampin and estrogen-containing oral contraceptives have also been shown to increase the apparent clearance of lamotrigine (see PRECAUTIONS: Drug Interactions).For Patients Taking ValproateFor Patients Taking AEDs Other Than Carbamazepine, Phenytoin, Phenobarbital, Primidone, or Valproate *For Patients Taking Carbamazepine, Phenytoin, PhenobarbitaL, Primidone *and Not Taking ValproateWeeks 1 and 225 mg every other day25 mg every day50 mg/dayWeeks 3 and 425 mg every day50 mg/day100 mg/day (in 2 divided doses)Weeks 5 onwards to maintenanceIncrease by 25 to 50 mg/ day every 1 to 2 weeksIncrease by 50 mg/ day every 1 to 2 weeksIncrease by 100 mg/ day every 1 to 2 weeks.Usual Maintenance Dose100 to 400 mg/day (1 or 2 divided doses) 100 to 200 mg/day with Valproate alone225 to 375 mg/day (in 2 divided doses).300 to 500 mg/day (in 2 divided doses).Conversion from Adjunctive Therapy With Carbamazepine, Phenytoin, Phenobarbital, Primidone, or Valproate as the Single AED to Monotherapy With Lamotrigine in PatientsYears of Age With Epilepsy:
  The goal of the transition regimen is to effect the conversion to monotherapy with Lamotrigine under conditions that ensure adequate seizure control while mitigating the risk of serious rash associated with the rapid titration of lamotrigine.
  The recommended maintenance dose of lamotrigine as monotherapy is 500 mg/day given in 2 divided doses.
  To avoid an increased risk of rash, the recommended initial dose and subsequent dose escalations of lamotrigine should not be exceeded (see BOX WARNING).
  Conversion From Adjunctive Therapy With Carbamazepine, Phenytoin, Phenobarbital, or Primidone to Monotherapy With Lamotrigine:
  After achieving a dose of 500 mg/day of lamotrigine according to the guidelines in Table 11, the concomitant AED should be withdrawn by 20% decrements each week over a 4-week period. The regimen for the withdrawal of the concomitant AED is based on experience gained in the controlled monotherapy clinical trial.
  Conversion from Adjunctive Therapy With Valproate to Monotherapy With Lamotrigine The conversion regimen involves 4 steps (see Table 12).
  
  Table 12. Conversion From Adjunctive Therapy With Valproate to Monotherapy With Lamotrigine in PatientsYears of Age With Epilepsy
  LamotrigineValproateStep 1Achieve a dose of 200 mg/day according to guidelines in Table 11 (if not already on 200 mg/ day).Maintain previous stable dose.Step 2Maintain at 200 mg/day.Decrease to 500 mg/day by decrements no greater than 500 mg/day per week and then maintain the dose of 500 mg/day for 1 week.Step 3Increase to 300 mg/day and maintain for 1 week.Simultaneously decrease to 250 mg/day and maintain for 1 week.Step 4Increase by 100 mg/day every week to achieve maintenance dose of 500 mg/day.Discontinue. Conversion from Adjunctive Therapy With Antiepileptic Drugs Other Than Carbamazepine, Phenytoin, Phenobarbital, Primidone, or Valproate to Monotherapy With Lamotrigine:
  No specific dosing guidelines can be provided for conversion to monotherapy with lamotrigine with AEDs other than carbamazepine, phenobarbital, phenytoin, primidone, or valproate.
  Usual Maintenance Dose for Epilepsy
  The usual maintenance doses identified in Tables 9-11 are derived from dosing regimens employed in the placebo-controlled adjunctive studies in which the efficacy of lamotrigine was established. In patients receiving multidrug regimens employing carbamazepine, phenytoin, phenobarbital, or primidone without valproate, maintenance doses of adjunctive Lamotrigine as high as 700 mg/day have been used. In patients receiving valproate alone, maintenance doses of adjunctive Lamotrigine as high as 200 mg/ day have been used. The advantage of using doses above those recommended in Tables 9-12 has not been established in controlled trials.
  Discontinuation Strategy for Patients With Epilepsy:
  For patients receiving lamotrigine in combination with other AEDs, a reevaluation of all AEDs in the regimen should be considered if a change in seizure control or an appearance or worsening of adverse experiences is observed.
  If a decision is made to discontinue therapy with Lamotrigine, a step-wise reduction of dose over at least 2 weeks (approximately 50% per week) is recommended unless safety concerns require a more rapid withdrawal (see PRECAUTIONS).
  Discontinuing carbamazepine, phenytoin, phenobarbital, or primidone should prolong the half-life of lamotrigine; discontinuing valproate should shorten the half-life of lamotrigine.
  Bipolar Disorder
  The goal of maintenance treatment with lamotrigine is to delay the time to occurrence of mood episodes (depression, mania, hypomania, mixed episodes) in patients treated for acute mood episodes with standard therapy. The target dose of lamotrigine is 200 mg/day (100 mg/day in patients taking valproate,which decreases the apparent clearance of lamotrigine, and 400 mg/day in patients not taking valproate and taking either carbamazepine, phenytoin, phenobarbital, primidone, or rifampin, which increase the apparent clearance of lamotrigine). In the clinical trials, doses up to 400 mg/day as monotherapy were evaluated, however, no additional benefit was seen at 400 mg/day compared to 200 mg/day (see CLINICAL STUDIES: Bipolar Disorder). Accordingly, doses above 200 mg/ day are not recommended. Treatment with lamotrigine is introduced, based on concurrent medications, according to the regimen outlined in Table 13. If other psychotropic medications are withdrawn following stabilization, the dose of lamotrigine should be adjusted. For patients discontinuing valproate, the dose of lamotrigine should be doubled over a 2-week period in equal weekly increments (see Table 14). For patients discontinuing carbamazepine, phenytoin, phenobarbital, primidone, or rifampin, the dose of lamotrigine should remain constant for the first week and then should be decreased by half over a 2-week period in equal weekly decrements (see Table 14). The dose of lamotrigine may then be further adjusted to the target dose (200 mg) as clinically indicated.
  Dosage adjustments will be necessary in most patients who start or stop estrogen-containing oral contraceptives while taking lamotrigine (see DOSAGE AND ADMINISTRATION: Special Populations: Women and Oral Contraceptives: Adjustments to the Maintenace Dose of Lamotrigine).
  If other drugs are subsequently introduced, the dose of Lamotrigine may need to be adjusted.
  In particular, the introduction of valproate requires reduction in the dose of Lamotrigine (see CLINICAL PHARMACOLOGY: Drug Interactions). To avoid an increased risk of rash, the recommended initial dose and subsequent dose escalations of Lamotrigine should not be exceeded (see BOX WARNING).
  
  Table 13. Escalation Regimen for Lamotrigine for Patients With Bipolar Disorder *
  *See CLINICAL PHARMACOLOGY: Drug Interactions:and PRECAUTIONS: Drug Interactionsfor a description of known drug interactions. Carbamazepine, phenytoin, phenobarbital, primidone, rifampin, have been shown to increase the apparent clearance of lamotrigine. Valproate has been shown to decrease the apparent clearance of lamotrigine.For Patients Not Taking Carbamazepine, Phenytoin, Phenobarbital, Primidone or Rifampin and Not Taking Valproate For Patients Taking Valproate For Patients Taking Carbamazepine (or Other Enzyme-Inducing Drugs) and Not Taking Valproate Weeks 1 and 225 mg daily25 mg every other day50 mg dailyWeeks 3 and 450 mg daily25 mg daily100 mg daily, in divided dosesWeek 5100 mg daily50 mg daily200 mg daily, in divided dosesWeek 6200 mg daily100 mg daily300 mg daily, in divided dosesWeek 7200 mg daily100 mg dailyup to 400 mg daily, in divided doses
  Table 14. Adjustments to Lamotrigine Dosing for Patients With Bipolar Disorder Following Discontinuation of Psychotropic Medications *
  *See CLINICAL PHARMACOLOGY: Drug Interactions:and PRECAUTIONS: Drug Interactionsfor a description of known drug interactions. Carbamazepine, phenytoin, phenobarbital, primidone, and rifampin have been shown to increase the apparent clearance of lamotrigine. Valproate has been shown to decrease the apparent clearance of lamotrigine.Discontinuation of Psychotropic Drugs (excluding Valproate , Carbamazepine, or Other Enzyme-Inducing Drugs )After Discontinuation of Valproate After Discontinuation of Carbamazepine or Other Enzyme-Inducing Drugs Current Lamotrigine dose (mg/day) 100Current Lamotrigine dose (mg/day) 400Week 1Maintain current lamotrigine dose150400Week 2Maintain current lamotrigine dose200300Week 3 onwardMaintain current lamotrigine dose200200There is no body of evidence available to answer the question of how long the patient should remain on lamotrigine therapy. Systematic evaluation of the efficacy of lamotrigine in patients with either depression or mania who responded to standard therapy during an acute 8 to 16 week treatment phase and were then randomized to lamotrigine or placebo for up to 76 weeks of observation for affective relapse demonstrated a benefit of such maintenance treatment (see CLINICAL STUDIES: Bipolar Disorder). Nevertheless, patients should be periodically reassessed to determine the need for maintenance treatment.
  Discontinuation Strategy in Bipolar Disorder:
  As with other AEDs, lamotrigine should not be abruptly discontinued. In the controlled clinical trials, there was no increase in the incidence, type, or severity of adverse experiences following abrupt termination of lamotrigine. In clinical trials in patients with bipolar disorder, 2 patients experienced seizures shortly after abrupt withdrawal of lamotrigine. However, there were confounding factors that may have contributed to the occurrence of seizures in these bipolar patients. Discontinuation of lamotrigine should involve a step-wise reduction of dose over at least 2 weeks (approximately 50% per week) unless safety concerns require a more rapid withdrawal.
  Administration of Lamotrigine Tablets (Chewable, Dispersible)
  Lamotrigine tablets (Chewable, Dispersible) may be swallowed whole, chewed, or dispersed in water or diluted fruit juice. If the tablets are chewed, consume a small amount of water or diluted fruit juice to aid in swallowing.
  To disperse lamotrigine tablets (chewable, dispersible), add the tablets to a small amount of liquid (1 teaspoon, or enough to cover the medication). Approximately 1 minute later, when the tablets are completely dispersed, swirl the solution and consume the entire quantity immediately.
  No attempt should be made to administer partial quantities of the dispersed tablets.
  
  

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  Epilepsy
  Adjunctive Use:
  Lamotrigine is indicated as adjunctive therapy for partial seizures and the generalized seizures of Lennox-Gastaut syndrome in adult and pediatric patients (years of age).
  Monotherapy Use:
  Lamotrigine tablets and lamotrigine tablets (chewable, dispersible) are indicated for conversion to monotherapy in adults with partial seizures who are receiving treatment with carbamazepine, phenytoin, phenobarbital, primidone, or valproate as the single AED.
  Safety and effectiveness of lamotrigine tablets and lamotrigine tablets (chewable, dispersible)have not been established. (1) as initial monotherapy, (2) for conversion to monotherapy from AEDs other than carbamazepine, phenytoin, phenobarbital, primidone, or valproate, or (3) for simultaneous conversion to monotherapy from 2 or more concomitant AEDs.
  Bipolar Disorder
  Lamotrigine tablets and lamotrigine tablets (chewable, dispersible) are indicated for the maintenance treatment of Bipolar I Disorder to delay the time to occurrence of mood episodes (depression, mania, hypomania, mixed episodes) in patients treated for acute mood episodes with standard therapy. The effectiveness of lamotrigine in the acute treatment of mood episodes has not been established.
  General Dosing Considerations for Epilepsy and Bipolar Disorder Patients:
  The risk of nonserious rash is increased when the recommended initial dose and/or the rate of dose escalation of Lamotrigine is exceeded. There are suggestions, yet to be proven, that the risk of severe, potentially life-threatening rash may be increased by (1) coadministration of lamotrigine with valproate, (2) exceeding the recommended initial dose of lamotrigine, or (3) exceeding the recommended dose escalation for lamotrigine. However, cases have been reported in the absence of these factors (see BOX WARNING). Therefore, it is important that the dosing recommendations be followed closely.
  It is recommended that lamotrigine not be restarted in patients who discontinued due to rash associated with prior treatment with lamotrigine, unless the potential benefits clearly outweigh the risks. If the decision is made to restart a patient who has discontinued lamotrigine, the need to restart with the initial dosing recommendations should be assessed. The greater the interval of time since the previous dose, the greater consideration should be given to restarting with the initial dosing recommendations. If a patient has discontinued lamotrigine for a period of more than 5 half-lives, it is recommended that initial dosing recommendations and guidelines be followed.
  Lamotrigine Tablets and Lamotrigine Tablets (Chewable, Dispersible)Added to Drugs Known to Induce or Inhibit Glucuronidation:
  Drugs other than those listed in PRECAUTIONS: Drug Interactionshave not been systematically evaluated in
  combination with Lamotrigine. Since lamotrigine is metabolized predominantly by glucuronic acid conjugation, drugs that are known to induce or inhibit glucuronidation may affect the apparent clearance of lamotrigine, and doses of Lamotrigine may require adjustment based on clinical response.
  Target Plasma Levels for Patients With Epilepsy or Bipolar Disorder:
  A therapeutic plasma concentration range has not been established for lamotrigine. Dosing of lamotrigine should be based on therapeutic response.
  The half-life of lamotrigine is affected by other concomitant medications (see CLINICAL PHARMACOLOGY: Pharmacokinetics and Drug Metabolism).
  See also DOSAGE AND ADMINISTRATION: Special Populations.
  Special Populations: Women and Oral Contraceptives: Starting Lamotrigine Tablets and LamotrigineTablets (Chewable, Dispersible)in Women Taking Oral Contraceptives
  Although estrogen-containing oral contraceptives have been shown to increase the clearance of lamotrigine (see PRECAUTIONS: Drug Interactions), no adjustments to the recommended dose escalation guidelines for lamotrigine should be necessary solely based on the use of estrogen-containing oral contraceptives. Therefore, dose escalation should follow the recommended guidelines for initiating adjunctive therapy with lamotrigine based on the concomitant AED (see Table 11). See below for adjustments to maintenance doses of lamotrigine in women taking estrogen-containing oral contraceptives.
  Adjustments to the Maintenance Dose of Lamotrigine Tablets and Lamotrigine Tablets (Chewable, Dispersible)
       Taking Estrogen-Containing Oral Contraceptives:
  For women not taking carbamazepine, phenytoin, phenobarbital, primidone,
  or rifampin, the maintenance dose of Lamotrigine will in most cases need to be increased, by as much as 2-fold over the recommended target maintenance dose, in order to maintain a consistent lamotrigine plasma level (see PRECAUTIONS: Drug Interactions). (2) Starting Estrogen-Containing Oral Contraceptives: In women taking a stable dose of Lamotrigine and not taking carbamazepine, phenytoin, phenobarbital, primidone, or rifampin, the maintenance dose will in most cases need to be increased by as much as 2-fold, in order to maintain a consistent lamotrigine plasma level. The dose increases should begin at the same time that the oral contraceptive is introduced and continue, based on clinical response, no more rapidly than 50 to 100 mg/day every week. Dose increases should not exceed the recommended rate unless lamotrigine plasma levels or clinical response support larger increases (see Table 11, column 2,). Gradual transient increases in lamotrigine plasma levels may occur during the week of inactive hormonal preparation ("pill-free" week), and these increases will be greater if dose increases are made in the days before or during the week of inactive hormonal preparation. Increased lamotrigine plasma levels could result in additional adverse events, such as dizziness, ataxia, and diplopia (see PRECAUTIONS: Drug Interactions). If adverse events attributable to lamotrigine consistently occur during the "pill-free" week, dose adjustments to the overall maintenance dose may be necessary. Dose adjustments limited to the "pill-free" week are not recommended. For women taking Lamotrigine in addition to carbamazepine, phenytoin, phenobarbital, primidone, or rifampin, no adjustment should be necessary to the dose of Lamotrigine. (3) Stopping Estrogen-Containing Oral Contraceptives: For women not taking carbamazepine, phenytoin, phenobarbital, primidone, or rifampin, the maintenance dose of lamotrigine will in most cases need to be decreased by as much as 50%, in order to maintain a consistent lamotrigine plasma level. The decrease in dose of Lamotrigine should not exceed 25% of the total daily dose per week over a 2-week period, unless clinical response or lamotrigine plasma levels indicate otherwise (see PRECAUTIONS: Drug Interactions). For women taking lamotrigine in addition to carbamazepine, phenytoin, phenobarbital, primidone, or rifampin, no adjustment to the dose of lamotrigine should be necessary.
  Women and Other Hormonal Contraceptive Preparations or Hormone Replacement Therapy:
  The effect of other hormonal contraceptive preparations or hormone replacement therapy on the pharmacokinetics of lamotrigine has not been systematically evaluated. It has been reported that ethinylestradiol, not progestogens, increased the clearance of lamotrigine up to 2-fold, and the progestin only pills had no effect on lamotrigine plasma levels. Therefore, adjustments to the dosage of lamotrigine in the presence of progestogens alone will likely not be needed.
  Patients With Hepatic Impairment:
  Experience in patients with hepatic impairment is limited. Based on a clinical pharmacology study in 24 patients with mild, moderate, and severe liver dysfunction (see CLINICAL PHARMACOLOGY), the following general recommendations can be made. No dosage adjustment is needed in patients with mild liver impairment. Initial, escalation, and maintenance doses should generally be reduced by approximately 25% in patients with moderate and severe liver impairment without
  ascites and 50% in patients with severe liver impairment with ascites. Escalation and maintenance doses may be adjusted according to clinical response.
  Patients With Renal Functional Impairment:
  Initial doses of lamotrigine tablets and lamotrigine tablets (chewable, dispersible) should be based on patients' AED regimen (see above); reduced maintenance doses may be effective for patients with significant renal functional impairment (see CLINICAL PHARMACOLOGY). Few patients with severe renal impairment have been evaluated during chronic treatment with lamotrigine. Because there is inadequate experience in this population, lamotrigine should be used with caution in these patients.
  Epilepsy:
  Adjunctive Therapy With Lamotrigine Tablets and Lamotrigine Tablets (Chewable, Dispersible) for Epilepsy:
  This section provides specific dosing recommendations for patients 2 to 12 years of age and patients greater than 12 years of age. Within each of these age-groups, specific dosing recommendations are provided depending upon concomitant AED (Table 9 for patients 2 to 12 years of age and Table 11 for patients greater than 12 years of age). A weight based dosing guide for pediatric patients on concomitant valproate is provided in Table 10.
  Patients 2 to 12 Years of Age:
  Recommended dosing guidelines are summarized in Table 9.
  Note that some of the starting doses and dose escalations listed in Table 9 are different than those used in clinical trials; however, the maintenance doses are the same as in clinical trials. Smaller starting doses and slower dose escalations than those used in clinical trials are recommended because of the suggestions that the risk of rash may be decreased by smaller starting doses and slower dose escalations. Therefore, maintenance doses will take longer to reach in clinical practice than in clinical trials. It may take several weeks to months to achieve an individualized maintenance dose. Maintenance doses in patients weighing less than 30 kg, regardless of age or concomitant AED, may need to be increased as much as 50%, based on clinical response.
  
  Table 9. Escalation Regimen for Lamotrigine in Patients 2 to 12 Years of Age With Epilepsy
  *Rifampin and estrogen-containing oral contraceptives have also been shown to increase the apparent clearance of lamotrigine (see PRECAUTIONS: Drug Interactions).For Patients Taking Valproate (see Table 10 for weight- based dosing guide)For Patients Taking AEDs Other Than Carbamazepine, Phenytoi n, Phenobarbital, Primidone *, or ValproateFor Patients Taking Carbamazepine, Phenytoin, Phenobarbital, Primidone *and Not Taking ValproateWeeks 1 and 20.15 mg/kg/day in 1 or 2 divided doses, rounded down to the nearest whole tablet (see Table 10 for weight-based dosing guide).0.3 mg/kg/day in 1 or 2 divided doses, rounded down to the nearest whole tablet.0.6 mg/kg/day in 2 divided doses, rounded down to the nearest whole tablet.Weeks 3 and 40.3 mg/kg/day in 1 or 2 divided doses, rounded down to the nearest whole tablet (see Table 10 for weight-based dosing guide).0.6 mg/kg/day in 2 divided doses, rounded down to the nearest whole tablet.1.2 mg/kg/day in 2 divided doses, rounded down to the nearest whole tablet.Weeks 5 onwards to maintenanceThe dose should be increased every 1 to 2 weeks as follows: calculate 0.3 mg/kg/day, round this amount down to the nearest whole tablet, and add this amount to the previously administered daily dose.The dose should be increased every 1 to 2 weeks as follows: calculate 0.6 mg/kg/day, round this amount down to the nearest whole tablet, and add this amount to the previously administered daily doseThe dose should be increased every 1 to 2 weeks as follows: calculate 1.2 mg/kg/day, round this amount down to the nearest whole tablet, and add this amount to the previously administered daily doseUsual Maintenance Dose1 to 5 mg/kg/day (maximum 200 mg/day in 1 or 2 divided doses). 1 to 3 mg/kg/day with valproate alone4.5 to 7.5 mg/kg/day (maximum 300 mg/day in 2 divided doses)5 to 15 mg/kg/day (maximum 400 mg/day in 2 divided doses)Maintenance dose in patients less than 30 kgMay need to be increased by as much as 50%, based on clinical responseMay need to be increased by as much as 50%, based on clinical responseMay need to be increased by as much as 50%, based on clinical responseNote: Only whole tablets should be used for dosing
  
  Table 10. The Initial Weight-Based Dosing Guide for Patients 2 to 12 Years Taking Valproate (Weeks 1 to 4) With Epilepsy
  If the patient's weight isGive this daily dose, using the most appropriate combination of lamotrigine tablets (chewable, dispersible), 5 mgGreater thanAnd less thanWeeks 1 and 2Weeks 3 and 434.1 kg40 kg5 mg every day10 mg every dayPatients Over 12 Years of Age:
  Recommended dosing guidelines are summarized in Table 11.
  
  Table 11. Escalation Regimen for Lamotrigine in Patients Over 12 Years of Age With Epilepsy
  *Rifampin and estrogen-containing oral contraceptives have also been shown to increase the apparent clearance of lamotrigine (see PRECAUTIONS: Drug Interactions).For Patients Taking ValproateFor Patients Taking AEDs Other Than Carbamazepine, Phenytoin, Phenobarbital, Primidone, or Valproate *For Patients Taking Carbamazepine, Phenytoin, PhenobarbitaL, Primidone *and Not Taking ValproateWeeks 1 and 225 mg every other day25 mg every day50 mg/dayWeeks 3 and 425 mg every day50 mg/day100 mg/day (in 2 divided doses)Weeks 5 onwards to maintenanceIncrease by 25 to 50 mg/ day every 1 to 2 weeksIncrease by 50 mg/ day every 1 to 2 weeksIncrease by 100 mg/ day every 1 to 2 weeks.Usual Maintenance Dose100 to 400 mg/day (1 or 2 divided doses) 100 to 200 mg/day with Valproate alone225 to 375 mg/day (in 2 divided doses).300 to 500 mg/day (in 2 divided doses).Conversion from Adjunctive Therapy With Carbamazepine, Phenytoin, Phenobarbital, Primidone, or Valproate as the Single AED to Monotherapy With Lamotrigine in PatientsYears of Age With Epilepsy:
  The goal of the transition regimen is to effect the conversion to monotherapy with Lamotrigine under conditions that ensure adequate seizure control while mitigating the risk of serious rash associated with the rapid titration of lamotrigine.
  The recommended maintenance dose of lamotrigine as monotherapy is 500 mg/day given in 2 divided doses.
  To avoid an increased risk of rash, the recommended initial dose and subsequent dose escalations of lamotrigine should not be exceeded (see BOX WARNING).
  Conversion From Adjunctive Therapy With Carbamazepine, Phenytoin, Phenobarbital, or Primidone to Monotherapy With Lamotrigine:
  After achieving a dose of 500 mg/day of lamotrigine according to the guidelines in Table 11, the concomitant AED should be withdrawn by 20% decrements each week over a 4-week period. The regimen for the withdrawal of the concomitant AED is based on experience gained in the controlled monotherapy clinical trial.
  Conversion from Adjunctive Therapy With Valproate to Monotherapy With Lamotrigine The conversion regimen involves 4 steps (see Table 12).
  
  Table 12. Conversion From Adjunctive Therapy With Valproate to Monotherapy With Lamotrigine in PatientsYears of Age With Epilepsy
  LamotrigineValproateStep 1Achieve a dose of 200 mg/day according to guidelines in Table 11 (if not already on 200 mg/ day).Maintain previous stable dose.Step 2Maintain at 200 mg/day.Decrease to 500 mg/day by decrements no greater than 500 mg/day per week and then maintain the dose of 500 mg/day for 1 week.Step 3Increase to 300 mg/day and maintain for 1 week.Simultaneously decrease to 250 mg/day and maintain for 1 week.Step 4Increase by 100 mg/day every week to achieve maintenance dose of 500 mg/day.Discontinue.Conversion from Adjunctive Therapy With Antiepileptic Drugs Other Than Carbamazepine, Phenytoin, Phenobarbital, Primidone, or Valproate to Monotherapy With Lamotrigine:
  No specific dosing guidelines can be provided for conversion to monotherapy with lamotrigine with AEDs other than carbamazepine, phenobarbital, phenytoin, primidone, or valproate.
  Usual Maintenance Dose for Epilepsy
  The usual maintenance doses identified in Tables 9-11 are derived from dosing regimens employed in the placebo-controlled adjunctive studies in which the efficacy of lamotrigine was established. In patients receiving multidrug regimens employing carbamazepine, phenytoin, phenobarbital, or primidone without valproate, maintenance doses of adjunctive Lamotrigine as high as 700 mg/day have been used. In patients receiving valproate alone, maintenance doses of adjunctive Lamotrigine as high as 200 mg/ day have been used. The advantage of using doses above those recommended in Tables 9-12 has not been established in controlled trials.
  Discontinuation Strategy for Patients With Epilepsy:
  For patients receiving lamotrigine in combination with other AEDs, a reevaluation of all AEDs in the regimen should be considered if a change in seizure control or an appearance or worsening of adverse experiences is observed.
  If a decision is made to discontinue therapy with Lamotrigine, a step-wise reduction of dose over at least 2 weeks (approximately 50% per week) is recommended unless safety concerns require a more rapid withdrawal (see PRECAUTIONS).
  Discontinuing carbamazepine, phenytoin, phenobarbital, or primidone should prolong the half-life of lamotrigine; discontinuing valproate should shorten the half-life of lamotrigine.
  Bipolar Disorder
  The goal of maintenance treatment with lamotrigine is to delay the time to occurrence of mood episodes (depression, mania, hypomania, mixed episodes) in patients treated for acute mood episodes with standard therapy. The target dose of lamotrigine is 200 mg/day (100 mg/day in patients taking valproate,which decreases the apparent clearance of lamotrigine, and 400 mg/day in patients not taking valproate and taking either carbamazepine, phenytoin, phenobarbital, primidone, or rifampin, which increase the apparent clearance of lamotrigine). In the clinical trials, doses up to 400 mg/day as monotherapy were evaluated, however, no additional benefit was seen at 400 mg/day compared to 200 mg/day (see CLINICAL STUDIES: Bipolar Disorder). Accordingly, doses above 200 mg/ day are not recommended. Treatment with lamotrigine is introduced, based on concurrent medications, according to the regimen outlined in Table 13. If other psychotropic medications are withdrawn following stabilization, the dose of lamotrigine should be adjusted. For patients discontinuing valproate, the dose of lamotrigine should be doubled over a 2-week period in equal weekly increments (see Table 14). For patients discontinuing carbamazepine, phenytoin, phenobarbital, primidone, or rifampin, the dose of lamotrigine should remain constant for the first week and then should be decreased by half over a 2-week period in equal weekly decrements (see Table 14). The dose of lamotrigine may then be further adjusted to the target dose (200 mg) as clinically indicated.
  Dosage adjustments will be necessary in most patients who start or stop estrogen-containing oral contraceptives while taking lamotrigine (see DOSAGE AND ADMINISTRATION: Special Populations: Women and Oral Contraceptives: Adjustments to the Maintenace Dose of Lamotrigine).
  If other drugs are subsequently introduced, the dose of Lamotrigine may need to be adjusted.
  In particular, the introduction of valproate requires reduction in the dose of Lamotrigine (see CLINICAL PHARMACOLOGY: Drug Interactions). To avoid an increased risk of rash, the recommended initial dose and subsequent dose escalations of Lamotrigine should not be exceeded (see BOX WARNING).
  
  Table 13. Escalation Regimen for Lamotrigine for Patients With Bipolar Disorder *
  *See CLINICAL PHARMACOLOGY: Drug Interactions:and PRECAUTIONS: Drug Interactionsfor a description of known drug interactions. Carbamazepine, phenytoin, phenobarbital, primidone, rifampin, have been shown to increase the apparent clearance of lamotrigine. Valproate has been shown to decrease the apparent clearance of lamotrigine.For Patients Not Taking Carbamazepine, Phenytoin, Phenobarbital, Primidone or Rifampin and Not Taking Valproate For Patients Taking Valproate For Patients Taking Carbamazepine (or Other Enzyme-Inducing Drugs) and Not Taking Valproate Weeks 1 and 225 mg daily25 mg every other day50 mg dailyWeeks 3 and 450 mg daily25 mg daily100 mg daily, in divided dosesWeek 5100 mg daily50 mg daily200 mg daily, in divided dosesWeek 6200 mg daily100 mg daily300 mg daily, in divided dosesWeek 7200 mg daily100 mg dailyup to 400 mg daily, in divided doses
  Table 14. Adjustments to Lamotrigine Dosing for Patients With Bipolar Disorder Following Discontinuation of Psychotropic Medications *
  *See CLINICAL PHARMACOLOGY: Drug Interactions:and PRECAUTIONS: Drug Interactionsfor a description of known drug interactions. Carbamazepine, phenytoin, phenobarbital, primidone, and rifampin have been shown to increase the apparent clearance of lamotrigine. Valproate has been shown to decrease the apparent clearance of lamotrigine.Discontinuation of Psychotropic Drugs (excluding Valproate , Carbamazepine, or Other Enzyme-Inducing Drugs )After Discontinuation of Valproate After Discontinuation of Carbamazepine or Other Enzyme-Inducing Drugs Current Lamotrigine dose (mg/day) 100Current Lamotrigine dose (mg/day) 400Week 1Maintain current lamotrigine dose150400Week 2Maintain current lamotrigine dose200300Week 3 onwardMaintain current lamotrigine dose200200There is no body of evidence available to answer the question of how long the patient should remain on lamotrigine therapy. Systematic evaluation of the efficacy of lamotrigine in patients with either depression or mania who responded to standard therapy during an acute 8 to 16 week treatment phase and were then randomized to lamotrigine or placebo for up to 76 weeks of observation for affective relapse demonstrated a benefit of such maintenance treatment (see CLINICAL STUDIES: Bipolar Disorder). Nevertheless, patients should be periodically reassessed to determine the need for maintenance treatment.
  Discontinuation Strategy in Bipolar Disorder:
  As with other AEDs, lamotrigine should not be abruptly discontinued. In the controlled clinical trials, there was no increase in the incidence, type, or severity of adverse experiences following abrupt termination of lamotrigine. In clinical trials in patients with bipolar disorder, 2 patients experienced seizures shortly after abrupt withdrawal of lamotrigine. However, there were confounding factors that may have contributed to the occurrence of seizures in these bipolar patients. Discontinuation of lamotrigine should involve a step-wise reduction of dose over at least 2 weeks (approximately 50% per week) unless safety concerns require a more rapid withdrawal.
  Administration of Lamotrigine Tablets (Chewable, Dispersible)
  Lamotrigine tablets (Chewable, Dispersible) may be swallowed whole, chewed, or dispersed in water or diluted fruit juice. If the tablets are chewed, consume a small amount of water or diluted fruit juice to aid in swallowing.
  To disperse lamotrigine tablets (chewable, dispersible), add the tablets to a small amount of liquid (1 teaspoon, or enough to cover the medication). Approximately 1 minute later, when the tablets are completely dispersed, swirl the solution and consume the entire quantity immediately.
  No attempt should be made to administer partial quantities of the dispersed tablets.
  
  

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  Epilepsy
  Adjunctive Use:
  Lamotrigine is indicated as adjunctive therapy for partial seizures and the generalized seizures of Lennox-Gastaut syndrome in adult and pediatric patients (years of age).
  Monotherapy Use:
  Lamotrigine tablets and lamotrigine tablets (chewable, dispersible) are indicated for conversion to monotherapy in adults with partial seizures who are receiving treatment with carbamazepine, phenytoin, phenobarbital, primidone, or valproate as the single AED.
  Safety and effectiveness of lamotrigine tablets and lamotrigine tablets (chewable, dispersible)have not been established. (1) as initial monotherapy, (2) for conversion to monotherapy from AEDs other than carbamazepine, phenytoin, phenobarbital, primidone, or valproate, or (3) for simultaneous conversion to monotherapy from 2 or more concomitant AEDs.
  Bipolar Disorder
  Lamotrigine tablets and lamotrigine tablets (chewable, dispersible) are indicated for the maintenance treatment of Bipolar I Disorder to delay the time to occurrence of mood episodes (depression, mania, hypomania, mixed episodes) in patients treated for acute mood episodes with standard therapy. The effectiveness of lamotrigine in the acute treatment of mood episodes has not been established.
  General Dosing Considerations for Epilepsy and Bipolar Disorder Patients:
  The risk of nonserious rash is increased when the recommended initial dose and/or the rate of dose escalation of Lamotrigine is exceeded. There are suggestions, yet to be proven, that the risk of severe, potentially life-threatening rash may be increased by (1) coadministration of lamotrigine with valproate, (2) exceeding the recommended initial dose of lamotrigine, or (3) exceeding the recommended dose escalation for lamotrigine. However, cases have been reported in the absence of these factors (see BOX WARNING). Therefore, it is important that the dosing recommendations be followed closely.
  It is recommended that lamotrigine not be restarted in patients who discontinued due to rash associated with prior treatment with lamotrigine, unless the potential benefits clearly outweigh the risks. If the decision is made to restart a patient who has discontinued lamotrigine, the need to restart with the initial dosing recommendations should be assessed. The greater the interval of time since the previous dose, the greater consideration should be given to restarting with the initial dosing recommendations. If a patient has discontinued lamotrigine for a period of more than 5 half-lives, it is recommended that initial dosing recommendations and guidelines be followed.
  Lamotrigine Tablets and Lamotrigine Tablets (Chewable, Dispersible)Added to Drugs Known to Induce or Inhibit Glucuronidation:
  Drugs other than those listed in PRECAUTIONS: Drug Interactionshave not been systematically evaluated in
  combination with Lamotrigine. Since lamotrigine is metabolized predominantly by glucuronic acid conjugation, drugs that are known to induce or inhibit glucuronidation may affect the apparent clearance of lamotrigine, and doses of Lamotrigine may require adjustment based on clinical response.
  Target Plasma Levels for Patients With Epilepsy or Bipolar Disorder:
  A therapeutic plasma concentration range has not been established for lamotrigine. Dosing of lamotrigine should be based on therapeutic response.
  The half-life of lamotrigine is affected by other concomitant medications (see CLINICAL PHARMACOLOGY: Pharmacokinetics and Drug Metabolism).
  See also DOSAGE AND ADMINISTRATION: Special Populations.
  Special Populations: Women and Oral Contraceptives: Starting Lamotrigine Tablets and LamotrigineTablets (Chewable, Dispersible)in Women Taking Oral Contraceptives
  Although estrogen-containing oral contraceptives have been shown to increase the clearance of lamotrigine (see PRECAUTIONS: Drug Interactions), no adjustments to the recommended dose escalation guidelines for lamotrigine should be necessary solely based on the use of estrogen-containing oral contraceptives. Therefore, dose escalation should follow the recommended guidelines for initiating adjunctive therapy with lamotrigine based on the concomitant AED (see Table 11). See below for adjustments to maintenance doses of lamotrigine in women taking estrogen-containing oral contraceptives.
  Adjustments to the Maintenance Dose of Lamotrigine Tablets and Lamotrigine Tablets (Chewable, Dispersible)
       1. Taking Estrogen-Containing Oral Contraceptives:
  For women not taking carbamazepine, phenytoin, phenobarbital, primidone,
  or rifampin, the maintenance dose of Lamotrigine will in most cases need to be increased, by as much as 2-fold over the recommended target maintenance dose, in order to maintain a consistent lamotrigine plasma level (see PRECAUTIONS: Drug Interactions). (2) Starting Estrogen-Containing Oral Contraceptives: In women taking a stable dose of Lamotrigine and not taking carbamazepine, phenytoin, phenobarbital, primidone, or rifampin, the maintenance dose will in most cases need to be increased by as much as 2-fold, in order to maintain a consistent lamotrigine plasma level. The dose increases should begin at the same time that the oral contraceptive is introduced and continue, based on clinical response, no more rapidly than 50 to 100 mg/day every week. Dose increases should not exceed the recommended rate unless lamotrigine plasma levels or clinical response support larger increases (see Table 11, column 2,). Gradual transient increases in lamotrigine plasma levels may occur during the week of inactive hormonal preparation ("pill-free" week), and these increases will be greater if dose increases are made in the days before or during the week of inactive hormonal preparation. Increased lamotrigine plasma levels could result in additional adverse events, such as dizziness, ataxia, and diplopia (see PRECAUTIONS: Drug Interactions). If adverse events attributable to lamotrigine consistently occur during the "pill-free" week, dose adjustments to the overall maintenance dose may be necessary. Dose adjustments limited to the "pill-free" week are not recommended. For women taking Lamotrigine in addition to carbamazepine, phenytoin, phenobarbital, primidone, or rifampin, no adjustment should be necessary to the dose of Lamotrigine. (3) Stopping Estrogen-Containing Oral Contraceptives: For women not taking carbamazepine, phenytoin, phenobarbital, primidone, or rifampin, the maintenance dose of lamotrigine will in most cases need to be decreased by as much as 50%, in order to maintain a consistent lamotrigine plasma level. The decrease in dose of Lamotrigine should not exceed 25% of the total daily dose per week over a 2-week period, unless clinical response or lamotrigine plasma levels indicate otherwise (see PRECAUTIONS: Drug Interactions). For women taking lamotrigine in addition to carbamazepine, phenytoin, phenobarbital, primidone, or rifampin, no adjustment to the dose of lamotrigine should be necessary.
  Women and Other Hormonal Contraceptive Preparations or Hormone Replacement Therapy:
  The effect of other hormonal contraceptive preparations or hormone replacement therapy on the pharmacokinetics of lamotrigine has not been systematically evaluated. It has been reported that ethinylestradiol, not progestogens, increased the clearance of lamotrigine up to 2-fold, and the progestin only pills had no effect on lamotrigine plasma levels. Therefore, adjustments to the dosage of lamotrigine in the presence of progestogens alone will likely not be needed.
  Patients With Hepatic Impairment:
  Experience in patients with hepatic impairment is limited. Based on a clinical pharmacology study in 24 patients with mild, moderate, and severe liver dysfunction (see CLINICAL PHARMACOLOGY), the following general recommendations can be made. No dosage adjustment is needed in patients with mild liver impairment. Initial, escalation, and maintenance doses should generally be reduced by approximately 25% in patients with moderate and severe liver impairment without
  ascites and 50% in patients with severe liver impairment with ascites. Escalation and maintenance doses may be adjusted according to clinical response.
  Patients With Renal Functional Impairment:
  Initial doses of lamotrigine tablets and lamotrigine tablets (chewable, dispersible) should be based on patients' AED regimen (see above); reduced maintenance doses may be effective for patients with significant renal functional impairment (see CLINICAL PHARMACOLOGY). Few patients with severe renal impairment have been evaluated during chronic treatment with lamotrigine. Because there is inadequate experience in this population, lamotrigine should be used with caution in these patients.
  Epilepsy:
  Adjunctive Therapy With Lamotrigine Tablets and Lamotrigine Tablets (Chewable, Dispersible) for Epilepsy:
  This section provides specific dosing recommendations for patients 2 to 12 years of age and patients greater than 12 years of age. Within each of these age-groups, specific dosing recommendations are provided depending upon concomitant AED (Table 9 for patients 2 to 12 years of age and Table 11 for patients greater than 12 years of age). A weight based dosing guide for pediatric patients on concomitant valproate is provided in Table 10.
  Patients 2 to 12 Years of Age:
  Recommended dosing guidelines are summarized in Table 9.
  Note that some of the starting doses and dose escalations listed in Table 9 are different than those used in clinical trials; however, the maintenance doses are the same as in clinical trials. Smaller starting doses and slower dose escalations than those used in clinical trials are recommended because of the suggestions that the risk of rash may be decreased by smaller starting doses and slower dose escalations. Therefore, maintenance doses will take longer to reach in clinical practice than in clinical trials. It may take several weeks to months to achieve an individualized maintenance dose. Maintenance doses in patients weighing less than 30 kg, regardless of age or concomitant AED, may need to be increased as much as 50%, based on clinical response.
  
  Table 9. Escalation Regimen for Lamotrigine in Patients 2 to 12 Years of Age With Epilepsy
  *Rifampin and estrogen-containing oral contraceptives have also been shown to increase the apparent clearance of lamotrigine (see PRECAUTIONS: Drug Interactions).For Patients Taking Valproate (see Table 10 for weight- based dosing guide)For Patients Taking AEDs Other Than Carbamazepine, Phenytoi n, Phenobarbital, Primidone *, or ValproateFor Patients Taking Carbamazepine, Phenytoin, Phenobarbital, Primidone *and Not Taking ValproateWeeks 1 and 20.15 mg/kg/day in 1 or 2 divided doses, rounded down to the nearest whole tablet (see Table 10 for weight-based dosing guide).0.3 mg/kg/day in 1 or 2 divided doses, rounded down to the nearest whole tablet.0.6 mg/kg/day in 2 divided doses, rounded down to the nearest whole tablet.Weeks 3 and 40.3 mg/kg/day in 1 or 2 divided doses, rounded down to the nearest whole tablet (see Table 10 for weight-based dosing guide).0.6 mg/kg/day in 2 divided doses, rounded down to the nearest whole tablet.1.2 mg/kg/day in 2 divided doses, rounded down to the nearest whole tablet.Weeks 5 onwards to maintenanceThe dose should be increased every 1 to 2 weeks as follows: calculate 0.3 mg/kg/day, round this amount down to the nearest whole tablet, and add this amount to the previously administered daily dose.The dose should be increased every 1 to 2 weeks as follows: calculate 0.6 mg/kg/day, round this amount down to the nearest whole tablet, and add this amount to the previously administered daily doseThe dose should be increased every 1 to 2 weeks as follows: calculate 1.2 mg/kg/day, round this amount down to the nearest whole tablet, and add this amount to the previously administered daily doseUsual Maintenance Dose1 to 5 mg/kg/day (maximum 200 mg/day in 1 or 2 divided doses). 1 to 3 mg/kg/day with valproate alone4.5 to 7.5 mg/kg/day (maximum 300 mg/day in 2 divided doses)5 to 15 mg/kg/day (maximum 400 mg/day in 2 divided doses)Maintenance dose in patients less than 30 kgMay need to be increased by as much as 50%, based on clinical responseMay need to be increased by as much as 50%, based on clinical responseMay need to be increased by as much as 50%, based on clinical responseNote: Only whole tablets should be used for dosing
  
  Table 10. The Initial Weight-Based Dosing Guide for Patients 2 to 12 Years Taking Valproate (Weeks 1 to 4) With Epilepsy
  If the patient's weight isGive this daily dose, using the most appropriate combination of lamotrigine tablets (chewable, dispersible), 5 mgGreater thanAnd less thanWeeks 1 and 2Weeks 3 and 434.1 kg40 kg5 mg every day10 mg every dayPatients Over 12 Years of Age:
  Recommended dosing guidelines are summarized in Table 11.
  
  Table 11. Escalation Regimen for Lamotrigine in Patients Over 12 Years of Age With Epilepsy
  *Rifampin and estrogen-containing oral contraceptives have also been shown to increase the apparent clearance of lamotrigine (see PRECAUTIONS: Drug Interactions).For Patients Taking ValproateFor Patients Taking AEDs Other Than Carbamazepine, Phenytoin, Phenobarbital, Primidone, or Valproate *For Patients Taking Carbamazepine, Phenytoin, PhenobarbitaL, Primidone *and Not Taking ValproateWeeks 1 and 225 mg every other day25 mg every day50 mg/dayWeeks 3 and 425 mg every day50 mg/day100 mg/day (in 2 divided doses)Weeks 5 onwards to maintenanceIncrease by 25 to 50 mg/ day every 1 to 2 weeksIncrease by 50 mg/ day every 1 to 2 weeksIncrease by 100 mg/ day every 1 to 2 weeks.Usual Maintenance Dose100 to 400 mg/day (1 or 2 divided doses) 100 to 200 mg/day with Valproate alone225 to 375 mg/day (in 2 divided doses).300 to 500 mg/day (in 2 divided doses). Conversion from Adjunctive Therapy With Carbamazepine, Phenytoin, Phenobarbital, Primidone, or Valproate as the Single AED to Monotherapy With Lamotrigine in PatientsYears of Age With Epilepsy:
  The goal of the transition regimen is to effect the conversion to monotherapy with Lamotrigine under conditions that ensure adequate seizure control while mitigating the risk of serious rash associated with the rapid titration of lamotrigine.
  The recommended maintenance dose of lamotrigine as monotherapy is 500 mg/day given in 2 divided doses.
  To avoid an increased risk of rash, the recommended initial dose and subsequent dose escalations of lamotrigine should not be exceeded (see BOX WARNING).
  Conversion From Adjunctive Therapy With Carbamazepine, Phenytoin, Phenobarbital, or Primidone to Monotherapy With Lamotrigine:
  After achieving a dose of 500 mg/day of lamotrigine according to the guidelines in Table 11, the concomitant AED should be withdrawn by 20% decrements each week over a 4-week period. The regimen for the withdrawal of the concomitant AED is based on experience gained in the controlled monotherapy clinical trial.
  Conversion from Adjunctive Therapy With Valproate to Monotherapy With LamotrigineThe conversion regimen involves 4 steps (see Table 12).
  
  Table 12. Conversion From Adjunctive Therapy With Valproate to Monotherapy With Lamotrigine in PatientsYears of Age With Epilepsy
  LamotrigineValproateStep 1Achieve a dose of 200 mg/day according to guidelines in Table 11 (if not already on 200 mg/ day).Maintain previous stable dose.Step 2Maintain at 200 mg/day.Decrease to 500 mg/day by decrements no greater than 500 mg/day per week and then maintain the dose of 500 mg/day for 1 week.Step 3Increase to 300 mg/day and maintain for 1 week.Simultaneously decrease to 250 mg/day and maintain for 1 week.Step 4Increase by 100 mg/day every week to achieve maintenance dose of 500 mg/day.Discontinue. Conversion from Adjunctive Therapy With Antiepileptic Drugs Other Than Carbamazepine, Phenytoin, Phenobarbital, Primidone, or Valproate to Monotherapy With Lamotrigine:
  No specific dosing guidelines can be provided for conversion to monotherapy with lamotrigine with AEDs other than carbamazepine, phenobarbital, phenytoin, primidone, or valproate.
  Usual Maintenance Dose for Epilepsy
  The usual maintenance doses identified in Tables 9-11 are derived from dosing regimens employed in the placebo-controlled adjunctive studies in which the efficacy of lamotrigine was established. In patients receiving multidrug regimens employing carbamazepine, phenytoin, phenobarbital, or primidone without valproate, maintenance doses of adjunctive Lamotrigine as high as 700 mg/day have been used. In patients receiving valproate alone, maintenance doses of adjunctive Lamotrigine as high as 200 mg/ day have been used. The advantage of using doses above those recommended in Tables 9-12 has not been established in controlled trials.
  Discontinuation Strategy for Patients With Epilepsy:
  For patients receiving lamotrigine in combination with other AEDs, a reevaluation of all AEDs in the regimen should be considered if a change in seizure control or an appearance or worsening of adverse experiences is observed.
  If a decision is made to discontinue therapy with Lamotrigine, a step-wise reduction of dose over at least 2 weeks (approximately 50% per week) is recommended unless safety concerns require a more rapid withdrawal (see PRECAUTIONS).
  Discontinuing carbamazepine, phenytoin, phenobarbital, or primidone should prolong the half-life of lamotrigine; discontinuing valproate should shorten the half-life of lamotrigine.
  Bipolar Disorder
  The goal of maintenance treatment with lamotrigine is to delay the time to occurrence of mood episodes (depression, mania, hypomania, mixed episodes) in patients treated for acute mood episodes with standard therapy. The target dose of lamotrigine is 200 mg/day (100 mg/day in patients taking valproate,which decreases the apparent clearance of lamotrigine, and 400 mg/day in patients not taking valproate and taking either carbamazepine, phenytoin, phenobarbital, primidone, or rifampin, which increase the apparent clearance of lamotrigine). In the clinical trials, doses up to 400 mg/day as monotherapy were evaluated, however, no additional benefit was seen at 400 mg/day compared to 200 mg/day (see CLINICAL STUDIES: Bipolar Disorder). Accordingly, doses above 200 mg/ day are not recommended. Treatment with lamotrigine is introduced, based on concurrent medications, according to the regimen outlined in Table 13. If other psychotropic medications are withdrawn following stabilization, the dose of lamotrigine should be adjusted. For patients discontinuing valproate, the dose of lamotrigine should be doubled over a 2-week period in equal weekly increments (see Table 14). For patients discontinuing carbamazepine, phenytoin, phenobarbital, primidone, or rifampin, the dose of lamotrigine should remain constant for the first week and then should be decreased by half over a 2-week period in equal weekly decrements (see Table 14). The dose of lamotrigine may then be further adjusted to the target dose (200 mg) as clinically indicated.
  Dosage adjustments will be necessary in most patients who start or stop estrogen-containing oral contraceptives while taking lamotrigine (see DOSAGE AND ADMINISTRATION: Special Populations: Women and Oral Contraceptives: Adjustments to the Maintenace Dose of Lamotrigine).
  If other drugs are subsequently introduced, the dose of Lamotrigine may need to be adjusted.
  In particular, the introduction of valproate requires reduction in the dose of Lamotrigine (see CLINICAL PHARMACOLOGY: Drug Interactions). To avoid an increased risk of rash, the recommended initial dose and subsequent dose escalations of Lamotrigine should not be exceeded (see BOX WARNING).
  
  Table 13. Escalation Regimen for Lamotrigine for Patients With Bipolar Disorder*
  *See CLINICAL PHARMACOLOGY: Drug Interactions:and PRECAUTIONS: Drug Interactionsfor a description of known drug interactions. Carbamazepine, phenytoin, phenobarbital, primidone, rifampin, have been shown to increase the apparent clearance of lamotrigine. Valproate has been shown to decrease the apparent clearance of lamotrigine.For Patients Not Taking Carbamazepine, Phenytoin, Phenobarbital, Primidone or Rifampin and Not Taking Valproate For Patients Taking Valproate For Patients Taking Carbamazepine (or Other Enzyme-Inducing Drugs) and Not Taking Valproate Weeks 1 and 225 mg daily25 mg every other day50 mg dailyWeeks 3 and 450 mg daily25 mg daily100 mg daily, in divided dosesWeek 5100 mg daily50 mg daily200 mg daily, in divided dosesWeek 6200 mg daily100 mg daily300 mg daily, in divided dosesWeek 7200 mg daily100 mg dailyup to 400 mg daily, in divided doses
  Table 14. Adjustments to Lamotrigine Dosing for Patients With Bipolar Disorder Following Discontinuation of Psychotropic Medications *
  *See CLINICAL PHARMACOLOGY: Drug Interactions:and PRECAUTIONS: Drug Interactionsfor a description of known drug interactions. Carbamazepine, phenytoin, phenobarbital, primidone, and rifampin have been shown to increase the apparent clearance of lamotrigine. Valproate has been shown to decrease the apparent clearance of lamotrigine.Discontinuation of Psychotropic Drugs (excluding Valproate , Carbamazepine, or Other Enzyme-Inducing Drugs )After Discontinuation of Valproate After Discontinuation of Carbamazepine or Other Enzyme-Inducing Drugs Current Lamotrigine dose (mg/day) 100Current Lamotrigine dose (mg/day) 400Week 1Maintain current lamotrigine dose150400Week 2Maintain current lamotrigine dose200300Week 3 onwardMaintain current lamotrigine dose200200There is no body of evidence available to answer the question of how long the patient should remain on lamotrigine therapy. Systematic evaluation of the efficacy of lamotrigine in patients with either depression or mania who responded to standard therapy during an acute 8 to 16 week treatment phase and were then randomized to lamotrigine or placebo for up to 76 weeks of observation for affective relapse demonstrated a benefit of such maintenance treatment (see CLINICAL STUDIES: Bipolar Disorder). Nevertheless, patients should be periodically reassessed to determine the need for maintenance treatment.
  Discontinuation Strategy in Bipolar Disorder:
  As with other AEDs, lamotrigine should not be abruptly discontinued. In the controlled clinical trials, there was no increase in the incidence, type, or severity of adverse experiences following abrupt termination of lamotrigine. In clinical trials in patients with bipolar disorder, 2 patients experienced seizures shortly after abrupt withdrawal of lamotrigine. However, there were confounding factors that may have contributed to the occurrence of seizures in these bipolar patients. Discontinuation of lamotrigine should involve a step-wise reduction of dose over at least 2 weeks (approximately 50% per week) unless safety concerns require a more rapid withdrawal.
  Administration of Lamotrigine Tablets (Chewable, Dispersible)
  Lamotrigine tablets (Chewable, Dispersible) may be swallowed whole, chewed, or dispersed in water or diluted fruit juice. If the tablets are chewed, consume a small amount of water or diluted fruit juice to aid in swallowing.
  To disperse lamotrigine tablets (chewable, dispersible), add the tablets to a small amount of liquid (1 teaspoon, or enough to cover the medication). Approximately 1 minute later, when the tablets are completely dispersed, swirl the solution and consume the entire quantity immediately.
  No attempt should be made to administer partial quantities of the dispersed tablets.
  
  

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  Epilepsy
  Adjunctive Use:
  Lamotrigine is indicated as adjunctive therapy for partial seizures and the generalized seizures of Lennox-Gastaut syndrome in adult and pediatric patients (years of age).
  Monotherapy Use:
  Lamotrigine tablets and lamotrigine tablets (chewable, dispersible) are indicated for conversion to monotherapy in adults with partial seizures who are receiving treatment with carbamazepine, phenytoin, phenobarbital, primidone, or valproate as the single AED.
  Safety and effectiveness of lamotrigine tablets and lamotrigine tablets (chewable, dispersible)have not been established. (1) as initial monotherapy, (2) for conversion to monotherapy from AEDs other than carbamazepine, phenytoin, phenobarbital, primidone, or valproate, or (3) for simultaneous conversion to monotherapy from 2 or more concomitant AEDs.
  Bipolar Disorder
  Lamotrigine tablets and lamotrigine tablets (chewable, dispersible) are indicated for the maintenance treatment of Bipolar I Disorder to delay the time to occurrence of mood episodes (depression, mania, hypomania, mixed episodes) in patients treated for acute mood episodes with standard therapy. The effectiveness of lamotrigine in the acute treatment of mood episodes has not been established.
  General Dosing Considerations for Epilepsy and Bipolar Disorder Patients:
  The risk of nonserious rash is increased when the recommended initial dose and/or the rate of dose escalation of Lamotrigine is exceeded. There are suggestions, yet to be proven, that the risk of severe, potentially life-threatening rash may be increased by (1) coadministration of lamotrigine with valproate, (2) exceeding the recommended initial dose of lamotrigine, or (3) exceeding the recommended dose escalation for lamotrigine. However, cases have been reported in the absence of these factors (see BOX WARNING). Therefore, it is important that the dosing recommendations be followed closely.
  It is recommended that lamotrigine not be restarted in patients who discontinued due to rash associated with prior treatment with lamotrigine, unless the potential benefits clearly outweigh the risks. If the decision is made to restart a patient who has discontinued lamotrigine, the need to restart with the initial dosing recommendations should be assessed. The greater the interval of time since the previous dose, the greater consideration should be given to restarting with the initial dosing recommendations. If a patient has discontinued lamotrigine for a period of more than 5 half-lives, it is recommended that initial dosing recommendations and guidelines be followed.
  Lamotrigine Tablets and Lamotrigine Tablets (Chewable, Dispersible)Added to Drugs Known to Induce or Inhibit Glucuronidation:
  Drugs other than those listed in PRECAUTIONS: Drug Interactionshave not been systematically evaluated in
  combination with Lamotrigine. Since lamotrigine is metabolized predominantly by glucuronic acid conjugation, drugs that are known to induce or inhibit glucuronidation may affect the apparent clearance of lamotrigine, and doses of Lamotrigine may require adjustment based on clinical response.
  Target Plasma Levels for Patients With Epilepsy or Bipolar Disorder:
  A therapeutic plasma concentration range has not been established for lamotrigine. Dosing of lamotrigine should be based on therapeutic response.
  The half-life of lamotrigine is affected by other concomitant medications (see CLINICAL PHARMACOLOGY: Pharmacokinetics and Drug Metabolism).
  See also DOSAGE AND ADMINISTRATION: Special Populations.
  Special Populations: Women and Oral Contraceptives: Starting Lamotrigine Tablets and LamotrigineTablets (Chewable, Dispersible)in Women Taking Oral Contraceptives
  Although estrogen-containing oral contraceptives have been shown to increase the clearance of lamotrigine (see PRECAUTIONS: Drug Interactions), no adjustments to the recommended dose escalation guidelines for lamotrigine should be necessary solely based on the use of estrogen-containing oral contraceptives. Therefore, dose escalation should follow the recommended guidelines for initiating adjunctive therapy with lamotrigine based on the concomitant AED (see Table 11). See below for adjustments to maintenance doses of lamotrigine in women taking estrogen-containing oral contraceptives.
  Adjustments to the Maintenance Dose of Lamotrigine Tablets and Lamotrigine Tablets (Chewable, Dispersible)
       Taking Estrogen-Containing Oral Contraceptives:
  For women not taking carbamazepine, phenytoin, phenobarbital, primidone,
  or rifampin, the maintenance dose of Lamotrigine will in most cases need to be increased, by as much as 2-fold over the recommended target maintenance dose, in order to maintain a consistent lamotrigine plasma level (see PRECAUTIONS: Drug Interactions). (2) Starting Estrogen-Containing Oral Contraceptives: In women taking a stable dose of Lamotrigine and not taking carbamazepine, phenytoin, phenobarbital, primidone, or rifampin, the maintenance dose will in most cases need to be increased by as much as 2-fold, in order to maintain a consistent lamotrigine plasma level. The dose increases should begin at the same time that the oral contraceptive is introduced and continue, based on clinical response, no more rapidly than 50 to 100 mg/day every week. Dose increases should not exceed the recommended rate unless lamotrigine plasma levels or clinical response support larger increases (see Table 11, column 2,). Gradual transient increases in lamotrigine plasma levels may occur during the week of inactive hormonal preparation ("pill-free" week), and these increases will be greater if dose increases are made in the days before or during the week of inactive hormonal preparation. Increased lamotrigine plasma levels could result in additional adverse events, such as dizziness, ataxia, and diplopia (see PRECAUTIONS: Drug Interactions). If adverse events attributable to lamotrigine consistently occur during the "pill-free" week, dose adjustments to the overall maintenance dose may be necessary. Dose adjustments limited to the "pill-free" week are not recommended. For women taking Lamotrigine in addition to carbamazepine, phenytoin, phenobarbital, primidone, or rifampin, no adjustment should be necessary to the dose of Lamotrigine. (3) Stopping Estrogen-Containing Oral Contraceptives: For women not taking carbamazepine, phenytoin, phenobarbital, primidone, or rifampin, the maintenance dose of lamotrigine will in most cases need to be decreased by as much as 50%, in order to maintain a consistent lamotrigine plasma level. The decrease in dose of Lamotrigine should not exceed 25% of the total daily dose per week over a 2-week period, unless clinical response or lamotrigine plasma levels indicate otherwise (see PRECAUTIONS: Drug Interactions). For women taking lamotrigine in addition to carbamazepine, phenytoin, phenobarbital, primidone, or rifampin, no adjustment to the dose of lamotrigine should be necessary.
  Women and Other Hormonal Contraceptive Preparations or Hormone Replacement Therapy:
  The effect of other hormonal contraceptive preparations or hormone replacement therapy on the pharmacokinetics of lamotrigine has not been systematically evaluated. It has been reported that ethinylestradiol, not progestogens, increased the clearance of lamotrigine up to 2-fold, and the progestin only pills had no effect on lamotrigine plasma levels. Therefore, adjustments to the dosage of lamotrigine in the presence of progestogens alone will likely not be needed.
  Patients With Hepatic Impairment:
  Experience in patients with hepatic impairment is limited. Based on a clinical pharmacology study in 24 patients with mild, moderate, and severe liver dysfunction (see CLINICAL PHARMACOLOGY), the following general recommendations can be made. No dosage adjustment is needed in patients with mild liver impairment. Initial, escalation, and maintenance doses should generally be reduced by approximately 25% in patients with moderate and severe liver impairment without
  ascites and 50% in patients with severe liver impairment with ascites. Escalation and maintenance doses may be adjusted according to clinical response.
  Patients With Renal Functional Impairment:
  Initial doses of lamotrigine tablets and lamotrigine tablets (chewable, dispersible) should be based on patients' AED regimen (see above); reduced maintenance doses may be effective for patients with significant renal functional impairment (see CLINICAL PHARMACOLOGY). Few patients with severe renal impairment have been evaluated during chronic treatment with lamotrigine. Because there is inadequate experience in this population, lamotrigine should be used with caution in these patients.
  Epilepsy:
  Adjunctive Therapy With Lamotrigine Tablets and Lamotrigine Tablets (Chewable, Dispersible) for Epilepsy:
  This section provides specific dosing recommendations for patients 2 to 12 years of age and patients greater than 12 years of age. Within each of these age-groups, specific dosing recommendations are provided depending upon concomitant AED (Table 9 for patients 2 to 12 years of age and Table 11 for patients greater than 12 years of age). A weight based dosing guide for pediatric patients on concomitant valproate is provided in Table 10.
  Patients 2 to 12 Years of Age:
  Recommended dosing guidelines are summarized in Table 9.
  Note that some of the starting doses and dose escalations listed in Table 9 are different than those used in clinical trials; however, the maintenance doses are the same as in clinical trials. Smaller starting doses and slower dose escalations than those used in clinical trials are recommended because of the suggestions that the risk of rash may be decreased by smaller starting doses and slower dose escalations. Therefore, maintenance doses will take longer to reach in clinical practice than in clinical trials. It may take several weeks to months to achieve an individualized maintenance dose. Maintenance doses in patients weighing less than 30 kg, regardless of age or concomitant AED, may need to be increased as much as 50%, based on clinical response.
  
  Table 9. Escalation Regimen for Lamotrigine in Patients 2 to 12 Years of Age With Epilepsy
  *Rifampin and estrogen-containing oral contraceptives have also been shown to increase the apparent clearance of lamotrigine (see PRECAUTIONS: Drug Interactions).For Patients Taking Valproate (see Table 10 for weight- based dosing guide)For Patients Taking AEDs Other Than Carbamazepine, Phenytoi n, Phenobarbital, Primidone *, or ValproateFor Patients Taking Carbamazepine, Phenytoin, Phenobarbital, Primidone *and Not Taking ValproateWeeks 1 and 20.15 mg/kg/day in 1 or 2 divided doses, rounded down to the nearest whole tablet (see Table 10 for weight-based dosing guide).0.3 mg/kg/day in 1 or 2 divided doses, rounded down to the nearest whole tablet.0.6 mg/kg/day in 2 divided doses, rounded down to the nearest whole tablet.Weeks 3 and 40.3 mg/kg/day in 1 or 2 divided doses, rounded down to the nearest whole tablet (see Table 10 for weight-based dosing guide).0.6 mg/kg/day in 2 divided doses, rounded down to the nearest whole tablet.1.2 mg/kg/day in 2 divided doses, rounded down to the nearest whole tablet.Weeks 5 onwards to maintenanceThe dose should be increased every 1 to 2 weeks as follows: calculate 0.3 mg/kg/day, round this amount down to the nearest whole tablet, and add this amount to the previously administered daily dose.The dose should be increased every 1 to 2 weeks as follows: calculate 0.6 mg/kg/day, round this amount down to the nearest whole tablet, and add this amount to the previously administered daily doseThe dose should be increased every 1 to 2 weeks as follows: calculate 1.2 mg/kg/day, round this amount down to the nearest whole tablet, and add this amount to the previously administered daily doseUsual Maintenance Dose1 to 5 mg/kg/day (maximum 200 mg/day in 1 or 2 divided doses). 1 to 3 mg/kg/day with valproate alone4.5 to 7.5 mg/kg/day (maximum 300 mg/day in 2 divided doses)5 to 15 mg/kg/day (maximum 400 mg/day in 2 divided doses)Maintenance dose in patients less than 30 kgMay need to be increased by as much as 50%, based on clinical responseMay need to be increased by as much as 50%, based on clinical responseMay need to be increased by as much as 50%, based on clinical responseNote: Only whole tablets should be used for dosing
  
  Table 10. The Initial Weight-Based Dosing Guide for Patients 2 to 12 Years Taking Valproate (Weeks 1 to 4) With Epilepsy
  If the patient's weight isGive this daily dose, using the most appropriate combination of lamotrigine tablets (chewable, dispersible), 5 mgGreater thanAnd less thanWeeks 1 and 2Weeks 3 and 434.1 kg40 kg5 mg every day10 mg every dayPatients Over 12 Years of Age:
  Recommended dosing guidelines are summarized in Table 11.
  
  Table 11. Escalation Regimen for Lamotrigine in Patients Over 12 Years of Age With Epilepsy
  *Rifampin and estrogen-containing oral contraceptives have also been shown to increase the apparent clearance of lamotrigine (see PRECAUTIONS: Drug Interactions).For Patients Taking ValproateFor Patients Taking AEDs Other Than Carbamazepine, Phenytoin, Phenobarbital, Primidone, or Valproate *For Patients Taking Carbamazepine, Phenytoin, PhenobarbitaL, Primidone *and Not Taking ValproateWeeks 1 and 225 mg every other day25 mg every day50 mg/dayWeeks 3 and 425 mg every day50 mg/day100 mg/day (in 2 divided doses)Weeks 5 onwards to maintenanceIncrease by 25 to 50 mg/ day every 1 to 2 weeksIncrease by 50 mg/ day every 1 to 2 weeksIncrease by 100 mg/ day every 1 to 2 weeks.Usual Maintenance Dose100 to 400 mg/day (1 or 2 divided doses) 100 to 200 mg/day with Valproate alone225 to 375 mg/day (in 2 divided doses).300 to 500 mg/day (in 2 divided doses).Conversion from Adjunctive Therapy With Carbamazepine, Phenytoin, Phenobarbital, Primidone, or Valproate as the Single AED to Monotherapy With Lamotrigine in PatientsYears of Age With Epilepsy:
  The goal of the transition regimen is to effect the conversion to monotherapy with Lamotrigine under conditions that ensure adequate seizure control while mitigating the risk of serious rash associated with the rapid titration of lamotrigine.
  The recommended maintenance dose of lamotrigine as monotherapy is 500 mg/day given in 2 divided doses.
  To avoid an increased risk of rash, the recommended initial dose and subsequent dose escalations of lamotrigine should not be exceeded (see BOX WARNING).
  Conversion From Adjunctive Therapy With Carbamazepine, Phenytoin, Phenobarbital, or Primidone to Monotherapy With Lamotrigine:
  After achieving a dose of 500 mg/day of lamotrigine according to the guidelines in Table 11, the concomitant AED should be withdrawn by 20% decrements each week over a 4-week period. The regimen for the withdrawal of the concomitant AED is based on experience gained in the controlled monotherapy clinical trial.
  Conversion from Adjunctive Therapy With Valproate to Monotherapy With Lamotrigine The conversion regimen involves 4 steps (see Table 12).
  
  Table 12. Conversion From Adjunctive Therapy With Valproate to Monotherapy With Lamotrigine in PatientsYears of Age With Epilepsy
  LamotrigineValproateStep 1Achieve a dose of 200 mg/day according to guidelines in Table 11 (if not already on 200 mg/ day).Maintain previous stable dose.Step 2Maintain at 200 mg/day.Decrease to 500 mg/day by decrements no greater than 500 mg/day per week and then maintain the dose of 500 mg/day for 1 week.Step 3Increase to 300 mg/day and maintain for 1 week.Simultaneously decrease to 250 mg/day and maintain for 1 week.Step 4Increase by 100 mg/day every week to achieve maintenance dose of 500 mg/day.Discontinue.Conversion from Adjunctive Therapy With Antiepileptic Drugs Other Than Carbamazepine, Phenytoin, Phenobarbital, Primidone, or Valproate to Monotherapy With Lamotrigine:
  No specific dosing guidelines can be provided for conversion to monotherapy with lamotrigine with AEDs other than carbamazepine, phenobarbital, phenytoin, primidone, or valproate.
  Usual Maintenance Dose for Epilepsy
  The usual maintenance doses identified in Tables 9-11 are derived from dosing regimens employed in the placebo-controlled adjunctive studies in which the efficacy of lamotrigine was established. In patients receiving multidrug regimens employing carbamazepine, phenytoin, phenobarbital, or primidone without valproate, maintenance doses of adjunctive Lamotrigine as high as 700 mg/day have been used. In patients receiving valproate alone, maintenance doses of adjunctive Lamotrigine as high as 200 mg/ day have been used. The advantage of using doses above those recommended in Tables 9-12 has not been established in controlled trials.
  Discontinuation Strategy for Patients With Epilepsy:
  For patients receiving lamotrigine in combination with other AEDs, a reevaluation of all AEDs in the regimen should be considered if a change in seizure control or an appearance or worsening of adverse experiences is observed.
  If a decision is made to discontinue therapy with Lamotrigine, a step-wise reduction of dose over at least 2 weeks (approximately 50% per week) is recommended unless safety concerns require a more rapid withdrawal (see PRECAUTIONS).
  Discontinuing carbamazepine, phenytoin, phenobarbital, or primidone should prolong the half-life of lamotrigine; discontinuing valproate should shorten the half-life of lamotrigine.
  Bipolar Disorder
  The goal of maintenance treatment with lamotrigine is to delay the time to occurrence of mood episodes (depression, mania, hypomania, mixed episodes) in patients treated for acute mood episodes with standard therapy. The target dose of lamotrigine is 200 mg/day (100 mg/day in patients taking valproate,which decreases the apparent clearance of lamotrigine, and 400 mg/day in patients not taking valproate and taking either carbamazepine, phenytoin, phenobarbital, primidone, or rifampin, which increase the apparent clearance of lamotrigine). In the clinical trials, doses up to 400 mg/day as monotherapy were evaluated, however, no additional benefit was seen at 400 mg/day compared to 200 mg/day (see CLINICAL STUDIES: Bipolar Disorder). Accordingly, doses above 200 mg/ day are not recommended. Treatment with lamotrigine is introduced, based on concurrent medications, according to the regimen outlined in Table 13. If other psychotropic medications are withdrawn following stabilization, the dose of lamotrigine should be adjusted. For patients discontinuing valproate, the dose of lamotrigine should be doubled over a 2-week period in equal weekly increments (see Table 14). For patients discontinuing carbamazepine, phenytoin, phenobarbital, primidone, or rifampin, the dose of lamotrigine should remain constant for the first week and then should be decreased by half over a 2-week period in equal weekly decrements (see Table 14). The dose of lamotrigine may then be further adjusted to the target dose (200 mg) as clinically indicated.
  Dosage adjustments will be necessary in most patients who start or stop estrogen-containing oral contraceptives while taking lamotrigine (see DOSAGE AND ADMINISTRATION: Special Populations: Women and Oral Contraceptives: Adjustments to the Maintenace Dose of Lamotrigine).
  If other drugs are subsequently introduced, the dose of Lamotrigine may need to be adjusted.
  In particular, the introduction of valproate requires reduction in the dose of Lamotrigine (see CLINICAL PHARMACOLOGY: Drug Interactions). To avoid an increased risk of rash, the recommended initial dose and subsequent dose escalations of Lamotrigine should not be exceeded (see BOX WARNING).
  
  Table 13. Escalation Regimen for Lamotrigine for Patients With Bipolar Disorder *
  *See CLINICAL PHARMACOLOGY: Drug Interactions:and PRECAUTIONS: Drug Interactionsfor a description of known drug interactions. Carbamazepine, phenytoin, phenobarbital, primidone, rifampin, have been shown to increase the apparent clearance of lamotrigine. Valproate has been shown to decrease the apparent clearance of lamotrigine.For Patients Not Taking Carbamazepine, Phenytoin, Phenobarbital, Primidone or Rifampin and Not Taking Valproate For Patients Taking Valproate For Patients Taking Carbamazepine (or Other Enzyme-Inducing Drugs) and Not Taking Valproate Weeks 1 and 225 mg daily25 mg every other day50 mg dailyWeeks 3 and 450 mg daily25 mg daily100 mg daily, in divided dosesWeek 5100 mg daily50 mg daily200 mg daily, in divided dosesWeek 6200 mg daily100 mg daily300 mg daily, in divided dosesWeek 7200 mg daily100 mg dailyup to 400 mg daily, in divided doses
  Table 14. Adjustments to Lamotrigine Dosing for Patients With Bipolar Disorder Following Discontinuation of Psychotropic Medications *
  *See CLINICAL PHARMACOLOGY: Drug Interactions:and PRECAUTIONS: Drug Interactionsfor a description of known drug interactions. Carbamazepine, phenytoin, phenobarbital, primidone, and rifampin have been shown to increase the apparent clearance of lamotrigine. Valproate has been shown to decrease the apparent clearance of lamotrigine.Discontinuation of Psychotropic Drugs (excluding Valproate , Carbamazepine, or Other Enzyme-Inducing Drugs )After Discontinuation of Valproate After Discontinuation of Carbamazepine or Other Enzyme-Inducing Drugs Current Lamotrigine dose (mg/day) 100Current Lamotrigine dose (mg/day) 400Week 1Maintain current lamotrigine dose150400Week 2Maintain current lamotrigine dose200300Week 3 onwardMaintain current lamotrigine dose200200There is no body of evidence available to answer the question of how long the patient should remain on lamotrigine therapy. Systematic evaluation of the efficacy of lamotrigine in patients with either depression or mania who responded to standard therapy during an acute 8 to 16 week treatment phase and were then randomized to lamotrigine or placebo for up to 76 weeks of observation for affective relapse demonstrated a benefit of such maintenance treatment (see CLINICAL STUDIES: Bipolar Disorder). Nevertheless, patients should be periodically reassessed to determine the need for maintenance treatment.
  Discontinuation Strategy in Bipolar Disorder:
  As with other AEDs, lamotrigine should not be abruptly discontinued. In the controlled clinical trials, there was no increase in the incidence, type, or severity of adverse experiences following abrupt termination of lamotrigine. In clinical trials in patients with bipolar disorder, 2 patients experienced seizures shortly after abrupt withdrawal of lamotrigine. However, there were confounding factors that may have contributed to the occurrence of seizures in these bipolar patients. Discontinuation of lamotrigine should involve a step-wise reduction of dose over at least 2 weeks (approximately 50% per week) unless safety concerns require a more rapid withdrawal.
  Administration of Lamotrigine Tablets (Chewable, Dispersible)
  Lamotrigine tablets (Chewable, Dispersible) may be swallowed whole, chewed, or dispersed in water or diluted fruit juice. If the tablets are chewed, consume a small amount of water or diluted fruit juice to aid in swallowing.
  To disperse lamotrigine tablets (chewable, dispersible), add the tablets to a small amount of liquid (1 teaspoon, or enough to cover the medication). Approximately 1 minute later, when the tablets are completely dispersed, swirl the solution and consume the entire quantity immediately.
  No attempt should be made to administer partial quantities of the dispersed tablets.
  
  

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  Epilepsy
  Adjunctive Use:
  Lamotrigine is indicated as adjunctive therapy for partial seizures and the generalized seizures of Lennox-Gastaut syndrome in adult and pediatric patients (years of age).
  Monotherapy Use:
  Lamotrigine tablets and lamotrigine tablets (chewable, dispersible) are indicated for conversion to monotherapy in adults with partial seizures who are receiving treatment with carbamazepine, phenytoin, phenobarbital, primidone, or valproate as the single AED.
  Safety and effectiveness of lamotrigine tablets and lamotrigine tablets (chewable, dispersible)have not been established. (1) as initial monotherapy, (2) for conversion to monotherapy from AEDs other than carbamazepine, phenytoin, phenobarbital, primidone, or valproate, or (3) for simultaneous conversion to monotherapy from 2 or more concomitant AEDs.
  Bipolar Disorder
  Lamotrigine tablets and lamotrigine tablets (chewable, dispersible) are indicated for the maintenance treatment of Bipolar I Disorder to delay the time to occurrence of mood episodes (depression, mania, hypomania, mixed episodes) in patients treated for acute mood episodes with standard therapy. The effectiveness of lamotrigine in the acute treatment of mood episodes has not been established.
  General Dosing Considerations for Epilepsy and Bipolar Disorder Patients:
  The risk of nonserious rash is increased when the recommended initial dose and/or the rate of dose escalation of Lamotrigine is exceeded. There are suggestions, yet to be proven, that the risk of severe, potentially life-threatening rash may be increased by (1) coadministration of lamotrigine with valproate, (2) exceeding the recommended initial dose of lamotrigine, or (3) exceeding the recommended dose escalation for lamotrigine. However, cases have been reported in the absence of these factors (see BOX WARNING). Therefore, it is important that the dosing recommendations be followed closely.
  It is recommended that lamotrigine not be restarted in patients who discontinued due to rash associated with prior treatment with lamotrigine, unless the potential benefits clearly outweigh the risks. If the decision is made to restart a patient who has discontinued lamotrigine, the need to restart with the initial dosing recommendations should be assessed. The greater the interval of time since the previous dose, the greater consideration should be given to restarting with the initial dosing recommendations. If a patient has discontinued lamotrigine for a period of more than 5 half-lives, it is recommended that initial dosing recommendations and guidelines be followed.
  Lamotrigine Tablets and Lamotrigine Tablets (Chewable, Dispersible)Added to Drugs Known to Induce or Inhibit Glucuronidation:
  Drugs other than those listed in PRECAUTIONS: Drug Interactionshave not been systematically evaluated in
  combination with Lamotrigine. Since lamotrigine is metabolized predominantly by glucuronic acid conjugation, drugs that are known to induce or inhibit glucuronidation may affect the apparent clearance of lamotrigine, and doses of Lamotrigine may require adjustment based on clinical response.
  Target Plasma Levels for Patients With Epilepsy or Bipolar Disorder:
  A therapeutic plasma concentration range has not been established for lamotrigine. Dosing of lamotrigine should be based on therapeutic response.
  The half-life of lamotrigine is affected by other concomitant medications (see CLINICAL PHARMACOLOGY: Pharmacokinetics and Drug Metabolism).
  See also DOSAGE AND ADMINISTRATION: Special Populations.
  Special Populations: Women and Oral Contraceptives: Starting Lamotrigine Tablets and LamotrigineTablets (Chewable, Dispersible)in Women Taking Oral Contraceptives
  Although estrogen-containing oral contraceptives have been shown to increase the clearance of lamotrigine (see PRECAUTIONS: Drug Interactions), no adjustments to the recommended dose escalation guidelines for lamotrigine should be necessary solely based on the use of estrogen-containing oral contraceptives. Therefore, dose escalation should follow the recommended guidelines for initiating adjunctive therapy with lamotrigine based on the concomitant AED (see Table 11). See below for adjustments to maintenance doses of lamotrigine in women taking estrogen-containing oral contraceptives.
  Adjustments to the Maintenance Dose of Lamotrigine Tablets and Lamotrigine Tablets (Chewable, Dispersible)
       1. Taking Estrogen-Containing Oral Contraceptives:
  For women not taking carbamazepine, phenytoin, phenobarbital, primidone,
  or rifampin, the maintenance dose of Lamotrigine will in most cases need to be increased, by as much as 2-fold over the recommended target maintenance dose, in order to maintain a consistent lamotrigine plasma level (see PRECAUTIONS: Drug Interactions). (2) Starting Estrogen-Containing Oral Contraceptives:In women taking a stable dose of Lamotrigine and not taking carbamazepine, phenytoin, phenobarbital, primidone, or rifampin, the maintenance dose will in most cases need to be increased by as much as 2-fold, in order to maintain a consistent lamotrigine plasma level. The dose increases should begin at the same time that the oral contraceptive is introduced and continue, based on clinical response, no more rapidly than 50 to 100 mg/day every week. Dose increases should not exceed the recommended rate unless lamotrigine plasma levels or clinical response support larger increases (see Table 11, column 2,). Gradual transient increases in lamotrigine plasma levels may occur during the week of inactive hormonal preparation ("pill-free" week), and these increases will be greater if dose increases are made in the days before or during the week of inactive hormonal preparation. Increased lamotrigine plasma levels could result in additional adverse events, such as dizziness, ataxia, and diplopia (see PRECAUTIONS: Drug Interactions). If adverse events attributable to lamotrigine consistently occur during the "pill-free" week, dose adjustments to the overall maintenance dose may be necessary. Dose adjustments limited to the "pill-free" week are not recommended. For women taking Lamotrigine in addition to carbamazepine, phenytoin, phenobarbital, primidone, or rifampin, no adjustment should be necessary to the dose of Lamotrigine. (3) Stopping Estrogen-Containing Oral Contraceptives:For women not taking carbamazepine, phenytoin, phenobarbital, primidone, or rifampin, the maintenance dose of lamotrigine will in most cases need to be decreased by as much as 50%, in order to maintain a consistent lamotrigine plasma level. The decrease in dose of Lamotrigine should not exceed 25% of the total daily dose per week over a 2-week period, unless clinical response or lamotrigine plasma levels indicate otherwise (see PRECAUTIONS: Drug Interactions). For women taking lamotrigine in addition to carbamazepine, phenytoin, phenobarbital, primidone, or rifampin, no adjustment to the dose of lamotrigine should be necessary.
  Women and Other Hormonal Contraceptive Preparations or Hormone Replacement Therapy:
  The effect of other hormonal contraceptive preparations or hormone replacement therapy on the pharmacokinetics of lamotrigine has not been systematically evaluated. It has been reported that ethinylestradiol, not progestogens, increased the clearance of lamotrigine up to 2-fold, and the progestin only pills had no effect on lamotrigine plasma levels. Therefore, adjustments to the dosage of lamotrigine in the presence of progestogens alone will likely not be needed.
  Patients With Hepatic Impairment:
  Experience in patients with hepatic impairment is limited. Based on a clinical pharmacology study in 24 patients with mild, moderate, and severe liver dysfunction (see CLINICAL PHARMACOLOGY), the following general recommendations can be made. No dosage adjustment is needed in patients with mild liver impairment. Initial, escalation, and maintenance doses should generally be reduced by approximately 25% in patients with moderate and severe liver impairment without
  ascites and 50% in patients with severe liver impairment with ascites. Escalation and maintenance doses may be adjusted according to clinical response.
  Patients With Renal Functional Impairment:
  Initial doses of lamotrigine tablets and lamotrigine tablets (chewable, dispersible) should be based on patients' AED regimen (see above); reduced maintenance doses may be effective for patients with significant renal functional impairment (see CLINICAL PHARMACOLOGY). Few patients with severe renal impairment have been evaluated during chronic treatment with lamotrigine. Because there is inadequate experience in this population, lamotrigine should be used with caution in these patients.
  Epilepsy:
  Adjunctive Therapy With Lamotrigine Tablets and Lamotrigine Tablets (Chewable, Dispersible) for Epilepsy:
  This section provides specific dosing recommendations for patients 2 to 12 years of age and patients greater than 12 years of age. Within each of these age-groups, specific dosing recommendations are provided depending upon concomitant AED (Table 9 for patients 2 to 12 years of age and Table 11 for patients greater than 12 years of age). A weight based dosing guide for pediatric patients on concomitant valproate is provided in Table 10.
  Patients 2 to 12 Years of Age:
  Recommended dosing guidelines are summarized in Table 9.
  Note that some of the starting doses and dose escalations listed in Table 9 are different than those used in clinical trials; however, the maintenance doses are the same as in clinical trials. Smaller starting doses and slower dose escalations than those used in clinical trials are recommended because of the suggestions that the risk of rash may be decreased by smaller starting doses and slower dose escalations. Therefore, maintenance doses will take longer to reach in clinical practice than in clinical trials. It may take several weeks to months to achieve an individualized maintenance dose. Maintenance doses in patients weighing less than 30 kg, regardless of age or concomitant AED, may need to be increased as much as 50%, based on clinical response.
  
  Table 9. Escalation Regimen for Lamotrigine in Patients 2 to 12 Years of Age With Epilepsy
  *Rifampin and estrogen-containing oral contraceptives have also been shown to increase the apparent clearance of lamotrigine (see PRECAUTIONS: Drug Interactions).For Patients Taking Valproate (see Table 10 for weight- based dosing guide)For Patients Taking AEDs Other Than Carbamazepine, Phenytoi n, Phenobarbital, Primidone *, or ValproateFor Patients Taking Carbamazepine, Phenytoin, Phenobarbital, Primidone *and Not Taking ValproateWeeks 1 and 20.15 mg/kg/day in 1 or 2 divided doses, rounded down to the nearest whole tablet (see Table 10 for weight-based dosing guide).0.3 mg/kg/day in 1 or 2 divided doses, rounded down to the nearest whole tablet.0.6 mg/kg/day in 2 divided doses, rounded down to the nearest whole tablet.Weeks 3 and 40.3 mg/kg/day in 1 or 2 divided doses, rounded down to the nearest whole tablet (see Table 10 for weight-based dosing guide).0.6 mg/kg/day in 2 divided doses, rounded down to the nearest whole tablet.1.2 mg/kg/day in 2 divided doses, rounded down to the nearest whole tablet.Weeks 5 onwards to maintenanceThe dose should be increased every 1 to 2 weeks as follows: calculate 0.3 mg/kg/day, round this amount down to the nearest whole tablet, and add this amount to the previously administered daily dose.The dose should be increased every 1 to 2 weeks as follows: calculate 0.6 mg/kg/day, round this amount down to the nearest whole tablet, and add this amount to the previously administered daily doseThe dose should be increased every 1 to 2 weeks as follows: calculate 1.2 mg/kg/day, round this amount down to the nearest whole tablet, and add this amount to the previously administered daily doseUsual Maintenance Dose1 to 5 mg/kg/day (maximum 200 mg/day in 1 or 2 divided doses). 1 to 3 mg/kg/day with valproate alone4.5 to 7.5 mg/kg/day (maximum 300 mg/day in 2 divided doses)5 to 15 mg/kg/day (maximum 400 mg/day in 2 divided doses)Maintenance dose in patients less than 30 kgMay need to be increased by as much as 50%, based on clinical responseMay need to be increased by as much as 50%, based on clinical responseMay need to be increased by as much as 50%, based on clinical response Note: Only whole tablets should be used for dosing
  
  Table 10. The Initial Weight-Based Dosing Guide for Patients 2 to 12 Years Taking Valproate (Weeks 1 to 4) With Epilepsy
  If the patient's weight isGive this daily dose, using the most appropriate combination of lamotrigine tablets (chewable, dispersible), 5 mgGreater thanAnd less thanWeeks 1 and 2Weeks 3 and 434.1 kg40 kg5 mg every day10 mg every day Patients Over 12 Years of Age:
  Recommended dosing guidelines are summarized in Table 11.
  
  Table 11. Escalation Regimen for Lamotrigine in Patients Over 12 Years of Age With Epilepsy
  *Rifampin and estrogen-containing oral contraceptives have also been shown to increase the apparent clearance of lamotrigine (see PRECAUTIONS: Drug Interactions).For Patients Taking ValproateFor Patients Taking AEDs Other Than Carbamazepine, Phenytoin, Phenobarbital, Primidone, or Valproate *For Patients Taking Carbamazepine, Phenytoin, PhenobarbitaL, Primidone *and Not Taking ValproateWeeks 1 and 225 mg every other day25 mg every day50 mg/dayWeeks 3 and 425 mg every day50 mg/day100 mg/day (in 2 divided doses)Weeks 5 onwards to maintenanceIncrease by 25 to 50 mg/ day every 1 to 2 weeksIncrease by 50 mg/ day every 1 to 2 weeksIncrease by 100 mg/ day every 1 to 2 weeks.Usual Maintenance Dose100 to 400 mg/day (1 or 2 divided doses) 100 to 200 mg/day with Valproate alone225 to 375 mg/day (in 2 divided doses).300 to 500 mg/day (in 2 divided doses). Conversion from Adjunctive Therapy With Carbamazepine, Phenytoin, Phenobarbital, Primidone, or Valproate as the Single AED to Monotherapy With Lamotrigine in PatientsYears of Age With Epilepsy:
  The goal of the transition regimen is to effect the conversion to monotherapy with Lamotrigine under conditions that ensure adequate seizure control while mitigating the risk of serious rash associated with the rapid titration of lamotrigine.
  The recommended maintenance dose of lamotrigine as monotherapy is 500 mg/day given in 2 divided doses.
  To avoid an increased risk of rash, the recommended initial dose and subsequent dose escalations of lamotrigine should not be exceeded (see BOX WARNING).
  Conversion From Adjunctive Therapy With Carbamazepine, Phenytoin, Phenobarbital, or Primidone to Monotherapy With Lamotrigine:
  After achieving a dose of 500 mg/day of lamotrigine according to the guidelines in Table 11, the concomitant AED should be withdrawn by 20% decrements each week over a 4-week period. The regimen for the withdrawal of the concomitant AED is based on experience gained in the controlled monotherapy clinical trial.
  Conversion from Adjunctive Therapy With Valproate to Monotherapy With LamotrigineThe conversion regimen involves 4 steps (see Table 12).
  
  Table 12. Conversion From Adjunctive Therapy With Valproate to Monotherapy With Lamotrigine in PatientsYears of Age With Epilepsy
  LamotrigineValproateStep 1Achieve a dose of 200 mg/day according to guidelines in Table 11 (if not already on 200 mg/ day).Maintain previous stable dose.Step 2Maintain at 200 mg/day.Decrease to 500 mg/day by decrements no greater than 500 mg/day per week and then maintain the dose of 500 mg/day for 1 week.Step 3Increase to 300 mg/day and maintain for 1 week.Simultaneously decrease to 250 mg/day and maintain for 1 week.Step 4Increase by 100 mg/day every week to achieve maintenance dose of 500 mg/day.Discontinue. Conversion from Adjunctive Therapy With Antiepileptic Drugs Other Than Carbamazepine, Phenytoin, Phenobarbital, Primidone, or Valproate to Monotherapy With Lamotrigine:
  No specific dosing guidelines can be provided for conversion to monotherapy with lamotrigine with AEDs other than carbamazepine, phenobarbital, phenytoin, primidone, or valproate.
  Usual Maintenance Dose for Epilepsy
  The usual maintenance doses identified in Tables 9-11 are derived from dosing regimens employed in the placebo-controlled adjunctive studies in which the efficacy of lamotrigine was established. In patients receiving multidrug regimens employing carbamazepine, phenytoin, phenobarbital, or primidone without valproate, maintenance doses of adjunctive Lamotrigine as high as 700 mg/day have been used. In patients receiving valproate alone, maintenance doses of adjunctive Lamotrigine as high as 200 mg/ day have been used. The advantage of using doses above those recommended in Tables 9-12 has not been established in controlled trials.
  Discontinuation Strategy for Patients With Epilepsy:
  For patients receiving lamotrigine in combination with other AEDs, a reevaluation of all AEDs in the regimen should be considered if a change in seizure control or an appearance or worsening of adverse experiences is observed.
  If a decision is made to discontinue therapy with Lamotrigine, a step-wise reduction of dose over at least 2 weeks (approximately 50% per week) is recommended unless safety concerns require a more rapid withdrawal (see PRECAUTIONS).
  Discontinuing carbamazepine, phenytoin, phenobarbital, or primidone should prolong the half-life of lamotrigine; discontinuing valproate should shorten the half-life of lamotrigine.
  Bipolar Disorder
  The goal of maintenance treatment with lamotrigine is to delay the time to occurrence of mood episodes (depression, mania, hypomania, mixed episodes) in patients treated for acute mood episodes with standard therapy. The target dose of lamotrigine is 200 mg/day (100 mg/day in patients taking valproate,which decreases the apparent clearance of lamotrigine, and 400 mg/day in patients not taking valproate and taking either carbamazepine, phenytoin, phenobarbital, primidone, or rifampin, which increase the apparent clearance of lamotrigine). In the clinical trials, doses up to 400 mg/day as monotherapy were evaluated, however, no additional benefit was seen at 400 mg/day compared to 200 mg/day (see CLINICAL STUDIES: Bipolar Disorder). Accordingly, doses above 200 mg/ day are not recommended. Treatment with lamotrigine is introduced, based on concurrent medications, according to the regimen outlined in Table 13. If other psychotropic medications are withdrawn following stabilization, the dose of lamotrigine should be adjusted. For patients discontinuing valproate, the dose of lamotrigine should be doubled over a 2-week period in equal weekly increments (see Table 14). For patients discontinuing carbamazepine, phenytoin, phenobarbital, primidone, or rifampin, the dose of lamotrigine should remain constant for the first week and then should be decreased by half over a 2-week period in equal weekly decrements (see Table 14). The dose of lamotrigine may then be further adjusted to the target dose (200 mg) as clinically indicated.
  Dosage adjustments will be necessary in most patients who start or stop estrogen-containing oral contraceptives while taking lamotrigine (see DOSAGE AND ADMINISTRATION: Special Populations: Women and Oral Contraceptives: Adjustments to the Maintenace Dose of Lamotrigine).
  If other drugs are subsequently introduced, the dose of Lamotrigine may need to be adjusted.
  In particular, the introduction of valproate requires reduction in the dose of Lamotrigine (see CLINICAL PHARMACOLOGY: Drug Interactions). To avoid an increased risk of rash, the recommended initial dose and subsequent dose escalations of Lamotrigine should not be exceeded (see BOX WARNING).
  
  Table 13. Escalation Regimen for Lamotrigine for Patients With Bipolar Disorder *
  *See CLINICAL PHARMACOLOGY: Drug Interactions:and PRECAUTIONS: Drug Interactionsfor a description of known drug interactions. Carbamazepine, phenytoin, phenobarbital, primidone, rifampin, have been shown to increase the apparent clearance of lamotrigine. Valproate has been shown to decrease the apparent clearance of lamotrigine.For Patients Not Taking Carbamazepine, Phenytoin, Phenobarbital, Primidone or Rifampin and Not Taking Valproate For Patients Taking Valproate For Patients Taking Carbamazepine (or Other Enzyme-Inducing Drugs) and Not Taking Valproate Weeks 1 and 225 mg daily25 mg every other day50 mg dailyWeeks 3 and 450 mg daily25 mg daily100 mg daily, in divided dosesWeek 5100 mg daily50 mg daily200 mg daily, in divided dosesWeek 6200 mg daily100 mg daily300 mg daily, in divided dosesWeek 7200 mg daily100 mg dailyup to 400 mg daily, in divided doses
  Table 14. Adjustments to Lamotrigine Dosing for Patients With Bipolar Disorder Following Discontinuation of Psychotropic Medications *
  *See CLINICAL PHARMACOLOGY: Drug Interactions:and PRECAUTIONS: Drug Interactionsfor a description of known drug interactions. Carbamazepine, phenytoin, phenobarbital, primidone, and rifampin have been shown to increase the apparent clearance of lamotrigine. Valproate has been shown to decrease the apparent clearance of lamotrigine.Discontinuation of Psychotropic Drugs (excluding Valproate , Carbamazepine, or Other Enzyme-Inducing Drugs )After Discontinuation of Valproate After Discontinuation of Carbamazepine or Other Enzyme-Inducing Drugs Current Lamotrigine dose (mg/day) 100Current Lamotrigine dose (mg/day) 400Week 1Maintain current lamotrigine dose150400Week 2Maintain current lamotrigine dose200300Week 3 onwardMaintain current lamotrigine dose200200There is no body of evidence available to answer the question of how long the patient should remain on lamotrigine therapy. Systematic evaluation of the efficacy of lamotrigine in patients with either depression or mania who responded to standard therapy during an acute 8 to 16 week treatment phase and were then randomized to lamotrigine or placebo for up to 76 weeks of observation for affective relapse demonstrated a benefit of such maintenance treatment (see CLINICAL STUDIES: Bipolar Disorder). Nevertheless, patients should be periodically reassessed to determine the need for maintenance treatment.
  Discontinuation Strategy in Bipolar Disorder:
  As with other AEDs, lamotrigine should not be abruptly discontinued. In the controlled clinical trials, there was no increase in the incidence, type, or severity of adverse experiences following abrupt termination of lamotrigine. In clinical trials in patients with bipolar disorder, 2 patients experienced seizures shortly after abrupt withdrawal of lamotrigine. However, there were confounding factors that may have contributed to the occurrence of seizures in these bipolar patients. Discontinuation of lamotrigine should involve a step-wise reduction of dose over at least 2 weeks (approximately 50% per week) unless safety concerns require a more rapid withdrawal.
  Administration of Lamotrigine Tablets (Chewable, Dispersible)
  Lamotrigine tablets (Chewable, Dispersible) may be swallowed whole, chewed, or dispersed in water or diluted fruit juice. If the tablets are chewed, consume a small amount of water or diluted fruit juice to aid in swallowing.
  To disperse lamotrigine tablets (chewable, dispersible), add the tablets to a small amount of liquid (1 teaspoon, or enough to cover the medication). Approximately 1 minute later, when the tablets are completely dispersed, swirl the solution and consume the entire quantity immediately.
  No attempt should be made to administer partial quantities of the dispersed tablets.
  
  

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  2.1 General Dosing Considerations

  Rash: There are suggestions, yet to be proven, that the risk of severe, potentially life-threatening rash may be increased by (1) coadministration of lamotrigine with valproate, (2) exceeding the recommended initial dose of lamotrigine, or (3) exceeding the recommended dose escalation for lamotrigine. However, cases have occurred in the absence of these factors [see Boxed Warning]. Therefore, it is important that the dosing recommendations be followed closely.

  The risk of nonserious rash may be increased when the recommended initial dose and/or the rate of dose escalation of lamotrigine is exceeded and in patients with a history of allergy or rash to other AEDs.

  It is recommended that lamotrigine not be restarted in patients who discontinued due to rash associated with prior treatment with lamotrigine, unless the potential benefits clearly outweigh the risks. If the decision is made to restart a patient who has discontinued lamotrigine, the need to restart with the initial dosing recommendations should be assessed. The greater the interval of time since the previous dose, the greater consideration should be given to restarting with the initial dosing recommendations. If a patient has discontinued lamotrigine for a period of more than 5 half-lives, it is recommended that initial dosing recommendations and guidelines be followed. The half-life of lamotrigine is affected by other concomitant medications [see Clinical Pharmacology (12.3)].

  Lamotrigine Added to Drugs Known to Induce or Inhibit Glucuronidation: Drugs other than those listed in the Clinical Pharmacology section [see Clinical Pharmacology (12.3)] have not been systematically evaluated in combination with lamotrigine. Because lamotrigine is metabolized predominantly by glucuronic acid conjugation, drugs that are known to induce or inhibit glucuronidation may affect the apparent clearance of lamotrigine and doses of lamotrigine may require adjustment based on clinical response.

  Target Plasma Levels for Patients With Epilepsy or Bipolar Disorder: A therapeutic plasma concentration range has not been established for lamotrigine. Dosing of lamotrigine should be based on therapeutic response [see Clinical Pharmacology (12.3)].

  Women Taking Estrogen-Containing Oral Contraceptives:Starting lamotrigine in Women Taking Estrogen-Containing Oral Contraceptives: Although estrogen-containing oral contraceptives have been shown to increase the clearance of lamotrigine [see Clinical Pharmacology (12.3)], no adjustments to the recommended dose-escalation guidelines for lamotrigine should be necessary solely based on the use of estrogen-containing oral contraceptives. Therefore, dose escalation should follow the recommended guidelines for initiating adjunctive therapy with lamotrigine based on the concomitant AED or other concomitant medications (see Table 1 or Table 5). See below for adjustments to maintenance doses of lamotrigine in women taking estrogen-containing oral contraceptives.

  Adjustments to the Maintenance Dose of lamotrigine in Women Taking Estrogen-Containing Oral Contraceptives:(1) Taking Estrogen-Containing Oral Contraceptives: For women not taking carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin that induce lamotrigine glucuronidation [see Drug Interactions (7), Clinical Pharmacology (12.3)], the maintenance dose of lamotrigine will in most cases need to be increased, by as much as 2-fold over the recommended target maintenance dose, in order to maintain a consistent lamotrigine plasma level [see Clinical Pharmacology (12.3)].

  (2) Starting Estrogen-Containing Oral Contraceptives: In women taking a stable dose of lamotrigine and not taking carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin that induce lamotrigine glucuronidation [see Drug Interactions (7), Clinical Pharmacology (12.3)], the maintenance dose will in most cases need to be increased by as much as 2-fold in order to maintain a consistent lamotrigine plasma level. The dose increases should begin at the same time that the oral contraceptive is introduced and continue, based on clinical response, no more rapidly than 50 to 100 mg/day every week. Dose increases should not exceed the recommended rate (see Table 1 or Table 5) unless lamotrigine plasma levels or clinical response support larger increases. Gradual transient increases in lamotrigine plasma levels may occur during the week of inactive hormonal preparation (pill-free week), and these increases will be greater if dose increases are made in the days before or during the week of inactive hormonal preparation. Increased lamotrigine plasma levels could result in additional adverse reactions, such as dizziness, ataxia, and diplopia. If adverse reactions attributable to lamotrigine consistently occur during the pill-free week, dose adjustments to the overall maintenance dose may be necessary. Dose adjustments limited to the pill-free week are not recommended. For women taking lamotrigine in addition to carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin that induce lamotrigine glucuronidation [see Drug Interactions (7), Clinical Pharmacology (12.3)], no adjustment to the dose of lamotrigine should be necessary.

  (3) Stopping Estrogen-Containing Oral Contraceptives: For women not taking carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin that induce lamotrigine glucuronidation [see Drug Interactions (7), Clinical Pharmacology (12.3)], the maintenance dose of lamotrigine will in most cases need to be decreased by as much as 50% in order to maintain a consistent lamotrigine plasma level. The decrease in dose of lamotrigine should not exceed 25% of the total daily dose per week over a 2-week period, unless clinical response or lamotrigine plasma levels indicate otherwise [see Clinical Pharmacology (12.3)]. For women taking lamotrigine in addition to carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin that induce lamotrigine glucuronidation [see Drug Interactions (7), Clinical Pharmacology (12.3)], no adjustment to the dose of lamotrigine should be necessary.

  Women and Other Hormonal Contraceptive Preparations or Hormone Replacement Therapy: The effect of other hormonal contraceptive preparations or hormone replacement therapy on the pharmacokinetics of lamotrigine has not been systematically evaluated. It has been reported that ethinylestradiol, not progestogens, increased the clearance of lamotrigine up to 2-fold, and the progestin-only pills had no effect on lamotrigine plasma levels. Therefore, adjustments to the dosage of lamotrigine in the presence of progestogens alone will likely not be needed.

  Patients With Hepatic Impairment: Experience in patients with hepatic impairment is limited. Based on a clinical pharmacology study in 24 patients with mild, moderate, and severe liver impairment [see Use in Specific Populations (8.6), Clinical Pharmacology (12.3)], the following general recommendations can be made. No dosage adjustment is needed in patients with mild liver impairment. Initial, escalation, and maintenance doses should generally be reduced by approximately 25% in patients with moderate and severe liver impairment without ascites and 50% in patients with severe liver impairment with ascites. Escalation and maintenance doses may be adjusted according to clinical response.

  Patients With Renal Impairment: Initial doses of lamotrigine should be based on patients' concomitant medications (see Tables 1-3 or Table 5); reduced maintenance doses may be effective for patients with significant renal impairment [see Use in Specific Populations (8.7), Clinical Pharmacology (12.3)]. Few patients with severe renal impairment have been evaluated during chronic treatment with lamotrigine. Because there is inadequate experience in this population, lamotrigine should be used with caution in these patients.

  Discontinuation Strategy:Epilepsy: For patients receiving lamotrigine in combination with other AEDs, a reevaluation of all AEDs in the regimen should be considered if a change in seizure control or an appearance or worsening of adverse reactions is observed.

  If a decision is made to discontinue therapy with lamotrigine, a step-wise reduction of dose over at least 2 weeks (approximately 50% per week) is recommended unless safety concerns require a more rapid withdrawal [see Warnings and Precautions (5.9)].

  Discontinuing carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin that induce lamotrigine glucuronidation should prolong the half-life of lamotrigine; discontinuing valproate should shorten the half-life of lamotrigine.

  Bipolar Disorder: In the controlled clinical trials, there was no increase in the incidence, type, or severity of adverse reactions following abrupt termination of lamotrigine. In clinical trials in patients with Bipolar Disorder, 2 patients experienced seizures shortly after abrupt withdrawal of lamotrigine. However, there were confounding factors that may have contributed to the occurrence of seizures in these bipolar patients. Discontinuation of lamotrigine should involve a step-wise reduction of dose over at least 2 weeks (approximately 50% per week) unless safety concerns require a more rapid withdrawal [see Warnings and Precautions (5.9)].

  2.2 Epilepsy – Adjunctive Therapy

  This section provides specific dosing recommendations for patients greater than 12 years of age and patients aged 2 to 12 years. Within each of these age-groups, specific dosing recommendations are provided depending upon concomitant AED or other concomitant medications (Table 1 for patients greater than 12 years of age and Table 2 for patients aged 2 to 12 years). A weight-based dosing guide for patients aged 2 to 12 years on concomitant valproate is provided in Table 3.

  Patients Greater Than 12 Years of Age: Recommended dosing guidelines are summarized in Table 1.

  Table 1. Escalation Regimen for Lamotrigine in Patients Greater Than 12 Years of Age With Epilepsy    For Patients TAKING Valproatea  For Patients NOT TAKING Carbamazepine, Phenytoin, Phenobarbital, Primidone,b or Valproatea  For Patients TAKING Carbamazepine, Phenytoin, Phenobarbital, or Primidoneb and NOT TAKING Valproatea  Weeks 1 and 2  25 mg every other day  25 mg every day  50 mg/day  Weeks 3 and 4  25 mg every day  50 mg/day  

  100 mg/day

  (in 2 divided doses)  Week 5 onwards to maintenance  Increase by 25 to 50 mg/day every 1 to 2 weeks  Increase by 50 mg/day every 1 to 2 weeks  Increase by 100 mg/day every 1 to 2 weeks.  Usual maintenance dose  

  100 to 200 mg/day with valproate alone

  100 to 400 mg/day with valproate and other drugs that induce glucuronidation

  (in 1 or 2 divided doses)  

  225 to 375 mg/day

  (in 2 divided doses)  

  300 to 500 mg/day

  (in 2 divided doses)

  aValproate has been shown to inhibit glucuronidation and decrease the apparent clearance of lamotrigine [see Drug Interactions (7), Clinical Pharmacology (12.3)].

  bThese drugs induce lamotrigine glucuronidation and increase clearance [see Drug Interactions (7), Clinical Pharmacology (12.3)]. Other drugs that have similar effects include estrogen-containing oral contraceptives [see Drug Interactions (7), Clinical Pharmacology (12.3)]. Dosing recommendations for oral contraceptives can be found in General Dosing Considerations [see Dosage and Administration (2.1)]. Patients on rifampin, or other drugs that induce lamotrigine glucuronidation and increase clearance, should follow the same dosing titration/maintenance regimen as that used with anticonvulsants that have this effect.

  Patients Aged 2 to 12 Years: Recommended dosing guidelines are summarized in Table 2.

  Smaller starting doses and slower dose escalations than those used in clinical trials are recommended because of the suggestion that the risk of rash may be decreased by smaller starting doses and slower dose escalations. Therefore, maintenance doses will take longer to reach in clinical practice than in clinical trials. It may take several weeks to months to achieve an individualized maintenance dose. Maintenance doses in patients weighing less than 30 kg, regardless of age or concomitant AED, may need to be increased as much as 50%, based on clinical response.

  Table 2. Escalation Regimen for Lamotrigine in Patients Aged 2 to 12 Years With Epilepsy    For Patients TAKING Valproatea  For Patients NOT TAKING Carbamazepine, Phenytoin, Phenobarbital, Primidone,b or Valproatea  For Patients TAKING Carbamazepine, Phenytoin, Phenobarbital, or Primidoneb and NOT TAKING Valproate a  Weeks 1 and 2  

  0.15 mg/kg/day

  in 1 or 2 divided doses, rounded down to the nearest whole tablet (see Table 3 for weight-based dosing guide)  

  0.3 mg/kg/day

  in 1 or 2 divided doses, rounded down to the nearest whole tablet

   

  0.6 mg/kg/day

  in 2 divided doses, rounded down to the nearest whole tablet

   Weeks 3 and 4  

  0.3 mg/kg/day

  in 1 or 2 divided doses, rounded down to the nearest whole tablet (see Table 3 for weight-based dosing guide)  

  0.6 mg/kg/day

  in 2 divided doses, rounded down to the nearest whole tablet

   

  1.2 mg/kg/day

  in 2 divided doses, rounded down to the nearest whole tablet

   Week 5 onwards to maintenance  The dose should be increased every 1 to 2 weeks as follows: calculate 0.3 mg/kg/day, round this amount down to the nearest whole tablet, and add this amount to the previously administered daily dose  The dose should be increased every 1 to 2 weeks as follows: calculate 0.6 mg/kg/day, round this amount down to the nearest whole tablet, and add this amount to the previously administered daily dose  The dose should be increased every 1 to 2 weeks as follows: calculate 1.2 mg/kg/day, round this amount down to the nearest whole tablet, and add this amount to the previously administered daily dose  Usual maintenance dose  

  1 to 5 mg/kg/day (maximum 200 mg/day in 1 or 2 divided doses)

  1 to 3 mg/kg/day with valproate alone  

  4.5 to 7.5 mg/kg/day

  (maximum 300 mg/day in 2 divided doses)  5 to 15 mg/kg/day (maximum 400 mg/day in 2 divided doses)  Maintenance dose in patients less than 30 kg  May need to be increased by as much as 50%, based on clinical response  May need to be increased by as much as 50%, based on clinical response  May need to be increased by as much as 50%, based on clinical response

  Note: Only whole tablets should be used for dosing.

  aValproate has been shown to inhibit glucuronidation and decrease the apparent clearance of lamotrigine [see Drug Interactions (7), Clinical Pharmacology (12.3)].

  bThese drugs induce lamotrigine glucuronidation and increase clearance [see Drug Interactions (7), Clinical Pharmacology (12.3)]. Other drugs that have similar effects include estrogen-containing oral contraceptives [see Drug Interactions (7), Clinical Pharmacology (12.3)]. Dosing recommendations for oral contraceptives can be found in General Dosing Considerations [see Dosage and Administration (2.1)]. Patients on rifampin, or other drugs that induce lamotrigine glucuronidation and increase clearance, should follow the same dosing titration/maintenance regimen as that used with anticonvulsants that have this effect.

  Table 3. The Initial Weight-Based Dosing Guide for Patients Aged 2 to 12 Years Taking Valproate (Weeks 1 to 4) With Epilepsy  If the patient’s weight is  Give this daily dose, using the most appropriate combination of lamotrigine 2-mg and 5-mg tablets  Greater than  And less than  Weeks 1 and 2  Weeks 3 and 4  6.7 kg  14 kg  2 mg every other day  2 mg every day  14.1 kg  27 kg  2 mg every day  4 mg every day  27.1 kg  34 kg  4 mg every day  8 mg every day  34.1 kg  40 kg  5 mg every day  10 mg every day

  Usual Adjunctive Maintenance Dose for Epilepsy: The usual maintenance doses identified in Tables 1 and 2 are derived from dosing regimens employed in the placebo-controlled adjunctive studies in which the efficacy of lamotrigine was established. In patients receiving multidrug regimens employing carbamazepine, phenytoin, phenobarbital, or primidone without valproate, maintenance doses of adjunctive lamotrigine as high as 700 mg/day have been used. In patients receiving valproate alone, maintenance doses of adjunctive lamotrigine as high as 200 mg/day have been used. The advantage of using doses above those recommended in Tables 1 through 4 has not been established in controlled trials.

  2.3 Epilepsy – Conversion From Adjunctive Therapy to Monotherapy

  The goal of the transition regimen is to effect the conversion to monotherapy with lamotrigine under conditions that ensure adequate seizure control while mitigating the risk of serious rash associated with the rapid titration of lamotrigine.

  The recommended maintenance dose of lamotrigine as monotherapy is 500 mg/day given in 2 divided doses.

  To avoid an increased risk of rash, the recommended initial dose and subsequent dose escalations of lamotrigine should not be exceeded [see Boxed Warning].

  Conversion From Adjunctive Therapy With Carbamazepine, Phenytoin, Phenobarbital, or Primidone to Monotherapy With Lamotrigine: After achieving a dose of 500 mg/day of lamotrigine according to the guidelines in Table 1, the concomitant AED should be withdrawn by 20% decrements each week over a 4-week period. The regimen for the withdrawal of the concomitant AED is based on experience gained in the controlled monotherapy clinical trial.

  Conversion From Adjunctive Therapy With Valproate to Monotherapy With Lamotrigine: The conversion regimen involves 4 steps outlined in Table 4.

  Table 4. Conversion From Adjunctive Therapy With Valproate to Monotherapy With Lamotrigine in Patients ≥16 Years of Age With Epilepsy    Lamotrigine  Valproate  Step 1  Achieve a dose of 200 mg/day according to guidelines in Table 1 (if not already on 200 mg/day).  

  Maintain previous stable dose.

   Step 2  Maintain at 200 mg/day.  Decrease to 500 mg/day by decrements no greater than 500 mg/day/week and then maintain the dose of 500 mg/day for 1 week.  Step 3  Increase to 300 mg/day and maintain for 1 week.  Simultaneously decrease to 250 mg/day and maintain for 1 week.  Step 4  Increase by 100 mg/day every week to achieve maintenance dose of 500 mg/day.  Discontinue.

  Conversion From Adjunctive Therapy With Antiepileptic Drugs Other Than Carbamazepine, Phenytoin, Phenobarbital, Primidone, or Valproate to Monotherapy With Lamotrigine: No specific dosing guidelines can be provided for conversion to monotherapy with LAMICTAL with AEDs other than carbamazepine, phenobarbital, phenytoin, primidone, or valproate.

  2.4 Bipolar Disorder

  The goal of maintenance treatment with lamotrigine is to delay the time to occurrence of mood episodes (depression, mania, hypomania, mixed episodes) in patients treated for acute mood episodes with standard therapy. The target dose of lamotrigine is 200 mg/day (100 mg/day in patients taking valproate, which decreases the apparent clearance of lamotrigine, and 400 mg/day in patients not taking valproate and taking either carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin that increase the apparent clearance of lamotrigine). In the clinical trials, doses up to 400 mg/day as monotherapy were evaluated; however, no additional benefit was seen at 400 mg/day compared with 200 mg/day [see Clinical Studies (14.2)]. Accordingly, doses above 200 mg/day are not recommended. Treatment with lamotrigine is introduced, based on concurrent medications, according to the regimen outlined in Table 5. If other psychotropic medications are withdrawn following stabilization, the dose of lamotrigine should be adjusted. For patients discontinuing valproate, the dose of lamotrigine should be doubled over a 2-week period in equal weekly increments (see Table 6). For patients discontinuing carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin that induce lamotrigine glucuronidation, the dose of lamotrigine should remain constant for the first week and then should be decreased by half over a 2-week period in equal weekly decrements (see Table 6). The dose of lamotrigine may then be further adjusted to the target dose (200 mg) as clinically indicated.

  If other drugs are subsequently introduced, the dose of lamotrigine may need to be adjusted. In particular, the introduction of valproate requires reduction in the dose of lamotrigine [see Drug Interactions (7), Clinical Pharmacology (12.3)].

  To avoid an increased risk of rash, the recommended initial dose and subsequent dose escalations of lamotrigine should not be exceeded [see Boxed Warning].

  Table 5. Escalation Regimen for Lamotrigine for Patients With Bipolar Disorder    For Patients TAKING Valproatea  For Patients NOT TAKING Carbamazepine, Phenytoin, Phenobarbital, Primidone,b or Valproatea  For Patients TAKING Carbamazepine, Phenytoin, Phenobarbital, or Primidoneb and NOT TAKING Valproatea  Weeks 1 and 2  25 mg every other day  25 mg daily  50 mg daily  Weeks 3 and 4  25 mg daily  50 mg daily  100 mg daily, in divided doses  Week 5  50 mg daily  100 mg daily  200 mg daily, in divided doses  Week 6  100 mg daily  200 mg daily  300 mg daily, in divided doses  Week 7  100 mg daily  200 mg daily  up to 400 mg daily, in divided doses

  aValproate has been shown to inhibit glucuronidation and decrease the apparent clearance of lamotrigine [see Drug Interactions (7), Clinical Pharmacology (12.3)].

  bThese drugs induce lamotrigine glucuronidation and increase clearance [see Drug Interactions (7), Clinical Pharmacology (12.3)]. Other drugs that have similar effects include estrogen-containing oral contraceptives [see Drug Interactions (7), Clinical Pharmacology (12.3)]. Dosing recommendations for oral contraceptives can be found in General Dosing Considerations [see Dosage and Administration (2.1)]. Patients on rifampin, or other drugs that induce lamotrigine glucuronidation and increase clearance, should follow the same dosing titration/maintenance regimen as that used with anticonvulsants that have this effect.

  Table 6. Dosage Adjustments to Lamotrigine for Patients With Bipolar Disorder Following Discontinuation of Psychotropic Medications    Discontinuation of Psychotropic Drugs (excluding Carbamazepine, Phenytoin, Phenobarbital, Primidone,b or Valproatea)  After Discontinuation of Valproatea  After Discontinuation of Carbamazepine, Phenytoin, Phenobarbital, or Primidoneb  

  Current dose of LAMICTAL (mg/day)

  100  

  Current dose of LAMICTAL (mg/day)

  400  Week 1  Maintain current dose of lamotrigine  150  400  Week 2  Maintain current dose of lamotrigine  200  300  Week 3 onward  Maintain current dose of lamotrigine  200  200

  aValproate has been shown to inhibit glucuronidation and decrease the apparent clearance of lamotrigine [see Drug Interactions (7), Clinical Pharmacology (12.3)].

  bThese drugs induce lamotrigine glucuronidation and increase clearance [see Drug Interactions (7), Clinical Pharmacology (12.3)]. Other drugs that have similar effects include estrogen-containing oral contraceptives [see Drug Interactions (7), Clinical Pharmacology (12.3)]. Dosing recommendations for oral contraceptives can be found in General Dosing Considerations [see Dosage and Administration (2.1)]. Patients on rifampin, or other drugs that induce lamotrigine glucuronidation and increase clearance, should follow the same dosing titration/maintenance regimen as that used with anticonvulsants that have this effect.

  The benefit of continuing treatment in patients who had been stabilized in an 8- to 16-week open-label phase with lamotrigine was established in 2 randomized, placebo-controlled clinical maintenance trials [see Clinical Studies (14.2)]. However, the optimal duration of treatment with lamotrigine has not been established. Thus, patients should be periodically reassessed to determine the need for maintenance treatment.

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  Lamotrigine | Hikma Pharmaceutical

  

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  2.1 General Dosing Considerations

  Rash: There are suggestions, yet to be proven, that the risk of severe, potentially life-threatening rash may be increased by (1) coadministration of lamotrigine with valproate, (2) exceeding the recommended initial dose of lamotrigine, or (3) exceeding the recommended dose escalation for lamotrigine. However, cases have occurred in the absence of these factors [see Boxed Warning]. Therefore, it is important that the dosing recommendations be followed closely.

  The risk of nonserious rash may be increased when the recommended initial dose and/or the rate of dose escalation of lamotrigine is exceeded and in patients with a history of allergy or rash to other AEDs.

  It is recommended that lamotrigine not be restarted in patients who discontinued due to rash associated with prior treatment with lamotrigine, unless the potential benefits clearly outweigh the risks. If the decision is made to restart a patient who has discontinued lamotrigine, the need to restart with the initial dosing recommendations should be assessed. The greater the interval of time since the previous dose, the greater consideration should be given to restarting with the initial dosing recommendations. If a patient has discontinued lamotrigine for a period of more than 5 half-lives, it is recommended that initial dosing recommendations and guidelines be followed. The half-life of lamotrigine is affected by other concomitant medications [see Clinical Pharmacology (12.3)].

  Lamotrigine Added to Drugs Known to Induce or Inhibit Glucuronidation: Drugs other than those listed in the Clinical Pharmacology section [see Clinical Pharmacology (12.3)] have not been systematically evaluated in combination with lamotrigine. Because lamotrigine is metabolized predominantly by glucuronic acid conjugation, drugs that are known to induce or inhibit glucuronidation may affect the apparent clearance of lamotrigine and doses of lamotrigine may require adjustment based on clinical response.

  Target Plasma Levels for Patients With Epilepsy or Bipolar Disorder: A therapeutic plasma concentration range has not been established for lamotrigine. Dosing of lamotrigine should be based on therapeutic response [see Clinical Pharmacology (12.3)].

  Women Taking Estrogen-Containing Oral Contraceptives:Starting lamotrigine in Women Taking Estrogen-Containing Oral Contraceptives: Although estrogen-containing oral contraceptives have been shown to increase the clearance of lamotrigine [see Clinical Pharmacology (12.3)], no adjustments to the recommended dose-escalation guidelines for lamotrigine should be necessary solely based on the use of estrogen-containing oral contraceptives. Therefore, dose escalation should follow the recommended guidelines for initiating adjunctive therapy with lamotrigine based on the concomitant AED or other concomitant medications (see Table 1 or Table 5). See below for adjustments to maintenance doses of lamotrigine in women taking estrogen-containing oral contraceptives.

  Adjustments to the Maintenance Dose of lamotrigine in Women Taking Estrogen-Containing Oral Contraceptives:(1) Taking Estrogen-Containing Oral Contraceptives: For women not taking carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin that induce lamotrigine glucuronidation [see Drug Interactions (7), Clinical Pharmacology (12.3)], the maintenance dose of lamotrigine will in most cases need to be increased, by as much as 2-fold over the recommended target maintenance dose, in order to maintain a consistent lamotrigine plasma level [see Clinical Pharmacology (12.3)].

  (2) Starting Estrogen-Containing Oral Contraceptives: In women taking a stable dose of lamotrigine and not taking carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin that induce lamotrigine glucuronidation [see Drug Interactions (7), Clinical Pharmacology (12.3)], the maintenance dose will in most cases need to be increased by as much as 2-fold in order to maintain a consistent lamotrigine plasma level. The dose increases should begin at the same time that the oral contraceptive is introduced and continue, based on clinical response, no more rapidly than 50 to 100 mg/day every week. Dose increases should not exceed the recommended rate (see Table 1 or Table 5) unless lamotrigine plasma levels or clinical response support larger increases. Gradual transient increases in lamotrigine plasma levels may occur during the week of inactive hormonal preparation (pill-free week), and these increases will be greater if dose increases are made in the days before or during the week of inactive hormonal preparation. Increased lamotrigine plasma levels could result in additional adverse reactions, such as dizziness, ataxia, and diplopia. If adverse reactions attributable to lamotrigine consistently occur during the pill-free week, dose adjustments to the overall maintenance dose may be necessary. Dose adjustments limited to the pill-free week are not recommended. For women taking lamotrigine in addition to carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin that induce lamotrigine glucuronidation [see Drug Interactions (7), Clinical Pharmacology (12.3)], no adjustment to the dose of lamotrigine should be necessary.

  (3) Stopping Estrogen-Containing Oral Contraceptives: For women not taking carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin that induce lamotrigine glucuronidation [see Drug Interactions (7), Clinical Pharmacology (12.3)], the maintenance dose of lamotrigine will in most cases need to be decreased by as much as 50% in order to maintain a consistent lamotrigine plasma level. The decrease in dose of lamotrigine should not exceed 25% of the total daily dose per week over a 2-week period, unless clinical response or lamotrigine plasma levels indicate otherwise [see Clinical Pharmacology (12.3)]. For women taking lamotrigine in addition to carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin that induce lamotrigine glucuronidation [see Drug Interactions (7), Clinical Pharmacology (12.3)], no adjustment to the dose of lamotrigine should be necessary.

  Women and Other Hormonal Contraceptive Preparations or Hormone Replacement Therapy: The effect of other hormonal contraceptive preparations or hormone replacement therapy on the pharmacokinetics of lamotrigine has not been systematically evaluated. It has been reported that ethinylestradiol, not progestogens, increased the clearance of lamotrigine up to 2-fold, and the progestin-only pills had no effect on lamotrigine plasma levels. Therefore, adjustments to the dosage of lamotrigine in the presence of progestogens alone will likely not be needed.

  Patients With Hepatic Impairment: Experience in patients with hepatic impairment is limited. Based on a clinical pharmacology study in 24 patients with mild, moderate, and severe liver impairment [see Use in Specific Populations (8.6), Clinical Pharmacology (12.3)], the following general recommendations can be made. No dosage adjustment is needed in patients with mild liver impairment. Initial, escalation, and maintenance doses should generally be reduced by approximately 25% in patients with moderate and severe liver impairment without ascites and 50% in patients with severe liver impairment with ascites. Escalation and maintenance doses may be adjusted according to clinical response.

  Patients With Renal Impairment: Initial doses of lamotrigine should be based on patients' concomitant medications (see Tables 1-3 or Table 5); reduced maintenance doses may be effective for patients with significant renal impairment [see Use in Specific Populations (8.7), Clinical Pharmacology (12.3)]. Few patients with severe renal impairment have been evaluated during chronic treatment with lamotrigine. Because there is inadequate experience in this population, lamotrigine should be used with caution in these patients.

  Discontinuation Strategy:Epilepsy: For patients receiving lamotrigine in combination with other AEDs, a reevaluation of all AEDs in the regimen should be considered if a change in seizure control or an appearance or worsening of adverse reactions is observed.

  If a decision is made to discontinue therapy with lamotrigine, a step-wise reduction of dose over at least 2 weeks (approximately 50% per week) is recommended unless safety concerns require a more rapid withdrawal [see Warnings and Precautions (5.9)].

  Discontinuing carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin that induce lamotrigine glucuronidation should prolong the half-life of lamotrigine; discontinuing valproate should shorten the half-life of lamotrigine.

  Bipolar Disorder: In the controlled clinical trials, there was no increase in the incidence, type, or severity of adverse reactions following abrupt termination of lamotrigine. In clinical trials in patients with Bipolar Disorder, 2 patients experienced seizures shortly after abrupt withdrawal of lamotrigine. However, there were confounding factors that may have contributed to the occurrence of seizures in these bipolar patients. Discontinuation of lamotrigine should involve a step-wise reduction of dose over at least 2 weeks (approximately 50% per week) unless safety concerns require a more rapid withdrawal [see Warnings and Precautions (5.9)].

  2.2 Epilepsy – Adjunctive Therapy

  This section provides specific dosing recommendations for patients greater than 12 years of age and patients aged 2 to 12 years. Within each of these age-groups, specific dosing recommendations are provided depending upon concomitant AED or other concomitant medications (Table 1 for patients greater than 12 years of age and Table 2 for patients aged 2 to 12 years). A weight-based dosing guide for patients aged 2 to 12 years on concomitant valproate is provided in Table 3.

  Patients Greater Than 12 Years of Age: Recommended dosing guidelines are summarized in Table 1.

  Table 1. Escalation Regimen for Lamotrigine in Patients Greater Than 12 Years of Age With Epilepsy      For Patients TAKING Valproatea   For Patients NOT TAKING Carbamazepine, Phenytoin, Phenobarbital, Primidone,b or Valproatea   For Patients TAKING Carbamazepine, Phenytoin, Phenobarbital, or Primidoneb and NOT TAKING Valproatea   Weeks 1 and 2   25 mg every other day   25 mg every day   50 mg/day   Weeks 3 and 4   25 mg every day   50 mg/day   

  100 mg/day

  (in 2 divided doses)   Week 5 onwards to maintenance   Increase by 25 to 50 mg/day every 1 to 2 weeks   Increase by 50 mg/day every 1 to 2 weeks   Increase by 100 mg/day every 1 to 2 weeks.   Usual maintenance dose   

  100 to 200 mg/day with valproate alone

  100 to 400 mg/day with valproate and other drugs that induce glucuronidation

  (in 1 or 2 divided doses)   

  225 to 375 mg/day

  (in 2 divided doses)   

  300 to 500 mg/day

  (in 2 divided doses)

  aValproate has been shown to inhibit glucuronidation and decrease the apparent clearance of lamotrigine [see Drug Interactions (7), Clinical Pharmacology (12.3)].

  bThese drugs induce lamotrigine glucuronidation and increase clearance [see Drug Interactions (7), Clinical Pharmacology (12.3)]. Other drugs that have similar effects include estrogen-containing oral contraceptives [see Drug Interactions (7), Clinical Pharmacology (12.3)]. Dosing recommendations for oral contraceptives can be found in General Dosing Considerations [see Dosage and Administration (2.1)]. Patients on rifampin, or other drugs that induce lamotrigine glucuronidation and increase clearance, should follow the same dosing titration/maintenance regimen as that used with anticonvulsants that have this effect.

  Patients Aged 2 to 12 Years: Recommended dosing guidelines are summarized in Table 2.

  Smaller starting doses and slower dose escalations than those used in clinical trials are recommended because of the suggestion that the risk of rash may be decreased by smaller starting doses and slower dose escalations. Therefore, maintenance doses will take longer to reach in clinical practice than in clinical trials. It may take several weeks to months to achieve an individualized maintenance dose. Maintenance doses in patients weighing less than 30 kg, regardless of age or concomitant AED, may need to be increased as much as 50%, based on clinical response.

  Table 2. Escalation Regimen for Lamotrigine in Patients Aged 2 to 12 Years With Epilepsy      For Patients TAKING Valproatea   For Patients NOT TAKING Carbamazepine, Phenytoin, Phenobarbital, Primidone,b or Valproatea   For Patients TAKING Carbamazepine, Phenytoin, Phenobarbital, or Primidoneb and NOT TAKING Valproate a   Weeks 1 and 2   

  0.15 mg/kg/day

  in 1 or 2 divided doses, rounded down to the nearest whole tablet (see Table 3 for weight-based dosing guide)   

  0.3 mg/kg/day

  in 1 or 2 divided doses, rounded down to the nearest whole tablet

    

  0.6 mg/kg/day

  in 2 divided doses, rounded down to the nearest whole tablet

    Weeks 3 and 4   

  0.3 mg/kg/day

  in 1 or 2 divided doses, rounded down to the nearest whole tablet (see Table 3 for weight-based dosing guide)   

  0.6 mg/kg/day

  in 2 divided doses, rounded down to the nearest whole tablet

    

  1.2 mg/kg/day

  in 2 divided doses, rounded down to the nearest whole tablet

    Week 5 onwards to maintenance   The dose should be increased every 1 to 2 weeks as follows: calculate 0.3 mg/kg/day, round this amount down to the nearest whole tablet, and add this amount to the previously administered daily dose   The dose should be increased every 1 to 2 weeks as follows: calculate 0.6 mg/kg/day, round this amount down to the nearest whole tablet, and add this amount to the previously administered daily dose   The dose should be increased every 1 to 2 weeks as follows: calculate 1.2 mg/kg/day, round this amount down to the nearest whole tablet, and add this amount to the previously administered daily dose   Usual maintenance dose   

  1 to 5 mg/kg/day (maximum 200 mg/day in 1 or 2 divided doses)

  1 to 3 mg/kg/day with valproate alone   

  4.5 to 7.5 mg/kg/day

  (maximum 300 mg/day in 2 divided doses)   5 to 15 mg/kg/day (maximum 400 mg/day in 2 divided doses)   Maintenance dose in patients less than 30 kg   May need to be increased by as much as 50%, based on clinical response   May need to be increased by as much as 50%, based on clinical response   May need to be increased by as much as 50%, based on clinical response

  Note: Only whole tablets should be used for dosing.

  aValproate has been shown to inhibit glucuronidation and decrease the apparent clearance of lamotrigine [see Drug Interactions (7), Clinical Pharmacology (12.3)].

  bThese drugs induce lamotrigine glucuronidation and increase clearance [see Drug Interactions (7), Clinical Pharmacology (12.3)]. Other drugs that have similar effects include estrogen-containing oral contraceptives [see Drug Interactions (7), Clinical Pharmacology (12.3)]. Dosing recommendations for oral contraceptives can be found in General Dosing Considerations [see Dosage and Administration (2.1)]. Patients on rifampin, or other drugs that induce lamotrigine glucuronidation and increase clearance, should follow the same dosing titration/maintenance regimen as that used with anticonvulsants that have this effect.

  Table 3. The Initial Weight-Based Dosing Guide for Patients Aged 2 to 12 Years Taking Valproate (Weeks 1 to 4) With Epilepsy   If the patient’s weight is   Give this daily dose, using the most appropriate combination of lamotrigine 2-mg and 5-mg tablets   Greater than   And less than   Weeks 1 and 2   Weeks 3 and 4   6.7 kg   14 kg   2 mg every other day   2 mg every day   14.1 kg   27 kg   2 mg every day   4 mg every day   27.1 kg   34 kg   4 mg every day   8 mg every day   34.1 kg   40 kg   5 mg every day   10 mg every day

  Usual Adjunctive Maintenance Dose for Epilepsy: The usual maintenance doses identified in Tables 1 and 2 are derived from dosing regimens employed in the placebo-controlled adjunctive studies in which the efficacy of lamotrigine was established. In patients receiving multidrug regimens employing carbamazepine, phenytoin, phenobarbital, or primidone without valproate, maintenance doses of adjunctive lamotrigine as high as 700 mg/day have been used. In patients receiving valproate alone, maintenance doses of adjunctive lamotrigine as high as 200 mg/day have been used. The advantage of using doses above those recommended in Tables 1 through 4 has not been established in controlled trials.

  2.3 Epilepsy – Conversion From Adjunctive Therapy to Monotherapy

  The goal of the transition regimen is to effect the conversion to monotherapy with lamotrigine under conditions that ensure adequate seizure control while mitigating the risk of serious rash associated with the rapid titration of lamotrigine.

  The recommended maintenance dose of lamotrigine as monotherapy is 500 mg/day given in 2 divided doses.

  To avoid an increased risk of rash, the recommended initial dose and subsequent dose escalations of lamotrigine should not be exceeded [see Boxed Warning].

  Conversion From Adjunctive Therapy With Carbamazepine, Phenytoin, Phenobarbital, or Primidone to Monotherapy With Lamotrigine: After achieving a dose of 500 mg/day of lamotrigine according to the guidelines in Table 1, the concomitant AED should be withdrawn by 20% decrements each week over a 4-week period. The regimen for the withdrawal of the concomitant AED is based on experience gained in the controlled monotherapy clinical trial.

  Conversion From Adjunctive Therapy With Valproate to Monotherapy With Lamotrigine: The conversion regimen involves 4 steps outlined in Table 4.

  Table 4. Conversion From Adjunctive Therapy With Valproate to Monotherapy With Lamotrigine in Patients ≥16 Years of Age With Epilepsy      Lamotrigine   Valproate   Step 1   Achieve a dose of 200 mg/day according to guidelines in Table 1 (if not already on 200 mg/day).   

  Maintain previous stable dose.

    Step 2   Maintain at 200 mg/day.   Decrease to 500 mg/day by decrements no greater than 500 mg/day/week and then maintain the dose of 500 mg/day for 1 week.   Step 3   Increase to 300 mg/day and maintain for 1 week.   Simultaneously decrease to 250 mg/day and maintain for 1 week.   Step 4   Increase by 100 mg/day every week to achieve maintenance dose of 500 mg/day.   Discontinue.

  Conversion From Adjunctive Therapy With Antiepileptic Drugs Other Than Carbamazepine, Phenytoin, Phenobarbital, Primidone, or Valproate to Monotherapy With Lamotrigine: No specific dosing guidelines can be provided for conversion to monotherapy with lamotrigine with AEDs other than carbamazepine, phenobarbital, phenytoin, primidone, or valproate.

  2.4 Bipolar Disorder

  The goal of maintenance treatment with lamotrigine is to delay the time to occurrence of mood episodes (depression, mania, hypomania, mixed episodes) in patients treated for acute mood episodes with standard therapy. The target dose of lamotrigine is 200 mg/day (100 mg/day in patients taking valproate, which decreases the apparent clearance of lamotrigine, and 400 mg/day in patients not taking valproate and taking either carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin that increase the apparent clearance of lamotrigine). In the clinical trials, doses up to 400 mg/day as monotherapy were evaluated; however, no additional benefit was seen at 400 mg/day compared with 200 mg/day [see Clinical Studies (14.2)]. Accordingly, doses above 200 mg/day are not recommended. Treatment with lamotrigine is introduced, based on concurrent medications, according to the regimen outlined in Table 5. If other psychotropic medications are withdrawn following stabilization, the dose of lamotrigine should be adjusted. For patients discontinuing valproate, the dose of lamotrigine should be doubled over a 2-week period in equal weekly increments (see Table 6). For patients discontinuing carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin that induce lamotrigine glucuronidation, the dose of lamotrigine should remain constant for the first week and then should be decreased by half over a 2-week period in equal weekly decrements (see Table 6). The dose of lamotrigine may then be further adjusted to the target dose (200 mg) as clinically indicated.

  If other drugs are subsequently introduced, the dose of lamotrigine may need to be adjusted. In particular, the introduction of valproate requires reduction in the dose of lamotrigine [see Drug Interactions (7), Clinical Pharmacology (12.3)].

  To avoid an increased risk of rash, the recommended initial dose and subsequent dose escalations of lamotrigine should not be exceeded [see Boxed Warning].

  Table 5. Escalation Regimen for Lamotrigine for Patients With Bipolar Disorder      For Patients TAKING Valproatea   For Patients NOT TAKING Carbamazepine, Phenytoin, Phenobarbital, Primidone,b or Valproatea   For Patients TAKING Carbamazepine, Phenytoin, Phenobarbital, or Primidoneb and NOT TAKING Valproatea   Weeks 1 and 2   25 mg every other day   25 mg daily   50 mg daily   Weeks 3 and 4   25 mg daily   50 mg daily   100 mg daily, in divided doses   Week 5   50 mg daily   100 mg daily   200 mg daily, in divided doses   Week 6   100 mg daily   200 mg daily   300 mg daily, in divided doses   Week 7   100 mg daily   200 mg daily   up to 400 mg daily, in divided doses

  aValproate has been shown to inhibit glucuronidation and decrease the apparent clearance of lamotrigine [see Drug Interactions (7), Clinical Pharmacology (12.3)].

  bThese drugs induce lamotrigine glucuronidation and increase clearance [see Drug Interactions (7), Clinical Pharmacology (12.3)]. Other drugs that have similar effects include estrogen-containing oral contraceptives [see Drug Interactions (7), Clinical Pharmacology (12.3)]. Dosing recommendations for oral contraceptives can be found in General Dosing Considerations [see Dosage and Administration (2.1)]. Patients on rifampin, or other drugs that induce lamotrigine glucuronidation and increase clearance, should follow the same dosing titration/maintenance regimen as that used with anticonvulsants that have this effect.

  Table 6. Dosage Adjustments to Lamotrigine for Patients With Bipolar Disorder Following Discontinuation of Psychotropic Medications      Discontinuation of Psychotropic Drugs (excluding Carbamazepine, Phenytoin, Phenobarbital, Primidone,b or Valproatea)   After Discontinuation of Valproatea   After Discontinuation of Carbamazepine, Phenytoin, Phenobarbital, or Primidoneb   

  Current dose of LAMICTAL (mg/day)

  100   

  Current dose of LAMICTAL (mg/day)

  400   Week 1   Maintain current dose of lamotrigine   150   400   Week 2   Maintain current dose of lamotrigine   200   300   Week 3 onward   Maintain current dose of lamotrigine   200   200

  aValproate has been shown to inhibit glucuronidation and decrease the apparent clearance of lamotrigine [see Drug Interactions (7), Clinical Pharmacology (12.3)].

  bThese drugs induce lamotrigine glucuronidation and increase clearance [see Drug Interactions (7), Clinical Pharmacology (12.3)]. Other drugs that have similar effects include estrogen-containing oral contraceptives [see Drug Interactions (7), Clinical Pharmacology (12.3)]. Dosing recommendations for oral contraceptives can be found in General Dosing Considerations [see Dosage and Administration (2.1)]. Patients on rifampin, or other drugs that induce lamotrigine glucuronidation and increase clearance, should follow the same dosing titration/maintenance regimen as that used with anticonvulsants that have this effect.

  The benefit of continuing treatment in patients who had been stabilized in an 8- to 16-week open-label phase with lamotrigine was established in 2 randomized, placebo-controlled clinical maintenance trials [see Clinical Studies (14.2)]. However, the optimal duration of treatment with lamotrigine has not been established. Thus, patients should be periodically reassessed to determine the need for maintenance treatment.

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  Lamotrigine | Ncs Healthcare Of Ky, Inc Dba Vangard Labs

  

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  2.1 General Dosing Considerations

  Rash: There are suggestions, yet to be proven, that the risk of severe, potentially life-threatening rash may be increased by (1) coadministration of lamotrigine tablets with valproate, (2) exceeding the recommended initial dose of lamotrigine tablets, or (3) exceeding the recommended dose escalation for lamotrigine tablets. However, cases have occurred in the absence of these factors [see Boxed Warning]. Therefore, it is important that the dosing recommendations be followed closely.

  The risk of nonserious rash may be increased when the recommended initial dose and/or the rate of dose escalation of lamotrigine tablets is exceeded and in patients with a history of allergy or rash to other AEDs.

  It is recommended that lamotrigine tablets not be restarted in patients who discontinued due to rash associated with prior treatment with lamotrigine, unless the potential benefits clearly outweigh the risks. If the decision is made to restart a patient who has discontinued lamotrigine, the need to restart with the initial dosing recommendations should be assessed. The greater the interval of time since the previous dose, the greater consideration should be given to restarting with the initial dosing recommendations. If a patient has discontinued lamotrigine for a period of more than 5 half-lives, it is recommended that initial dosing recommendations and guidelines be followed. The half-life of lamotrigine is affected by other concomitant medications [see Clinical Pharmacology (12.3)].

  Lamotrigine Added to Drugs Known to Induce or Inhibit Glucuronidation: Drugs other than those listed in the Clinical Pharmacology section [see Clinical Pharmacology (12.3)] have not been systematically evaluated in combination with lamotrigine. Because lamotrigine is metabolized predominantly by glucuronic acid conjugation, drugs that are known to induce or inhibit glucuronidation may affect the apparent clearance of lamotrigine and doses of lamotrigine tablets may require adjustment based on clinical response.

  Target Plasma Levels for Patients With Epilepsy or Bipolar Disorder: A therapeutic plasma concentration range has not been established for lamotrigine. Dosing of lamotrigine tablets should be based on therapeutic response [see Clinical Pharmacology (12.3)].

  Women Taking Estrogen-Containing Oral Contraceptives:  Starting Lamotrigine Tablets in Women Taking Estrogen-Containing Oral Contraceptives: Although estrogen-containing oral contraceptives have been shown to increase the clearance of lamotrigine [see Clinical Pharmacology (12.3)], no adjustments to the recommended dose-escalation guidelines for lamotrigine tablets should be necessary solely based on the use of estrogen-containing oral contraceptives. Therefore, dose escalation should follow the recommended guidelines for initiating adjunctive therapy with lamotrigine tablets based on the concomitant AED or other concomitant medications (see Table 1 or Table 5). See below for adjustments to maintenance doses of lamotrigine tablets in women taking estrogen-containing oral contraceptives.

  Adjustments to the Maintenance Dose of Lamotrigine Tablets in Women Taking Estrogen-Containing Oral Contraceptives:

  (1) Taking Estrogen-Containing Oral Contraceptives: For women not taking carbamazepine, phenytoin, phenobarbital, primidone, or rifampin, the maintenance dose of lamotrigine tablets will in most cases need to be increased, by as much as 2 fold over the recommended target maintenance dose, in order to maintain a consistent lamotrigine plasma level [see Clinical Pharmacology (12.3)].

  (2) Starting Estrogen-Containing Oral Contraceptives: In women taking a stable dose of lamotrigine tablets and not taking carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin that induce lamotrigine glucuronidation [see Drug Interactions (7), Clinical Pharmacology (112.3)], the maintenance dose will in most cases need to be increased by as much as 2 fold in order to maintain a consistent lamotrigine plasma level. The dose increases should begin at the same time that the oral contraceptive is introduced and continue, based on clinical response, no more rapidly than 50 to 100 mg/day every week. Dose increases should not exceed the recommended rate (see Table 1 or Table 5) unless lamotrigine plasma levels or clinical response support larger increases. Gradual transient increases in lamotrigine plasma levels may occur during the week of inactive hormonal preparation (“pill-free” week), and these increases will be greater if dose increases are made in the days before or during the week of inactive hormonal preparation. Increased lamotrigine plasma levels could result in additional adverse reactions, such as dizziness, ataxia, and diplopia. If adverse reactions attributable to lamotrigine tablets consistently occur during the “pill-free” week, dose adjustments to the overall maintenance dose may be necessary. Dose adjustments limited to the “pill-free” week are not recommended. For women taking lamotrigine tablets in addition to carbamazepine, phenytoin, phenobarbital, primidone, or other druds such as rifampin that induce lamotrigine glucuronidation [see Drug Interactions (7), Clinical Pharmacology (12.3)], no adjustment to the dose of lamotrigine tablets should be necessary.

  (3) Stopping Estrogen-Containing Oral Contraceptives: For women not taking carbamazepine, phenytoin, phenobarbital, primidone, or rifampin, the maintenance dose of lamotrigine tablets will in most cases need to be decreased by as much as 50% in order to maintain a consistent lamotrigine plasma level. The decrease in dose of lamotrigine tablets should not exceed 25% of the total daily dose per week over a 2 week period, unless clinical response or lamotrigine plasma levels indicate otherwise [see Clinical Pharmacology (12.3)]. For women taking lamotrigine tablets in addition to carbamazepine, phenytoin, phenobarbital, primidone, or rifampin, no adjustment to the dose of lamotrigine tablets should be necessary.

  Women and Other Hormonal Contraceptive Preparations or Hormone Replacement Therapy: The effect of other hormonal contraceptive preparations or hormone replacement therapy on the pharmacokinetics of lamotrigine has not been systematically evaluated. It has been reported that ethinylestradiol, not progestogens, increased the clearance of lamotrigine up to 2 fold, and the progestin-only pills had no effect on lamotrigine plasma levels. Therefore, adjustments to the dosage of lamotrigine tablets in the presence of progestogens alone will likely not be needed.

  Patients With Hepatic Impairment: Experience in patients with hepatic impairment is limited. Based on a clinical pharmacology study in 24 patients with mild, moderate, and severe liver impairment [see Use in Specific Populations (8.6), Clinical Pharmacology (12.3)], the following general recommendations can be made. No dosage adjustment is needed in patients with mild liver impairment. Initial, escalation, and maintenance doses should generally be reduced by approximately 25% in patients with moderate and severe liver impairment without ascites and 50% in patients with severe liver impairment with ascites. Escalation and maintenance doses may be adjusted according to clinical response.

  Patients With Renal Impairment: Initial doses of lamotrigine tablets should be based on patients' concomitant medications (see Tables 1 to 3 or Table 5); reduced maintenance doses may be effective for patients with significant renal impairment [see Use in Specific Populations (8.7), Clinical Pharmacology (12.3)]. Few patients with severe renal impairment have been evaluated during chronic treatment with lamotrigine tablets. Because there is inadequate experience in this population, lamotrigine tablets should be used with caution in these patients.

  Discontinuation Strategy:  Epilepsy: For patients receiving lamotrigine tablets in combination with other AEDs, a re-evaluation of all AEDs in the regimen should be considered if a change in seizure control or an appearance or worsening of adverse reactions is observed.

  If a decision is made to discontinue therapy with lamotrigine tablets, a step-wise reduction of dose over at least 2 weeks (approximately 50% per week) is recommended unless safety concerns require a more rapid withdrawal [see Warnings and Precautions (5.9)].

  Discontinuing carbamazepine, phenytoin, phenobarbital, or primidone should prolong the half-life of lamotrigine; discontinuing valproate should shorten the half-life of lamotrigine.

  Bipolar Disorder: In the controlled clinical trials, there was no increase in the incidence, type, or severity of adverse reactions following abrupt termination of lamotrigine tablets. In clinical trials in patients with Bipolar Disorder, 2 patients experienced seizures shortly after abrupt withdrawal of lamotrigine tablets. However, there were confounding factors that may have contributed to the occurrence of seizures in these bipolar patients. Discontinuation of lamotrigine tablets should involve a step-wise reduction of dose over at least 2 weeks (approximately 50% per week) unless safety concerns require a more rapid withdrawal [see Warnings and Precautions (5.9)].

  2.2 Epilepsy – Adjunctive Therapy

  This section provides specific dosing recommendations for patients greater than 12 years of age and patients 2 to 12 years of age. Within each of these age-groups, specific dosing recommendations are provided depending upon concomitant AED or other concomitant medications (Table 1 for patients greater than 12 years of age and Table 2 for patients 2 to 12 years of age). A weight-based dosing guide for patients 2 to 12 years of age on concomitant valproate is provided in Table 3.

  Patients Over 12 Years of Age: Recommended dosing guidelines are summarized in Table 1.

  Table 1. Escalation Regimen for Lamotrigine in Patients Over 12 Years of Age With Epilepsy  * Valproate has been shown to inhibit glucuronidation and decrease the apparent clearance of lamotrigine [ see Drug Interactions (7), Clinical Pharmacology (12.3)] . † These drugs induce lamotrigine glucuronidation and increase clearance [ see Drug Interactions (7) Clinical Pharmacology (12.3)]. Other drugs, which have similar effects include estrogen-containing oral contraceptives [ see Drug Interactions (7), Clinical Pharmacology (12.3)] . Other drugs which have similar effects include estrogen containing oral contraceptives [see Drug Interactions (7), Clinical Pharmacologu (12.3)]. Dosing recommendations for oral contraceptives can be found in General Dosing Considerations [ see Dosage and Administration (2.1)] . Patients on rifampin, or other drugs that induce lamitrigine glucuronidation and increase clearance, should follow the same dosing titration/maintenance regimen as that used with anticonvulsdants that have this effect.    For Patients Taking Valproate*  For Patients Taking AEDs Other Than Carbamazepine, Phenytoin, Phenobarbital, or Primidone†, and Not Taking Valproate  For Patients Taking Carbamazepine, Phenytoin, Phenobarbital, or Primidone† and Not Taking Valproate  Weeks 1 and 2  25 mg every other day  25 mg every day  50 mg/day  Weeks 3 and 4  25 mg every day  50 mg/day  100 mg/day (in 2 divided doses)  Weeks 5 onwards to maintenance  Increase by 25 to 50 mg/day every 1 to 2 weeks  Increase by 50 mg/day every 1 to 2 weeks  Increase by 100 mg/day every 1 to 2 weeks  Usual Maintenance Dose  

  100 to 200 mg/day with valproate alone

  100 to 400 mg/day with valproate and other drugs that induce glucuronication

  (in 1 or 2 divided doses)

   225 to 375 mg/day (in 2 divided doses)  

  300 to 500 mg/day

   (in 2 divided doses)

  Patients 2 to 12 Years of Age: Recommended dosing guidelines are summarized in Table 2.

  Smaller starting doses and slower dose escalations than those used in clinical trials are recommended because of the suggestion that the risk of rash may be decreased by smaller starting doses and slower dose escalations. Therefore, maintenance doses will take longer to reach in clinical practice than in clinical trials. It may take several weeks to months to achieve an individualized maintenance dose. Maintenance doses in patients weighing less than 30 kg, regardless of age or concomitant AED, may need to be increased as much as 50%, based on clinical response.

  Table 2. Escalation Regimen for Lamotrigine in Patients 2 to 12 Years of Age With Epilepsy * Valproate has been shown to inhibit glucuronidation and decrease the apparent clearance of lamotrigine [ see Drug Interactions (7), Pharmacokinetics (12.3)] . † These drugs induce glucuronidation and increase clearance [see Drug Interactions (7) Pharmacokinetics (12.3)]. Other drugs, which have similar effects include estrogen-containing oral contraceptives and rifampin [ see Drug Interactions (7), Pharmacokinetics (12.3)] . Dosing recommendations for oral contraceptives can be found in General Dosing Considerations [ see Dosage and Administration (2.1)] . Patients on rifampin should follow the same dosing titration/maintenance regimen used with drugs that induce glucuronidation.    For Patients Taking Valproate*  For Patients Taking AEDs Other Than Carbamazepine, Phenytoin, Phenobarbital, or Primidone†, and Not Taking Valproate  For Patients Taking Carbamazepine, Phenytoin, Phenobarbital, or Primidone† and Not Taking Valproate  Weeks 1 and 2  0.15 mg/kg/day in 1 or 2 divided doses, rounded down to the nearest whole tablet (see Table 3 for weight based dosing guide)  0.3 mg/kg/day in 1 or 2 divided doses, rounded down to the nearest whole tablet  0.6 mg/kg/day in 2 divided doses, rounded down to the nearest whole tablet  Weeks 3 and 4  0.3 mg/kg/day in 1 or 2 divided doses, rounded down to the nearest whole tablet (see Table 3 for weight based dosing guide)  0.6 mg/kg/day in 2 divided doses, rounded down to the nearest whole tablet  1.2 mg/kg/day in 2 divided doses, rounded down to the nearest whole tablet  Weeks 5 onwards to maintenance  The dose should be increased every 1 to 2 weeks as follows: calculate 0.3 mg/kg/day, round this amount down to the nearest whole tablet, and add this amount to the previously administered daily dose  The dose should be increased every 1 to 2 weeks as follows: calculate 0.6 mg/kg/day, round this amount down to the nearest whole tablet, and add this amount to the previously administered daily dose  The dose should be increased every 1 to 2 weeks as follows: calculate 1.2 mg/kg/day, round this amount down to the nearest whole tablet, and add this amount to the previously administered daily dose  Usual Maintenance Dose  1 to 5 mg/kg/day (maximum 200 mg/day in 1 or 2 divided doses).
  1 to 3 mg/kg/day with valproate alone  4.5 to 7.5 mg/kg/day (maximum 300 mg/day in 2 divided doses)  5 to 15 mg/kg/day (maximum 400 mg/day in 2 divided doses)  Maintenance dose in patients less than 30 kg  May need to be increased by as much as 50%, based on clinical response  May need to be increased by as much as 50%, based on clinical response  May need to be increased by as much as 50%, based on clinical response  

  Note: Only whole tablets should be used for dosing.

  Table 3. The Initial Weight-Based Dosing Guide for Patients 2 to 12 Years Taking Valproate (Weeks 1 to 4) With Epilepsy  If the patient’s weight is  Give this daily dose, using the most appropriate combination of lamotrigine tablets, 2 mg and 5 mg  Greater than  And less than  Weeks 1 and 2  Weeks 3 and 4  6.7 kg  14 kg  2 mg every other day  2 mg every day  14.1 kg  27 kg  2 mg every day  4 mg every day  27.1 kg  34 kg  4 mg every day  8 mg every day  34.1 kg  40 kg  5 mg every day  10 mg every day

  Usual Adjunctive Maintenance Dose for Epilepsy: The usual maintenance doses identified in Tables 1 and 2 are derived from dosing regimens employed in the placebo-controlled adjunctive studies in which the efficacy of lamotrigine tablets was established. In patients receiving multidrug regimens employing carbamazepine, phenytoin, phenobarbital, or primidone without valproate, maintenance doses of adjunctive lamotrigine tablets as high as 700 mg/day have been used. In patients receiving valproate alone, maintenance doses of adjunctive lamotrigine tablets as high as 200 mg/day have been used. The advantage of using doses above those recommended in Tables 1 through 4 has not been established in controlled trials.

  2.3 Epilepsy – Conversion From Adjunctive Therapy to Monotherapy

  The goal of the transition regimen is to effect the conversion to monotherapy with lamotrigine tablets under conditions that ensure adequate seizure control while mitigating the risk of serious rash associated with the rapid titration of lamotrigine tablets.

  The recommended maintenance dose of lamotrigine tablets as monotherapy is 500 mg/day given in 2 divided doses.

  To avoid an increased risk of rash, the recommended initial dose and subsequent dose escalations of lamotrigine tablets should not be exceeded [see Boxed Warning].

  Conversion From Adjunctive Therapy With Carbamazepine, Phenytoin, Phenobarbital, or Primidone to Monotherapy With Lamotrigine Tablets: After achieving a dose of 500 mg/day of lamotrigine tablets according to the guidelines in Table 1, the concomitant AED should be withdrawn by 20% decrements each week over a 4 week period. The regimen for the withdrawal of the concomitant AED is based on experience gained in the controlled monotherapy clinical trial.

  Conversion From Adjunctive Therapy With Valproate to Monotherapy With Lamotrigine Tablets: The conversion regimen involves 4 steps outlined in Table 4.

  Table 4. Conversion From Adjunctive Therapy With Valproate to Monotherapy With Lamotrigine in Patients ≥ 16 Years of Age With Epilepsy     Lamotrigine  Valproate  Step 1  Achieve a dose of 200 mg/day according to guidelines in Table 1 (if not already on 200 mg/day).  Maintain previous stable dose.  Step 2  Maintain at 200 mg/day.  Decrease to 500 mg/day by decrements no greater than 500 mg/day/week and then maintain the dose of 500 mg/day for 1 week.  Step 3  Increase to 300 mg/day and maintain for 1 week.  Simultaneously decrease to 250 mg/day and maintain for 1 week.  Step 4  Increase by 100 mg/day every week to achieve maintenance dose of 500 mg/day.  Discontinue.

  Conversion From Adjunctive Therapy With AEDs Other Than Carbamazepine, Phenytoin, Phenobarbital, Primidone, or Valproate to Monotherapy With Lamotrigine Tablets: No specific dosing guidelines can be provided for conversion to monotherapy with lamotrigine tablets with AEDs other than carbamazepine, phenobarbital, phenytoin, primidone, or valproate.

  2.4 Bipolar Disorder

  The goal of maintenance treatment with lamotrigine tablets is to delay the time to occurrence of mood episodes (depression, mania, hypomania, mixed episodes) in patients treated for acute mood episodes with standard therapy. The target dose of lamotrigine tablets is 200 mg/day (100 mg/day in patients taking valproate, which decreases the apparent clearance of lamotrigine, and 400 mg/day in patients not taking valproate and taking either carbamazepine, phenytoin, phenobarbital, primidone, or rifampin, which increase the apparent clearance of lamotrigine). In the clinical trials, doses up to 400 mg/day as monotherapy were evaluated; however, no additional benefit was seen at 400 mg/day compared with 200 mg/day [see Clinical Studies (14.2)]. Accordingly, doses above 200 mg/day are not recommended. Treatment with lamotrigine tablets is introduced, based on concurrent medications, according to the regimen outlined in Table 5. If other psychotropic medications are withdrawn following stabilization, the dose of lamotrigine tablets should be adjusted. For patients discontinuing valproate, the dose of lamotrigine tablets should be doubled over a 2 week period in equal weekly increments (see Table 6). For patients discontinuing carbamazepine, phenytoin, phenobarbital, primidone, or rifampin, the dose of lamotrigine tablets should remain constant for the first week and then should be decreased by half over a 2 week period in equal weekly decrements (see Table 6). The dose of lamotrigine tablets may then be further adjusted to the target dose (200 mg) as clinically indicated.

  If other drugs are subsequently introduced, the dose of lamotrigine tablets may need to be adjusted. In particular, the introduction of valproate requires reduction in the dose of lamotrigine tablets [see Drug Interactions (7), Clinical Pharmacology (12.3)].

  To avoid an increased risk of rash, the recommended initial dose and subsequent dose escalations of lamotrigine tablets should not be exceeded [see Boxed Warning].

  Table 5. Escalation Regimen for Lamotrigine for Patients With Bipolar Disorder* * See Drug Interactions (7) and Clinical Pharmacology (12.3) for a description of known drug interactions. † Valproate has been shown to decrease the apparent clearance of lamotrigine. ‡ Carbamazepine, phenytoin, phenobarbital, primidone, and rifampin have been shown to increase the apparent clearance of lamotrigine.    For Patients Taking Valproate†  For Patients Not Taking Carbamazepine, Phenytoin, Phenobarbital, Primidone, or Rifampin‡ and Not Taking Valproate†  For Patients Taking Carbamazepine, Phenytoin, Phenobarbital, Primidone, or Rifampin‡ and Not Taking Valproate†  Weeks 1 and 2  25 mg every other day  25 mg daily  50 mg daily  Weeks 3 and 4  25 mg daily  50 mg daily  100 mg daily, in divided doses  Week 5  50 mg daily  100 mg daily  200 mg daily, in divided doses  Week 6  100 mg daily  200 mg daily  300 mg daily, in divided doses  Week 7  100 mg daily  200 mg daily  up to 400 mg daily, in divided doses Table 6. Dosage Adjustments to Lamotrigine for Patients With Bipolar Disorder Following Discontinuation of Psychotropic Medications* * See Drug Interactions (7) and Clinical Pharmacology (12.3) for a description of known drug interactions. † Carbamazepine, phenytoin, phenobarbital, primidone, and rifampin have been shown to increase the apparent clearance of lamotrigine. ‡ Valproate has been shown to decrease the apparent clearance of lamotrigine.     Discontinuation of Psychotropic Drugs (excluding Carbamazepine, Phenytoin, Phenobarbital, Primidone, Rifampin†, or Valproate‡)  After Discontinuation of Valproate‡  After Discontinuation of Carbamazepine, Phenytoin, Phenobarbital, Primidone, or Rifampin†  Current dose of Lamotrigine (mg/day) 100  

  Current dose of Lamotrigine (mg/day)

  400

   Week 1  Maintain current dose of lamotrigine  150  400  Week 2  Maintain current dose of lamotrigine  200  300  Week 3 onward  Maintain current dose of lamotrigine  200  200

  The benefit of continuing treatment in patients who had been stabilized in an 8 to 16 week open-label phase with lamotrigine tablets was established in 2 randomized, placebo-controlled clinical maintenance trials [see Clinical Studies (14.2)]. However, the optimal duration of treatment with lamotrigine tablets has not been established. Thus, patients should be periodically reassessed to determine the need for maintenance treatment.

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  Epilepsy
  Adjunctive Use:
  Lamotrigine is indicated as adjunctive therapy for partial seizures and the generalized seizures of Lennox-Gastaut syndrome in adult and pediatric patients (years of age).
  Monotherapy Use:
  Lamotrigine tablets and lamotrigine tablets (chewable, dispersible) are indicated for conversion to monotherapy in adults with partial seizures who are receiving treatment with carbamazepine, phenytoin, phenobarbital, primidone, or valproate as the single AED.
  Safety and effectiveness of lamotrigine tablets and lamotrigine tablets (chewable, dispersible)have not been established. (1) as initial monotherapy, (2) for conversion to monotherapy from AEDs other than carbamazepine, phenytoin, phenobarbital, primidone, or valproate, or (3) for simultaneous conversion to monotherapy from 2 or more concomitant AEDs.
  Bipolar Disorder
  Lamotrigine tablets and lamotrigine tablets (chewable, dispersible) are indicated for the maintenance treatment of Bipolar I Disorder to delay the time to occurrence of mood episodes (depression, mania, hypomania, mixed episodes) in patients treated for acute mood episodes with standard therapy. The effectiveness of lamotrigine in the acute treatment of mood episodes has not been established.
  General Dosing Considerations for Epilepsy and Bipolar Disorder Patients:
  The risk of nonserious rash is increased when the recommended initial dose and/or the rate of dose escalation of Lamotrigine is exceeded. There are suggestions, yet to be proven, that the risk of severe, potentially life-threatening rash may be increased by (1) coadministration of lamotrigine with valproate, (2) exceeding the recommended initial dose of lamotrigine, or (3) exceeding the recommended dose escalation for lamotrigine. However, cases have been reported in the absence of these factors (see BOX WARNING). Therefore, it is important that the dosing recommendations be followed closely.
  It is recommended that lamotrigine not be restarted in patients who discontinued due to rash associated with prior treatment with lamotrigine, unless the potential benefits clearly outweigh the risks. If the decision is made to restart a patient who has discontinued lamotrigine, the need to restart with the initial dosing recommendations should be assessed. The greater the interval of time since the previous dose, the greater consideration should be given to restarting with the initial dosing recommendations. If a patient has discontinued lamotrigine for a period of more than 5 half-lives, it is recommended that initial dosing recommendations and guidelines be followed.
  Lamotrigine Tablets and Lamotrigine Tablets (Chewable, Dispersible)Added to Drugs Known to Induce or Inhibit Glucuronidation:
  Drugs other than those listed in PRECAUTIONS: Drug Interactionshave not been systematically evaluated in
  combination with Lamotrigine. Since lamotrigine is metabolized predominantly by glucuronic acid conjugation, drugs that are known to induce or inhibit glucuronidation may affect the apparent clearance of lamotrigine, and doses of Lamotrigine may require adjustment based on clinical response.
  Target Plasma Levels for Patients With Epilepsy or Bipolar Disorder:
  A therapeutic plasma concentration range has not been established for lamotrigine. Dosing of lamotrigine should be based on therapeutic response.
  The half-life of lamotrigine is affected by other concomitant medications (see CLINICAL PHARMACOLOGY: Pharmacokinetics and Drug Metabolism).
  See also DOSAGE AND ADMINISTRATION: Special Populations.
  Special Populations: Women and Oral Contraceptives: Starting Lamotrigine Tablets and LamotrigineTablets (Chewable, Dispersible)in Women Taking Oral Contraceptives
  Although estrogen-containing oral contraceptives have been shown to increase the clearance of lamotrigine (see PRECAUTIONS: Drug Interactions), no adjustments to the recommended dose escalation guidelines for lamotrigine should be necessary solely based on the use of estrogen-containing oral contraceptives. Therefore, dose escalation should follow the recommended guidelines for initiating adjunctive therapy with lamotrigine based on the concomitant AED (see Table 11). See below for adjustments to maintenance doses of lamotrigine in women taking estrogen-containing oral contraceptives.
  Adjustments to the Maintenance Dose of Lamotrigine Tablets and Lamotrigine Tablets (Chewable, Dispersible)
       1. Taking Estrogen-Containing Oral Contraceptives:
  For women not taking carbamazepine, phenytoin, phenobarbital, primidone,
  or rifampin, the maintenance dose of Lamotrigine will in most cases need to be increased, by as much as 2-fold over the recommended target maintenance dose, in order to maintain a consistent lamotrigine plasma level (see PRECAUTIONS: Drug Interactions). (2) Starting Estrogen-Containing Oral Contraceptives: In women taking a stable dose of Lamotrigine and not taking carbamazepine, phenytoin, phenobarbital, primidone, or rifampin, the maintenance dose will in most cases need to be increased by as much as 2-fold, in order to maintain a consistent lamotrigine plasma level. The dose increases should begin at the same time that the oral contraceptive is introduced and continue, based on clinical response, no more rapidly than 50 to 100 mg/day every week. Dose increases should not exceed the recommended rate unless lamotrigine plasma levels or clinical response support larger increases (see Table 11, column 2,). Gradual transient increases in lamotrigine plasma levels may occur during the week of inactive hormonal preparation ("pill-free" week), and these increases will be greater if dose increases are made in the days before or during the week of inactive hormonal preparation. Increased lamotrigine plasma levels could result in additional adverse events, such as dizziness, ataxia, and diplopia (see PRECAUTIONS: Drug Interactions). If adverse events attributable to lamotrigine consistently occur during the "pill-free" week, dose adjustments to the overall maintenance dose may be necessary. Dose adjustments limited to the "pill-free" week are not recommended. For women taking Lamotrigine in addition to carbamazepine, phenytoin, phenobarbital, primidone, or rifampin, no adjustment should be necessary to the dose of Lamotrigine. (3) Stopping Estrogen-Containing Oral Contraceptives:For women not taking carbamazepine, phenytoin, phenobarbital, primidone, or rifampin, the maintenance dose of lamotrigine will in most cases need to be decreased by as much as 50%, in order to maintain a consistent lamotrigine plasma level. The decrease in dose of Lamotrigine should not exceed 25% of the total daily dose per week over a 2-week period, unless clinical response or lamotrigine plasma levels indicate otherwise (see PRECAUTIONS: Drug Interactions). For women taking lamotrigine in addition to carbamazepine, phenytoin, phenobarbital, primidone, or rifampin, no adjustment to the dose of lamotrigine should be necessary.
  Women and Other Hormonal Contraceptive Preparations or Hormone Replacement Therapy:
  The effect of other hormonal contraceptive preparations or hormone replacement therapy on the pharmacokinetics of lamotrigine has not been systematically evaluated. It has been reported that ethinylestradiol, not progestogens, increased the clearance of lamotrigine up to 2-fold, and the progestin only pills had no effect on lamotrigine plasma levels. Therefore, adjustments to the dosage of lamotrigine in the presence of progestogens alone will likely not be needed.
  Patients With Hepatic Impairment:
  Experience in patients with hepatic impairment is limited. Based on a clinical pharmacology study in 24 patients with mild, moderate, and severe liver dysfunction (see CLINICAL PHARMACOLOGY), the following general recommendations can be made. No dosage adjustment is needed in patients with mild liver impairment. Initial, escalation, and maintenance doses should generally be reduced by approximately 25% in patients with moderate and severe liver impairment without
  ascites and 50% in patients with severe liver impairment with ascites. Escalation and maintenance doses may be adjusted according to clinical response.
  Patients With Renal Functional Impairment:
  Initial doses of lamotrigine tablets and lamotrigine tablets (chewable, dispersible) should be based on patients' AED regimen (see above); reduced maintenance doses may be effective for patients with significant renal functional impairment (see CLINICAL PHARMACOLOGY). Few patients with severe renal impairment have been evaluated during chronic treatment with lamotrigine. Because there is inadequate experience in this population, lamotrigine should be used with caution in these patients.
  Epilepsy:
  Adjunctive Therapy With Lamotrigine Tablets and Lamotrigine Tablets (Chewable, Dispersible) for Epilepsy:
  This section provides specific dosing recommendations for patients 2 to 12 years of age and patients greater than 12 years of age. Within each of these age-groups, specific dosing recommendations are provided depending upon concomitant AED (Table 9 for patients 2 to 12 years of age and Table 11 for patients greater than 12 years of age). A weight based dosing guide for pediatric patients on concomitant valproate is provided in Table 10.
  Patients 2 to 12 Years of Age:
  Recommended dosing guidelines are summarized in Table 9.
  Note that some of the starting doses and dose escalations listed in Table 9 are different than those used in clinical trials; however, the maintenance doses are the same as in clinical trials. Smaller starting doses and slower dose escalations than those used in clinical trials are recommended because of the suggestions that the risk of rash may be decreased by smaller starting doses and slower dose escalations. Therefore, maintenance doses will take longer to reach in clinical practice than in clinical trials. It may take several weeks to months to achieve an individualized maintenance dose. Maintenance doses in patients weighing less than 30 kg, regardless of age or concomitant AED, may need to be increased as much as 50%, based on clinical response.
  
  Table 9. Escalation Regimen for Lamotrigine in Patients 2 to 12 Years of Age With Epilepsy
  *Rifampin and estrogen-containing oral contraceptives have also been shown to increase the apparent clearance of lamotrigine (see PRECAUTIONS: Drug Interactions).For Patients Taking Valproate (see Table 10 for weight- based dosing guide)For Patients Taking AEDs Other Than Carbamazepine, Phenytoi n, Phenobarbital, Primidone *, or ValproateFor Patients Taking Carbamazepine, Phenytoin, Phenobarbital, Primidone *and Not Taking ValproateWeeks 1 and 20.15 mg/kg/day in 1 or 2 divided doses, rounded down to the nearest whole tablet (see Table 10 for weight-based dosing guide).0.3 mg/kg/day in 1 or 2 divided doses, rounded down to the nearest whole tablet.0.6 mg/kg/day in 2 divided doses, rounded down to the nearest whole tablet.Weeks 3 and 40.3 mg/kg/day in 1 or 2 divided doses, rounded down to the nearest whole tablet (see Table 10 for weight-based dosing guide).0.6 mg/kg/day in 2 divided doses, rounded down to the nearest whole tablet.1.2 mg/kg/day in 2 divided doses, rounded down to the nearest whole tablet.Weeks 5 onwards to maintenanceThe dose should be increased every 1 to 2 weeks as follows: calculate 0.3 mg/kg/day, round this amount down to the nearest whole tablet, and add this amount to the previously administered daily dose.The dose should be increased every 1 to 2 weeks as follows: calculate 0.6 mg/kg/day, round this amount down to the nearest whole tablet, and add this amount to the previously administered daily doseThe dose should be increased every 1 to 2 weeks as follows: calculate 1.2 mg/kg/day, round this amount down to the nearest whole tablet, and add this amount to the previously administered daily doseUsual Maintenance Dose1 to 5 mg/kg/day (maximum 200 mg/day in 1 or 2 divided doses). 1 to 3 mg/kg/day with valproate alone4.5 to 7.5 mg/kg/day (maximum 300 mg/day in 2 divided doses)5 to 15 mg/kg/day (maximum 400 mg/day in 2 divided doses)Maintenance dose in patients less than 30 kgMay need to be increased by as much as 50%, based on clinical responseMay need to be increased by as much as 50%, based on clinical responseMay need to be increased by as much as 50%, based on clinical responseNote: Only whole tablets should be used for dosing
  
  Table 10. The Initial Weight-Based Dosing Guide for Patients 2 to 12 Years Taking Valproate (Weeks 1 to 4) With Epilepsy
  If the patient's weight isGive this daily dose, using the most appropriate combination of lamotrigine tablets (chewable, dispersible), 5 mgGreater thanAnd less thanWeeks 1 and 2Weeks 3 and 434.1 kg40 kg5 mg every day10 mg every dayPatients Over 12 Years of Age:
  Recommended dosing guidelines are summarized in Table 11.
  
  Table 11. Escalation Regimen for Lamotrigine in Patients Over 12 Years of Age With Epilepsy
  *Rifampin and estrogen-containing oral contraceptives have also been shown to increase the apparent clearance of lamotrigine (see PRECAUTIONS: Drug Interactions).For Patients Taking ValproateFor Patients Taking AEDs Other Than Carbamazepine, Phenytoin, Phenobarbital, Primidone, or Valproate *For Patients Taking Carbamazepine, Phenytoin, PhenobarbitaL, Primidone *and Not Taking ValproateWeeks 1 and 225 mg every other day25 mg every day50 mg/dayWeeks 3 and 425 mg every day50 mg/day100 mg/day (in 2 divided doses)Weeks 5 onwards to maintenanceIncrease by 25 to 50 mg/ day every 1 to 2 weeksIncrease by 50 mg/ day every 1 to 2 weeksIncrease by 100 mg/ day every 1 to 2 weeks.Usual Maintenance Dose100 to 400 mg/day (1 or 2 divided doses) 100 to 200 mg/day with Valproate alone225 to 375 mg/day (in 2 divided doses).300 to 500 mg/day (in 2 divided doses).Conversion from Adjunctive Therapy With Carbamazepine, Phenytoin, Phenobarbital, Primidone, or Valproate as the Single AED to Monotherapy With Lamotrigine in PatientsYears of Age With Epilepsy:
  The goal of the transition regimen is to effect the conversion to monotherapy with Lamotrigine under conditions that ensure adequate seizure control while mitigating the risk of serious rash associated with the rapid titration of lamotrigine.
  The recommended maintenance dose of lamotrigine as monotherapy is 500 mg/day given in 2 divided doses.
  To avoid an increased risk of rash, the recommended initial dose and subsequent dose escalations of lamotrigine should not be exceeded (see BOX WARNING).
  Conversion From Adjunctive Therapy With Carbamazepine, Phenytoin, Phenobarbital, or Primidone to Monotherapy With Lamotrigine:
  After achieving a dose of 500 mg/day of lamotrigine according to the guidelines in Table 11, the concomitant AED should be withdrawn by 20% decrements each week over a 4-week period. The regimen for the withdrawal of the concomitant AED is based on experience gained in the controlled monotherapy clinical trial.
  Conversion from Adjunctive Therapy With Valproate to Monotherapy With Lamotrigine The conversion regimen involves 4 steps (see Table 12).
  
  Table 12. Conversion From Adjunctive Therapy With Valproate to Monotherapy With Lamotrigine in PatientsYears of Age With Epilepsy
  LamotrigineValproateStep 1Achieve a dose of 200 mg/day according to guidelines in Table 11 (if not already on 200 mg/ day).Maintain previous stable dose.Step 2Maintain at 200 mg/day.Decrease to 500 mg/day by decrements no greater than 500 mg/day per week and then maintain the dose of 500 mg/day for 1 week.Step 3Increase to 300 mg/day and maintain for 1 week.Simultaneously decrease to 250 mg/day and maintain for 1 week.Step 4Increase by 100 mg/day every week to achieve maintenance dose of 500 mg/day.Discontinue. Conversion from Adjunctive Therapy With Antiepileptic Drugs Other Than Carbamazepine, Phenytoin, Phenobarbital, Primidone, or Valproate to Monotherapy With Lamotrigine:
  No specific dosing guidelines can be provided for conversion to monotherapy with lamotrigine with AEDs other than carbamazepine, phenobarbital, phenytoin, primidone, or valproate.
  Usual Maintenance Dose for Epilepsy
  The usual maintenance doses identified in Tables 9-11 are derived from dosing regimens employed in the placebo-controlled adjunctive studies in which the efficacy of lamotrigine was established. In patients receiving multidrug regimens employing carbamazepine, phenytoin, phenobarbital, or primidone without valproate, maintenance doses of adjunctive Lamotrigine as high as 700 mg/day have been used. In patients receiving valproate alone, maintenance doses of adjunctive Lamotrigine as high as 200 mg/ day have been used. The advantage of using doses above those recommended in Tables 9-12 has not been established in controlled trials.
  Discontinuation Strategy for Patients With Epilepsy:
  For patients receiving lamotrigine in combination with other AEDs, a reevaluation of all AEDs in the regimen should be considered if a change in seizure control or an appearance or worsening of adverse experiences is observed.
  If a decision is made to discontinue therapy with Lamotrigine, a step-wise reduction of dose over at least 2 weeks (approximately 50% per week) is recommended unless safety concerns require a more rapid withdrawal (see PRECAUTIONS).
  Discontinuing carbamazepine, phenytoin, phenobarbital, or primidone should prolong the half-life of lamotrigine; discontinuing valproate should shorten the half-life of lamotrigine.
  Bipolar Disorder
  The goal of maintenance treatment with lamotrigine is to delay the time to occurrence of mood episodes (depression, mania, hypomania, mixed episodes) in patients treated for acute mood episodes with standard therapy. The target dose of lamotrigine is 200 mg/day (100 mg/day in patients taking valproate,which decreases the apparent clearance of lamotrigine, and 400 mg/day in patients not taking valproate and taking either carbamazepine, phenytoin, phenobarbital, primidone, or rifampin, which increase the apparent clearance of lamotrigine). In the clinical trials, doses up to 400 mg/day as monotherapy were evaluated, however, no additional benefit was seen at 400 mg/day compared to 200 mg/day (see CLINICAL STUDIES: Bipolar Disorder). Accordingly, doses above 200 mg/ day are not recommended. Treatment with lamotrigine is introduced, based on concurrent medications, according to the regimen outlined in Table 13. If other psychotropic medications are withdrawn following stabilization, the dose of lamotrigine should be adjusted. For patients discontinuing valproate, the dose of lamotrigine should be doubled over a 2-week period in equal weekly increments (see Table 14). For patients discontinuing carbamazepine, phenytoin, phenobarbital, primidone, or rifampin, the dose of lamotrigine should remain constant for the first week and then should be decreased by half over a 2-week period in equal weekly decrements (see Table 14). The dose of lamotrigine may then be further adjusted to the target dose (200 mg) as clinically indicated.
  Dosage adjustments will be necessary in most patients who start or stop estrogen-containing oral contraceptives while taking lamotrigine (see DOSAGE AND ADMINISTRATION: Special Populations: Women and Oral Contraceptives: Adjustments to the Maintenace Dose of Lamotrigine).
  If other drugs are subsequently introduced, the dose of Lamotrigine may need to be adjusted.
  In particular, the introduction of valproate requires reduction in the dose of Lamotrigine (see CLINICAL PHARMACOLOGY: Drug Interactions). To avoid an increased risk of rash, the recommended initial dose and subsequent dose escalations of Lamotrigine should not be exceeded (see BOX WARNING).
  
  Table 13. Escalation Regimen for Lamotrigine for Patients With Bipolar Disorder *
  *See CLINICAL PHARMACOLOGY: Drug Interactions:and PRECAUTIONS: Drug Interactionsfor a description of known drug interactions. Carbamazepine, phenytoin, phenobarbital, primidone, rifampin, have been shown to increase the apparent clearance of lamotrigine. Valproate has been shown to decrease the apparent clearance of lamotrigine.For Patients Not Taking Carbamazepine, Phenytoin, Phenobarbital, Primidone or Rifampin and Not Taking Valproate For Patients Taking Valproate For Patients Taking Carbamazepine (or Other Enzyme-Inducing Drugs) and Not Taking Valproate Weeks 1 and 225 mg daily25 mg every other day50 mg dailyWeeks 3 and 450 mg daily25 mg daily100 mg daily, in divided dosesWeek 5100 mg daily50 mg daily200 mg daily, in divided dosesWeek 6200 mg daily100 mg daily300 mg daily, in divided dosesWeek 7200 mg daily100 mg dailyup to 400 mg daily, in divided doses
  Table 14. Adjustments to Lamotrigine Dosing for Patients With Bipolar Disorder Following Discontinuation of Psychotropic Medications *
  *See CLINICAL PHARMACOLOGY: Drug Interactions:and PRECAUTIONS: Drug Interactionsfor a description of known drug interactions. Carbamazepine, phenytoin, phenobarbital, primidone, and rifampin have been shown to increase the apparent clearance of lamotrigine. Valproate has been shown to decrease the apparent clearance of lamotrigine.Discontinuation of Psychotropic Drugs (excluding Valproate , Carbamazepine, or Other Enzyme-Inducing Drugs )After Discontinuation of Valproate After Discontinuation of Carbamazepine or Other Enzyme-Inducing Drugs Current Lamotrigine dose (mg/day) 100Current Lamotrigine dose (mg/day) 400Week 1Maintain current lamotrigine dose150400Week 2Maintain current lamotrigine dose200300Week 3 onwardMaintain current lamotrigine dose200200There is no body of evidence available to answer the question of how long the patient should remain on lamotrigine therapy. Systematic evaluation of the efficacy of lamotrigine in patients with either depression or mania who responded to standard therapy during an acute 8 to 16 week treatment phase and were then randomized to lamotrigine or placebo for up to 76 weeks of observation for affective relapse demonstrated a benefit of such maintenance treatment (see CLINICAL STUDIES: Bipolar Disorder). Nevertheless, patients should be periodically reassessed to determine the need for maintenance treatment.
  Discontinuation Strategy in Bipolar Disorder:
  As with other AEDs, lamotrigine should not be abruptly discontinued. In the controlled clinical trials, there was no increase in the incidence, type, or severity of adverse experiences following abrupt termination of lamotrigine. In clinical trials in patients with bipolar disorder, 2 patients experienced seizures shortly after abrupt withdrawal of lamotrigine. However, there were confounding factors that may have contributed to the occurrence of seizures in these bipolar patients. Discontinuation of lamotrigine should involve a step-wise reduction of dose over at least 2 weeks (approximately 50% per week) unless safety concerns require a more rapid withdrawal.
  Administration of Lamotrigine Tablets (Chewable, Dispersible)
  Lamotrigine tablets (Chewable, Dispersible) may be swallowed whole, chewed, or dispersed in water or diluted fruit juice. If the tablets are chewed, consume a small amount of water or diluted fruit juice to aid in swallowing.
  To disperse lamotrigine tablets (chewable, dispersible), add the tablets to a small amount of liquid (1 teaspoon, or enough to cover the medication). Approximately 1 minute later, when the tablets are completely dispersed, swirl the solution and consume the entire quantity immediately.
  No attempt should be made to administer partial quantities of the dispersed tablets.
  
  

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  2.1 General Dosing Considerations

  Rash: There are suggestions, yet to be proven, that the risk of severe, potentially life-threatening rash may be increased by (1) coadministration of LAMOTRIGINE with valproate, (2) exceeding the recommended initial dose of LAMOTRIGINE, or (3) exceeding the recommended dose escalation for LAMOTRIGINE. However, cases have occurred in the absence of these factors [see Boxed Warning]. Therefore, it is important that the dosing recommendations be followed closely.

  The risk of nonserious rash may be increased when the recommended initial dose and/or the rate of dose escalation of LAMOTRIGINE is exceeded and in patients with a history of allergy or rash to other AEDs.

  LAMOTRIGINE Starter Kits provide LAMOTRIGINE at doses consistent with the recommended titration schedule for the first 5 weeks of treatment, based upon concomitant medications for patients with epilepsy (>12 years of age) and Bipolar I Disorder (≥18 years of age) and are intended to help reduce the potential for rash. The use of LAMOTRIGINE Starter Kits is recommended for appropriate patients who are starting or restarting LAMOTRIGINE [see How Supplied/Storage and Handling (16)].

  It is recommended that LAMOTRIGINE not be restarted in patients who discontinued due to rash associated with prior treatment with lamotrigine, unless the potential benefits clearly outweigh the risks. If the decision is made to restart a patient who has discontinued lamotrigine, the need to restart with the initial dosing recommendations should be assessed. The greater the interval of time since the previous dose, the greater consideration should be given to restarting with the initial dosing recommendations. If a patient has discontinued lamotrigine for a period of more than 5 half-lives, it is recommended that initial dosing recommendations and guidelines be followed. The half-life of lamotrigine is affected by other concomitant medications [see Clinical Pharmacology (12.3)].

  LAMOTRIGINE Added to Drugs Known to Induce or Inhibit Glucuronidation: Drugs other than those listed in the Clinical Pharmacology section [see Clinical Pharmacology (12.3)] have not been systematically evaluated in combination with lamotrigine. Because lamotrigine is metabolized predominantly by glucuronic acid conjugation, drugs that are known to induce or inhibit glucuronidation may affect the apparent clearance of lamotrigine and doses of LAMOTRIGINE may require adjustment based on clinical response.

  Target Plasma Levels for Patients With Epilepsy or Bipolar Disorder: A therapeutic plasma concentration range has not been established for lamotrigine. Dosing of LAMOTRIGINE should be based on therapeutic response [see Clinical Pharmacology (12.3)].

  Women Taking Estrogen-Containing Oral Contraceptives: Starting LAMOTRIGINE in Women Taking Estrogen-Containing Oral Contraceptives: Although estrogen-containing oral contraceptives have been shown to increase the clearance of lamotrigine [see Clinical Pharmacology (12.3)], no adjustments to the recommended dose-escalation guidelines for LAMOTRIGINE should be necessary solely based on the use of estrogen-containing oral contraceptives. Therefore, dose escalation should follow the recommended guidelines for initiating adjunctive therapy with LAMOTRIGINE based on the concomitant AED or other concomitant medications (see Table 1 or Table 5). See below for adjustments to maintenance doses of LAMOTRIGINE in women taking estrogen-containing oral contraceptives.

  Adjustments to the Maintenance Dose of LAMOTRIGINE In Women Taking Estrogen-Containing Oral Contraceptives:

  (1) Taking Estrogen-Containing Oral Contraceptives: For women not taking carbamazepine, phenytoin, phenobarbital, primidone, or rifampin, the maintenance dose of LAMOTRIGINE will in most cases need to be increased, by as much as 2-fold over the recommended target maintenance dose, in order to maintain a consistent lamotrigine plasma level [see Clinical Pharmacology (12.3)].

  (2) Starting Estrogen-Containing Oral Contraceptives: In women taking a stable dose of LAMOTRIGINE and not taking carbamazepine, phenytoin, phenobarbital, primidone, or rifampin, the maintenance dose will in most cases need to be increased by as much as 2-fold in order to maintain a consistent lamotrigine plasma level. The dose increases should begin at the same time that the oral contraceptive is introduced and continue, based on clinical response, no more rapidly than 50 to 100 mg/day every week. Dose increases should not exceed the recommended rate (see Table 1 or Table 5) unless lamotrigine plasma levels or clinical response support larger increases. Gradual transient increases in lamotrigine plasma levels may occur during the week of inactive hormonal preparation ("pill-free" week), and these increases will be greater if dose increases are made in the days before or during the week of inactive hormonal preparation. Increased lamotrigine plasma levels could result in additional adverse reactions, such as dizziness, ataxia, and diplopia. If adverse reactions attributable to LAMOTRIGINE consistently occur during the "pill-free" week, dose adjustments to the overall maintenance dose may be necessary. Dose adjustments limited to the "pill-free" week are not recommended. For women taking LAMOTRIGINE in addition to carbamazepine, phenytoin, phenobarbital, primidone, or rifampin, no adjustment should be necessary to the dose of LAMOTRIGINE.

  (3) Stopping Estrogen-Containing Oral Contraceptives: For women not taking carbamazepine, phenytoin, phenobarbital, primidone, or rifampin, the maintenance dose of LAMOTRIGINE will in most cases need to be decreased by as much as 50% in order to maintain a consistent lamotrigine plasma level. The decrease in dose of LAMOTRIGINE should not exceed 25% of the total daily dose per week over a 2-week period, unless clinical response or lamotrigine plasma levels indicate otherwise [see Clinical Pharmacology (12.3)]. For women taking LAMOTRIGINE in addition to carbamazepine, phenytoin, phenobarbital, primidone, or rifampin, no adjustment to the dose of LAMOTRIGINE should be necessary.

  Women and Other Hormonal Contraceptive Preparations or Hormone Replacement Therapy: The effect of other hormonal contraceptive preparations or hormone replacement therapy on the pharmacokinetics of lamotrigine has not been systematically evaluated. It has been reported that ethinylestradiol, not progestogens, increased the clearance of lamotrigine up to 2-fold, and the progestin-only pills had no effect on lamotrigine plasma levels. Therefore, adjustments to the dosage of LAMOTRIGINE in the presence of progestogens alone will likely not be needed.

  Patients With Hepatic Impairment: Experience in patients with hepatic impairment is limited. Based on a clinical pharmacology study in 24 patients with mild, moderate, and severe liver impairment [see Use in Specific Populations (8.6), Clinical Pharmacology (12.3)], the following general recommendations can be made. No dosage adjustment is needed in patients with mild liver impairment. Initial, escalation, and maintenance doses should generally be reduced by approximately 25% in patients with moderate and severe liver impairment without ascites and 50% in patients with severe liver impairment with ascites. Escalation and maintenance doses may be adjusted according to clinical response.

  Patients With Renal Impairment: Initial doses of LAMOTRIGINE should be based on patients' concomitant medications (see Tables 1-3 or Table 5); reduced maintenance doses may be effective for patients with significant renal impairment [see Use in Specific Populations (8.7), Clinical Pharmacology (12.3)]. Few patients with severe renal impairment have been evaluated during chronic treatment with LAMOTRIGINE. Because there is inadequate experience in this population, LAMOTRIGINE should be used with caution in these patients.

  Discontinuation Strategy: Epilepsy: For patients receiving LAMOTRIGINE in combination with other AEDs, a re-evaluation of all AEDs in the regimen should be considered if a change in seizure control or an appearance or worsening of adverse reactions is observed.

  If a decision is made to discontinue therapy with LAMOTRIGINE, a step-wise reduction of dose over at least 2 weeks (approximately 50% per week) is recommended unless safety concerns require a more rapid withdrawal [see Warnings and Precautions (5.9)].

  Discontinuing carbamazepine, phenytoin, phenobarbital, or primidone should prolong the half-life of lamotrigine; discontinuing valproate should shorten the half-life of lamotrigine.

  Bipolar Disorder: In the controlled clinical trials, there was no increase in the incidence, type, or severity of adverse reactions following abrupt termination of LAMOTRIGINE. In clinical trials in patients with Bipolar Disorder, 2 patients experienced seizures shortly after abrupt withdrawal of LAMOTRIGINE. However, there were confounding factors that may have contributed to the occurrence of seizures in these bipolar patients. Discontinuation of LAMOTRIGINE should involve a step-wise reduction of dose over at least 2 weeks (approximately 50% per week) unless safety concerns require a more rapid withdrawal [see Warnings and Precautions (5.9)].

  2.2 Epilepsy – Adjunctive Therapy

  This section provides specific dosing recommendations for patients greater than 12 years of age and patients 2 to 12 years of age. Within each of these age-groups, specific dosing recommendations are provided depending upon concomitant AED or other concomitant medications (Table 1 for patients greater than 12 years of age and Table 2 for patients 2 to 12 years of age). A weight-based dosing guide for patients 2 to 12 years of age on concomitant valproate is provided in Table 3.

  Patients Over 12 Years of Age: Recommended dosing guidelines are summarized in Table 1.

  Table 1. Escalation Regimen for LAMOTRIGINE in Patients Over 12 Years of Age With Epilepsy For Patients Taking Valproate * For Patients Taking AEDs Other Than Carbamazepine, Phenytoin, Phenobarbital, or Primidone†, and Not Taking Valproate For Patients Taking Carbamazepine, Phenytoin, Phenobarbital, or Primidone† and Not Taking Valproate * Valproate has been shown to inhibit glucuronidation and decrease the apparent clearance of lamotrigine [see Drug Interactions (7), Pharmacokinetics (12.3)]. † These drugs induce glucuronidation and increase clearance [see Drug Interactions (7), Pharmacokinetics (12.3)]. Other drugs which have similar effects include estrogen-containing oral contraceptives and rifampin [see Drug Interactions (7), Pharmacokinetics (12.3)]. Weeks 1 and 2 25 mg every other day 25 mg every day 50 mg/day Weeks 3 and 4 25 mg every day 50 mg/day 100 mg/day
  (in 2 divided doses) Weeks 5 onwards to maintenance Increase by 25 to 50 mg/day every 1 to 2 weeks Increase by 50 mg/day every 1 to 2 weeks Increase by 100 mg/day every 1 to 2 weeks. Usual Maintenance Dose 100 to 200 mg/day with valproate alone 100 to 400 mg/day with valproate and other drugs that induce glucuronication
  (in 1 or 2 divided doses) 225 to 375 mg/day
  (in 2 divided doses) 300 to 500 mg/day
  (in 2 divided doses)

  Dosing recommendations for oral contraceptives can be found in General Dosing Considerations [see Dosage and Administration (2.1)]. Patients on rifampin should follow the same dosing titration/maintenance regimen used with drugs that induce glucuronidation and increase clearance.

  Patients 2 to 12 Years of Age: Recommended dosing guidelines are summarized in Table 2.

  Smaller starting doses and slower dose escalations than those used in clinical trials are recommended because of the suggestion that the risk of rash may be decreased by smaller starting doses and slower dose escalations. Therefore, maintenance doses will take longer to reach in clinical practice than in clinical trials. It may take several weeks to months to achieve an individualized maintenance dose. Maintenance doses in patients weighing less than 30 kg, regardless of age or concomitant AED, may need to be increased as much as 50%, based on clinical response.

  Table 2. Escalation Regimen for LAMOTRIGINE in Patients 2 to 12 Years of Age With Epilepsy For Patients Taking Valproate * For Patients Taking AEDs Other Than Carbamazepine, Phenytoin, Phenobarbital, or Primidone†, and Not Taking Valproate For Patients Taking Carbamazepine, Phenytoin, Phenobarbital, or Primidone† and Not Taking Valproate Note: Only whole tablets should be used for dosing. * Valproate has been shown to inhibit glucuronidation and decrease the apparent clearance of lamotrigine [see Drug Interactions (7), Pharmacokinetics (12.3)]. † These drugs induce glucuronidation and increase clearance [see Drug Interactions (7), Pharmacokinetics (12.3)]. Other drugs which have similar effects include estrogen-containing oral contraceptives and rifampin [see Drug Interactions (7), Pharmacokinetics (12.3)]. Weeks 1 and 2 0.15 mg/kg/day
  in 1 or 2 divided doses, rounded down to the nearest whole tablet (see Table 3 for weight based dosing guide) 0.3 mg/kg/day
  in 1 or 2 divided doses, rounded down to the nearest whole tablet 0.6 mg/kg/day
  in 2 divided doses, rounded down to the nearest whole tablet Weeks 3 and 4 0.3 mg/kg/day
  in 1 or 2 divided doses, rounded down to the nearest whole tablet (see Table 3 for weight based dosing guide) 0.6 mg/kg/day
  in 2 divided doses, rounded down to the nearest whole tablet 1.2 mg/kg/day
  in 2 divided doses, rounded down to the nearest whole tablet Weeks 5 onwards to maintenance The dose should be increased every 1 to 2 weeks as follows: calculate 0.3 mg/kg/day, round this amount down to the nearest whole tablet, and add this amount to the previously administered daily dose The dose should be increased every 1 to 2 weeks as follows: calculate 0.6 mg/kg/day, round this amount down to the nearest whole tablet, and add this amount to the previously administered daily dose The dose should be increased every 1 to 2 weeks as follows: calculate 1.2 mg/kg/day, round this amount down to the nearest whole tablet, and add this amount to the previously administered daily dose Usual Maintenance Dose 1 to 5 mg/kg/day (maximum 200 mg/day in 1 or 2 divided doses). 1 to 3 mg/kg/day with valproate alone 4.5 to 7.5 mg/kg/day
  (maximum 300 mg/day in 2 divided doses) 5 to 15 mg/kg/day
  (maximum 400 mg/day in 2 divided doses) Maintenance dose in patients less than 30 kg May need to be increased by as much as 50%, based on clinical response May need to be increased by as much as 50%, based on clinical response May need to be increased by as much as 50%, based on clinical response

  Dosing recommendations for oral contraceptives can be found in General Dosing Considerations [see Dosage and Administration (2.1)]. Patients on rifampin should follow the same dosing titration/maintenance regimen used with drugs that induce glucuronidation and increase clearance.

  Table 3. The Initial Weight-Based Dosing Guide for Patients 2 to 12 Years Taking Valproate (Weeks 1 to 4) With Epilepsy If the patient's weight is Give this daily dose, using the most appropriate combination of LAMOTRIGINE 2-mg and 5-mg tablets Greater than And less than Weeks 1 and 2 Weeks 3 and 4 6.7 kg 14 kg 2 mg every other day 2 mg every day 14.1 kg 27 kg 2 mg every day 4 mg every day 27.1 kg 34 kg 4 mg every day 8 mg every day 34.1 kg 40 kg 5 mg every day 10 mg every day

  Usual Adjunctive Maintenance Dose for Epilepsy: The usual maintenance doses identified in Tables 1 and 2 are derived from dosing regimens employed in the placebo-controlled adjunctive studies in which the efficacy of LAMOTRIGINE was established. In patients receiving multidrug regimens employing carbamazepine, phenytoin, phenobarbital, or primidone without valproate, maintenance doses of adjunctive LAMOTRIGINE as high as 700 mg/day have been used. In patients receiving valproate alone, maintenance doses of adjunctive LAMOTRIGINE as high as 200 mg/day have been used. The advantage of using doses above those recommended in Tables 1 through 4 has not been established in controlled trials.

  2.3 Epilepsy – Conversion From Adjunctive Therapy to Monotherapy

  The goal of the transition regimen is to effect the conversion to monotherapy with LAMOTRIGINE under conditions that ensure adequate seizure control while mitigating the risk of serious rash associated with the rapid titration of LAMOTRIGINE.

  The recommended maintenance dose of LAMOTRIGINE as monotherapy is 500 mg/day given in 2 divided doses.

  To avoid an increased risk of rash, the recommended initial dose and subsequent dose escalations of LAMOTRIGINE should not be exceeded [see Boxed Warning].

  Conversion From Adjunctive Therapy With Carbamazepine, Phenytoin, Phenobarbital, or Primidone to Monotherapy With LAMOTRIGINE: After achieving a dose of 500 mg/day of LAMOTRIGINE according to the guidelines in Table 1, the concomitant AED should be withdrawn by 20% decrements each week over a 4-week period. The regimen for the withdrawal of the concomitant AED is based on experience gained in the controlled monotherapy clinical trial.

  Conversion from Adjunctive Therapy With Valproate to Monotherapy With LAMOTRIGINE: The conversion regimen involves 4 steps outlined in Table 4.

  Table 4. Conversion From Adjunctive Therapy With Valproate to Monotherapy With LAMOTRIGINE in Patients ≥16 Years of Age with Epilepsy LAMOTRIGINE Valproate Step 1 Achieve a dose of 200 mg/day according to guidelines in Table 1 (if not already on200 mg/day). Maintain previous stable dose. Step 2 Maintain at 200 mg/day. Decrease to 500 mg/day by decrements no greater than 500 mg/day/week and then maintain the dose of 500 mg/day for 1 week. Step 3 Increase to 300 mg/day and maintain for 1 week. Simultaneously decrease to 250 mg/day and maintain for 1 week. Step 4 Increase by 100 mg/day every week to achieve maintenance dose of 500 mg/day. Discontinue.

  Conversion from Adjunctive Therapy With AEDs Other Than Carbamazepine, Phenytoin, Phenobarbital, Primidone, or Valproate to Monotherapy With LAMOTRIGINE: No specific dosing guidelines can be provided for conversion to monotherapy with LAMOTRIGINE with AEDs other than carbamazepine, phenobarbital, phenytoin, primidone, or valproate.

  2.4 Bipolar Disorder

  The goal of maintenance treatment with LAMOTRIGINE is to delay the time to occurrence of mood episodes (depression, mania, hypomania, mixed episodes) in patients treated for acute mood episodes with standard therapy. The target dose of LAMOTRIGINE is 200 mg/day (100 mg/day in patients taking valproate, which decreases the apparent clearance of lamotrigine, and 400 mg/day in patients not taking valproate and taking either carbamazepine, phenytoin, phenobarbital, primidone, or rifampin, which increase the apparent clearance of lamotrigine). In the clinical trials, doses up to 400 mg/day as monotherapy were evaluated; however, no additional benefit was seen at 400 mg/day compared with 200 mg/day [see Clinical Studies (14.2)]. Accordingly, doses above 200 mg/day are not recommended. Treatment with LAMOTRIGINE is introduced, based on concurrent medications, according to the regimen outlined in Table 5. If other psychotropic medications are withdrawn following stabilization, the dose of LAMOTRIGINE should be adjusted. For patients discontinuing valproate, the dose of LAMOTRIGINE should be doubled over a 2-week period in equal weekly increments (see Table 6). For patients discontinuing carbamazepine, phenytoin, phenobarbital, primidone, or rifampin, the dose of LAMOTRIGINE should remain constant for the first week and then should be decreased by half over a 2-week period in equal weekly decrements (see Table 6). The dose of LAMOTRIGINE may then be further adjusted to the target dose (200 mg) as clinically indicated.

  If other drugs are subsequently introduced, the dose of LAMOTRIGINE may need to be adjusted. In particular, the introduction of valproate requires reduction in the dose of LAMOTRIGINE [see Drug Interactions (7), Clinical Pharmacology (12.3)].

  To avoid an increased risk of rash, the recommended initial dose and subsequent dose escalations of LAMOTRIGINE should not be exceeded [see Boxed Warning].

  Table 5. Escalation Regimen for LAMOTRIGINE for Patients With Bipolar Disorder* For Patients Taking Valproate† For Patients Not Taking Carbamazepine, Phenytoin, Phenobarbital, Primidone, or Rifampin‡ and Not Taking Valproate† For Patients Taking Carbamazepine, Phenytoin, Phenobarbital, Primidone, or Rifampin‡ and Not Taking Valproate† * See Drug Interactions (7) and Clinical Pharmacology (12.3) for a description of known drug interactions. † Valproate has been shown to decrease the apparent clearance of lamotrigine. ‡ Carbamazepine, phenytoin, phenobarbital, primidone, and rifampin have been shown to increase the apparent clearance of lamotrigine. Weeks 1 and 2 25 mg every other day 25 mg daily 50 mg daily Weeks 3 and 4 25 mg daily 50 mg daily 100 mg daily, in divided doses Week 5 50 mg daily 100 mg daily 200 mg daily, in divided doses Week 6 100 mg daily 200 mg daily 300 mg daily, in divided doses Week 7 100 mg daily 200 mg daily up to 400 mg daily, in divided doses Table 6. Dosage Adjustments to LAMOTRIGINE for Patients With Bipolar Disorder Following Discontinuation of Psychotropic Medications* Discontinuation of Psychotropic Drugs (excluding Carbamazepine, Phenytoin, Phenobarbital, Primidone, Rifampin†, or Valproate‡) After Discontinuation of Valproate‡ After Discontinuation of Carbamazepine, Phenytoin, Phenobarbital, Primidone, or Rifampin† Current dose of LAMOTRIGINE (mg/day) 100 Current dose of LAMOTRIGINE (mg/day) 400 * See Drug Interactions (7) and Clinical Pharmacology (12.3) for a description of known drug interactions. † Carbamazepine, phenytoin, phenobarbital, primidone, and rifampin have been shown to increase the apparent clearance of lamotrigine. ‡ Valproate has been shown to decrease the apparent clearance of lamotrigine. Week 1 Maintain current dose of LAMOTRIGINE 150 400 Week 2 Maintain current dose of LAMOTRIGINE 200 300 Week 3 onward Maintain current dose of LAMOTRIGINE 200 200

  The benefit of continuing treatment in patients who had been stabilized in an 8- to 16-week open-label phase with LAMOTRIGINE was established in 2 randomized, placebo-controlled clinical maintenance trials [see Clinical Studies (14.2)]. However, the optimal duration of treatment with LAMOTRIGINE has not been established. Thus, patients should be periodically reassessed to determine the need for maintenance treatment.

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  2.1 General Dosing Considerations

  Rash: There are suggestions, yet to be proven, that the risk of severe, potentially life-threatening rash may be increased by (1) coadministration of lamotrigine with valproate, (2) exceeding the recommended initial dose of lamotrigine, or (3) exceeding the recommended dose escalation for lamotrigine. However, cases have occurred in the absence of these factors [see Boxed Warning]. Therefore, it is important that the dosing recommendations be followed closely.

  The risk of nonserious rash may be increased when the recommended initial dose and/or the rate of dose escalation of lamotrigine is exceeded and in patients with a history of allergy or rash to other AEDs.

  Lamotrigine Starter Kits provide lamotrigine at doses consistent with the recommended titration schedule for the first 5 weeks of treatment, based upon concomitant medications for patients with epilepsy (>12 years of age) and Bipolar I Disorder (≥18 years of age) and are intended to help reduce the potential for rash. The use of Lamotrigine Starter Kits is recommended for appropriate patients who are starting or restarting lamotrigine [see How Supplied/Storage and Handling (16)].

  It is recommended that lamotrigine not be restarted in patients who discontinued due to rash associated with prior treatment with lamotrigine, unless the potential benefits clearly outweigh the risks. If the decision is made to restart a patient who has discontinued lamotrigine, the need to restart with the initial dosing recommendations should be assessed. The greater the interval of time since the previous dose, the greater consideration should be given to restarting with the initial dosing recommendations. If a patient has discontinued lamotrigine for a period of more than 5 half-lives, it is recommended that initial dosing recommendations and guidelines be followed. The half-life of lamotrigine is affected by other concomitant medications [see Clinical Pharmacology (12.3)].

  Lamotrigine Added to Drugs Known to Induce or Inhibit Glucuronidation: Drugs other than those listed in the Clinical Pharmacology section [see Clinical Pharmacology (12.3)] have not been systematically evaluated in combination with lamotrigine. Because lamotrigine is metabolized predominantly by glucuronic acid conjugation, drugs that are known to induce or inhibit glucuronidation may affect the apparent clearance of lamotrigine and doses of lamotrigine may require adjustment based on clinical response.

  Target Plasma Levels for Patients With Epilepsy or Bipolar Disorder: A therapeutic plasma concentration range has not been established for lamotrigine. Dosing of lamotrigine should be based on therapeutic response [see Clinical Pharmacology (12.3)].

  Women Taking Estrogen-Containing Oral Contraceptives: Starting Lamotrigine in Women Taking Estrogen-Containing Oral Contraceptives: Although estrogen-containing oral contraceptives have been shown to increase the clearance of lamotrigine [see Clinical Pharmacology (12.3)], no adjustments to the recommended dose-escalation guidelines for lamotrigine should be necessary solely based on the use of estrogen-containing oral contraceptives. Therefore, dose escalation should follow the recommended guidelines for initiating adjunctive therapy with lamotrigine based on the concomitant AED or other concomitant medications (see Table 1 or Table 5). See below for adjustments to maintenance doses of lamotrigine in women taking estrogen-containing oral contraceptives.

  Adjustments to the Maintenance Dose of Lamotrigine In Women Taking Estrogen-Containing Oral Contraceptives:

  (1) Taking Estrogen-Containing Oral Contraceptives: For women not taking carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin that induce lamotrigine glucuronidation [see Drug Interactions (7), Clinical Pharmacology (12.3)], the maintenance dose of lamotrigine will in most cases need to be increased, by as much as 2-fold over the recommended target maintenance dose, in order to maintain a consistent lamotrigine plasma level [see Clinical Pharmacology (12.3)].

  (2) Starting Estrogen-Containing Oral Contraceptives: In women taking a stable dose of lamotrigine and not taking carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin that induce lamotrigine glucuronidation [see Drug Interactions (7), Clinical Pharmacology (12.3)], the maintenance dose will in most cases need to be increased by as much as 2-fold in order to maintain a consistent lamotrigine plasma level. The dose increases should begin at the same time that the oral contraceptive is introduced and continue, based on clinical response, no more rapidly than 50 to 100 mg/day every week. Dose increases should not exceed the recommended rate (see Table 1 or Table 5) unless lamotrigine plasma levels or clinical response support larger increases. Gradual transient increases in lamotrigine plasma levels may occur during the week of inactive hormonal preparation ("pill-free" week), and these increases will be greater if dose increases are made in the days before or during the week of inactive hormonal preparation. Increased lamotrigine plasma levels could result in additional adverse reactions, such as dizziness, ataxia, and diplopia. If adverse reactions attributable to lamotrigine consistently occur during the "pill-free" week, dose adjustments to the overall maintenance dose may be necessary. Dose adjustments limited to the "pill-free" week are not recommended. For women taking lamotrigine in addition to carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin that induce lamotrigine glucuronidation [see Drug Interactions (7), Clinical Pharmacology (12.3)], no adjustment to the dose of lamotrigine should be necessary.

  (3) Stopping Estrogen-Containing Oral Contraceptives: For women not taking carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin that induce lamotrigine glucuronidation [see Drug Interactions (7), Clinical Pharmacology (12.3)], the maintenance dose of lamotrigine will in most cases need to be decreased by as much as 50% in order to maintain a consistent lamotrigine plasma level. The decrease in dose of lamotrigine should not exceed 25% of the total daily dose per week over a 2-week period, unless clinical response or lamotrigine plasma levels indicate otherwise [see Clinical Pharmacology (12.3)]. For women taking lamotrigine in addition to carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin that induce lamotrigine glucuronidation [see Drug Interactions (7), Clinical Pharmacology (12.3)], no adjustment to the dose of lamotrigine should be necessary.

  Women and Other Hormonal Contraceptive Preparations or Hormone Replacement Therapy: The effect of other hormonal contraceptive preparations or hormone replacement therapy on the pharmacokinetics of lamotrigine has not been systematically evaluated. It has been reported that ethinylestradiol, not progestogens, increased the clearance of lamotrigine up to 2-fold, and the progestin-only pills had no effect on lamotrigine plasma levels. Therefore, adjustments to the dosage of lamotrigine in the presence of progestogens alone will likely not be needed.

  Patients With Hepatic Impairment: Experience in patients with hepatic impairment is limited. Based on a clinical pharmacology study in 24 patients with mild, moderate, and severe liver impairment [see Use in Specific Populations (8.6), Clinical Pharmacology (12.3)], the following general recommendations can be made. No dosage adjustment is needed in patients with mild liver impairment. Initial, escalation, and maintenance doses should generally be reduced by approximately 25% in patients with moderate and severe liver impairment without ascites and 50% in patients with severe liver impairment with ascites. Escalation and maintenance doses may be adjusted according to clinical response.

  Patients With Renal Impairment: Initial doses of lamotrigine should be based on patients' concomitant medications (see Tables 1-3 or Table 5); reduced maintenance doses may be effective for patients with significant renal impairment [see Use in Specific Populations (8.7), Clinical Pharmacology (12.3)]. Few patients with severe renal impairment have been evaluated during chronic treatment with lamotrigine. Because there is inadequate experience in this population, lamotrigine should be used with caution in these patients.

  Discontinuation Strategy: Epilepsy: For patients receiving lamotrigine in combination with other AEDs, a reevaluation of all AEDs in the regimen should be considered if a change in seizure control or an appearance or worsening of adverse reactions is observed.

  If a decision is made to discontinue therapy with lamotrigine, a step-wise reduction of dose over at least 2 weeks (approximately 50% per week) is recommended unless safety concerns require a more rapid withdrawal [see Warnings and Precautions (5.10)].

  Discontinuing carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin that induce lamotrigine glucuronidation should prolong the half-life of lamotrigine; discontinuing valproate should shorten the half-life of lamotrigine.

  Bipolar Disorder: In the controlled clinical trials, there was no increase in the incidence, type, or severity of adverse reactions following abrupt termination of lamotrigine. In clinical trials in patients with Bipolar Disorder, 2 patients experienced seizures shortly after abrupt withdrawal of lamotrigine. However, there were confounding factors that may have contributed to the occurrence of seizures in these bipolar patients. Discontinuation of lamotrigine should involve a step-wise reduction of dose over at least 2 weeks (approximately 50% per week) unless safety concerns require a more rapid withdrawal [see Warnings and Precautions (5.10)].

  2.2 Epilepsy – Adjunctive Therapy

  This section provides specific dosing recommendations for patients greater than 12 years of age and patients 2 to 12 years of age. Within each of these age-groups, specific dosing recommendations are provided depending upon concomitant AED or other concomitant medications (Table 1 for patients greater than 12 years of age and Table 2 for patients 2 to 12 years of age). A weight-based dosing guide for patients 2 to 12 years of age on concomitant valproate is provided in Table 3.

  Patients Over 12 Years of Age: Recommended dosing guidelines are summarized in Table 1.

  Table 1. Escalation Regimen for Lamotrigine in Patients Over 12 Years of Age With Epilepsy For Patients TAKING Valproate * For Patients NOT TAKING Carbamazepine, Phenytoin, Phenobarbital, Primidone†, or Valproate* For Patients TAKING Carbamazepine, Phenytoin, Phenobarbital, or Primidone† and NOT TAKING Valproate* * Valproate has been shown to inhibit glucuronidation and decrease the apparent clearance of lamotrigine [see Drug Interactions (7), Clinical Pharmacology (12.3)]. † These drugs induce lamotrigine glucuronidation and increase clearance [see Drug Interactions (7), Clinical Pharmacology (12.3)]. Other drugs which have similar effects include estrogen-containing oral contraceptives [see Drug Interactions (7), Clinical Pharmacology (12.3)]. Weeks 1 and 2 25 mg every other day 25 mg every day 50 mg/day Weeks 3 and 4 25 mg every day 50 mg/day 100 mg/day
  (in 2 divided doses) Week 5 onwards to maintenance Increase by 25 to 50 mg/day every 1 to 2 weeks Increase by 50 mg/day every 1 to 2 weeks Increase by 100 mg/day every 1 to 2 weeks Usual Maintenance Dose 100 to 200 mg/day with valproate alone
  100 to 400 mg/day with valproate and other drugs that induce glucuronidation
  (in 1 or 2 divided doses) 225 to 375 mg/day
  (in 2 divided doses) 300 to 500 mg/day
  (in 2 divided doses)

  Dosing recommendations for oral contraceptives can be found in General Dosing Considerations [see Dosage and Administration (2.1)]. Patients on rifampin, or other drugs that induce lamotrigine glucuronidation and increase clearance, should follow the same dosing titration/maintenance regimen as that used with anticonvulsants that have this effect.

  Patients 2 to 12 Years of Age: Recommended dosing guidelines are summarized in Table 2.

  Smaller starting doses and slower dose escalations than those used in clinical trials are recommended because of the suggestion that the risk of rash may be decreased by smaller starting doses and slower dose escalations. Therefore, maintenance doses will take longer to reach in clinical practice than in clinical trials. It may take several weeks to months to achieve an individualized maintenance dose. Maintenance doses in patients weighing less than 30 kg, regardless of age or concomitant AED, may need to be increased as much as 50%, based on clinical response.

  Table 2. Escalation Regimen for Lamotrigine in Patients 2 to 12 Years of Age With Epilepsy For Patients TAKING Valproate * For Patients NOT TAKING Carbamazepine, Phenytoin, Phenobarbital, Primidone†, or Valproate* For Patients TAKING Carbamazepine, Phenytoin, Phenobarbital, or Primidone† and NOT TAKING Valproate* Note: Only whole tablets should be used for dosing. * Valproate has been shown to inhibit glucuronidation and decrease the apparent clearance of lamotrigine [see Drug Interactions (7), Clinical Pharmacology (12.3)]. † These drugs induce lamotrigine glucuronidation and increase clearance [see Drug Interactions (7), Clinical Pharmacology (12.3)]. Other drugs which have similar effects include estrogen-containing oral contraceptives [see Drug Interactions (7), Clinical Pharmacology (12.3)]. Weeks 1 and 2 0.15 mg/kg/day
  in 1 or 2 divided doses, rounded down to the nearest whole tablet (see Table 3 for weight based dosing guide) 0.3 mg/kg/day
  in 1 or 2 divided doses, rounded down to the nearest whole tablet 0.6 mg/kg/day
  in 2 divided doses, rounded down to the nearest whole tablet Weeks 3 and 4 0.3 mg/kg/day
  in 1 or 2 divided doses, rounded down to the nearest whole tablet (see Table 3 for weight based dosing guide) 0.6 mg/kg/day
  in 2 divided doses, rounded down to the nearest whole tablet 1.2 mg/kg/day
  in 2 divided doses, rounded down to the nearest whole tablet Week 5 onwards to maintenance The dose should be increased every 1 to 2 weeks as follows: calculate 0.3 mg/kg/day, round this amount down to the nearest whole tablet, and add this amount to the previously administered daily dose The dose should be increased every 1 to 2 weeks as follows: calculate 0.6 mg/kg/day, round this amount down to the nearest whole tablet, and add this amount to the previously administered daily dose The dose should be increased every 1 to 2 weeks as follows: calculate 1.2 mg/kg/day, round this amount down to the nearest whole tablet, and add this amount to the previously administered daily dose Usual Maintenance Dose 1 to 5 mg/kg/day
  (maximum 200 mg/day in 1 or 2 divided doses)
  1 to 3 mg/kg/day with valproate alone 4.5 to 7.5 mg/kg/day
  (maximum 300 mg/day in 2 divided doses) 5 to 15 mg/kg/day
  (maximum 400 mg/day in 2 divided doses) Maintenance dose in patients less than 30 kg May need to be increased by as much as 50%, based on clinical response May need to be increased by as much as 50%, based on clinical response May need to be increased by as much as 50%, based on clinical response

  Dosing recommendations for oral contraceptives can be found in General Dosing Considerations [see Dosage and Administration (2.1)]. Patients on rifampin, or other drugs that induce lamotrigine glucuronidation and increase clearance, should follow the same dosing titration/maintenance regimen as that used with anticonvulsants that have this effect.

  Table 3. The Initial Weight-Based Dosing Guide for Patients 2 to 12 Years Taking Valproate (Weeks 1 to 4) With Epilepsy If the patient's weight is Give this daily dose, using the most appropriate combination of Lamotrigine 2-mg and 5-mg tablets Greater than And less than Weeks 1 and 2 Weeks 3 and 4 6.7 kg 14 kg 2 mg every other day 2 mg every day 14.1 kg 27 kg 2 mg every day 4 mg every day 27.1 kg 34 kg 4 mg every day 8 mg every day 34.1 kg 40 kg 5 mg every day 10 mg every day

  Usual Adjunctive Maintenance Dose for Epilepsy: The usual maintenance doses identified in Tables 1 and 2 are derived from dosing regimens employed in the placebo-controlled adjunctive studies in which the efficacy of lamotrigine was established. In patients receiving multidrug regimens employing carbamazepine, phenytoin, phenobarbital, or primidone without valproate, maintenance doses of adjunctive lamotrigine as high as 700 mg/day have been used. In patients receiving valproate alone, maintenance doses of adjunctive lamotrigine as high as 200 mg/day have been used. The advantage of using doses above those recommended in Tables 1 through 4 has not been established in controlled trials.

  2.3 Epilepsy – Conversion From Adjunctive Therapy to Monotherapy

  The goal of the transition regimen is to effect the conversion to monotherapy with lamotrigine under conditions that ensure adequate seizure control while mitigating the risk of serious rash associated with the rapid titration of lamotrigine.

  The recommended maintenance dose of lamotrigine as monotherapy is 500 mg/day given in 2 divided doses.

  To avoid an increased risk of rash, the recommended initial dose and subsequent dose escalations of lamotrigine should not be exceeded [see Boxed Warning].

  Conversion From Adjunctive Therapy With Carbamazepine, Phenytoin, Phenobarbital, or Primidone to Monotherapy With Lamotrigine: After achieving a dose of 500 mg/day of lamotrigine according to the guidelines in Table 1, the concomitant AED should be withdrawn by 20% decrements each week over a 4-week period. The regimen for the withdrawal of the concomitant AED is based on experience gained in the controlled monotherapy clinical trial.

  Conversion From Adjunctive Therapy With Valproate to Monotherapy With Lamotrigine: The conversion regimen involves 4 steps outlined in Table 4.

  Table 4. Conversion From Adjunctive Therapy With Valproate to Monotherapy With Lamotrigine in Patients ≥16 Years of Age With Epilepsy Lamotrigine Valproate Step 1 Achieve a dose of 200 mg/day according to guidelines in Table 1 (if not already on 200 mg/day). Maintain previous stable dose. Step 2 Maintain at 200 mg/day. Decrease to 500 mg/day by decrements no greater than 500 mg/day/week and then maintain the dose of 500 mg/day for 1 week. Step 3 Increase to 300 mg/day and maintain for 1 week. Simultaneously decrease to 250 mg/day and maintain for 1 week. Step 4 Increase by 100 mg/day every week to achieve maintenance dose of 500 mg/day. Discontinue.

  Conversion From Adjunctive Therapy With AEDs Other Than Carbamazepine, Phenytoin, Phenobarbital, Primidone, or Valproate to Monotherapy With Lamotrigine: No specific dosing guidelines can be provided for conversion to monotherapy with lamotrigine with AEDs other than carbamazepine, phenobarbital, phenytoin, primidone, or valproate.

  2.4 Bipolar Disorder

  The goal of maintenance treatment with lamotrigine is to delay the time to occurrence of mood episodes (depression, mania, hypomania, mixed episodes) in patients treated for acute mood episodes with standard therapy. The target dose of lamotrigine is 200 mg/day (100 mg/day in patients taking valproate, which decreases the apparent clearance of lamotrigine, and 400 mg/day in patients not taking valproate and taking either carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin that increase the apparent clearance of lamotrigine). In the clinical trials, doses up to 400 mg/day as monotherapy were evaluated; however, no additional benefit was seen at 400 mg/day compared with 200 mg/day [see Clinical Studies (14.2)]. Accordingly, doses above 200 mg/day are not recommended. Treatment with lamotrigine is introduced, based on concurrent medications, according to the regimen outlined in Table 5. If other psychotropic medications are withdrawn following stabilization, the dose of lamotrigine should be adjusted. For patients discontinuing valproate, the dose of lamotrigine should be doubled over a 2-week period in equal weekly increments (see Table 6). For patients discontinuing carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin that induce lamotrigine glucuronidation, the dose of lamotrigine should remain constant for the first week and then should be decreased by half over a 2-week period in equal weekly decrements (see Table 6). The dose of lamotrigine may then be further adjusted to the target dose (200 mg) as clinically indicated.

  If other drugs are subsequently introduced, the dose of lamotrigine may need to be adjusted. In particular, the introduction of valproate requires reduction in the dose of lamotrigine [see Drug Interactions (7), Clinical Pharmacology (12.3)].

  To avoid an increased risk of rash, the recommended initial dose and subsequent dose escalations of lamotrigine should not be exceeded [see Boxed Warning].

  Table 5. Escalation Regimen for Lamotrigine for Patients With Bipolar Disorder For Patients TAKING Valproate* For Patients NOT TAKING Carbamazepine, Phenytoin, Phenobarbital, Primidone†, or Valproate* For Patients TAKING Carbamazepine, Phenytoin, Phenobarbital, or Primidone†, and NOT TAKING Valproate* * Valproate has been shown to inhibit glucuronidation and decrease the apparent clearance of lamotrigine [see Drug Interactions (7), Clinical Pharmacology (12.3)]. † These drugs induce lamotrigine glucuronidation and increase clearance [see Drug Interactions (7), Clinical Pharmacology (12.3)]. Other drugs which have similar effects include estrogen-containing oral contraceptives [see Drug Interactions (7), Clinical Pharmacology (12.3)]. Dosing recommendations for oral contraceptives can be found in General Dosing Considerations [see Dosage and Administration (2.1)]. Patients on rifampin, or other drugs that induce lamotrigine glucuronidation and increase clearance, should follow the same dosing titration/maintenance regimen as that used with anticonvulsants that have this effect. Weeks 1 and 2 25 mg every other day 25 mg daily 50 mg daily Weeks 3 and 4 25 mg daily 50 mg daily 100 mg daily, in divided doses Week 5 50 mg daily 100 mg daily 200 mg daily, in divided doses Week 6 100 mg daily 200 mg daily 300 mg daily, in divided doses Week 7 100 mg daily 200 mg daily up to 400 mg daily, in divided doses Table 6. Dosage Adjustments to Lamotrigine for Patients With Bipolar Disorder Following Discontinuation of Psychotropic Medications Discontinuation of Psychotropic Drugs (excluding Carbamazepine, Phenytoin, Phenobarbital, Primidone*, or Valproate†) After Discontinuation of Valproate† After Discontinuation of Carbamazepine, Phenytoin, Phenobarbital or Primidone* Current dose of Lamotrigine (mg/day) 100 Current dose of Lamotrigine (mg/day) 400 * These drugs induce lamotrigine glucuronidation and increase clearance [see Drug Interactions (7), Clinical Pharmacology (12.3)]. Other drugs which have similar effects include estrogen-containing oral contraceptives [see Drug Interactions (7), Clinical Pharmacology (12.3)]. Dosing recommendations for oral contraceptives can be found in General Dosing Considerations [see Dosage and Administration (2.1)]. Patients on rifampin, or other drugs that induce lamotrigine glucuronidation and increase clearance, should follow the same dosing titration/maintenance regimen as that used with anticonvulsants that have this effect. † Valproate has been shown to inhibit glucuronidation and decrease the apparent clearance of lamotrigine [see Drug Interactions (7), Clinical Pharmacology (12.3)]. Week 1 Maintain current dose of Lamotrigine 150 400 Week 2 Maintain current dose of Lamotrigine 200 300 Week 3 onward Maintain current dose of Lamotrigine 200 200

  The benefit of continuing treatment in patients who had been stabilized in an 8- to 16-week open-label phase with lamotrigine was established in 2 randomized, placebo-controlled clinical maintenance trials [see Clinical Studies (14.2)]. However, the optimal duration of treatment with lamotrigine has not been established. Thus, patients should be periodically reassessed to determine the need for maintenance treatment.

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  Lamotrigine | Mylan Pharmaceuticals Inc.

  

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  The dose of zaleplon capsules should be individualized. The recommended dose of zaleplon capsules for most non-elderly adults is 10 mg. For certain low weight individuals, 5 mg may be a sufficient dose. Although the risk of certain adverse events associated with the use of zaleplon capsules appears to be dose dependent, the 20 mg dose has been shown to be adequately tolerated and may be considered for the occasional patient who does not benefit from a trial of a lower dose. Doses above 20 mg have not been adequately evaluated and are not recommended.

  Zaleplon capsules should be taken immediately before bedtime or after the patient has gone to bed and has experienced difficulty falling asleep (see PRECAUTIONS). Taking zaleplon capsules with or immediately after a heavy, high fat meal results in slower absorption and would be expected to reduce the effect of zaleplon on sleep latency (see CLINICAL PHARMACOLOGY: Pharmacokinetics).

  Special Populations

  Elderly patients and debilitated patients appear to be more sensitive to the effects of hypnotics, and respond to 5 mg of zaleplon. The recommended dose for these patients is therefore 5 mg. Doses over 10 mg are not recommended.

  Hepatic Insufficiency

  Patients with mild to moderate hepatic impairment should be treated with zaleplon capsules 5 mg because clearance is reduced in this population. Zaleplon capsules are not recommended for use in patients with severe hepatic impairment.

  Renal Insufficiency

  No dose adjustment is necessary in patients with mild to moderate renal impairment. Zaleplon capsules have not been adequately studied in patients with severe renal impairment.

  An initial dose of 5 mg should be given to patients concomitantly taking cimetidine because zaleplon clearance is reduced in this population (see PRECAUTIONS: Drug Interactions).

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  2.1 General Dosing Considerations

  Rash

  There are suggestions, yet to be proven, that the risk of severe, potentially life-threatening rash may be increased by (1) coadministration of lamotrigine with valproate, (2) exceeding the recommended initial dose of lamotrigine, or (3) exceeding the recommended dose escalation for lamotrigine. However, cases have occurred in the absence of these factors [see BOXED WARNING]. Therefore, it is important that the dosing recommendations be followed closely.

  The risk of nonserious rash may be increased when the recommended initial dose and/or the rate of dose escalation of lamotrigine is exceeded and in patients with a history of allergy or rash to other AEDs.

  It is recommended that lamotrigine not be restarted in patients who discontinued due to rash associated with prior treatment with lamotrigine, unless the potential benefits clearly outweigh the risks. If the decision is made to restart a patient who has discontinued lamotrigine, the need to restart with the initial dosing recommendations should be assessed. The greater the interval of time since the previous dose, the greater consideration should be given to restarting with the initial dosing recommendations. If a patient has discontinued lamotrigine for a period of more than 5 half-lives, it is recommended that initial dosing recommendations and guidelines be followed. The half-life of lamotrigine is affected by other concomitant medications [see CLINICAL PHARMACOLOGY (12.3)].

  Lamotrigine Added to Drugs Known to Induce or Inhibit Glucuronidation

  Drugs other than those listed in the Clinical Pharmacology section [see CLINICAL PHARMACOLOGY (12.3)] have not been systematically evaluated in combination with lamotrigine. Because lamotrigine is metabolized predominantly by glucuronic acid conjugation, drugs that are known to induce or inhibit glucuronidation may affect the apparent clearance of lamotrigine and doses of lamotrigine may require adjustment based on clinical response.

  Target Plasma Levels for Patients with Epilepsy or Bipolar Disorder

  A therapeutic plasma concentration range has not been established for lamotrigine. Dosing of lamotrigine should be based on therapeutic response [see CLINICAL PHARMACOLOGY (12.3)].

  Women Taking Estrogen-Containing Oral Contraceptives

  Starting Lamotrigine in Women Taking Estrogen-Containing Oral Contraceptives

  Although estrogen-containing oral contraceptives have been shown to increase the clearance of lamotrigine [see CLINICAL PHARMACOLOGY (12.3)], no adjustments to the recommended dose-escalation guidelines for lamotrigine should be necessary solely based on the use of estrogen-containing oral contraceptives. Therefore, dose escalation should follow the recommended guidelines for initiating adjunctive therapy with lamotrigine based on the concomitant AED or other concomitant medications (see Table 1 or Table 5). See below for adjustments to maintenance doses of lamotrigine in women taking estrogen-containing oral contraceptives.

  Adjustments to the Maintenance Dose of Lamotrigine in Women Taking Estrogen-Containing Oral Contraceptives

  (1) Taking Estrogen-Containing Oral Contraceptives

  For women not taking carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin that induce  lamotrigine glucuronidation [see DRUG INTERACTIONS (7), CLINICAL PHARMACOLOGY (12.3)], the maintenance dose of lamotrigine will in most cases need to be increased, by as much as 2-fold over the recommended target maintenance dose, in order to maintain a consistent lamotrigine plasma level [see CLINICAL PHARMACOLOGY (12.3)].

  (2) Starting Estrogen-Containing Oral Contraceptives

  In women taking a stable dose of lamotrigine and not taking carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin that induce  lamotrigine glucuronidation [see DRUG INTERACTIONS (7), CLINICAL PHARMACOLOGY (12.3)], the maintenance dose will in most cases need to be increased by as much as 2-fold in order to maintain a consistent lamotrigine plasma level. The dose increases should begin at the same time that the oral contraceptive is introduced and continue, based on clinical response, no more rapidly than 50 to 100 mg/day every week. Dose increases should not exceed the recommended rate (see Table 1 or Table 5) unless lamotrigine plasma levels or clinical response support larger increases. Gradual transient increases in lamotrigine plasma levels may occur during the week of inactive hormonal preparation ("pill-free" week), and these increases will be greater if dose increases are made in the days before or during the week of inactive hormonal preparation. Increased lamotrigine plasma levels could result in additional adverse reactions, such as dizziness, ataxia, and diplopia. If adverse reactions attributable to lamotrigine consistently occur during the "pill-free" week, dose adjustments to the overall maintenance dose may be necessary. Dose adjustments limited to the "pill-free" week are not recommended. For women taking lamotrigine in addition to carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin that induce  lamotrigine glucuronidation [see DRUG INTERACTIONS (7), CLINICAL PHARMACOLOGY (12.3)], no adjustment to the dose of lamotrigine should be necessary.

  (3) Stopping Estrogen-Containing Oral Contraceptives

  For women not taking carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin that induce  lamotrigine glucuronidation [see DRUG INTERACTIONS (7), CLINICAL PHARMACOLOGY (12.3)], the maintenance dose of lamotrigine will in most cases need to be decreased by as much as 50% in order to maintain a consistent lamotrigine plasma level. The decrease in dose of lamotrigine should not exceed 25% of the total daily dose per week over a 2-week period, unless clinical response or lamotrigine plasma levels indicate otherwise [see CLINICAL PHARMACOLOGY (12.3)]. For women taking lamotrigine in addition to carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin that induce  lamotrigine glucuronidation [see DRUG INTERACTIONS (7), CLINICAL PHARMACOLOGY (12.3)], no adjustment to the dose of lamotrigine should be necessary.

  Women and Other Hormonal Contraceptive Preparations or Hormone Replacement Therapy

  The effect of other hormonal contraceptive preparations or hormone replacement therapy on the pharmacokinetics of lamotrigine has not been systematically evaluated. It has been reported that ethinylestradiol, not progestogens, increased the clearance of lamotrigine up to 2-fold, and the progestin-only pills had no effect on lamotrigine plasma levels. Therefore, adjustments to the dosage of lamotrigine in the presence of progestogens alone will likely not be needed.

  Patients with Hepatic Impairment

  Experience in patients with hepatic impairment is limited. Based on a clinical pharmacology study in 24 patients with mild, moderate, and severe liver impairment [see USE IN SPECIFIC POPULATIONS (8.6), CLINICAL PHARMACOLOGY (12.3)], the following general recommendations can be made. No dosage adjustment is needed in patients with mild liver impairment. Initial, escalation, and maintenance doses should generally be reduced by approximately 25% in patients with moderate and severe liver impairment without ascites and 50% in patients with severe liver impairment with ascites. Escalation and maintenance doses may be adjusted according to clinical response.

  Patients with Renal Impairment

  Initial doses of lamotrigine should be based on patients’ concomitant medications (see Tables 1-3 or Table 5); reduced maintenance doses may be effective for patients with significant renal impairment [see USE IN SPECIFIC POPULATIONS (8.6), CLINICAL PHARMACOLOGY (12.3)]. Few patients with severe renal impairment have been evaluated during chronic treatment with lamotrigine. Because there is inadequate experience in this population, lamotrigine should be used with caution in these patients.

  Discontinuation Strategy

  Epilepsy

  For patients receiving lamotrigine in combination with other AEDs, a re-evaluation of all AEDs in the regimen should be considered if a change in seizure control or an appearance or worsening of adverse reactions is observed.

  If a decision is made to discontinue therapy with lamotrigine, a step-wise reduction of dose over at least 2 weeks (approximately 50% per week) is recommended unless safety concerns require a more rapid withdrawal [see WARNINGS AND PRECAUTIONS (5.10)].

  Discontinuing carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin that induce lamotrigine glucuronidation should prolong the half-life of lamotrigine; discontinuing valproate should shorten the half-life of lamotrigine.

  Bipolar Disorder

  In the controlled clinical trials, there was no increase in the incidence, type, or severity of adverse reactions following abrupt termination of lamotrigine. In clinical trials in patients with Bipolar Disorder, 2 patients experienced seizures shortly after abrupt withdrawal of lamotrigine. However, there were confounding factors that may have contributed to the occurrence of seizures in these bipolar patients. Discontinuation of lamotrigine should involve a step-wise reduction of dose over at least 2 weeks (approximately 50% per week) unless safety concerns require a more rapid withdrawal [see WARNINGS AND PRECAUTIONS (5.10)].

  2.2 Epilepsy – Adjunctive Therapy

  This section provides specific dosing recommendations for patients greater than 12 years of age and patients 2 to 12 years of age. Within each of these age-groups, specific dosing recommendations are provided depending upon concomitant AED or other concomitant medications (Table 1 for patients greater than 12 years of age and Table 2 for patients 2 to 12 years of age). A weight-based dosing guide for patients 2 to 12 years of age on concomitant valproate is provided in Table 3.

  Patients Over 12 Years of Age

  Recommended dosing guidelines are summarized in Table 1.

  Table 1 Escalation Regimen for Lamotrigine in Patients Over 12 Years of Age With Epilepsy
  For Patients Taking Valproate*
  For Patients NOT TAKING Carbamazepine, Phenytoin, Phenobarbital, Primidone†, or Valproate*
  For Patients TAKING Carbamazepine, Phenytoin, Phenobarbital, or Primidone† and  NOT TAKING Valproate*
  * Valproate has been shown to inhibit glucuronidation and decrease the apparent clearance of lamotrigine [see DRUG INTERACTIONS ( 7), CLINICAL PHARMACOLOGY ( 12.3)]. † These drugs induce lamotrigine glucuronidation and increase clearance [see DRUG INTERACTIONS ( 7), CLINICAL PHARMACOLOGY ( 12.3)]. Other drugs which have similar effects include estrogen-containing oral contraceptives [see DRUG INTERACTIONS ( 7), CLINICAL PHARMACOLOGY ( 12.3)]. Dosing recommendations for oral contraceptives can be found in General Dosing Considerations [see DOSAGE AND ADMINISTRATION ( 2.1)]. Patients on rifampin, or other drugs that induce lamotrigine glucuronidation and increase clearance, should follow the same dosing titration/maintenance regimen as that used with anticonvulsants that have this effect. Weeks 1 and 2 
  25 mg every other day
  25 mg every day
  50 mg/day
  Weeks 3 and 4 
  25 mg every day
  50 mg/day
  100 mg/day
  (in 2 divided doses)
  Week 5 onwards to maintenance 
  Increase by 25 to 50 mg/day every 1 to 2 weeks
  Increase by 50 mg/day every 1 to 2 weeks
  Increase by 100 mg/day every 1 to 2 weeks.
  Usual Maintenance Dose 
  100 to 200 mg/day with valproate alone
  
  100 to 400 mg/day with valproate and other drugs that induce glucuronidation
  
  (in 1 or 2 divided doses)
  225 to 375 mg/day
  (in 2 divided doses)
  300 to 500 mg/day
  (in 2 divided doses)
  

  Patients 2 to 12 Years of Age

  Recommended dosing guidelines are summarized in Table 2.

  Smaller starting doses and slower dose escalations than those used in clinical trials are recommended because of the suggestion that the risk of rash may be decreased by smaller starting doses and slower dose escalations. Therefore, maintenance doses will take longer to reach in clinical practice than in clinical trials. It may take several weeks to months to achieve an individualized maintenance dose. Maintenance doses in patients weighing less than 30 kg, regardless of age or concomitant AED, may need to be increased as much as 50%, based on clinical response.

  Table 2 Escalation Regimen for Lamotrigine in Patients 2 to 12 Years of Age With Epilepsy
  
  For Patients TAKING Valproatea
  For Patients NOT TAKING Carbamazepine, Phenytoin, Phenobarbital, or Primidoneb, or Valproatea
  For Patients TAKING Carbamazepine, Phenytoin, Phenobarbital, or Primidoneb and  NOT TAKING Valproatea
  

  Note: Only whole tablets should be used for dosing.

  *Valproate has been shown to inhibit glucuronidation and decrease the apparent clearance of lamotrigine [see DRUG INTERACTIONS (7), Pharmacokinetics (12.3)].

  bThese drugs induce lamotrigine glucuronidation and increase clearance [see DRUG INTERACTIONS (7), CLINICAL PHARMACOLOGY (12.3)]. Other drugs which have similar effects include estrogen-containing oral contraceptives [see DRUG INTERACTIONS (7), CLINICAL PHARMACOLOGY (12.3)]. Dosing recommendations for oral contraceptives can be found in General Dosing Considerations [see DOSAGE AND ADMINISTRATION (2.1)]. Patients on rifampin, or other drugs that induce lamotrigine glucuronidation and increase clearance, should follow the same dosing titration/maintenance regimen as that used with anticonvulsants that have this effect.

  Weeks 1 and 2 
  0.15 mg/kg/day
  in 1 or 2 divided doses, rounded down to the nearest
  whole tablet (see Table 3 for weight based dosing guide)
  0.3 mg/kg/day
  in 1 or 2 divided doses, rounded down to the nearest whole tablet
  0.6 mg/kg/day
  in 2 divided doses, rounded down to the nearest whole tablet
  Weeks 3 and 4 
  0.3 mg/kg/day
  in 1 or 2 divided doses, rounded down to the nearest
  whole tablet (see Table 3 for weight based dosing guide)
  0.6 mg/kg/day
  in 2 divided doses, rounded down to the nearest whole tablet
  1.2 mg/kg/day
  in 2 divided doses, rounded down to the nearest whole tablet
  Weeks 5 onwards to maintenance 
  The dose should be increased every 1 to 2 weeks as follows: calculate 0.3 mg/kg/day, round this amount down to the nearest whole tablet, and add this amount to the previously administered daily dose
  The dose should be increased every 1 to 2 weeks as follows: calculate 0.6 mg/kg/day, round this amount down to the nearest whole tablet, and add this amount to the previously administered daily dose
  The dose should be increased every 1 to 2 weeks as follows: calculate 1.2 mg/kg/day, round this amount down to the nearest whole tablet, and add this amount to the previously administered daily dose
  Usual Maintenance Dose 
  1 to 5 mg/kg/day (maximum 200 mg/day in 1 or 2 divided doses)
  1 to 3 mg/kg/day with valproate alone
  4.5 to 7.5 mg/kg/day
  (maximum 300 mg/day in 2 divided doses)
  5 to 15 mg/kg/day (maximum 400 mg/day in 2 divided doses)
  Maintenance dose in patients less than 30 kg 
  May need to be increased by as much as 50%,
  based on clinical response
  May need to be increased by as much as 50%,
  based on clinical response
  May need to be increased by as much as 50%,
  based on clinical response
  Table 3 The Initial Weight-Based Dosing Guide for Patients 2 to 12 Years Taking Valproate (Weeks 1 to 4) With Epilepsy If the patient’s weight is
  Give this daily dose, using the most appropriate combination of Lamotrigine 5 mg tablets
  Greater than 
  And less than 
  Weeks 1 and 2 
  Weeks 3 and 4 
  34.1 kg 
  40 kg 
  5 mg every day 
  10 mg every day 
  

  Usual Adjunctive Maintenance Dose for Epilepsy

  The usual maintenance doses identified in Tables 1 and 2 are derived from dosing regimens employed in the placebo-controlled adjunctive studies in which the efficacy of lamotrigine was established. In patients receiving multidrug regimens employing carbamazepine, phenytoin, phenobarbital, or primidone without valproate, maintenance doses of adjunctive lamotrigine as high as 700 mg/day have been used. In patients receiving valproate alone, maintenance doses of adjunctive lamotrigine as high as 200 mg/day have been used. The advantage of using doses above those recommended in Tables 1 through 4 has not been established in controlled trials.

  2.3 Epilepsy – Conversion from Adjunctive Therapy to Monotherapy

  The goal of the transition regimen is to effect the conversion to monotherapy with lamotrigine under conditions that ensure adequate seizure control while mitigating the risk of serious rash associated with the rapid titration of lamotrigine.

  The recommended maintenance dose of lamotrigine as monotherapy is 500 mg/day given in 2 divided doses.

  To avoid an increased risk of rash, the recommended initial dose and subsequent dose escalations of lamotrigine should not be exceeded [see BOXED WARNING].

  Conversion from Adjunctive Therapy with Carbamazepine, Phenytoin, Phenobarbital, or Primidone to Monotherapy with Lamotrigine

  After achieving a dose of 500 mg/day of lamotrigine according to the guidelines in Table 1, the concomitant AED should be withdrawn by 20% decrements each week over a 4-week period. The regimen for the withdrawal of the concomitant AED is based on experience gained in the controlled monotherapy clinical trial.

  Conversion from Adjunctive Therapy with Valproate to Monotherapy with Lamotrigine

  The conversion regimen involves 4 steps outlined in Table 4.

  Table 4 Conversion from Adjunctive Therapy With Valproate to Monotherapy With Lamotrigine in Patients ≥16 Years of Age With Epilepsy
  Lamotrigine
  Valproate 
  Step 1 
  Achieve a dose of 200 mg/day according to 
  guidelines in Table 1 (if not already on 200 mg/day). 
  Maintain previous stable dose. 
  Step 2 
  Maintain at 200 mg/day. 
  Decrease to 500 mg/day by decrements no greater than 500 mg/day/week and 
  then maintain the dose of 500 mg/day for 1 week. 
  Step 3 
  Increase to 300 mg/day and maintain for 1 week. 
  Simultaneously decrease to 250 mg/day and maintain for 1 week. 
  Step 4 
  Increase by 100 mg/day every week to achieve maintenance dose of 500 mg/day. 
  Discontinue. 
  

  Conversion from Adjunctive Therapy with AEDs Other Than Carbamazepine, Phenytoin, Phenobarbital, Primidone, or Valproate to Monotherapy with Lamotrigine

  No specific dosing guidelines can be provided for conversion to monotherapy with lamotrigine with AEDs other than carbamazepine, phenobarbital, phenytoin, primidone, or valproate.

  2.4 Bipolar Disorder

  The goal of maintenance treatment with lamotrigine is to delay the time to occurrence of mood episodes (depression, mania, hypomania, mixed episodes) in patients treated for acute mood episodes with standard therapy. The target dose of lamotrigine is 200 mg/day (100 mg/day in patients taking valproate, which decreases the apparent clearance of lamotrigine, and 400 mg/day in patients not taking valproate and taking either carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin  that increase the apparent clearance of lamotrigine). In the clinical trials, doses up to 400 mg/day as monotherapy were evaluated; however, no additional benefit was seen at 400 mg/day compared with 200 mg/day [see Clinical Studies (14.2)]. Accordingly, doses above 200 mg/day are not recommended. Treatment with lamotrigine is introduced, based on concurrent medications, according to the regimen outlined in Table 5. If other psychotropic medications are withdrawn following stabilization, the dose of lamotrigine should be adjusted. For patients discontinuing valproate, the dose of lamotrigine should be doubled over a 2-week period in equal weekly increments (see Table 6). For patients discontinuing carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin that induce lamotrigine glucuronidation, the dose of lamotrigine should remain constant for the first week and then should be decreased by half over a 2-week period in equal weekly decrements (see Table 6). The dose of lamotrigine may then be further adjusted to the target dose (200 mg) as clinically indicated.

  If other drugs are subsequently introduced, the dose of lamotrigine may need to be adjusted. In particular, the introduction of valproate requires reduction in the dose of lamotrigine [see DRUG INTERACTIONS (7), CLINICAL PHARMACOLOGY (12.3)].

  To avoid an increased risk of rash, the recommended initial dose and subsequent dose escalations of lamotrigine should not be exceeded [see BOXED WARNING].

  Table 5 Escalation Regimen for Lamotrigine for Patients With Bipolar Disorder *  Valproate has been shown to inhibit glucuronidation and decrease the apparent clearance of  lamotrigine [see DRUG INTERACTIONS ( 7), CLINICAL PHARMACOLOGY ( 12.3)]. †  These drugs induce lamotrigine glucuronidation and increase clearance [see DRUG INTERACTIONS  (7), CLINICAL PHARMACOLOGY ( 12.3)]. Other drugs which have similar effects include estrogen containing oral contraceptives [see DRUG INTERACTIONS ( 7), CLINICAL PHARMACOLOGY ( 12.3)]. Dosing recommendations for oral contraceptives can be found in General Dosing Considerations [see DOSAGE AND ADMINISTRATION ( 2.1)]. Patients on rifampin, or other drugs that induce lamotrigine glucuronidation and increase clearance, should follow the same dosing titration/maintenance regimen as that used with anticonvulsants that have this effect.
  For Patients TAKING Valproate*
  For Patients NOT TAKING Carbamazepine, Phenytoin, Phenobarbital, Primidone†, or Valproate*
  For Patients TAKING Carbamazepine, Phenytoin, Phenobarbital, or Primidone† and NOT TAKING Valproate*
  Weeks 1 and 2 
  25 mg every other day
  25 mg daily
  50 mg daily
  Weeks 3 and 4 
  25 mg daily
  50 mg daily
  100 mg daily, in divided doses
  Week 5 
  50 mg daily
  100 mg daily
  200 mg daily, in divided doses
  Week 6 
  100 mg daily
  200 mg daily
  300 mg daily, in divided doses
  Week 7 
  100 mg daily
  200 mg daily
  up to 400 mg daily, in divided doses
  Table 6 Dosage Adjustments to Lamotrigine for Patients With Bipolar Disorder Following Discontinuation of Psychotropic Medications * These drugs induce lamotrigine glucuronidation and increase clearance [see DRUG INTERACTIONS ( 7), CLINICAL PHARMACOLOGY ( 12.3)]. Other drugs which have similar effects include estrogen containing oral contraceptives [see DRUG INTERACTIONS ( 7), CLINICAL PHARMACOLOGY ( 12.3)]. Dosing recommendations for oral contraceptives can be found in General Dosing Considerations [see DOSAGE AND ADMINISTRATION ( 2.1)]. Patients on rifampin, or other drugs that induce lamotrigine glucuronidation and increase clearance, should follow the same dosing titration/maintenance regimen as that used with anticonvulsants that have this effect. † Valproate has been shown to inhibit glucuronidation and decrease the apparent clearance of lamotrigine [see DRUG INTERACTIONS ( 7), CLINICAL PHARMACOLOGY ( 12.3)].
  Discontinuation of Psychotropic Drugs (excluding Carbamazepine, Phenytoin, Phenobarbital, Primidone*, or Valproate†)
  After Discontinuation of Valproate†
  After Discontinuation of Carbamazepine, Phenytoin, Phenobarbital, or Primidone*
  
  
  Current dose of Lamotrigine (mg/day)
  100
  Current dose of Lamotrigine (mg/day)
  400
  Week 1 
  Maintain current dose of Lamotrigine
  150
  400
  Week 2 
  Maintain current dose of Lamotrigine
  200
  300
  Week 3 onward 
  Maintain current dose of Lamotrigine
  200
  200
  

  The benefit of continuing treatment in patients who had been stabilized in an 8- to 16-week open-label phase with lamotrigine was established in 2 randomized, placebo-controlled clinical maintenance trials [see Clinical Studies (14.2)]. However, the optimal duration of treatment with lamotrigine has not been established. Thus, patients should be periodically reassessed to determine the need for maintenance treatment.

  2.5 Administration of Lamotrigine Tablets (Chewable, Dispersible)

  Lamotrigine Tablets (Chewable, Dispersible) may be swallowed whole, chewed, or dispersed in water or diluted fruit juice. If the tablets are chewed, consume a small amount of water or diluted fruit juice to aid in swallowing.

  To disperse Lamotrigine Tablets (Chewable, Dispersible), add the tablets to a small amount of liquid (1 teaspoon, or enough to cover the medication). Approximately 1 minute later, when the tablets are completely dispersed, swirl the solution and consume the entire quantity immediately. No attempt should be made to administer partial quantities of the dispersed tablets.

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  2.1 General Dosing Considerations

  Rash: There are suggestions, yet to be proven, that the risk of severe, potentially life-threatening rash may be increased by (1) coadministration of lamotrigine tablets with valproate, (2) exceeding the recommended initial dose of lamotrigine tablets, or (3) exceeding the recommended dose escalation for lamotrigine tablets. However, cases have occurred in the absence of these factors [see Boxed Warning ]. Therefore, it is important that the dosing recommendations be followed closely.

  The risk of nonserious rash may be increased when the recommended initial dose and/or the rate of dose escalation of lamotrigine tablet is exceeded and in patients with a history of allergy or rash to other AEDs.

  It is recommended that lamotrigine tablets not be restarted in patients who discontinued due to rash associated with prior treatment with lamotrigine, unless the potential benefits clearly outweigh the risks. If the decision is made to restart a patient who has discontinued lamotrigine, the need to restart with the initial dosing recommendations should be assessed. The greater the interval of time since the previous dose, the greater consideration should be given to restarting with the initial dosing recommendations. If a patient has discontinued lamotrigine for a period of more than 5 half-lives, it is recommended that initial dosing recommendations and guidelines be followed. The half-life of lamotrigine is affected by other concomitant medications [see Clinical Pharmacology (12.3) ].

  Lamotrigine Tablets Added to Drugs Known to Induce or Inhibit Glucuronidation: Drugs other than those listed in the Clinical Pharmacology section [see Clinical Pharmacology (12.3) ] have not been systematically evaluated in combination with lamotrigine. Because lamotrigine is metabolized predominantly by glucuronic acid conjugation, drugs that are known to induce or inhibit glucuronidation may affect the apparent clearance of lamotrigine and doses of lamotrigine tablets may require adjustment based on clinical response.

  Target Plasma Levels for Patients With Epilepsy or Bipolar Disorder: A therapeutic plasma concentration range has not been established for lamotrigine. Dosing of lamotrigine tablets should be based on therapeutic response [see Clinical Pharmacology (12.3) ].

  Women Taking Estrogen-Containing Oral Contraceptives: Starting Lamotrigine Tablets  in Women Taking Estrogen-Containing Oral Contraceptives: Although estrogen-containing oral contraceptives have been shown to increase the clearance of lamotrigine [see Clinical Pharmacology (12.3) ], no adjustments to the recommended dose-escalation guidelines for lamotrigine tablets should be necessary solely based on the use of estrogen-containing oral contraceptives. Therefore, dose escalation should follow the recommended guidelines for initiating adjunctive therapy with lamotrigine tablets based on the concomitant AED or other concomitant medications (see Table 1 or Table 5). See below for adjustments to maintenance doses of lamotrigine tablets in women taking estrogen-containing oral contraceptives.

  Adjustments to the Maintenance Dose of Lamotrigine Tablets In Women Taking Estrogen-Containing Oral Contraceptives:

  (1) Taking Estrogen-Containing Oral Contraceptives: For women not taking carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin that induce lamotrigine glucuronidation [see Drug Interactions (7), Clinical Pharmacology (12.3)], the maintenance dose of lamotrigine  tablets will in most cases need to be increased, by as much as 2-fold over the recommended target maintenance dose, in order to maintain a consistent lamotrigine plasma level [see Clinical Pharmacology (12.3) ].

  (2) Starting Estrogen-Containing Oral Contraceptives: In women taking a stable dose of lamotrigine tablets and not taking carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin that induce lamotrigine glucuronidation [see Drug Interactions (7), Clinical Pharmacology (12.3)], the maintenance dose will in most cases need to be increased by as much as 2-fold in order to maintain a consistent lamotrigine plasma level. The dose increases should begin at the same time that the oral contraceptive is introduced and continue, based on clinical response, no more rapidly than 50 to 100 mg/day every week. Dose increases should not exceed the recommended rate (see Table 1 or Table 5) unless lamotrigine plasma levels or clinical response support larger increases. Gradual transient increases in lamotrigine plasma levels may occur during the week of inactive hormonal preparation ("pill-free" week), and these increases will be greater if dose increases are made in the days before or during the week of inactive hormonal preparation. Increased lamotrigine plasma levels could result in additional adverse reactions, such as dizziness, ataxia, and diplopia. If adverse reactions attributable to lamotrigine tablets consistently occur during the "pill-free" week, dose adjustments to the overall maintenance dose may be necessary. Dose adjustments limited to the "pill-free" week are not recommended. For women taking lamotrigine tablets in addition to carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin that induce lamotrigine glucuronidation [see Drug Interactions (7), Clinical Pharmacology (12.3)], no adjustment to the dose of lamotrigine tablets should be necessary.

  (3) Stopping Estrogen-Containing Oral Contraceptives: For women not taking carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin that induce lamotrigine glucuronidation [see Drug Interactions (7), Clinical Pharmacology (12.3)], the maintenance dose of lamotrigine tablets will in most cases need to be decreased by as much as 50% in order to maintain a consistent lamotrigine plasma level. The decrease in dose of lamotrigine tablets should not exceed 25% of the total daily dose per week over a 2-week period, unless clinical response or lamotrigine plasma levels indicate otherwise [see Clinical Pharmacology (12.3) ]. For women taking lamotrigine tablets in addition to carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin that induce lamotrigine glucuronidation [see Drug Interactions (7), Clinical Pharmacology (12.3)], no adjustment to the dose of lamotrigine tablets should be necessary.

  Women and Other Hormonal Contraceptive Preparations or Hormone Replacement Therapy: The effect of other hormonal contraceptive preparations or hormone replacement therapy on the pharmacokinetics of lamotrigine has not been systematically evaluated. It has been reported that ethinylestradiol, not progestogens, increased the clearance of lamotrigine up to 2-fold, and the progestin-only pills had no effect on lamotrigine plasma levels. Therefore, adjustments to the dosage of lamotrigine tablets in the presence of progestogens alone will likely not be needed.

  Patients With Hepatic Impairment: Experience in patients with hepatic impairment is limited. Based on a clinical pharmacology study in 24 patients with mild, moderate, and severe liver impairment [see Use in Specific Populations (8.6) , Clinical Pharmacology (12.3) ], the following general recommendations can be made. No dosage adjustment is needed in patients with mild liver impairment. Initial, escalation, and maintenance doses should generally be reduced by approximately 25% in patients with moderate and severe liver impairment without ascites and 50% in patients with severe liver impairment with ascites. Escalation and maintenance doses may be adjusted according to clinical response.

  Patients With Renal Impairment: Initial doses of lamotrigine tablets should be based on patients' concomitant medications (see Tables 1-3 or Table 5); reduced maintenance doses may be effective for patients with significant renal impairment [see Use in Specific Populations (8.7) , Clinical Pharmacology (12.3) ]. Few patients with severe renal impairment have been evaluated during chronic treatment with lamotrigine tablets. Because there is inadequate experience in this population, lamotrigine tablets should be used with caution in these patients.

  Discontinuation Strategy:

  Epilepsy: For patients receiving lamotrigine tablets in combination with other AEDs, a reevaluation of all AEDs in the regimen should be considered if a change in seizure control or an appearance or worsening of adverse reactions is observed.

  If a decision is made to discontinue therapy with lamotrigine tablets, a step-wise reduction of dose over at least 2 weeks (approximately 50% per week) is recommended unless safety concerns require a more rapid withdrawal [see Warnings and Precautions (5.9) ].

  Discontinuing carbamazepine, phenytoin, phenobarbital, primidone or other drugs such as rifampin that induce lamotrigine glucuronidation should prolong the half-life of lamotrigine; discontinuing valproate should shorten the half-life of lamotrigine.

  Bipolar Disorder: In the controlled clinical trials, there was no increase in the incidence, type, or severity of adverse reactions following abrupt termination of lamotrigine tablets. In clinical trials in patients with Bipolar Disorder, 2 patients experienced seizures shortly after abrupt withdrawal of lamotrigine tablets. However, there were confounding factors that may have contributed to the occurrence of seizures in these bipolar patients. Discontinuation of lamotrigine tablets should involve a step-wise reduction of dose over at least 2 weeks (approximately 50% per week) unless safety concerns require a more rapid withdrawal [see Warnings and Precautions (5.9) ].

  2.2 Epilepsy – Adjunctive Therapy

  This section provides specific dosing recommendations for patients greater than 12 years of age and patients 2 to 12 years of age. Within each of these age-groups, specific dosing recommendations are provided depending upon concomitant AED or other concomitant medications (Table 1 for patients greater than 12 years of age and Table 2 for patients 2 to 12 years of age). A weight-based dosing guide for patients 2 to 12 years of age on concomitant valproate is provided in Table 3.

  Patients Over 12 Years of Age: Recommended dosing guidelines are summarized in Table 1.

  Table 1. Escalation Regimen for Lamotrigine Tablets in Patients Over 12 Years of Age With Epilepsy

  a Valproate has been shown to inhibit glucuronidation and decrease the apparent clearance of lamotrigine [see Drug Interactions (7), Clinical Pharmacology (12.3)].

  b These drugs induce lamotrigine glucuronidation and increase clearance [see Drug Interactions (7), Clinical Pharmacology (12.3)]. Other drugs that have similar effects include estrogen-containing oral contraceptives [see Drug Interactions (7), Clinical Pharmacology (12.3)]. Dosing recommendations for oral contraceptives can be found in General Dosing Considerations [see Dosage and Administration (2.1)]. Patients on rifampin, or other drugs that induce lamotrigine glucuronidation and increase clearance, should follow the same dosing titration/maintenance regimen as that used with anticonvulsants that have this effect.

  
  For 
  For Patients NOT TAKING 
  For Patients 
  
  Patients
  Carbamazepine, 
  TAKING
  
  TAKING
  Phenytoin,
  Carbamazepine,
  
  Valproatea
  Phenobarbital,
  Phenytoin, 
  
  
  or Primidoneb,  
  Phenobarbital,
  
  
  or Valproatea
  or Primidoneb
  
  
  
  and NOT TAKING
  
  
  
  Valproatea
  Weeks 1 and 2
  25 mg every other day
  25 mg every day
  50 mg/day
  Weeks 3 and 4
  25 mg every day
  50 mg/day
  100 mg/day
  (in 2 divided doses)
  Weeks 5 onwards to 
  maintenance
  Increase by 25 to 
  50 mg/day every 1 to 2 weeks
  Increase by 50
  mg/day every 1
  to 2 weeks
  Increase by 
  100 mg/day every 
  1 to 2 weeks.
  Usual maintenance 
  dose
  100 to 200 mg/day
  with valproate alone
  225 to 375 mg/day
  (in 2 divided doses).
  300 to 500 mg/day
  (in 2 divided doses).
  
  100 to 400 mg/day
  with valproate
  and other drugs that induce glucuronidation
  
  
  
  (in 1 or 2 divided doses)
  
  
  

  Patients 2 to 12 Years Of Age: Recommended dosing guidelines are summarized in Table 2.

  Smaller starting doses and slower dose escalations than those used in clinical trials are recommended because of the suggestion that the risk of rash may be decreased by smaller starting doses and slower dose escalations. Therefore, maintenance doses will take longer to reach in clinical practice than in clinical trials. It may take several weeks to months to achieve an individualized maintenance dose. Maintenance doses in patients weighing less than 30 kg, regardless of age or concomitant AED, may need to be increased as much as 50%, based on clinical response.

  Table 2. Escalation Regimen for Lamotrigine Tablets in Patients 2 to 12 Years of Age With Epilepsy

  Note: Only whole tablets should be used for dosing.

  a Valproate has been shown to inhibit glucuronidation and decrease the apparent clearance of lamotrigine [see Drug Interactions (7), Clinical Pharmacology (12.3)].

  b These drugs induce lamotrigine glucuronidation and increase clearance [see Drug Interactions (7), Clinical Pharmacology (12.3)]. Other drugs which have similar effects include estrogen-containing oral contraceptives [see Drug Interactions (7), Clinical Pharmacology (12.3)]. Dosing recommendations for oral contraceptives can be found in General Dosing Considerations [see Dosage and Administration (2.1)]. Patients on rifampin, or other drugs that induce lamotrigine glucuronidation and increase clearance, should follow the same dosing titration/maintenance regimen as that used with anticonvulsants that have this effect.

  
  For Patients TAKING 
  Valproatea
  For Patients NOT 
  TAKING Carbamazepine, Phenytoin, 
  Phenobarbital, Primidoneb, or 
  Valproatea
  For Patients TAKING 
  Carbamazepine, Phenytoin, Phenobarbital, or 
  Primidoneb and NOT 
  TAKING Valproatea
  Weeks 1 and 2
  0.15 mg/kg/day
  in 1 or 2 divided doses, rounded down to the 
  nearest whole tablet (see Table 3 for weight 
  based dosing guide).
  0.3 mg/kg/day
  in 1 or 2 divided doses, rounded down to the 
  nearest whole tablet.
  0.6 mg/kg/day
  in 2 divided doses, rounded down to the 
  nearest whole tablet.
  Weeks 3 and 4
  0.3 mg/kg/day
  in 1 or 2 divided doses,
  rounded down to the 
  nearest whole tablet 
  (see Table 3 for weight 
  based dosing guide).
  0.6 mg/kg/day
  in 2 divided doses,
  rounded down to the 
  nearest whole tablet.
  1.2 mg/kg/day
  in 2 divided doses, 
  rounded down to the 
  nearest whole tablet.
  Weeks 5 
  onwards to 
  maintenance
  The dose should be increased every 
  1 to 2 weeks as follows:
  calculate 0.3 mg/kg/day, round this amount 
  down to the nearest whole tablet, and 
  add this amount to the 
  previously administered daily dose.
  The dose should be increased every 
  1 to 2 weeks as follows:
  calculate 0.6 mg/kg/day, round this amount 
  down to the nearest whole tablet, and 
  add this amount to the 
  previously administered daily dose
  The dose should be increased every 
  1 to 2 weeks as follows:
  calculate 1.2 mg/kg/day, round this amount 
  down to the nearest whole tablet, and 
  add this amount to the 
  previously administered daily dose
  Usual 
  Maintenance 
  Dose
  1 to 5 mg/kg/day
  (maximum 200 mg/day 
  in 1 or 2 divided doses).
  1 to 3 mg/kg/day with valproate alone
  4.5 to 7.5 mg/kg/day
  (maximum 300 mg/day 
  in 2 divided doses)
  5 to 15 mg/kg/day
  (maximum 400 mg/day 
  in 2 divided doses)
  Maintenance dose in 
  patients 
  less than 30 kg
  May need to be increased 
  by as much as 50%, 
  based on clinical response
  May need to be increased 
  by as much as 50%, 
  based on clinical response
  May need to be increased 
  by as much as 50%, based 
  on clinical response
  Table 3. The Initial Weight-Based Dosing Guide for Patients 2 to 12 Years Taking Valproate (Weeks 1 to 4) With Epilepsy If the patient’s weight is
  Give this daily dose, using the most appropriate combination of Lamotrigine 2-mg and 5-mg tablets
  Greater than
  And less than
  Weeks 1 and 2
  Weeks 3 and 4
  6.7 kg
  14 kg
  2 mg every other day
  2 mg every day
  14.1 kg
  27 kg
  2 mg every day
  4 mg every day
  27.1 kg
  34 kg
  4 mg every day
  8 mg every day
  34.1 kg
  40 kg
  5 mg every day
  10 mg every day
  

  Usual Adjunctive Maintenance Dose for Epilepsy: The usual maintenance doses identified in Tables 1 and 2 are derived from dosing regimens employed in the placebo-controlled adjunctive studies in which the efficacy of lamotrigine tablets was established. In patients receiving multidrug regimens employing carbamazepine, phenytoin, phenobarbital, or primidone without valproate, maintenance doses of adjunctive lamotrigine tablets as high as 700 mg/day have been used. In patients receiving valproate alone, maintenance doses of adjunctive lamotrigine tablets as high as 200 mg/day have been used. The advantage of using doses above those recommended in Tables 1 through 4 has not been established in controlled trials.

  2.3 Epilepsy – Conversion From Adjunctive Therapy to Monotherapy

  The goal of the transition regimen is to effect the conversion to monotherapy with lamotrigine tablets under conditions that ensure adequate seizure control while mitigating the risk of serious rash associated with the rapid titration of lamotrigine tablets.

  The recommended maintenance dose of lamotrigine tablets as monotherapy is 500 mg/day given in two divided doses.

  To avoid an increased risk of rash, the recommended initial dose and subsequent dose escalations of lamotrigine tablets should not be exceeded [see Boxed Warning].

  Conversion From Adjunctive Therapy With Carbamazepine, Phenytoin, Phenobarbital, or Primidone to Monotherapy With Lamotrigine Tablets: After achieving a dose of 500 mg/day of lamotrigine tablets according to the guidelines in Table 1, the concomitant AED should be withdrawn by 20% decrements each week over a 4-week period. The regimen for the withdrawal of the concomitant AED is based on experience gained in the controlled monotherapy clinical trial.

  Conversion from Adjunctive Therapy With Valproate to Monotherapy With Lamotrigine Tablets:

  The conversion regimen involves 4 steps outlined in Table 4.

  Table 4. Conversion From Adjunctive Therapy With Valproate to Monotherapy With Lamotrigine Tablets in Patients ≥16 Years of Age with Epilepsy
  Lamotrigine Tablets
  Valproate
  Step 1
  Achieve a dose of 200 mg/day according to
  guidelines in Table 1
  (if not already on 200 mg/day).
  Maintain previous stable dose.
  Step 2
  Maintain at 200 mg/day.
  Decrease to 500 mg/day by decrements no greater than
  500 mg/day/week and then maintain the dose of
  500 mg/day for 1 week.
  Step 3
  Increase to 300 mg/day and maintain for 1 week.
  Simultaneously decrease to
  250 mg/day and maintain for 1 week.
  Step 4
  Increase by 100 mg/day every
  week to achieve maintenance dose of 500 mg/day.
  Discontinue.
  

  Conversion from Adjunctive Therapy With AEDs Other Than Carbamazepine, Phenytoin, Phenobarbital, Primidone, or Valproate to Monotherapy With Lamotrigine Tablets: No specific dosing guidelines can be provided for conversion to monotherapy with lamotrigine tablets with AEDs other than carbamazepine, phenobarbital, phenytoin, primidone, or valproate.

  2.4 Bipolar Disorder

  The goal of maintenance treatment with lamotrigine tablets is to delay the time to occurrence of mood episodes (depression, mania, hypomania, mixed episodes) in patients treated for acute mood episodes with standard therapy. The target dose of lamotrigine tablets is 200 mg/day (100 mg/day in patients taking valproate, which decreases the apparent clearance of lamotrigine, and 400 mg/day in patients not taking valproate and taking either carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin that increase the apparent clearance of lamotrigine). In the clinical trials, doses up to 400 mg/day as monotherapy were evaluated; however, no additional benefit was seen at 400 mg/day compared with 200 mg/day [see Clinical Studies (14.2) ]. Accordingly, doses above 200 mg/day are not recommended. Treatment with lamotrigine tablets is introduced, based on concurrent medications, according to the regimen outlined in Table 5. If other psychotropic medications are withdrawn following stabilization, the dose of lamotrigine tablets should be adjusted. For patients discontinuing valproate, the dose of lamotrigine tablets should be doubled over a 2-week period in equal weekly increments (see Table 6). For patients discontinuing carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin that induce lamotrigine glucuronidation, the dose of lamotrigine tablets should remain constant for the first week and then should be decreased by half over a 2-week period in equal weekly decrements (see Table 6). The dose of lamotrigine tablets may then be further adjusted to the target dose (200 mg) as clinically indicated.

  If other drugs are subsequently introduced, the dose of lamotrigine tablets may need to be adjusted. In particular, the introduction of valproate requires reduction in the dose of lamotrigine tablets [see Drug Interactions (7) , Clinical Pharmacology (12.3) ].

  To avoid an increased risk of rash, the recommended initial dose and subsequent dose escalations of lamotrigine tablets should not be exceeded [see Boxed Warning ].

  Table 5. Escalation Regimen for Lamotrigine Tablets for Patients With Bipolar Disorder

  a Valproate has been shown to inhibit glucuronidation and decrease the apparent clearance of lamotrigine [see Drug Interactions (7), Clinical Pharmacology (12.3)].

  
  

  b These drugs induce lamotrigine glucuronidation and increase clearance [see Drug Interactions (7), Clinical Pharmacology (12.3)]. Other drugs which have similar effects include estrogen-containing oral contraceptives [see Drug Interactions (7), Clinical Pharmacology (12.3)]. Dosing recommendations for oral contraceptives can be found in General Dosing Considerations [see Dosage and Administration (2.1)]. Patients on rifampin, or other drugs that induce lamotrigine glucuronidation and increase clearance, should follow the same dosing titration/maintenance regimen as that used with anticonvulsants that have this effect.

  
  For Patients TAKING 
  Valproatea
  For Patients NOT TAKING 
  Carbamazepine, Phenytoin, Phenobarbital, 
  Primidoneb, or Valproatea
  For Patients TAKING 
  Carbamazepine, Phenytoin,
  Phenobarbital, or Primidoneb and NOT TAKING 
  Valproatea
  Weeks 1 and 2
  25 mg every 
  other day
  25 mg daily
  50 mg daily
  Weeks 3 and 4
  25 mg daily
  50 mg daily
  100 mg daily, in divided doses
  Week 5
  50 mg daily
  100 mg daily
  200 mg daily, in divided doses
  Week 6
  100 mg daily
  200 mg daily
  300 mg daily, in divided doses
  Week 7
  100 mg daily
  200 mg daily
  up to 400 mg daily, in divided doses
  Table 6. Dosage Adjustments to Lamotrigine Tablets for Patients With Bipolar Disorder Following Discontinuation of Psychotropic Medications
  Discontinuation of Psychotropic Drugs 
  (excluding Carbamazepine, Phenytoin, 
  Phenobarbital, Primidoneb, or 
  Valproatea)
  After Discontinuation of 
  Valproatea
  After Discontinuation of 
  Carbamazepine, Phenytoin, 
  Phenobarbital, or Primidoneb
  
  
  Current dose of lamotrigine tablets
  (mg/day)
  100
  Current dose of lamotrigine tablets
  (mg/day)
  400
  

  a Valproate has been shown to inhibit glucuronidation and decrease the apparent clearance of lamotrigine [see Drug Interactions (7), Clinical Pharmacology (12.3)].

  
  

  b These drugs induce lamotrigine glucuronidation and increase clearance [see Drug Interactions (7), Clinical Pharmacology (12.3)]. Other drugs which have similar effects include estrogen-containing oral contraceptives [see Drug Interactions (7), Clinical Pharmacology (12.3)]. Dosing recommendations for oral contraceptives can be found in General Dosing Considerations [see Dosage and Administration (2.1)]. Patients on rifampin, or other drugs that induce lamotrigine glucuronidation and increase clearance, should follow the same dosing titration/maintenance regimen as that used with anticonvulsants that have this effect.

  Week 1
  Maintain current dose of lamotrigine tablets
  150
  400
  Week 2
  Maintain current dose of lamotrigine tablets
  200
  300
  Week 3 onward
  Maintain current dose of lamotrigine tablets
  200
  200
  

  The benefit of continuing treatment in patients who had been stabilized in an 8- to 16-week open-label phase with lamotrigine tablets was established in two randomized, placebo-controlled clinical maintenance trials [see Clinical Studies (14.2) ]. However, the optimal duration of treatment with lamotrigine tablets has not been established. Thus, patients should be periodically reassessed to determine the need for maintenance treatment.

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  2.1 General Dosing Considerations 

  Rash: There are suggestions, yet to be proven, that the risk of severe, potentially life-threatening rash may be increased by (1) coadministration of lamotrigine tablets with valproate, (2) exceeding the recommended initial dose of lamotrigine tablets, or (3) exceeding the recommended dose escalation for lamotrigine tablets. However, cases have occurred in the absence of these factors [see Boxed Warning]. Therefore, it is important that the dosing recommendations be followed closely.

  The risk of nonserious rash may be increased when the recommended initial dose and/or the rate of dose escalation of lamotrigine tablets is exceeded and in patients with a history of allergy or rash to other AEDs.

  It is recommended that lamotrigine tablets not be restarted in patients who discontinued due to rash associated with prior treatment with lamotrigine, unless the potential benefits clearly outweigh the risks. If the decision is made to restart a patient who has discontinued lamotrigine, the need to restart with the initial dosing recommendations should be assessed. The greater the interval of time since the previous dose, the greater consideration should be given to restarting with the initial dosing recommendations. If a patient has discontinued lamotrigine for a period of more than 5 half-lives, it is recommended that initial dosing recommendations and guidelines be followed. The half-life of lamotrigine is affected by other concomitant medications [see Clinical Pharmacology (12.3)].

  Lamotrigine Added to Drugs Known to Induce or Inhibit Glucuronidation: Drugs other than those listed in the Clinical Pharmacology section [see Clinical Pharmacology (12.3)] have not been systematically evaluated in combination with lamotrigine. Because lamotrigine is metabolized predominantly by glucuronic acid conjugation, drugs that are known to induce or inhibit glucuronidation may affect the apparent clearance of lamotrigine and doses of lamotrigine tablets may require adjustment based on clinical response.

  Target Plasma Levels for Patients With Epilepsy or Bipolar Disorder: A therapeutic plasma concentration range has not been established for lamotrigine. Dosing of lamotrigine tablets should be based on therapeutic response [see Clinical Pharmacology (12.3)].

  Women Taking Estrogen-Containing Oral Contraceptives:  Starting Lamotrigine Tablets in Women Taking Estrogen-Containing Oral Contraceptives: Although estrogen-containing oral contraceptives have been shown to increase the clearance of lamotrigine [see Clinical Pharmacology (12.3)], no adjustments to the recommended dose-escalation guidelines for lamotrigine tablets should be necessary solely based on the use of estrogen-containing oral contraceptives. Therefore, dose escalation should follow the recommended guidelines for initiating adjunctive therapy with lamotrigine tablets based on the concomitant AED or other concomitant medications (see Table 1 or Table 5). See below for adjustments to maintenance doses of lamotrigine tablets in women taking estrogen-containing oral contraceptives.

  Adjustments to the Maintenance Dose of Lamotrigine Tablets In Women Taking Estrogen-Containing Oral Contraceptives:

  (1) Taking Estrogen-Containing Oral Contraceptives: For women not taking carbamazepine, phenytoin, phenobarbital, primidone, or rifampin, the maintenance dose of lamotrigine tablets will in most cases need to be increased, by as much as 2 fold over the recommended target maintenance dose, in order to maintain a consistent lamotrigine plasma level [see Clinical Pharmacology (12.3)].

  (2) Starting Estrogen-Containing Oral Contraceptives: In women taking a stable dose of lamotrigine tablets and not taking carbamazepine, phenytoin, phenobarbital, primidone, or rifampin, the maintenance dose will in most cases need to be increased by as much as 2 fold in order to maintain a consistent lamotrigine plasma level. The dose increases should begin at the same time that the oral contraceptive is introduced and continue, based on clinical response, no more rapidly than 50 to 100 mg/day every week. Dose increases should not exceed the recommended rate (see Table 1 or Table 5) unless lamotrigine plasma levels or clinical response support larger increases. Gradual transient increases in lamotrigine plasma levels may occur during the week of inactive hormonal preparation (“pill-free” week), and these increases will be greater if dose increases are made in the days before or during the week of inactive hormonal preparation. Increased lamotrigine plasma levels could result in additional adverse reactions, such as dizziness, ataxia, and diplopia. If adverse reactions attributable to lamotrigine tablets consistently occur during the “pill-free” week, dose adjustments to the overall maintenance dose may be necessary. Dose adjustments limited to the “pill-free” week are not recommended. For women taking lamotrigine tablets in addition to carbamazepine, phenytoin, phenobarbital, primidone, or rifampin, no adjustment should be necessary to the dose of lamotrigine tablets.

  (3) Stopping Estrogen-Containing Oral Contraceptives: For women not taking carbamazepine, phenytoin, phenobarbital, primidone, or rifampin, the maintenance dose of lamotrigine tablets will in most cases need to be decreased by as much as 50% in order to maintain a consistent lamotrigine plasma level. The decrease in dose of lamotrigine tablets should not exceed 25% of the total daily dose per week over a 2 week period, unless clinical response or lamotrigine plasma levels indicate otherwise [see Clinical Pharmacology (12.3)]. For women taking lamotrigine tablets in addition to carbamazepine, phenytoin, phenobarbital, primidone, or rifampin, no adjustment to the dose of lamotrigine tablets should be necessary.

  Women and Other Hormonal Contraceptive Preparations or Hormone Replacement Therapy: The effect of other hormonal contraceptive preparations or hormone replacement therapy on the pharmacokinetics of lamotrigine has not been systematically evaluated. It has been reported that ethinylestradiol, not progestogens, increased the clearance of lamotrigine up to 2 fold, and the progestin-only pills had no effect on lamotrigine plasma levels. Therefore, adjustments to the dosage of lamotrigine tablets in the presence of progestogens alone will likely not be needed.

  Patients With Hepatic Impairment: Experience in patients with hepatic impairment is limited. Based on a clinical pharmacology study in 24 patients with mild, moderate, and severe liver impairment [see Use in Specific Populations (8.6), Clinical Pharmacology (12.3)], the following general recommendations can be made. No dosage adjustment is needed in patients with mild liver impairment. Initial, escalation, and maintenance doses should generally be reduced by approximately 25% in patients with moderate and severe liver impairment without ascites and 50% in patients with severe liver impairment with ascites. Escalation and maintenance doses may be adjusted according to clinical response.

  Patients With Renal Impairment: Initial doses of lamotrigine tablets should be based on patients' concomitant medications (see Tables 1 to 3 or Table 5); reduced maintenance doses may be effective for patients with significant renal impairment [see Use in Specific Populations (8.7), Clinical Pharmacology (12.3)]. Few patients with severe renal impairment have been evaluated during chronic treatment with lamotrigine tablets. Because there is inadequate experience in this population, lamotrigine tablets should be used with caution in these patients.

  Discontinuation Strategy:  Epilepsy: For patients receiving lamotrigine tablets in combination with other AEDs, a re-evaluation of all AEDs in the regimen should be considered if a change in seizure control or an appearance or worsening of adverse reactions is observed.

  If a decision is made to discontinue therapy with lamotrigine tablets, a step-wise reduction of dose over at least 2 weeks (approximately 50% per week) is recommended unless safety concerns require a more rapid withdrawal [see Warnings and Precautions (5.9)].

  Discontinuing carbamazepine, phenytoin, phenobarbital, or primidone should prolong the half-life of lamotrigine; discontinuing valproate should shorten the half-life of lamotrigine.

  Bipolar Disorder: In the controlled clinical trials, there was no increase in the incidence, type, or severity of adverse reactions following abrupt termination of lamotrigine tablets. In clinical trials in patients with Bipolar Disorder, 2 patients experienced seizures shortly after abrupt withdrawal of lamotrigine tablets. However, there were confounding factors that may have contributed to the occurrence of seizures in these bipolar patients. Discontinuation of lamotrigine tablets should involve a step-wise reduction of dose over at least 2 weeks (approximately 50% per week) unless safety concerns require a more rapid withdrawal [see Warnings and Precautions (5.9)].

  2.2 Epilepsy – Adjunctive Therapy

  This section provides specific dosing recommendations for patients greater than 12 years of age and patients 2 to 12 years of age. Within each of these age-groups, specific dosing recommendations are provided depending upon concomitant AED or other concomitant medications (Table 1 for patients greater than 12 years of age and Table 2 for patients 2 to 12 years of age). A weight-based dosing guide for patients 2 to 12 years of age on concomitant valproate is provided in Table 3.

  Patients Over 12 Years of Age: Recommended dosing guidelines are summarized in Table 1.

  Table 1. Escalation Regimen for Lamotrigine in Patients Over 12 Years of Age With Epilepsy * Valproate has been shown to inhibit glucuronidation and decrease the apparent clearance of lamotrigine [ see Drug Interactions (7), Pharmacokinetics (12.3)] . † These drugs induce glucuronidation and increase clearance [ see Drug Interactions (7) Pharmacokinetics (12.3)]. Other drugs, which have similar effects include estrogen-containing oral contraceptives and rifampin [ see Drug Interactions (7), Pharmacokinetics (12.3)] . Dosing recommendations for oral contraceptives can be found in General Dosing Considerations [ see Dosage and Administration (2.1)] . Patients on rifampin should follow the same dosing titration/maintenance regimen used with drugs that induce glucuronidation and increase clearance. For Patients Taking Valproate* For Patients Taking AEDs Other Than Carbamazepine, Phenytoin, Phenobarbital, or Primidone†, and Not Taking Valproate For Patients Taking Carbamazepine, Phenytoin, Phenobarbital, or Primidone† and Not Taking Valproate Weeks 1 and 2 25 mg every other day 25 mg every day 50 mg/day Weeks 3 and 4 25 mg every day 50 mg/day 100 mg/day (in 2 divided doses) Weeks 5 onwards to maintenance Increase by 25 to 50 mg/day every 1 to 2 weeks Increase by 50 mg/day every 1 to 2 weeks Increase by 100 mg/day every 1 to 2 weeks Usual Maintenance Dose

  100 to 200 mg/day with valproate alone

  100 to 400 mg/day with valproate and other drugs that induce glucuronication

  (in 1 or 2 divided doses)

  225 to 375 mg/day (in 2 divided doses)

  300 to 500 mg/day

   (in 2 divided doses)

  Patients 2 to 12 Years of Age: Recommended dosing guidelines are summarized in Table 2.

  Smaller starting doses and slower dose escalations than those used in clinical trials are recommended because of the suggestion that the risk of rash may be decreased by smaller starting doses and slower dose escalations. Therefore, maintenance doses will take longer to reach in clinical practice than in clinical trials. It may take several weeks to months to achieve an individualized maintenance dose. Maintenance doses in patients weighing less than 30 kg, regardless of age or concomitant AED, may need to be increased as much as 50%, based on clinical response.

  Table 2. Escalation Regimen for Lamotrigine in Patients 2 to 12 Years of Age With Epilepsy * Valproate has been shown to inhibit glucuronidation and decrease the apparent clearance of lamotrigine [ see Drug Interactions (7), Pharmacokinetics (12.3)] . † These drugs induce glucuronidation and increase clearance [see Drug Interactions (7) Pharmacokinetics (12.3)]. Other drugs, which have similar effects include estrogen-containing oral contraceptives and rifampin [ see Drug Interactions (7), Pharmacokinetics (12.3)] . Dosing recommendations for oral contraceptives can be found in General Dosing Considerations [ see Dosage and Administration (2.1)] . Patients on rifampin should follow the same dosing titration/maintenance regimen used with drugs that induce glucuronidation. For Patients Taking Valproate* For Patients Taking AEDs Other Than Carbamazepine, Phenytoin, Phenobarbital, or Primidone†, and Not Taking Valproate For Patients Taking Carbamazepine, Phenytoin, Phenobarbital, or Primidone† and Not Taking Valproate Weeks 1 and 2 0.15 mg/kg/day in 1 or 2 divided doses, rounded down to the nearest whole tablet (see Table 3 for weight based dosing guide) 0.3 mg/kg/day in 1 or 2 divided doses, rounded down to the nearest whole tablet 0.6 mg/kg/day in 2 divided doses, rounded down to the nearest whole tablet Weeks 3 and 4 0.3 mg/kg/day in 1 or 2 divided doses, rounded down to the nearest whole tablet (see Table 3 for weight based dosing guide) 0.6 mg/kg/day in 2 divided doses, rounded down to the nearest whole tablet 1.2 mg/kg/day in 2 divided doses, rounded down to the nearest whole tablet Weeks 5 onwards to maintenance The dose should be increased every 1 to 2 weeks as follows: calculate 0.3 mg/kg/day, round this amount down to the nearest whole tablet, and add this amount to the previously administered daily dose The dose should be increased every 1 to 2 weeks as follows: calculate 0.6 mg/kg/day, round this amount down to the nearest whole tablet, and add this amount to the previously administered daily dose The dose should be increased every 1 to 2 weeks as follows: calculate 1.2 mg/kg/day, round this amount down to the nearest whole tablet, and add this amount to the previously administered daily dose Usual Maintenance Dose 1 to 5 mg/kg/day (maximum 200 mg/day in 1 or 2 divided doses).
  1 to 3 mg/kg/day with valproate alone 4.5 to 7.5 mg/kg/day (maximum 300 mg/day in 2 divided doses) 5 to 15 mg/kg/day (maximum 400 mg/day in 2 divided doses) Maintenance dose in patients less than 30 kg May need to be increased by as much as 50%, based on clinical response May need to be increased by as much as 50%, based on clinical response May need to be increased by as much as 50%, based on clinical response

  NOTE: Only whole tablets should be used for dosing.

  Table 3. The Initial Weight-Based Dosing Guide for Patients 2 to 12 Years Taking Valproate (Weeks 1 to 4) With Epilepsy If the patient’s weight is Give this daily dose, using the most appropriate combination of lamotrigine 2 mg and 5 mg tablets Greater than And less than Weeks 1 and 2 Weeks 3 and 4 6.7 kg 14 kg 2 mg every other day 2 mg every day 14.1 kg 27 kg 2 mg every day 4 mg every day 27.1 kg 34 kg 4 mg every day 8 mg every day 34.1 kg 40 kg 5 mg every day 10 mg every day

  Usual Adjunctive Maintenance Dose for Epilepsy: The usual maintenance doses identified in Tables 1 and 2 are derived from dosing regimens employed in the placebo-controlled adjunctive studies in which the efficacy of lamotrigine tablets was established. In patients receiving multidrug regimens employing carbamazepine, phenytoin, phenobarbital, or primidone without valproate, maintenance doses of adjunctive lamotrigine tablets as high as 700 mg/day have been used. In patients receiving valproate alone, maintenance doses of adjunctive lamotrigine tablets as high as 200 mg/day have been used. The advantage of using doses above those recommended in Tables 1 through 4 has not been established in controlled trials.

  2.3 Epilepsy – Conversion From Adjunctive Therapy to Monotherapy

  The goal of the transition regimen is to effect the conversion to monotherapy with lamotrigine tablets under conditions that ensure adequate seizure control while mitigating the risk of serious rash associated with the rapid titration of lamotrigine tablets.

  The recommended maintenance dose of lamotrigine tablets as monotherapy is 500 mg/day given in 2 divided doses.

  To avoid an increased risk of rash, the recommended initial dose and subsequent dose escalations of lamotrigine tablets should not be exceeded [see Boxed Warning].

  Conversion From Adjunctive Therapy With Carbamazepine, Phenytoin, Phenobarbital, or Primidone to Monotherapy With Lamotrigine Tablets: After achieving a dose of 500 mg/day of lamotrigine tablets according to the guidelines in Table 1, the concomitant AED should be withdrawn by 20% decrements each week over a 4 week period. The regimen for the withdrawal of the concomitant AED is based on experience gained in the controlled monotherapy clinical trial.

  Conversion from Adjunctive Therapy With Valproate to Monotherapy With Lamotrigine Tablets: The conversion regimen involves 4 steps outlined in Table 4.

  Table 4. Conversion From Adjunctive Therapy With Valproate to Monotherapy With Lamotrigine in Patients ≥ 16 Years of Age With Epilepsy   Lamotrigine Valproate Step 1 Achieve a dose of 200 mg/day according to guidelines in Table 1 (if not already on 200 mg/day). Maintain previous stable dose. Step 2 Maintain at 200 mg/day. Decrease to 500 mg/day by decrements no greater than 500 mg/day/week and then maintain the dose of 500 mg/day for 1 week. Step 3 Increase to 300 mg/day and maintain for 1 week. Simultaneously decrease to 250 mg/day and maintain for 1 week. Step 4 Increase by 100 mg/day every week to achieve maintenance dose of 500 mg/day. Discontinue.

  Conversion from Adjunctive Therapy With AEDs Other Than Carbamazepine, Phenytoin, Phenobarbital, Primidone, or Valproate to Monotherapy With Lamotrigine Tablets: No specific dosing guidelines can be provided for conversion to monotherapy with lamotrigine tablets with AEDs other than carbamazepine, phenobarbital, phenytoin, primidone, or valproate.

  2.4 Bipolar Disorder

  The goal of maintenance treatment with lamotrigine tablets is to delay the time to occurrence of mood episodes (depression, mania, hypomania, mixed episodes) in patients treated for acute mood episodes with standard therapy. The target dose of lamotrigine tablets is 200 mg/day (100 mg/day in patients taking valproate, which decreases the apparent clearance of lamotrigine, and 400 mg/day in patients not taking valproate and taking either carbamazepine, phenytoin, phenobarbital, primidone, or rifampin, which increase the apparent clearance of lamotrigine). In the clinical trials, doses up to 400 mg/day as monotherapy were evaluated; however, no additional benefit was seen at 400 mg/day compared with 200 mg/day [see Clinical Studies (14.2)]. Accordingly, doses above 200 mg/day are not recommended. Treatment with lamotrigine tablets is introduced, based on concurrent medications, according to the regimen outlined in Table 5. If other psychotropic medications are withdrawn following stabilization, the dose of lamotrigine tablets should be adjusted. For patients discontinuing valproate, the dose of lamotrigine tablets should be doubled over a 2 week period in equal weekly increments (see Table 6). For patients discontinuing carbamazepine, phenytoin, phenobarbital, primidone, or rifampin, the dose of lamotrigine tablets should remain constant for the first week and then should be decreased by half over a 2 week period in equal weekly decrements (see Table 6). The dose of lamotrigine tablets may then be further adjusted to the target dose (200 mg) as clinically indicated.

  If other drugs are subsequently introduced, the dose of lamotrigine tablets may need to be adjusted. In particular, the introduction of valproate requires reduction in the dose of lamotrigine tablets [see Drug Interactions (7), Clinical Pharmacology (12.3)].

  To avoid an increased risk of rash, the recommended initial dose and subsequent dose escalations of lamotrigine tablets should not be exceeded [see Boxed Warning].

   

  Table 5. Escalation Regimen for Lamotrigine for Patients With Bipolar Disorder* * See Drug Interactions (7) and Clinical Pharmacology (12.3) for a description of known drug interactions. † Valproate has been shown to decrease the apparent clearance of lamotrigine. ‡ Carbamazepine, phenytoin, phenobarbital, primidone, and rifampin have been shown to increase the apparent clearance of lamotrigine. For Patients Taking Valproate† For Patients Not Taking Carbamazepine, Phenytoin, Phenobarbital, Primidone, or Rifampin‡ and Not Taking Valproate† For Patients Taking Carbamazepine, Phenytoin, Phenobarbital, Primidone, or Rifampin‡ and Not Taking Valproate† Weeks 1 and 2 25 mg every other day 25 mg daily 50 mg daily Weeks 3 and 4 25 mg daily 50 mg daily 100 mg daily, in divided doses Week 5 50 mg daily 100 mg daily 200 mg daily, in divided doses Week 6 100 mg daily 200 mg daily 300 mg daily, in divided doses Week 7 100 mg daily 200 mg daily up to 400 mg daily, in divided doses Table 6. Dosage Adjustments to Lamotrigine for Patients With Bipolar Disorder Following Discontinuation of Psychotropic Medications* * See Drug Interactions (7) and Clinical Pharmacology (12.3) for a description of known drug interactions. † Carbamazepine, phenytoin, phenobarbital, primidone, and rifampin have been shown to increase the apparent clearance of lamotrigine. ‡ Valproate has been shown to decrease the apparent clearance of lamotrigine.   Discontinuation of Psychotropic Drugs (excluding Carbamazepine, Phenytoin, Phenobarbital, Primidone, Rifampin†, or Valproate‡) After Discontinuation of Valproate‡ After Discontinuation of Carbamazepine, Phenytoin, Phenobarbital, Primidone, or Rifampin† Current dose of Lamotrigine (mg/day) 100

  Current dose of Lamotrigine (mg/day)

  400

  Week 1 Maintain current dose of lamotrigine 150 400 Week 2 Maintain current dose of lamotrigine 200 300 Week 3 onward Maintain current dose of lamotrigine 200 200

  The benefit of continuing treatment in patients who had been stabilized in an 8 to 16 week open-label phase with lamotrigine tablets was established in 2 randomized, placebo-controlled clinical maintenance trials [see Clinical Studies (14.2)]. However, the optimal duration of treatment with lamotrigine tablets has not been established. Thus, patients should be periodically reassessed to determine the need for maintenance treatment.

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  2.1 General Dosing Considerations 

  : There are suggestions, yet to be proven, that the risk of severe, potentially life-threatening rash may be increased by (1) coadministration of Lamotrigine with valproate, (2) exceeding the recommended initial dose of Lamotrigine, or (3) exceeding the recommended dose escalation for Lamotrigine. However, cases have occurred in the absence of these factors . Therefore, it is important that the dosing recommendations be followed closely. Rash[seeBoxed Warning]

  The risk of nonserious rash may be increased when the recommended initial dose and/or the rate of dose escalation of Lamotrigine is exceeded and in patients with a history of allergy or rash to other AEDs.

  It is recommended that Lamotrigine not be restarted in patients who discontinued due to rash associated with prior treatment with Lamotrigine, unless the potential benefits clearly outweigh the risks. If the decision is made to restart a patient who has discontinued Lamotrigine, the need to restart with the initial dosing recommendations should be assessed. The greater the interval of time since the previous dose, the greater consideration should be given to restarting with the initial dosing recommendations. If a patient has discontinued Lamotrigine for a period of more than 5 half-lives, it is recommended that initial dosing recommendations and guidelines be followed. The half-life of Lamotrigine is affected by other concomitant medications . [see Clinical Pharmacology (12.3)]

  : Drugs other than those listed in the Clinical Pharmacology section have not been systematically evaluated in combination with Lamotrigine. Because Lamotrigine is metabolized predominantly by glucuronic acid conjugation, drugs that are known to induce or inhibit glucuronidation may affect the apparent clearance of Lamotrigine and doses of Lamotrigine may require adjustment based on clinical response. Lamotrigine Added to Drugs Known to Induce or Inhibit Glucuronidation[see Clinical Pharmacology (12.3)]

  A therapeutic plasma concentration range has not been established for Lamotrigine. Dosing of Lamotrigine should be based on therapeutic response . Target Plasma Levels for Patients With Epilepsy or Bipolar Disorder:[see Clinical Pharmacology (12.3)]

  :   Although estrogen-containing oral contraceptives have been shown to increase the clearance of Lamotrigine , no adjustments to the recommended dose-escalation guidelines for Lamotrigine should be necessary solely based on the use of estrogen-containing oral contraceptives. Therefore, dose escalation should follow the recommended guidelines for initiating adjunctive therapy with Lamotrigine based on the concomitant AED or other concomitant medications (see or ). See below for adjustments to maintenance doses of Lamotrigine in women taking estrogen-containing oral contraceptives. Women Taking Estrogen-Containing Oral ContraceptivesStarting Lamotrigine in Women Taking Estrogen-Containing Oral Contraceptives:[see Clinical Pharmacology (12.3)]Table 1Table 5

  Adjustments to the Maintenance Dose of Lamotrigine in Women Taking Estrogen-Containing Oral Contraceptives:

  For women not taking carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin that induce Lamotrigine glucuronidation , the maintenance dose of Lamotrigine will in most cases need to be increased, by as much as 2-fold over the recommended target maintenance dose, in order to maintain a consistent Lamotrigine plasma level . (1) Taking Estrogen-Containing Oral Contraceptives:[see Drug Interactions ( ), 7Clinical Pharmacology ( )] 12.3[see Clinical Pharmacology (12.3)]

  In women taking a stable dose of Lamotrigine and not taking carbamazepine, phenytoin, phenobarbital, primidone, or  other drugs such as rifampin that induce Lamotrigine glucuronidation the maintenance dose will in most cases need to be increased by as much as 2-fold in order to maintain a consistent Lamotrigine plasma level. The dose increases should begin at the same time that the oral contraceptive is introduced and continue, based on clinical response, no more rapidly than 50 to 100 mg/day every week. Dose increases should not exceed the recommended rate (see or ) unless Lamotrigine plasma levels or clinical response support larger increases. Gradual transient increases in Lamotrigine plasma levels may occur during the week of inactive hormonal preparation (“pill-free” week), and these increases will be greater if dose increases are made in the days before or during the week of inactive hormonal preparation. Increased Lamotrigine plasma levels could result in additional adverse reactions, such as dizziness, ataxia, and diplopia. If adverse reactions attributable to Lamotrigine consistently occur during the “pill-free” week, dose adjustments to the overall maintenance dose may be necessary. Dose adjustments limited to the “pill-free” week are not recommended. For women taking Lamotrigine in addition to carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin that induce Lamotrigine glucuronidation , no adjustment to the dose of Lamotrigine should be necessary. (2) Starting Estrogen-Containing Oral Contraceptives:[see Drug Interactions ( ), Clinical Pharmacology ( )], 712.3Table 1Table 5[see Drug Interactions ( ), Clinical Pharmacology ( )] 712.3

  For women not taking carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin that induce Lamotrigine glucuronidation , the maintenance dose of Lamotrigine will in most cases need to be decreased by as much as 50% in order to maintain a consistent Lamotrigine plasma level. The decrease in dose of Lamotrigine should not exceed 25% of the total daily dose per week over a 2-week period, unless clinical response or Lamotrigine plasma levels indicate otherwise . For women taking Lamotrigine in addition to carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin that induce Lamotrigine glucuronidation , no adjustment to the dose of Lamotrigine should be necessary. (3) Stopping Estrogen-Containing Oral Contraceptives:[see Drug Interactions ( ), Clinical Pharmacology ( )] 712.3[see Clinical Pharmacology ( )] 12.3[see Drug Interactions ( ), Clinical Pharmacology ( )] 712.3

  : The effect of other hormonal contraceptive preparations or hormone replacement therapy on the pharmacokinetics of Lamotrigine has not been systematically evaluated. It has been reported that ethinylestradiol, not progestogens, increased the clearance of Lamotrigine up to 2-fold, and the progestin-only pills had no effect on Lamotrigine plasma levels. Therefore, adjustments to the dosage of Lamotrigine in the presence of progestogens alone will likely not be needed. Women and Other Hormonal Contraceptive Preparations or Hormone Replacement Therapy

  : Experience in patients with hepatic impairment is limited. Based on a clinical pharmacology study in 24 patients with mild, moderate, and severe liver impairment , the following general recommendations can be made. No dosage adjustment is needed in patients with mild liver impairment. Initial, escalation, and maintenance doses should generally be reduced by approximately 25% in patients with moderate and severe liver impairment without ascites and 50% in patients with severe liver impairment with ascites. Escalation and maintenance doses may be adjusted according to clinical response. Patients With Hepatic Impairment[see Use in Specific Populations (8.6), Clinical Pharmacology (12.3)]

  : Initial doses of Lamotrigine should be based on patients' concomitant medications (see or ); reduced maintenance doses may be effective for patients with significant renal impairment . Few patients with severe renal impairment have been evaluated during chronic treatment with Lamotrigine. Because there is inadequate experience in this population, Lamotrigine should be used with caution in these patients. Patients With Renal ImpairmentTables 1-3Table 5[see Use in Specific Populations (8.7), Clinical Pharmacology (12.3)]

  :   For patients receiving Lamotrigine in combination with other AEDs, a re-evaluation of all AEDs in the regimen should be considered if a change in seizure control or an appearance or worsening of adverse experiences is observed. Discontinuation StrategyEpilepsy:

  If a decision is made to discontinue therapy with Lamotrigine, a step-wise reduction of dose over at least 2 weeks (approximately 50% per week) is recommended unless safety concerns require a more rapid withdrawal [see Warnings and Precautions (5.9)].

  Discontinuing carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin that induce Lamotrigine glucuronidation should prolong the half-life of Lamotrigine; discontinuing valproate should shorten the half-life of Lamotrigine.

  In the controlled clinical trials, there was no increase in the incidence, type, or severity of adverse reactions following abrupt termination of Lamotrigine. In clinical trials in patients with Bipolar Disorder, 2 patients experienced seizures shortly after abrupt withdrawal of Lamotrigine. However, there were confounding factors that may have contributed to the occurrence of seizures in these bipolar patients. Discontinuation of Lamotrigine should involve a step-wise reduction of dose over at least 2 weeks (approximately 50% per week) unless safety concerns require a more rapid withdrawal . Bipolar Disorder:[see Warnings and Precautions (5.9)]

  2.2 Epilepsy – Adjunctive Therapy

  This section provides specific dosing recommendations for patients greater than 12 years of age and patients 2 to 12 years of age. Within each of these age-groups, specific dosing recommendations are provided depending upon concomitant AED or other concomitant medications ( for patients greater than 12 years of age and for patients 2 to 12 years of age). A weight-based dosing guide for patients 2 to 12 years of age on concomitant valproate is provided in . Table 1Table 2Table 3

  Recommended dosing guidelines are summarized in . Patients Over 12 Years of Age:Table 1

  Table 1. Escalation Regimen for Lamotrigine in Patients Over 12 Years of Age With Epilepsy  * Valproate has been shown to inhibit glucuronidation and decrease the apparent clearance of Lamotrigine [see Drug Interactions ( 7 ), Clinical Pharmacology  ( 12.3 )]. † These drugs induce Lamotrigine glucuronidation and increase clearance Other drugs, which have similar effects include estrogen-containing oral contraceptives Dosing recommendations for oral contraceptives can be found in General Dosing Considerations Patients on rifampin, or other drugs that induce Lamotrigine glucuronidation and increase clearance, should follow the same dosing titration/maintenance regimen as that used with anticonvulsants that have this effect. [see Drug Interactions ( 7 ) Clinical Pharmacology ( 12.3 )]. [see Drug Interactions ( 7 ), Clinical Pharmacology  ( 12.3 )]. [see Dosage and Administration ( 2.1 )].   For Patients TAKING Valproate * For Patients NOT TAKING Carbamazepine, Phenytoin, Phenobarbital, Primidone ,or Valproate †* For Patients TAKING Carbamazepine, Phenytoin, Phenobarbital, or Primidone and NOT TAKING Valproate †* Weeks 1 and 2 25 mg every day other 25 mg every day 50 mg/day Weeks 3 and 4 25 mg every day 50 mg/day (in 2 divided doses) 100 mg/day Weeks 5 onwards to maintenance Increase by 25 to 50 mg/day every 1 to 2 weeks Increase by 50 mg/day every 1 to 2 weeks
  Increase by 100 mg/day every 1 to 2 weeks Usual Maintenance Dose (in 1 or 2 divided doses) 100 to 200 mg/day with valproate alone
  
  100 to 400 mg/day with valproate and other drugs that induce glucuronication
  (in 2 divided doses) 225 to 375 mg/day
   (in 2 divided doses) 300 to 500 mg/day

  Recommended dosing guidelines are summarized in . Patients 2 to 12 Years of Age:Table 2

  Smaller starting doses and slower dose escalations than those used in clinical trials are recommended because of the suggestion that the risk of rash may be decreased by smaller starting doses and slower dose escalations. Therefore, maintenance doses will take longer to reach in clinical practice than in clinical trials. It may take several weeks to months to achieve an individualized maintenance dose. Maintenance doses in patients weighing less than 30 kg, regardless of age or concomitant AED, may need to be increased as much as 50%, based on clinical response. 

  Table 2. Escalation Regimen for Lamotrigine in Patients 2 to 12 Years of Age With Epilepsy * Valproate has been shown to inhibit glucuronidation and decrease the apparent clearance of Lamotrigine [see Drug Interactions ( ), Clinical Pharmacology  ( )]. 712.3 † These drugs induce Lamotrigine glucuronidation and increase clearance . Other drugs, which have similar effects include estrogen-containing oral contraceptives . Dosing recommendations for oral contraceptives can be found in Patients on rifampin, or other drugs that induce Lamotrigine glucuronidation and increase clearance, should follow the same dosing titration/maintenance regimen as that used with anticonvulsants that have this effect. [see Drug Interactions ( ) Clinical Pharmacology  ( )] 712.3 [see Drug Interactions ( ) Clinical Pharmacology  ( )] 712.3
  General Dosing Considerations [see Dosage and Administration ( )]. 2.1   For Patients TAKING Valproate * For Patients NOT TAKING Carbamazepine, Phenytoin, Phenobarbital,   Primidone   or  Valproate
  
  
  †
  * For Patients TAKING Carbamazepine, Phenytoin, Phenobarbital, or  Primidone and NOT TAKING Valproate †* Weeks 1 and 2  in 1 or 2 divided doses, rounded down to the nearest whole tablet (see Table 3 for weight based dosing guide) 0.15 mg/kg/day
  in 1 or 2 divided doses, rounded down to the nearest whole tablet 0.3 mg/kg/day
  in 2 divided doses, rounded down to the nearest whole tablet 0.6 mg/kg/day
  Weeks 3 and 4 in 1 or 2 divided doses, rounded down to the nearest whole tablet (see Table 3 for weight based dosing guide) 0.3 mg/kg/day
  in 2 divided doses, rounded down to the nearest whole tablet 0.6 mg/kg/day  
  in 2 divided doses, rounded down to the nearest whole tablet 1.2 mg/kg/day  
  Weeks 5 onwards to maintenance The dose should be increased every 1 to 2 weeks as follows: calculate 0.3 mg/kg/day, round this amount down to the nearest whole tablet, and add this amount to the previously administered daily dose The dose should be increased every 1 to 2 weeks as follows: calculate 0.6 mg/kg/day, round this amount down to the nearest whole tablet, and add this amount to the previously administered daily dose The dose should be increased every 1 to 2 weeks as follows: calculate 1.2 mg/kg/day, round this amount down to the nearest whole tablet, and add this amount to the previously administered daily dose Usual Maintenance Dose (maximum 200 mg/day in 1 or 2 divided doses). with valproate alone 1 to 5 mg/kg/day1 to 3 mg/kg/day
   (maximum 300 mg/day in 2 divided doses) 4.5 to 7.5 mg/kg/day
   (maximum 400 mg/day in 2 divided doses) 5 to 15 mg/kg/day
  Maintenance dose in patients less than 30 kg May need to be increased by as much as 50%, based on clinical response May need to be increased by as much as 50%, based on clinical response May need to be increased by as much as 50%, based on clinical response Note: Only whole tablets should be used for dosing. Table 3. The Initial Weight-Based Dosing Guide for Patients 2 to 12 Years Taking Valproate (Weeks 1 to 4) With Epilepsy If the patient’s weight is Give this daily dose, using the most appropriate combination of Lamotrigine 2-mg and 5-mg tablets Greater than And less than Weeks 1 and 2 Weeks 3 and 4 6.7 kg 14 kg 2 mg every day other 2 mg every day 14.1 kg 27 kg 2 mg every day 4 mg every day 27.1 kg 34 kg 4 mg every day 8 mg every day 34.1 kg 40 kg 5 mg every day 10 mg every day

  The usual maintenance doses identified in Tables and are derived from dosing regimens employed in the placebo-controlled adjunctive studies in which the efficacy of Lamotrigine was established. In patients receiving multidrug regimens employing carbamazepine, phenytoin, phenobarbital, or primidone , maintenance doses of adjunctive Lamotrigine as high as 700 mg/day have been used. In patients receiving , maintenance doses of adjunctive Lamotrigine as high as 200 mg/day have been used. The advantage of using doses above those recommended in Tables has not been established in controlled trials. Usual Adjunctive Maintenance Dose for Epilepsy:12without valproatevalproate alone1 through 4

  2.3 Epilepsy – Conversion From Adjunctive Therapy to Monotherapy

  The goal of the transition regimen is to effect the conversion to monotherapy with Lamotrigine under conditions that ensure adequate seizure control while mitigating the risk of serious rash associated with the rapid titration of Lamotrigine.

  The recommended maintenance dose of Lamotrigine as monotherapy is 500 mg/day given in 2 divided doses.

  To avoid an increased risk of rash, the recommended initial dose and subsequent dose escalations of Lamotrigine should not be exceeded . [see ] Boxed Warning

  After achieving a dose of 500 mg/day of Lamotrigine according to the guidelines in , the concomitant AED should be withdrawn by 20% decrements each week over a 4-week period. The regimen for the withdrawal of the concomitant AED is based on experience gained in the controlled monotherapy clinical trial.  Conversion From Adjunctive Therapy With Carbamazepine, Phenytoin, Phenobarbital, or Primidone to Monotherapy With Lamotrigine:Table 1

  The conversion regimen involves 4 steps outlined in . Conversion from Adjunctive Therapy With Valproate to Monotherapy With Lamotrigine:Table 4

  Table 4. Conversion From Adjunctive Therapy With Valproate to Monotherapy With Lamotrigine in Patients ≥16 Years of Age with Epilepsy

  Lamotrigine

  Valproate

  Step 1

  Achieve a dose of 200 mg/day according to guidelines in (if not already on 200 mg/day). Table 1

  Maintain previous stable dose.

  Step 2

  Maintain at 200 mg/day.

  Decrease to 500 mg/day by decrements no greater than 500 mg/day/week and then maintain the dose of 500 mg/day for 1 week.

  Step 3

  Increase to 300 mg/day and maintain for 1 week.

  Simultaneously decrease to 250 mg/day and maintain for 1 week.

  Step 4

  Increase by 100 mg/day every week to achieve maintenance dose of 500 mg/day.

  Discontinue.

  No specific dosing guidelines can be provided for conversion to monotherapy with Lamotrigine with AEDs other than carbamazepine, phenobarbital, phenytoin, primidone, or valproate. Conversion from Adjunctive Therapy With AEDs Other Than Carbamazepine, Phenytoin, Phenobarbital, Primidone, or Valproate to Monotherapy With Lamotrigine:
  

  2.4 Bipolar Disorder

  The goal of maintenance treatment with Lamotrigine is to delay the time to occurrence of mood episodes (depression, mania, hypomania, mixed episodes) in patients treated for acute mood episodes with standard therapy. The target dose of Lamotrigine is 200 mg/day (100 mg/day in patients taking valproate, which decreases the apparent clearance of Lamotrigine, and 400 mg/day in patients not taking valproate and taking either carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin, that  increase the apparent clearance of Lamotrigine). In the clinical trials, doses up to 400 mg/day as monotherapy were evaluated; however, no additional benefit was seen at 400 mg/day compared with 200 mg/day . Accordingly, doses above 200 mg/day are not recommended. Treatment with Lamotrigine is introduced, based on concurrent medications, according to the regimen outlined in . If other psychotropic medications are withdrawn following stabilization, the dose of Lamotrigine should be adjusted. For patients discontinuing valproate, the dose of Lamotrigine should be doubled over a 2-week period in equal weekly increments (see ). For patients discontinuing carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin that induce Lamotrigine glucuronidation, the dose of Lamotrigine should remain constant for the first week and then should be decreased by half over a 2-week period in equal weekly decrements (see ). The dose of Lamotrigine may then be further adjusted to the target dose (200 mg) as clinically indicated. [see Clinical Studies ( )] 14.2Table 5Table 6Table 6

  If other drugs are subsequently introduced, the dose of Lamotrigine may need to be adjusted. In particular, the introduction of valproate requires reduction in the dose of Lamotrigine  [see Drug Interactions ( ), Clinical Pharmacology ( )] 712.3.

  To avoid an increased risk of rash, the recommended initial dose and subsequent dose escalations of Lamotrigine should not be exceeded . [see ] Boxed Warning

   

  Table 5. Escalation Regimen for Lamotrigine for Patients With Bipolar Disorder * Valproate has been shown to inhibit glucuronidation and decrease the apparent clearance of Lamotrigine [see Drug Interactions ( ), Clinical Pharmacology ( )]. 712.3 † These drugs induce Lamotrigine glucuronidation and increase clearance Other drugs which have similar effects include estrogen- containing oral contraceptives . Dosing recommendations for oral contraceptives can be found in General Dosing Considerations . Patients on rifampin, or other drugs that induce Lamotrigine glucuronidation and increase clearance, should follow the same dosing titration/ maintenance regimen as that used with anticonvulsants that have this effect. [see Drug Interactions ( ), Clinical Pharmacology ( )]. 712.3 [see Drug Interactions ( ), Clinical Pharmacology ( )] 712.3
  [see Dosage and Administration ( )] 2.1 For Patients TAKING Valproate * For Patients NOT TAKING Carbamazepine, Phenytoin, Phenobarbital, Primidone , or Valproate †* For Patients TAKING Carbamazepine, Phenytoin, Phenobarbital, or Primidone and NOT TAKING Valproate †* Weeks 1 and 2 25 mg every day other 25 mg daily 50 mg daily Weeks 3 and 4 25 mg daily 50 mg daily 100 mg daily, in divided doses Week 5 50 mg daily 100 mg daily 200 mg daily, in divided doses Week 6 100 mg daily 200 mg daily 300 mg daily, in divided doses Week 7 100 mg daily 200 mg daily up to 400 mg daily, in divided doses Table 6. Dosage Adjustments to Lamotrigine for Patients With Bipolar Disorder Following Discontinuation of Psychotropic Medications * These drugs induce Lamotrigine glucuronidation and increase clearance Other drugs which have similar effects include estrogen-containing oral contraceptives . Dosing recommendations for oral contraceptives can be found in General Dosing Considerations . Patients on rifampin, or other drugs that induce Lamotrigine glucuronidation and increase clearance, should follow the same dosing titration/ maintenance regimen as that used with anticonvulsants that have this effect. [see Drug Interactions ( ), Clinical Pharmacology ( )]. 712.3 [see Drug Interactions ( ), Clinical Pharmacology ( )] 712.3 [see Dosage and Administration ( )] 2.1 † Valproate has been shown to inhibit glucuronidation and decrease the apparent clearance of Lamotrigine [see Drug Interactions ( ), Clinical Pharmacology ( )]. 712.3  

  Discontinuation of Psychotropic Drugs (excluding Carbamazepine, Phenytoin, Phenobarbital, Primidone , or Valproate ) *†

  After Discontinuation of Valproate † After Discontinuation of Carbamazepine, Phenytoin, Phenobarbital, or Primidone * Current dose of Lamotrigine (mg/day) 100

  Current dose of Lamotrigine (mg/day) 400

  Week 1 Maintain current dose of Lamotrigine 150 400 Week 2 Maintain current dose of Lamotrigine 200 300 Week 3 onward Maintain current dose of Lamotrigine 200 200

  The benefit of continuing treatment in patients who had been stabilized in an 8- to 16-week open-label phase with Lamotrigine was established in 2 randomized, placebo-controlled clinical maintenance trials . However, the optimal duration of treatment with Lamotrigine has not been established. Thus, patients should be periodically reassessed to determine the need for maintenance treatment. [see Clinical Studies ( )] 14.2

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  2.1 General Dosing Considerations

  Rash: There are suggestions, yet to be proven, that the risk of severe, potentially life-threatening rash may be increased by (1) coadministration of  lamotrigine tablets (chewable, dispersible) with valproate, (2) exceeding the recommended initial dose of lamotrigine tablets (chewable, dispersible),  or (3) exceeding the recommended dose escalation for lamotrigine tablets (chewable, dispersible). However, cases have occurred in the absence of these factors [see Boxed Warning]. Therefore, it is important that the dosing recommendations be followed closely.

  The risk of nonserious rash may be increased when the recommended initial dose and/or the rate of dose escalation of lamotrigine tablets (chewable, dispersible) is exceeded and in patients with a history of allergy or rash to other AEDs.

  It is recommended that lamotrigine tablets (chewable, dispersible) not be restarted in patients who discontinued due to rash associated with prior treatment with lamotrigine, unless the potential benefits clearly outweigh the risks. If the decision is made to restart a patient who has discontinued lamotrigine, the need to restart with the initial dosing recommendations should be assessed. The greater the interval of time since the previous dose, the greater consideration should be given to restarting with the initial dosing recommendations. If a patient has discontinued lamotrigine for a period of more than 5 half-lives, it is recommended that initial dosing recommendations and guidelines be followed. The half-life of lamotrigine is affected by other concomitant medications [see Clinical Pharmacology (12.3)].

  Lamotrigine Added to Drugs Known to Induce or Inhibit Glucuronidation: Drugs other than those listed in the Clinical Pharmacology section [see Clinical Pharmacology (12.3)] have not been systematically evaluated in combination with lamotrigine. Because lamotrigine is metabolized predominantly by glucuronic acid conjugation, drugs that are known to induce or inhibit glucuronidation may affect the apparent clearance of lamotrigine and doses of lamotrigine tablets (chewable, dispersible) may require adjustment based on clinical response.

  Target Plasma Levels for Patients with Epilepsy or Bipolar Disorder: A therapeutic plasma concentration range has not been established for lamotrigine. Dosing of lamotrigine tablets (chewable, dispersible) should be based on therapeutic response [see Clinical Pharmacology (12.3)].

  Women Taking Estrogen-Containing Oral Contraceptives:

  Starting Lamotrigine in Women Taking Estrogen-Containing Oral Contraceptives: Although estrogen-containing oral contraceptives have been shown to increase the clearance of lamotrigine [see Clinical Pharmacology (12.3)], no adjustments to the recommended dose-escalation guidelines for lamotrigine tablets (chewable, dispersible)  should be necessary solely based on the use of estrogen-containing oral contraceptives. Therefore, dose escalation should follow the recommended guidelines for initiating adjunctive therapy with lamotrigine tablets (chewable, dispersible) based on the concomitant AED or other concomitant medications (see Table 1 or Table 5). See below for adjustments to maintenance doses of lamotrigine tablets (chewable, dispersible) in women taking estrogen-containing oral contraceptives.

  Adjustments to the Maintenance Dose of Lamotrigine in Women Taking Estrogen-Containing Oral Contraceptives:

  (1) Taking Estrogen-Containing Oral Contraceptives: For women not taking carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin that induce lamotrigine glucuronidation [see Drug Interactions (7), Clinical Pharmacology (12.3)], the maintenance dose of lamotrigine tablets (chewable, dispersible)  will in most cases need to be increased, by as much as 2-fold over the recommended target maintenance dose, in order to maintain a consistent lamotrigine plasma level [see Clinical Pharmacology (12.3)].

  (2) Starting Estrogen-Containing Oral Contraceptives: In women taking a stable dose of lamotrigine tablets (chewable, dispersible) and not taking carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin that induce lamotrigine glucuronidation [see Drug Interactions (7), Clinical Pharmacology (12.3)], the maintenance dose will in most cases need to be increased by as much as 2-fold in order to maintain a consistent lamotrigine plasma level. The dose increases should begin at the same time that the oral contraceptive is introduced and continue, based on clinical response, no more rapidly than 50 to 100 mg/day every week. Dose increases should not exceed the recommended rate (see Table 1 or Table 5) unless lamotrigine plasma levels or clinical response support larger increases. Gradual transient increases in lamotrigine plasma levels may occur during the week of inactive hormonal preparation (“pill-free” week), and these increases will be greater if dose increases are made in the days before or during the week of inactive hormonal preparation. Increased lamotrigine plasma levels could result in additional adverse reactions, such as dizziness, ataxia, and diplopia. If adverse reactions attributable to lamotrigine tablets (chewable, dispersible) consistently occur during the “pill-free” week, dose adjustments to the overall maintenance dose may be necessary. Dose adjustments limited to the “pill-free” week are not recommended. For women taking lamotrigine tablets (chewable, dispersible) in addition to carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin that induce lamotrigine glucuronidation [see Drug Interactions (7), Clinical Pharmacology (12.3)], no adjustment to the dose of lamotrigine tablets (chewable,dispersible) should be necessary.

  (3) Stopping Estrogen-Containing Oral Contraceptives: For women not taking carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin that induce lamotrigine glucuronidation [see Drug Interactions (7), Clinical Pharmacology (12.3)], the maintenance dose of lamotrigine tablets (chewable, dispersible) will in most cases need to be decreased by as much as 50% in order to maintain a consistent lamotrigine plasma level. The decrease in dose of lamotrigine tablets (chewable, dispersible) should not exceed 25% of the total daily dose per week over a 2-week period, unless clinical response or lamotrigine plasma levels indicate otherwise [see Clinical Pharmacology (12.3)]. For women taking lamotrigine tablets (chewable, dispersible) in addition to carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin that induce lamotrigine glucuronidation [see Drug Interactions (7), Clinical Pharmacology (12.3)], no adjustment to the dose of lamotrigine tablets (chewable, dispersible) should be necessary.

  Women and Other Hormonal Contraceptive Preparations or Hormone Replacement Therapy: The effect of other hormonal contraceptive preparations or hormone replacement therapy on the pharmacokinetics of lamotrigine has not been systematically evaluated. It has been reported that ethinylestradiol, not progestogens, increased the clearance of lamotrigine up to 2-fold, and the progestin-only pills had no effect on lamotrigine plasma levels. Therefore, adjustments to the dosage of lamotrigine tablets (chewable, dispersible) in the presence of progestogens alone will likely not be needed.

  Patients with Hepatic Impairment: Experience in patients with hepatic impairment is limited. Based on a clinical pharmacology study in 24 patients with mild, moderate, and severe liver impairment [see Use in Specific Populations (8.6), Clinical Pharmacology (12.3)], the following general recommendations can be made. No dosage adjustment is needed in patients with mild liver impairment. Initial, escalation, and maintenance doses should generally be reduced by approximately 25% in patients with moderate and severe liver impairment without ascites and 50% in patients with severe liver impairment with ascites. Escalation and maintenance doses may be adjusted according to clinical response.

  Patients with Renal Impairment: Initial doses of lamotrigine tablets (chewable, dispersible) should be based on patients' concomitant medications (see Tables 1-3 or Table 5); reduced maintenance doses may be effective for patients with significant renal impairment [see Use in Specific Populations (8.7), Clinical Pharmacology (12.3)]. Few patients with severe renal impairment have been evaluated during chronic treatment with lamotrigine tablets (chewable, dispersible). Because there is inadequate experience in this population, lamotrigine tablets (chewable, dispersible) should be used with caution in these patients.

  Discontinuation Strategy:

  Epilepsy: For patients receiving lamotrigine tablets (chewable, dispersible)  in combination with other AEDs, a re-evaluation of all AEDs in the regimen should be considered if a change in seizure control or an appearance or worsening of adverse reactions is observed.

  If a decision is made to discontinue therapy with lamotrigine tablets (chewable, dispersible), a step-wise reduction of dose over at least 2 weeks (approximately 50% per week) is recommended unless safety concerns require a more rapid withdrawal [see Warnings and Precautions (5.9)].

  Discontinuing carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin that induce lamotrigine glucuronidation should prolong the half-life of lamotrigine; discontinuing valproate should shorten the half-life of lamotrigine.

  Bipolar Disorder: In the controlled clinical trials, there was no increase in the incidence, type, or severity of adverse reactions following abrupt termination of lamotrigine tablets (chewable, dispersible). In clinical trials in patients with Bipolar Disorder, 2 patients experienced seizures shortly after abrupt withdrawal of lamotrigine tablets (chewable, dispersible). However, there were confounding factors that may have contributed to the occurrence of seizures in these bipolar patients. Discontinuation of lamotrigine tablets (chewable, dispersible) should involve a step-wise reduction of dose over at least 2 weeks (approximately 50% per week) unless safety concerns require a more rapid withdrawal [see Warnings and Precautions(5.9)].

  2.2 Epilepsy - Adjunctive Therapy

  mThis section provides specific dosing recommendations for patients greater than 12 years of age and patients 2 to 12 years of age. Within each of these age-groups, specific dosing recommendations are provided depending upon concomitant AED or other concomitant medications (Table 1 for patients greater than 12 years of age and Table 2 for patients 2 to 12 years of age). A weight-based dosing guide for patients 2 to 12 years of age on concomitant valproate is provided in Table 3.

  Patients over 12 Years of Age: Recommended dosing guidelines are summarized in Table 1.

  Table 1. Escalation Regimen for Lamotrigine in Patients Over 12 Years of Age With Epilepsy

       For Patients TAKING Valproatea For Patients NOT TAKING Carbamazepine, Phenytoin, Phenobarbital,  Primidoneb, or Valproatea FFor Patients TAKING Carbamazepine, Phenytoin, Phenobarbital, or Primidoneb and NOT TAKING Valproatea Weeks 1 and 2 25 mg every other day 25 mg every day 50 mg/day  Weeks 3 and 4 25 mg every day 50 mg/day 100 mg/day
  (in 2 divided doses) Weeks 5 onwards to maintenance Increase by 25 to 50 mg/day
  every 1 to 2 weeks Increase by 50 mg/day
  every 1 to 2 weeks  Increase by100 mg/day
  every 1 to2 weeks. Usual Maintenance Dose  100 to 200 mg/day with valproate alone 
  
  100 to 400 mg/day with valproate and other drugs that induceglucuronidation 
  
  (in 1 or 2 divided doses) 225 to 375 mg/day
  (in 2 divided doses)  300 to 500 mg/day
  (in 2 divided doses) 

  a     Valproate has been shown to inhibit glucuronidation and decrease the apparent clearance of    lamotrigine [see Drug Interactions (7), Clinical Pharmacology (12.3)].  

  b    These drugs induce lamotrigine glucuronidation and increase clearance [see Drug Interactions (7), Clinical Pharmacology (12.3)]. Other drugs which have similar effects include estrogen-containing oral contraceptives [see Drug Interactions (7), Clinical Pharmacology (12.3)]. Dosing recommendations for oral contraceptives can be found in General Dosing Considerations [see Dosage and Administration (2.1)]. Patients on rifampin or other drugs that induce lamotrigine glucuronidation and increase clearance, should follow the same dosing titration/maintenance regimen as that used with anticonvulsants that have this effect.

  Patients 2 to 12 Years of Age: Recommended dosing guidelines are summarized in Table 2.  

  Smaller starting doses and slower dose escalations than those used in clinical trials are recommended because of the suggestion that the risk of rash may be decreased by smaller starting doses and slower dose escalations. Therefore, maintenance doses will take longer to reach in clinical practice than in clinical trials. It may take several weeks to months to achieve  an individualized maintenance dose. Maintenance doses in patients weighing less than 30 kg, regardless of age or concomitant AED, may need to be increased as much as 50%, based on clinical response.

  The smallest available strength of lamotrigine tablets (chewable, dispersible) is 2 mg, and only whole tablets should be administered. If the calculated dose cannot be achieved using whole tablets, the dose should be rounded down to the nearest whole tablet [seeHow Supplied/Storage and Handling (16) and Medication Guide].

  Table 2. Escalation Regimen for Lamotrigine in Patients 2 to 12 Years of Age With Epilepsy

    For Patients TAKING Valproatea For Patients NOT TAKING Carbamazepine, Phenytoin, Phenobarbital,  Primidoneb, or Valproatea For Patients TAKING Carbamazepine, Phenytoin, Phenobarbital, or Primidoneb and NOT TAKING Valproatea Weeks 1 and 2 0.15 mg/kg/day in 1 or 2 divided doses, rounded down to the nearest whole tablet (see Table 3 for weight based dosing guide) 0.3 mg/kg/day in 1 or 2 divided doses, rounded down to the nearest whole tablet 0.6 mg/kg/day in 2 divided doses, rounded down to the nearest whole tablet Weeks 3 and 4 0.3 mg/kg/day in 1 or 2 divided doses, rounded down to the nearest whole tablet (see Table 3 for weight based dosing guide) 0.6 mg/kg/day in 2 divided doses, rounded down to the nearest whole tablet 1.2 mg/kg/day in 2 divided doses, rounded down to the nearest whole tablet Weeks 5 onwards to maintenance The dose should be increased every 1 to 2 weeks as follows: calculate 0.3 mg/kg/day, round this amount down to the nearest whole tablet, and add this amount to the previously administered daily dose The dose should be increased every 1 to 2 weeks as follows: calculate 0.6 mg/kg/day, round this amount down to the nearest whole tablet, and add this amount to the previously administered daily dose The dose should be increased every 1 to 2 weeks as follows: calculate 1.2 mg/kg/day, round this amount down to the nearest whole tablet, and add this amount to the previously administered daily dose Usual Maintenance Dose 1 to 5 mg/kg/day (maximum 200 mg/day in 1 or 2 divided doses).1 to 3 mg/kg/day with valproate alone 4.5 to 7.5 mg/kg/day(maximum 300 mg/day in 2 divided doses) 5 to 15 mg/kg/day (maximum 400 mg/day in 2 divided doses) Maintenance dose in patients less than 30 kg May need to be increased by as much as 50%, based on clinical response May need to be increased by as much as 50%, based on clinical response May need to be increased by as much as 50%, based on clinical response

  Note: Only whole tablets should be used for dosing.

  a     Valproate has been shown to inhibit glucuronidation and decrease the apparent clearance of lamotrigine [see Drug Interactions (7), Clinical Pharmacology (12.3)].  

  b     These drugs induce lamotrigine glucuronidation and increase clearance [see Drug Interactions (7), Clinical Pharmacology (12.3)]. Other drugs which have similar effects include estrogen-containing oral contraceptives [see Drug Interactions (7), Clinical Pharmacology (12.3)]. Dosing recommendations for oral contraceptives can be found in General Dosing Considerations [see Dosage and Administration (2.1)]. Patients on rifampin, or other drugs that induce lamotrigine glucuronidation and increase clearance should follow the same dosing titration/maintenance regimen as that used with anticonvulsants that have this effect.

  Table 3. The Initial Weight-Based Dosing Guide for Patients 2 to 12 Years Taking Valproate (Weeks 1 to 4) With Epilepsy

  If the patient’s weight is Give this daily dose, using the most appropriate combination of lamotrigine 2-mg and 5-mg tablets Greater than And less than Weeks 1 and 2 Weeks 3 and 4 6.7 kg 14 kg 2 mg every other day 2 mg every day 14.1 kg 27 kg 2 mg every day 4 mg every day 27.1 kg 34 kg 4 mg every day 8 mg every day 34.1 kg 40 kg 5 mg every day 10 mg every day

  Usual Adjunctive Maintenance Dose for Epilepsy: The usual maintenance doses identified in Tables 1 and 2 are derived from dosing regimens employed in the placebo-controlled adjunctive studies in which the efficacy of lamotrigine tablets (chewable, dispersible) was established. In patients receiving multidrug regimens employing carbamazepine, phenytoin, phenobarbital, or primidone without valproate, maintenance doses of adjunctive lamotrigine tablets (chewable, dispersible) as high as 700 mg/day have been used. In patients receiving valproate alone, maintenance doses of adjunctive lamotrigine tablets (chewable, dispersible) as high as 200 mg/day have been used. The advantage of using doses above those recommended in Tables 1 through 4 has not been established in controlled trials.

  2.3 Epilepsy – Conversion from Adjunctive Therapy to Monotherapy

  The goal of the transition regimen is to effect the conversion to monotherapy with lamotrigine tablets (chewable, dispersible) under conditions that ensure adequate seizure control while mitigating the risk of serious rash associated with the rapid titration of lamotrigine tablets (chewable, dispersible).

  The recommended maintenance dose of lamotrigine tablets (chewable, dispersible) as monotherapy is 500 mg/day given in 2 divided doses.

  To avoid an increased risk of rash, the recommended initial dose and subsequent dose escalations of lamotrigine tablets (chewable, dispersible) should not be exceeded [see Boxed Warning].

  Conversion from Adjunctive Therapy with Carbamazepine, Phenytoin, Phenobarbital, or Primidone to Monotherapy with Lamotrigine: After achieving a dose of 500 mg/day of lamotrigine tablets (chewable, dispersible) according to the guidelines in Table 1, the concomitant AED should be withdrawn by 20% decrements each week over a 4-week period. The regimen for the withdrawal of the concomitant AED is based on experience gained in the controlled monotherapy clinical trial.

  Conversion from Adjunctive Therapy with Valproate to Monotherapy with Lamotrigine: The conversion regimen involves 4 steps outlined in Table 4.

  Table 4. Conversion From Adjunctive Therapy With Valproate to Monotherapy With Lamotrigine in Patients ≥16 Years of Age with Epilepsy

    Lamotrigine Valproate Step 1 Achieve a dose of 200 mg/day according to guidelines in Table 1 (if not already on 200 mg/day). Maintain previous stable dose. Step 2 Maintain at 200 mg/day. Decrease to 500 mg/day by decrements no greater than 500 mg/day/week and then maintain the dose of 500 mg/day for 1 week. Step 3 Increase to 300 mg/day and maintain for 1 week. Simultaneously decrease to 250 mg/day and maintain for 1 week. Step 4 Increase by 100 mg/day every week to achieve maintenance dose of 500 mg/day. Discontinue.

  Conversion from Adjunctive Therapy with AEDs other than Carbamazepine, Phenytoin, Phenobarbital, Primidone, or Valproate to Monotherapy with Lamotrigine: No specific  dosing guidelines can be provided for conversion to monotherapy with lamotrigine tablets (chewable, dispersible) with AEDs other than carbamazepine, phenobarbital, phenytoin, primidone, or valproate.

  2.4 Bipolar Disorder

  The goal of maintenance treatment with lamotrigine tablets (chewable, dispersible) is to delay the time to occurrence of mood episodes (depression, mania, hypomania, mixed episodes) in patients treated for acute mood episodes with standard therapy. The target dose of lamotrigine tablets (chewable, dispersible)  is 200 mg/day (100 mg/day in patients taking valproate, which decreases the apparent clearance of lamotrigine, and 400 mg/day in patients not taking valproate and taking either carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin that which increase the apparent clearance of lamotrigine). In the clinical trials, doses up to 400 mg/day as monotherapy were evaluated; however, no additional benefit was seen at 400 mg/day compared with 200 mg/day [see Clinical Studies (14.2)]. Accordingly, doses above 200 mg/day are not recommended. Treatment with lamotrigine tablets (chewable, dispersible) is introduced, based on concurrent medications, according to the regimen outlined in Table 5. If other psychotropic medications are withdrawn following stabilization, the dose of lamotrigine tablets (chewable, dispersible) should be adjusted. For patients discontinuing valproate, the dose of lamotrigine tablets (chewable, dispersible) should be doubled over a 2-week period in equal weekly increments (see Table 6). For patients discontinuing carbamazepine, phenytoin, phenobarbital, primidone, or or other drugs such as rifampin that induce lamotrigine glucuronidation, the dose of lamotrigine tablets (chewable, dispersible) should remain constant for the first week and then should be decreased by half over a 2-week period in equal weekly decrements (see Table 6). The dose of lamotrigine tablets (chewable, dispersible) may then be further adjusted to the target dose (200 mg) as clinically indicated.

  If other drugs are subsequently introduced, the dose of lamotrigine tablets (chewable, dispersible) may need to be adjusted. In particular, the introduction of valproate requires reduction in the dose of lamotrigine tablets (chewable, dispersible) [see Drug Interactions (7), Clinical Pharmacology (12.3)].

  To avoid an increased risk of rash, the recommended initial dose and subsequent dose escalations of lamotrigine tablets (chewable, dispersible) should not be exceeded [see Boxed Warning].

  Table 5. Escalation Regimen for Lamotrigine for Patients With Bipolar Disorder

    For Patients TAKING Valproatea For Patients NOT TAKING Carbamazepine, Phenytoin, Phenobarbital, Primidoneb or Valproatea For Patients TAKING Carbamazepine, Phenytoin, Phenobarbital, or Primidone and NOT TAKING Valproatea Weeks 1 and 2 25 mg every other day 25 mg daily 50 mg daily Weeks 3 and 4 25 mg daily 50 mg daily 100 mg daily, in divided doses Week 5 50 mg daily 100 mg daily 200 mg daily, in divided doses Week 6 100 mg daily 200 mg daily 300 mg daily, in divided doses Week 7 100 mg daily 200 mg daily up to 400 mg daily, in divided doses

  a     Valproate has been shown to inhibit glucuronidation and decrease the apparent clearance of  lamotrigine [see Drug Interactions (7), Clinical Pharmacology (12.3)].  

  b     These drugs induce lamotrigine glucuronidation and increase clearance [see Drug Interactions 7), Clinical Pharmacology (12.3)]. Other drugs which have similar effects include estrogen-containing oral contraceptives [see Drug Interactions 7), Clinical Pharmacology (12.3)]. Dosing recommendations for oral contraceptives can be found in General Dosing Considerations [see Dosage and Administration (2.1)]. Patients on rifampin, or other drugs that induce lamotrigine glucuronidation and increase clearance, should follow the same dosing titration/maintenance regimen as that used with anticonvulsants that have this effect.

  Table 6. Dosage Adjustments to Lamotrigine for Patients With Bipolar Disorder Following Discontinuation of Psychotropic Medications

    Discontinuation of Psychotropic Drugs (excluding Carbamazepine, Phenytoin, Phenobarbital, Primidoneb ,or Valproatea) After Discontinuation of Valproatea After Discontinuation of Carbamazepine, Phenytoin, Phenobarbital, or  Primidoneb Current dose of lamotrigine (mg/day)
  100 Current dose of lamotrigine  (mg/day)
  
  400 Week 1 Maintain current dose of lamotrigine 150 400 Week 2 Maintain current dose of lamotrigine 200 300 Week 3 onward Maintain current dose of lamotrigine 200 200

  a     Valproate has been shown to inhibit glucuronidation and decrease the apparent clearance of  lamotrigine [see Drug Interactions (7), Clinical Pharmacology (12.3)].  

  b     These drugs induce lamotrigine glucuronidation and increase clearance [see Drug Interactions 7), Clinical Pharmacology (12.3)]. Other drugs which have similar effects include estrogen-containing oral contraceptives [see Drug Interactions 7), Clinical Pharmacology (12.3)]. Dosing recommendations for oral contraceptives can be found in General Dosing Considerations [see Dosage and Administration (2.1)]. Patients on rifampin, or other drugs that induce lamotrigine glucuronidation and increase clearance, should follow the same dosing titration/maintenance regimen as that used with anticonvulsants that have this effect.

  The benefit of continuing treatment in patients who had been stabilized in an 8- to 16-week open-label phase with lamotrigine tablets (chewable, dispersible) was established in 2 randomized, placebo-controlled clinical maintenance trials [see Clinical Studies(14.2)]. However, the optimal duration of treatment with lamotrigine tablets (chewable, dispersible) has not been established. Thus, patients should be periodically reassessed to determine the need for maintenance treatment.

  2.5 Administration of Lamotrigine Tablets (chewable, dispersible)

  Lamotrigine tablets (chewable, dispersible) may be swallowed whole, chewed, or dispersed in water or diluted fruit juice. If the tablets are chewed, consume a small amount of water or diluted fruit juice to aid in swallowing.

  To disperse lamotrigine tablets (chewable, dispersible), add the tablets to a small amount of liquid (1 teaspoon, or enough to cover the medication). Approximately 1 minute later, when the tablets are completely dispersed, swirl the solution and consume the entire quantity immediately. No attempt should be made to administer partial quantities of the dispersed tablets.

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  2.1 General Dosing Considerations

  Rash: There are suggestions, yet to be proven, that the risk of severe, potentially life-threatening rash may be increased by (1) coadministration of  lamotrigine tablets with valproate, (2) exceeding the recommended initial dose of lamotrigine tablets,  or (3) exceeding the recommended dose escalation for lamotrigine tablets. However, cases have occurred in the absence of these factors [see Boxed Warning]. Therefore, it is important that the dosing recommendations be followed closely. 

  The risk of nonserious rash may be increased when the recommended initial dose and/or the rate of dose escalation of lamotrigine tablets is exceeded and in patients with a history of allergy or rash to other AEDs. 

  It is recommended that lamotrigine tablets not be restarted in patients who discontinued due to rash associated with prior treatment with lamotrigine, unless the potential benefits clearly outweigh the risks. If the decision is made to restart a patient who has discontinued lamotrigine, the need to restart with the initial dosing recommendations should be assessed. The greater the interval of time since the previous dose, the greater consideration should be given to restarting with the initial dosing recommendations. If a patient has discontinued lamotrigine for a period of more than 5 half-lives, it is recommended that initial dosing recommendations and guidelines be followed. The half-life of lamotrigine is affected by other concomitant medications [see Clinical Pharmacology (12.3)].

  Lamotrigine Added to Drugs Known to Induce or Inhibit Glucuronidation: Drugs other than those listed in the Clinical Pharmacology section [see Clinical Pharmacology (12.3)] have not been systematically evaluated in combination with lamotrigine. Because lamotrigine is metabolized predominantly by glucuronic acid conjugation, drugs that are known to induce or inhibit glucuronidation may affect the apparent clearance of lamotrigine and doses of lamotrigine tablets may require adjustment based on clinical response.

  Target Plasma Levels for Patients with Epilepsy or Bipolar Disorder: A therapeutic plasma concentration range has not been established for lamotrigine. Dosing of lamotrigine tablets should be based on therapeutic response [see Clinical Pharmacology (12.3)]. 

  Women Taking Estrogen-Containing Oral Contraceptives: Starting Lamotrigine in Women Taking Estrogen-Containing Oral Contraceptives: Although estrogen-containing oral contraceptives have been shown to increase the clearance of lamotrigine [see Clinical Pharmacology (12.3)], no adjustments to the recommended dose-escalation guidelines for lamotrigine tablets should be necessary solely based on the use of estrogen-containing oral contraceptives. Therefore, dose escalation should follow the recommended guidelines for initiating adjunctive therapy with lamotrigine tablets based on the concomitant AED or other concomitant medications (see Table 1 or Table 5). See below for adjustments to maintenance doses of lamotrigine tablets in women taking estrogen-containing oral contraceptives. 

  Adjustments to the Maintenance Dose of Lamotrigine in Women Taking Estrogen-Containing Oral Contraceptives:(1) Taking Estrogen-Containing Oral Contraceptives: For women not taking carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin that induce lamotrigine glucuronidation [see Drug Interactions (7), Clinical Pharmacology (12.3)],   the maintenance dose of lamotrigine tablets  will in most cases need to be increased, by as much as 2-fold over the recommended target maintenance dose, in order to maintain a consistent lamotrigine plasma level [see Clinical Pharmacology (12.3)].

  (2) Starting Estrogen-Containing Oral Contraceptives: In women taking a stable dose of lamotrigine tablets and not taking carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin that induce lamotrigine glucuronidation [see Drug Interactions (7), Clinical Pharmacology (12.3)],   the maintenance dose will in most cases need to be increased by as much as 2-fold in order to maintain a consistent lamotrigine plasma level. The dose increases should begin at the same time that the oral contraceptive is introduced and continue, based on clinical response, no more rapidly than 50 to 100 mg/day every week. Dose increases should not exceed the recommended rate (see Table 1 or Table 5) unless lamotrigine plasma levels or clinical response support larger increases. Gradual transient increases in lamotrigine plasma levels may occur during the week of inactive hormonal preparation (“pill-free” week), and these increases will be greater if dose increases are made in the days before or during the week of inactive hormonal preparation. Increased lamotrigine plasma levels could result in additional adverse reactions, such as dizziness, ataxia, and diplopia. If adverse reactions attributable to lamotrigine tablets consistently occur during the “pill-free” week, dose adjustments to the overall maintenance dose may be necessary. Dose adjustments limited to the “pill-free” week are not recommended. For women taking lamotrigine tablets in addition to carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin that induce lamotrigine glucuronidation [see Drug Interactions (7), Clinical Pharmacology (12.3)],  no adjustment to the dose of lamotrigine tablets should be necessary.

  (3) Stopping Estrogen-Containing Oral Contraceptives: For women not taking carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin that induce lamotrigine glucuronidation [see Drug Interactions (7), Clinical Pharmacology (12.3)], the maintenance dose of lamotrigine tablets will in most cases need to be decreased by as much as 50% in order to maintain a consistent lamotrigine plasma level. The decrease in dose of lamotrigine tablets should not exceed 25% of the total daily dose per week over a 2-week period, unless clinical response or lamotrigine plasma levels indicate otherwise [see Clinical Pharmacology (12.3)]. For women taking lamotrigine tablets in addition to carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin that induce lamotrigine glucuronidation [see Drug Interactions (7), Clinical Pharmacology (12.3)], no adjustment to the dose of lamotrigine tablets should be necessary. 

  Women and Other Hormonal Contraceptive Preparations or Hormone Replacement Therapy: The effect of other hormonal contraceptive preparations or hormone replacement therapy on the pharmacokinetics of lamotrigine has not been systematically evaluated. It has been reported that ethinylestradiol, not progestogens, increased the clearance of lamotrigine up to 2-fold, and the progestin-only pills had no effect on lamotrigine plasma levels. Therefore, adjustments to the dosage of lamotrigine tablets in the presence of progestogens alone will likely not be needed. 

  Patients with Hepatic Impairment: Experience in patients with hepatic impairment is limited. Based on a clinical pharmacology study in 24 patients with mild, moderate, and severe liver impairment [see Use in Specific Populations (8.6), Clinical Pharmacology (12.3)], the following general recommendations can be made. No dosage adjustment is needed in patients with mild liver impairment. Initial, escalation, and maintenance doses should generally be reduced by approximately 25% in patients with moderate and severe liver impairment without ascites and 50% in patients with severe liver impairment with ascites. Escalation and maintenance doses may be adjusted according to clinical response. 

  Patients with Renal Impairment: Initial doses of lamotrigine tablets should be based on patients' concomitant medications (see Tables 1-3 or Table 5); reduced maintenance doses may be effective for patients with significant renal impairment [see Use in Specific Populations (8.7), Clinical Pharmacology (12.3)]. Few patients with severe renal impairment have been evaluated during chronic treatment with lamotrigine tablets. Because there is inadequate experience in this population, lamotrigine tablets should be used with caution in these patients. 

  Discontinuation Strategy: Epilepsy: For patients receiving lamotrigine tablets in combination with other AEDs, a re-evaluation of all AEDs in the regimen should be considered if a change in seizure control or an appearance or worsening of adverse reactions is observed. 

  If a decision is made to discontinue therapy with lamotrigine tablets, a step-wise reduction of dose over at least 2 weeks (approximately 50% per week) is recommended unless safety concerns require a more rapid withdrawal [see Warnings and Precautions (5.9)].

  Discontinuing carbamazepine, phenytoin, phenobarbital, primidone or other drugs such as rifampin that induce lamotrigine glucuronidation should prolong the half-life of lamotrigine; discontinuing valproate should shorten the half-life of lamotrigine. 

  Bipolar Disorder: In the controlled clinical trials, there was no increase in the incidence, type, or severity of adverse reactions following abrupt termination of lamotrigine tablets. In clinical trials in patients with Bipolar Disorder, 2 patients experienced seizures shortly after abrupt withdrawal of lamotrigine tablets. However, there were confounding factors that may have contributed to the occurrence of seizures in these bipolar patients. Discontinuation of lamotrigine tablets should involve a step-wise reduction of dose over at least 2 weeks (approximately 50% per week) unless safety concerns require a more rapid withdrawal [see Warnings and Precautions (5.9)].

  2.2 Epilepsy - Adjunctive Therapy

  This section provides specific dosing recommendations for patients greater than 12 years of age and patients 2 to 12 years of age. Within each of these age-groups, specific dosing recommendations are provided depending upon concomitant AED or other concomitant medications (Table 1 for patients greater than 12 years of age and Table 2 for patients 2 to 12 years of age). A weight-based dosing guide for patients 2 to 12 years of age on concomitant valproate is provided in Table 3. 

  Patients Over 12 Years of Age: Recommended dosing guidelines are summarized in Table 1. 

  Table 1. Escalation Regimen for Lamotrigine in Patients Over 12 Years of Age With Epilepsy

         For Patients TAKING Valproate a For Patients NOT TAKING Carbamazepine, Phenytoin, Phenobarbital, Primidoneb, or Valproatea For Patients TAKING Carbamazepine, Phenytoin, Phenobarbital, or Primidoneb and NOT TAKING Valproatea Weeks 1 and 2 25 mg every other day 25 mg every day 50 mg/day  Weeks 3 and 4 25 mg every day 50 mg/day 100 mg/day
  (in 2 divided doses) Weeks 5 onwards to maintenance Increase by 25 to 50 mg/day every 1 to 2 weeks Increase by 50 mg/day every 1 to 2 weeks  Increase by 100 mg/day every 1 to 2 weeks. Usual maintenance dose  100 to 200 mg/day with valproate alone 100 to 400 mg/day with valproate and other drugs that induceglucuronication 
  (in 1 or 2 divided doses) 225 to 375 mg/day
  (in 2 divided doses)  300 to 500 mg/day
  (in 2 divided doses) 

  a Valproate has been shown to inhibit glucuronidation and decrease the apparent clearance of    lamotrigine [see Drug Interactions (7), Clinical Pharmacology (12.3)].

  b   These drugs induce glucuronidation and increase clearance [see Drug Interactions (7) Clinical Pharmacology (12.3)]. Other drugs, that have similar effects include estrogen-containing oral contraceptives [see Drug Interactions (7),Clinical Pharmacology (12.3)].

  Dosing recommendations for oral contraceptives can be found in General Dosing Considerations [see Dosage and Administration (2.1)]. Patients on rifampin or other drugs that induce lamotrigine glucuronidation and increase clearance, should follow the same dosing titration/maintenance regimen as that used with anticonvulsants that have this effect..                                               

  Patients 2 to 12 Years of Age: Recommended dosing guidelines are summarized in Table 2.  Smaller starting doses and slower dose escalations than those used in clinical trials are recommended because of the suggestion that the risk of rash may be decreased by smaller starting doses and slower dose escalations. Therefore, maintenance doses will take longer to reach in clinical practice than in clinical trials. It may take several weeks to months to achieve an individualized maintenance dose. Maintenance doses in patients weighing less than 30 kg, regardless of age or concomitant AED, may need to be increased as much as 50%, based on clinical response.

  Table 2. Escalation Regimen for Lamotrigine in Patients 2 to 12 Years of Age With Epilepsy

    For Patients TAKING Valproatea For Patients NOT TAKING Carbamazepine, Phenytoin, Phenobarbital, Primidoneb, or Valproatea For Patients TAKING Carbamazepine, Phenytoin, Phenobarbital, or Primidoneb and NOT TAKING Valproatea Weeks 1 and 2 0.15 mg/kg/day
  in 1 or 2 divided doses, rounded down to the nearest whole tablet (see Table 3 for weight-based dosing guide) 0.3 mg/kg/day
  in 1 or 2 divided doses, rounded down to the nearest whole tablet 0.6 mg/kg/day
  in 2 divided doses, rounded down to the nearest whole tablet Weeks 3 and 4 0.3 mg/kg/day
  in 1 or 2 divided doses, rounded down to the nearest whole tablet (see Table 3 for weight-based dosing guide) 0.6 mg/kg/day
  in 2 divided doses, rounded down to the nearest whole tablet 1.2 mg/kg/day
  in 2 divided doses, rounded down to the nearest whole tablet Weeks 5 onwards to maintenance The dose should be increased every 1 to 2 weeks as follows: calculate 0.3 mg/kg/day, round this amount down to the nearest whole tablet, and add this amount to the previously administered daily dose The dose should be increased every 1 to 2 weeks as follows: calculate 0.6 mg/kg/day, round this amount down to the nearest whole tablet, and add this amount to the previously administered daily dose The dose should be increased every 1 to 2 weeks as follows: calculate 1.2 mg/kg/day, round this amount down to the nearest whole tablet, and add this amount to the previously administered daily dose Usual maintenance dose 1 to 5 mg/kg/day
  (maximum 200 mg/day in 1 or 2 divided doses).
  1 to 3 mg/kg/day with valproate alone 4.5 to 7.5 mg/kg/day
  (maximum 300 mg/day in 2 divided doses) 5 to 15 mg/kg/day
  (maximum 400 mg/day in 2 divided doses) Maintenance dose in patients less than 30 kg May need to be increased by as such much as 50%, based on clinical response May need to be increased by as much as 50%, based on clinical response May need to be increased by as much as 50%, based on clinical response

  Note: Only whole tablets should be used for dosing.

  a    Valproate has been shown to inhibit glucuronidation and decrease the apparent clearance of lamotrigine [see Drug Interactions (7), Clinical Pharmacology (12.3)].

   b    These drugs induce glucuronidation and increase clearance [see Drug Interactions (7)Clinical Pharmacology (12.3)]. Other drugs, that have similar effects include estrogen-containing oral contraceptives and rifampin [see Drug Interactions (7),Clinical Pharmacology Pharmacokinetics (12.3)]. Dosing recommendations for oral contraceptives can be found in General Dosing Considerations [see Dosage and Administration (2.1)]. Patients on rifampin or other drugs that induce lamotrigine glucuronidation and increase clearance, should follow the same dosing titration/maintenance regimen as that used with anticonvulsants that have this effect..                                               

  Table 3. The Initial Weight-Based Dosing Guide for Patients 2 to 12 Years Taking Valproate (Weeks 1 to 4) With Epilepsy 

  If the patient’s weight is Give this daily dose, using the most appropriate combination of lamotrigine 2 mg and 5 mg tablets Greater than And less than Weeks 1 and 2 Weeks 3 and 4 6.7 kg 14 kg 2 mg every other day 2 mg every day 14.1 kg 27 kg 2 mg every day 4 mg every day 27.1 kg 34 kg 4 mg every day 8 mg every day 34.1 kg 40 kg 5 mg every day 10 mg every day

  Usual Adjunctive Maintenance Dose for Epilepsy: The usual maintenance doses identified in Tables 1 and 2 are derived from dosing regimens employed in the placebo-controlled adjunctive studies in which the efficacy of lamotrigine tablets was established. In patients receiving multidrug regimens employing carbamazepine, phenytoin, phenobarbital, or primidone without valproate, maintenance doses of adjunctive lamotrigine tablets as high as 700 mg/day have been used. In patients receiving valproate alone, maintenance doses of adjunctive lamotrigine tablets as high as 200 mg/day have been used. The advantage of using doses above those recommended in Tables 1 through 4 has not been established in controlled trials.

  2.3 Epilepsy - Conversion from Adjunctive Therapy to Monotherapy

  The goal of the transition regimen is to effect the conversion to monotherapy with lamotrigine tablets under conditions that ensure adequate seizure control while mitigating the risk of serious rash associated with the rapid titration of lamotrigine tablets.  

  The recommended maintenance dose of lamotrigine tablets as monotherapy is 500 mg/day given in 2 divided doses.

   To avoid an increased risk of rash, the recommended initial dose and subsequent dose escalations of lamotrigine tablets should not be exceeded [see Boxed Warning].

  Conversion from Adjunctive Therapy with Carbamazepine, Phenytoin, Phenobarbital, or Primidone to Monotherapy with Lamotrigine: After achieving a dose of 500 mg/day of lamotrigine tablets according to the guidelines in Table 1, the concomitant AED should be withdrawn by 20% decrements each week over a 4-week period. The regimen for the withdrawal of the concomitant AED is based on experience gained in the controlled monotherapy clinical trial.  

  Conversion from Adjunctive Therapy with Valproate to Monotherapy with Lamotrigine: The conversion regimen involves 4 steps outlined in Table 4. 

  Table 4. Conversion From Adjunctive Therapy With Valproate to Monotherapy With Lamotrigine in Patients ≥16 Years of Age with Epilepsy

    Lamotrigine Valproate Step 1 Achieve a dose of 200 mg/day according to guidelines in Table 1 (if not already on 200 mg/day). Maintain previous stable dose. Step 2 Maintain at 200 mg/day. Decrease to 500 mg/day by decrements no greater than 500 mg/day/week and then maintain the dose of 500 mg/day for 1 week. Step 3 Increase to 300 mg/day and maintain for 1 week. Simultaneously decrease to 250 mg/day and maintain for 1 week. Step 4 Increase by 100 mg/day every week to achieve maintenance dose of
  500 mg/day. Discontinue.

  Conversion from Adjunctive Therapy with Antiepileptic Drugs other than Carbamazepine, Phenytoin, Phenobarbital, Primidone, or Valproate to Monotherapy with Lamotrigine: No specific  dosing guidelines can be provided for conversion to monotherapy with lamotrigine tablets with AEDs other than carbamazepine, phenobarbital, phenytoin, primidone, or valproate.  

  2.4 Bipolar Disorder

  The goal of maintenance treatment with lamotrigine tablets is to delay the time to occurrence of mood episodes (depression, mania, hypomania, mixed episodes) in patients treated for acute mood episodes with standard therapy. The target dose of lamotrigine tablets  is 200 mg/day (100 mg/day in patients taking valproate, which decreases the apparent clearance of lamotrigine, and 400 mg/day in patients not taking valproate and taking either carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin that increase the apparent clearance of lamotrigine). In the clinical trials, doses up to 400 mg/day as monotherapy were evaluated; however, no additional benefit was seen at 400 mg/day compared with 200 mg/day [see Clinical Studies (14.2)]. Accordingly, doses above 200 mg/day are not recommended. Treatment with lamotrigine tablets is introduced, based on concurrent medications, according to the regimen outlined in Table 5. If other psychotropic medications are withdrawn following stabilization, the dose of lamotrigine tablets should be adjusted. For patients discontinuing valproate, the dose of lamotrigine tablets should be doubled over a 2-week period in equal weekly increments (see Table 6). For patients discontinuing carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin that induce lamotrigine glucuronidation, the dose of lamotrigine tablets should remain constant for the first week and then should be decreased by half over a 2-week period in equal weekly decrements (see Table 6). The dose of lamotrigine tablets may then be further adjusted to the target dose (200 mg) as clinically indicated.

  If other drugs are subsequently introduced, the dose of lamotrigine tablets may need to be adjusted. In particular, the introduction of valproate requires reduction in the dose of lamotrigine tablets [see Drug Interactions (7), Clinical Pharmacology (12.3)].  

  To avoid an increased risk of rash, the recommended initial dose and subsequent dose escalations of lamotrigine tablets should not be exceeded [see Boxed Warning].

  Table 5. Escalation Regimen for Lamotrigine for Patients with Bipolar Disorder

    For Patients TAKING Valproatea For Patients NOT TAKING Carbamazepine, Phenytoin, Phenobarbital, Primidoneb, Valproatea For Patients TAKING Carbamazepine, Phenytoin, Phenobarbital, or Primidoneb, and NOT TAKING Valproatea Weeks 1 and 2 25 mg every other day 25 mg daily 50 mg daily Weeks 3 and 4 25 mg daily 50 mg daily 100 mg daily, in divided doses Week 5 50 mg daily 100 mg daily 200 mg daily, in divided doses Week 6 100 mg daily 200 mg daily 300 mg daily, in divided doses Week 7 100 mg daily 200 mg daily up to 400 mg daily, in divided doses

  a Valproate has been shown to inhibit glucuronidation and decrease the apparent clearance of  lamotrigine [see Drug Interactions (7), Clinical Pharmacology (12.3)].  

  b These drugs induce lamotrigine glucuronidation and increase clearance [see Drug Interactions  (7), Clinical Pharmacology (12.3)]. Other drugs that have similar effects include estrogen containing oral contraceptives [see Drug Interactions (7), Clinical Pharmacology (12.3)].  Dosing recommendations for oral contraceptives can be found in General Dosing  Considerations [see Dosage and Administration (2.1)]. Patients on rifampin, or other drugs  that induce lamotrigine glucuronidation and increase clearance, should follow the same dosing  titration/maintenance regimen as that used with anticonvulsants that have this effect.

  Table 6. Dosage Adjustments to Lamotrigine for Patients with Bipolar Disorder Following Discontinuation of Psychotropic Medications 

    Discontinuation of Psychotropic Drugs (excluding Carbamazepine, Phenytoin, Phenobarbital, Primidoneb, or Valproatea) After Discontinuation of Valproatea After Discontinuation of Valproatea Current dose of lamotrigine (mg/day) 100 Current dose of lamotrigine  (mg/day) 400 Week 1 Maintain current dose of lamotrigine 150 400 Week 2 Maintain current dose of lamotrigine 200 300 Week 3 onward Maintain current dose of lamotrigine 200 200

  a Valproate has been shown to inhibit glucuronidation and decrease the apparent clearance of  lamotrigine [see Drug Interactions (7), Clinical Pharmacology (12.3)].  

  b These drugs induce lamotrigine glucuronidation and increase clearance [see Drug Interactions  (7), Clinical Pharmacology (12.3)]. Other drugs that have similar effects include estrogen containing oral contraceptives [see Drug Interactions (7), Clinical Pharmacology (12.3)].  Dosing recommendations for oral contraceptives can be found in General Dosing  Considerations [see Dosage and Administration (2.1)]. Patients on rifampin, or other drugs  that induce lamotrigine glucuronidation and increase clearance, should follow the same dosing  titration/maintenance regimen as that used with anticonvulsants that have this effect.

   The benefit of continuing treatment in patients who had been stabilized in an 8- to 16-week open-label phase with lamotrigine tablets was established in 2 randomized, placebo-controlled clinical maintenance trials [see Clinical Studies (14.2)]. However, the optimal duration of treatment with lamotrigine tablets has not been established. Thus, patients should be periodically reassessed to determine the need for maintenance treatment.

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  2.1 General Dosing Considerations 

  Rash: There are suggestions, yet to be proven, that the risk of severe, potentially life-threatening rash may be increased by (1) coadministration of lamotrigine tablets with valproate, (2) exceeding the recommended initial dose of lamotrigine tablets, or (3) exceeding the recommended dose escalation for lamotrigine tablets. However, cases have occurred in the absence of these factors [see Boxed Warning]. Therefore, it is important that the dosing recommendations be followed closely.

  The risk of nonserious rash may be increased when the recommended initial dose and/or the rate of dose escalation of lamotrigine tablets is exceeded and in patients with a history of allergy or rash to other AEDs.

  It is recommended that lamotrigine tablets not be restarted in patients who discontinued due to rash associated with prior treatment with lamotrigine, unless the potential benefits clearly outweigh the risks. If the decision is made to restart a patient who has discontinued lamotrigine, the need to restart with the initial dosing recommendations should be assessed. The greater the interval of time since the previous dose, the greater consideration should be given to restarting with the initial dosing recommendations. If a patient has discontinued lamotrigine for a period of more than 5 half-lives, it is recommended that initial dosing recommendations and guidelines be followed. The half-life of lamotrigine is affected by other concomitant medications [see Clinical Pharmacology (12.3)].

  Lamotrigine Added to Drugs Known to Induce or Inhibit Glucuronidation: Drugs other than those listed in the Clinical Pharmacology section [see Clinical Pharmacology (12.3)] have not been systematically evaluated in combination with lamotrigine. Because lamotrigine is metabolized predominantly by glucuronic acid conjugation, drugs that are known to induce or inhibit glucuronidation may affect the apparent clearance of lamotrigine and doses of lamotrigine tablets may require adjustment based on clinical response.

  Target Plasma Levels for Patients With Epilepsy or Bipolar Disorder: A therapeutic plasma concentration range has not been established for lamotrigine. Dosing of lamotrigine tablets should be based on therapeutic response [see Clinical Pharmacology (12.3)].

  Women Taking Estrogen-Containing Oral Contraceptives:  Starting Lamotrigine Tablets in Women Taking Estrogen-Containing Oral Contraceptives: Although estrogen-containing oral contraceptives have been shown to increase the clearance of lamotrigine [see Clinical Pharmacology (12.3)], no adjustments to the recommended dose-escalation guidelines for lamotrigine tablets should be necessary solely based on the use of estrogen-containing oral contraceptives. Therefore, dose escalation should follow the recommended guidelines for initiating adjunctive therapy with lamotrigine tablets based on the concomitant AED or other concomitant medications (see Table 1 or Table 5). See below for adjustments to maintenance doses of lamotrigine tablets in women taking estrogen-containing oral contraceptives.

  Adjustments to the Maintenance Dose of Lamotrigine Tablets in Women Taking Estrogen-Containing Oral Contraceptives:

  (1) Taking Estrogen-Containing Oral Contraceptives: For women not taking carbamazepine, phenytoin, phenobarbital, primidone, or rifampin, the maintenance dose of lamotrigine tablets will in most cases need to be increased, by as much as 2 fold over the recommended target maintenance dose, in order to maintain a consistent lamotrigine plasma level [see Clinical Pharmacology (12.3)].

  (2) Starting Estrogen-Containing Oral Contraceptives: In women taking a stable dose of lamotrigine tablets and not taking carbamazepine, phenytoin, phenobarbital, primidone, or rifampin, the maintenance dose will in most cases need to be increased by as much as 2 fold in order to maintain a consistent lamotrigine plasma level. The dose increases should begin at the same time that the oral contraceptive is introduced and continue, based on clinical response, no more rapidly than 50 to 100 mg/day every week. Dose increases should not exceed the recommended rate (seeTable 1 or Table 5) unless lamotrigine plasma levels or clinical response support larger increases. Gradual transient increases in lamotrigine plasma levels may occur during the week of inactive hormonal preparation (“pill-free” week), and these increases will be greater if dose increases are made in the days before or during the week of inactive hormonal preparation. Increased lamotrigine plasma levels could result in additional adverse reactions, such as dizziness, ataxia, and diplopia. If adverse reactions attributable to lamotrigine tablets consistently occur during the “pill-free” week, dose adjustments to the overall maintenance dose may be necessary. Dose adjustments limited to the “pill-free” week are not recommended. For women taking lamotrigine tablets in addition to carbamazepine, phenytoin, phenobarbital, primidone, or rifampin, no adjustment should be necessary to the dose of lamotrigine tablets.

  (3) Stopping Estrogen-Containing Oral Contraceptives: For women not taking carbamazepine, phenytoin, phenobarbital, primidone, or rifampin, the maintenance dose of lamotrigine tablets will in most cases need to be decreased by as much as 50% in order to maintain a consistent lamotrigine plasma level. The decrease in dose of lamotrigine tablets should not exceed 25% of the total daily dose per week over a 2 week period, unless clinical response or lamotrigine plasma levels indicate otherwise [see Clinical Pharmacology (12.3)]. For women taking lamotrigine tablets in addition to carbamazepine, phenytoin, phenobarbital, primidone, or rifampin, no adjustment to the dose of lamotrigine tablets should be necessary.

  Women and Other Hormonal Contraceptive Preparations or Hormone Replacement Therapy: The effect of other hormonal contraceptive preparations or hormone replacement therapy on the pharmacokinetics of lamotrigine has not been systematically evaluated. It has been reported that ethinylestradiol, not progestogens, increased the clearance of lamotrigine up to 2 fold, and the progestin-only pills had no effect on lamotrigine plasma levels. Therefore, adjustments to the dosage of lamotrigine tablets in the presence of progestogens alone will likely not be needed.

  Patients With Hepatic Impairment: Experience in patients with hepatic impairment is limited. Based on a clinical pharmacology study in 24 patients with mild, moderate, and severe liver impairment [see Use in Specific Populations (8.6), Clinical Pharmacology (12.3)], the following general recommendations can be made. No dosage adjustment is needed in patients with mild liver impairment. Initial, escalation, and maintenance doses should generally be reduced by approximately 25% in patients with moderate and severe liver impairment without ascites and 50% in patients with severe liver impairment with ascites. Escalation and maintenance doses may be adjusted according to clinical response.

  Patients With Renal Impairment: Initial doses of lamotrigine tablets should be based on patients' concomitant medications (see Tables 1 to 3 or Table 5); reduced maintenance doses may be effective for patients with significant renal impairment [see Use in Specific Populations (8.7), Clinical Pharmacology (12.3)]. Few patients with severe renal impairment have been evaluated during chronic treatment with lamotrigine tablets. Because there is inadequate experience in this population, lamotrigine tablets should be used with caution in these patients.

  Discontinuation Strategy:  Epilepsy: For patients receiving lamotrigine tablets in combination with other AEDs, a re-evaluation of all AEDs in the regimen should be considered if a change in seizure control or an appearance or worsening of adverse reactions is observed.

  If a decision is made to discontinue therapy with lamotrigine tablets, a step-wise reduction of dose over at least 2 weeks (approximately 50% per week) is recommended unless safety concerns require a more rapid withdrawal [see Warnings and Precautions (5.9)].

  Discontinuing carbamazepine, phenytoin, phenobarbital, or primidone should prolong the half-life of lamotrigine; discontinuing valproate should shorten the half-life of lamotrigine.

  Bipolar Disorder: In the controlled clinical trials, there was no increase in the incidence, type, or severity of adverse reactions following abrupt termination of lamotrigine tablets. In clinical trials in patients with Bipolar Disorder, 2 patients experienced seizures shortly after abrupt withdrawal of lamotrigine tablets. However, there were confounding factors that may have contributed to the occurrence of seizures in these bipolar patients. Discontinuation of lamotrigine tablets should involve a step-wise reduction of dose over at least 2 weeks (approximately 50% per week) unless safety concerns require a more rapid withdrawal [see Warnings and Precautions (5.9)].

  2.2 Epilepsy – Adjunctive Therapy

  This section provides specific dosing recommendations for patients greater than 12 years of age and patients 2 to 12 years of age. Within each of these age-groups, specific dosing recommendations are provided depending upon concomitant AED or other concomitant medications (Table 1 for patients greater than 12 years of age and Table 2 for patients 2 to 12 years of age). A weight-based dosing guide for patients 2 to 12 years of age on concomitant valproate is provided in Table 3.

  Patients Over 12 Years of Age: Recommended dosing guidelines are summarized in Table 1.

  Table 1. Escalation Regimen for Lamotrigine in Patients Over 12 Years of Age With Epilepsy  * Valproate has been shown to inhibit glucuronidation and decrease the apparent clearance of lamotrigine [ see Drug Interactions (7), Pharmacokinetics (12.3)] . † These drugs induce glucuronidation and increase clearance [ see Drug Interactions (7) Pharmacokinetics (12.3)]. Other drugs, which have similar effects include estrogen-containing oral contraceptives and rifampin [ see Drug Interactions (7), Pharmacokinetics (12.3)] . Dosing recommendations for oral contraceptives can be found in General Dosing Considerations [ see Dosage and Administration (2.1)] . Patients on rifampin should follow the same dosing titration/maintenance regimen used with drugs that induce glucuronidation and increase clearance. For Patients Taking Valproate* For Patients Taking AEDs Other Than Carbamazepine, Phenytoin, Phenobarbital, or Primidone†, and Not Taking Valproate For Patients Taking Carbamazepine, Phenytoin, Phenobarbital, or Primidone† and Not Taking Valproate Weeks 1 and 2 25 mg every other day 25 mg every day 50 mg/day Weeks 3 and 4 25 mg every day 50 mg/day 100 mg/day (in 2 divided doses) Weeks 5 onwards to maintenance Increase by 25 to 50 mg/day every 1 to 2 weeks Increase by 50 mg/day every 1 to 2 weeks Increase by 100 mg/day every 1 to 2 weeks Usual Maintenance Dose

  100 to 200 mg/day with valproate alone

  100 to 400 mg/day with valproate and other drugs that induce glucuronication

  (in 1 or 2 divided doses)

  225 to 375 mg/day (in 2 divided doses)

  300 to 500 mg/day

   (in 2 divided doses)

  Patients 2 to 12 Years of Age: Recommended dosing guidelines are summarized in Table 2.

  Smaller starting doses and slower dose escalations than those used in clinical trials are recommended because of the suggestion that the risk of rash may be decreased by smaller starting doses and slower dose escalations. Therefore, maintenance doses will take longer to reach in clinical practice than in clinical trials. It may take several weeks to months to achieve an individualized maintenance dose. Maintenance doses in patients weighing less than 30 kg, regardless of age or concomitant AED, may need to be increased as much as 50%, based on clinical response.

  Table 2. Escalation Regimen for Lamotrigine in Patients 2 to 12 Years of Age With Epilepsy For Patients Taking Valproate* For Patients Taking AEDs Other Than Carbamazepine, Phenytoin, Phenobarbital, or Primidone† , and Not Taking Valproate For Patients Taking Carbamazepine, Phenytoin, Phenobarbital, or Primidone† and Not Taking Valproate Weeks 1 and 2 0.15 mg/kg/day in 1 or 2 divided doses, rounded down to the nearest whole tablet (see Table 3 for weight based dosing guide) 0.3 mg/kg/day in 1 or 2 divided doses, rounded down to the nearest whole tablet 0.6 mg/kg/day in 2 divided doses, rounded down to the nearest whole tablet Weeks 3 and 4 0.3 mg/kg/day in 1 or 2 divided doses, rounded down to the nearest whole tablet (see Table 3for weight based dosing guide) 0.6 mg/kg/day in 2 divided doses, rounded down to the nearest whole tablet 1.2 mg/kg/day in 2 divided doses, rounded down to the nearest whole tablet Weeks 5 onwards to maintenance The dose should be increased every 1 to 2 weeks as follows: calculate 0.3 mg/kg/day, round this amount down to the nearest whole tablet, and add this amount to the previously administered daily dose The dose should be increased every 1 to 2 weeks as follows: calculate 0.6 mg/kg/day, round this amount down to the nearest whole tablet, and add this amount to the previously administered daily dose The dose should be increased every 1 to 2 weeks as follows: calculate 1.2 mg/kg/day, round this amount down to the nearest whole tablet, and add this amount to the previously administered daily dose Usual Maintenance Dose 1 to 5 mg/kg/day (maximum 200 mg/day in 1 or 2 divided doses).
  1 to 3 mg/kg/day with valproate alone 4.5 to 7.5 mg/kg/day (maximum 300 mg/day in 2 divided doses) 5 to 15 mg/kg/day (maximum 400 mg/day in 2 divided doses) Maintenance dose in patients less than 30 kg May need to be increased by as much as 50%, based on clinical response May need to be increased by as much as 50%, based on clinical response May need to be increased by as much as 50%, based on clinical response

  Note: Only whole tablets should be used for dosing .

  *  Valproate has been shown to inhibit glucuronidation and decrease the apparent clearance of lamotrigine [see Drug Interactions (7), Pharmacokinetics (12.3)].
  † These drugs induce glucuronidation and increase clearance [see Drug Interactions (7) Pharmacokinetics (12.3)]. Other drugs, which have similar effects include estrogen-containing oral contraceptives and rifampin [see Drug Interactions (7), Pharmacokinetics (12.3)]. Dosing recommendations for oral contraceptives can be found in General Dosing Considerations [see Dosage and Administration (2.1)]. Patients on rifampin should follow the same dosing titration/maintenance regimen used with drugs that induce glucuronidation.

  Table 3. The Initial Weight-Based Dosing Guide for Patients 2 to 12 Years Taking Valproate (Weeks 1 to 4) With Epilepsy If the patient’s weight is Give this daily dose, using the most appropriate combination of lamotrigine tablets, 2 mg and 5 mg Greater than And less than Weeks 1 and 2 Weeks 3 and 4 6.7 kg 14 kg 2 mg every other day 2 mg every day 14.1 kg 27 kg 2 mg every day 4 mg every day 27.1 kg 34 kg 4 mg every day 8 mg every day 34.1 kg 40 kg 5 mg every day 10 mg every day

  Usual Adjunctive Maintenance Dose for Epilepsy: The usual maintenance doses identified in Tables 1 and 2 are derived from dosing regimens employed in the placebo-controlled adjunctive studies in which the efficacy of lamotrigine tablets was established. In patients receiving multidrug regimens employing carbamazepine, phenytoin, phenobarbital, or primidone without valproate, maintenance doses of adjunctive lamotrigine tablets as high as 700 mg/day have been used. In patients receiving valproate alone, maintenance doses of adjunctive lamotrigine tablets as high as 200 mg/day have been used. The advantage of using doses above those recommended in Tables 1 through 4 has not been established in controlled trials.

  2.3 Epilepsy – Conversion From Adjunctive Therapy to Monotherapy

  The goal of the transition regimen is to effect the conversion to monotherapy with lamotrigine tablets under conditions that ensure adequate seizure control while mitigating the risk of serious rash associated with the rapid titration of lamotrigine tablets.

  The recommended maintenance dose of lamotrigine tablets as monotherapy is 500 mg/day given in 2 divided doses.

  To avoid an increased risk of rash, the recommended initial dose and subsequent dose escalations of lamotrigine tablets should not be exceeded [see Boxed Warning].

  Conversion From Adjunctive Therapy With Carbamazepine, Phenytoin, Phenobarbital, or Primidone to Monotherapy With Lamotrigine Tablets: After achieving a dose of 500 mg/day of lamotrigine tablets according to the guidelines in Table 1, the concomitant AED should be withdrawn by 20% decrements each week over a 4 week period. The regimen for the withdrawal of the concomitant AED is based on experience gained in the controlled monotherapy clinical trial.

  Conversion From Adjunctive Therapy With Valproate to Monotherapy With Lamotrigine Tablets: The conversion regimen involves 4 steps outlined in Table 4.

  Table 4. Conversion From Adjunctive Therapy With Valproate to Monotherapy With Lamotrigine in Patients ≥16 Years of Age with Epilepsy

   

  Lamotrigine

  Valproate

  Step 1

  Achieve a dose of 200 mg/day according to guidelines in Table 1 (if not already on 200 mg/day).

  Maintain previous stable dose.

  Step 2

  Maintain at 200 mg/day.

  Decrease to 500 mg/day by decrements no greater than 500 mg/day/week and then maintain the dose of 500 mg/day for 1 week.

  Step 3

  Increase to 300 mg/day and maintain for 1 week.

  Simultaneously decrease to 250 mg/day and maintain for 1 week.

  Step 4

  Increase by 100 mg/day every week to achieve maintenance dose of 500 mg/day.

  Discontinue.

  Conversion From Adjunctive Therapy With AEDs Other Than Carbamazepine, Phenytoin, Phenobarbital, Primidone, or Valproate to Monotherapy With Lamotrigine Tablets: No specific dosing guidelines can be provided for conversion to monotherapy with lamotrigine tablets with AEDs other than carbamazepine, phenobarbital, phenytoin, primidone, or valproate.

  2.4 Bipolar Disorder

  The goal of maintenance treatment with lamotrigine tablets is to delay the time to occurrence of mood episodes (depression, mania, hypomania, mixed episodes) in patients treated for acute mood episodes with standard therapy. The target dose of lamotrigine tablets is 200 mg/day (100 mg/day in patients taking valproate, which decreases the apparent clearance of lamotrigine, and 400 mg/day in patients not taking valproate and taking either carbamazepine, phenytoin, phenobarbital, primidone, or rifampin, which increase the apparent clearance of lamotrigine). In the clinical trials, doses up to 400 mg/day as monotherapy were evaluated; however, no additional benefit was seen at 400 mg/day compared with 200 mg/day [see Clinical Studies (14.2)]. Accordingly, doses above 200 mg/day are not recommended. Treatment with lamotrigine tablets is introduced, based on concurrent medications, according to the regimen outlined in Table 5. If other psychotropic medications are withdrawn following stabilization, the dose of lamotrigine tablets should be adjusted. For patients discontinuing valproate, the dose of lamotrigine tablets should be doubled over a 2 week period in equal weekly increments (see Table 6). For patients discontinuing carbamazepine, phenytoin, phenobarbital, primidone, or rifampin, the dose of lamotrigine tablets should remain constant for the first week and then should be decreased by half over a 2 week period in equal weekly decrements (see Table 6). The dose of lamotrigine tablets may then be further adjusted to the target dose (200 mg) as clinically indicated.

  If other drugs are subsequently introduced, the dose of lamotrigine tablets may need to be adjusted. In particular, the introduction of valproate requires reduction in the dose of lamotrigine tablets [see Drug Interactions (7), Clinical Pharmacology (12.3)].

  To avoid an increased risk of rash, the recommended initial dose and subsequent dose escalations of lamotrigine tablets should not be exceeded [see Boxed Warning].

   

  Table 5. Escalation Regimen for Lamotrigine for Patients With Bipolar Disorder* * See Drug Interactions (7) and Clinical Pharmacology (12.3) for a description of known drug interactions. † Valproate has been shown to decrease the apparent clearance of lamotrigine. ‡ Carbamazepine, phenytoin, phenobarbital, primidone, and rifampin have been shown to increase the apparent clearance of lamotrigine. For Patients Taking Valproate† For Patients Not Taking Carbamazepine, Phenytoin, Phenobarbital, Primidone, or Rifampin‡ and Not Taking Valproate† For Patients Taking Carbamazepine, Phenytoin, Phenobarbital, Primidone, or Rifampin‡ and Not Taking Valproate† Weeks 1 and 2 25 mg every other day 25 mg daily 50 mg daily Weeks 3 and 4 25 mg daily 50 mg daily 100 mg daily, in divided doses Week 5 50 mg daily 100 mg daily 200 mg daily, in divided doses Week 6 100 mg daily 200 mg daily 300 mg daily, in divided doses Week 7 100 mg daily 200 mg daily up to 400 mg daily, in divided doses Table 6. Dosage Adjustments to Lamotrigine for Patients With Bipolar Disorder Following Discontinuation of Psychotropic Medications* * See Drug Interactions (7) and Clinical Pharmacology (12.3) for a description of known drug interactions. † Carbamazepine, phenytoin, phenobarbital, primidone, and rifampin have been shown to increase the apparent clearance of lamotrigine. ‡ Valproate has been shown to decrease the apparent clearance of lamotrigine.   Discontinuation of Psychotropic Drugs (excluding Carbamazepine, Phenytoin, Phenobarbital, Primidone, Rifampin†, or Valproate‡) After Discontinuation of Valproate‡ After Discontinuation of Carbamazepine, Phenytoin, Phenobarbital, Primidone, or Rifampin† Current dose of Lamotrigine (mg/day) 100

  Current dose of Lamotrigine (mg/day)

  400

  Week 1 Maintain current dose of lamotrigine 150 400 Week 2 Maintain current dose of lamotrigine 200 300 Week 3 onward Maintain current dose of lamotrigine 200 200

  The benefit of continuing treatment in patients who had been stabilized in an 8 to 16 week open-label phase with lamotrigine tablets was established in 2 randomized, placebo-controlled clinical maintenance trials [see Clinical Studies (14.2)]. However, the optimal duration of treatment with lamotrigine tablets has not been established. Thus, patients should be periodically reassessed to determine the need for maintenance treatment.

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  2.1 General Dosing Considerations 

  Rash: There are suggestions, yet to be proven, that the risk of severe, potentially life-threatening rash may be increased by (1) coadministration of lamotrigine tablets with valproate, (2) exceeding the recommended initial dose of lamotrigine tablets, or (3) exceeding the recommended dose escalation for lamotrigine tablets. However, cases have occurred in the absence of these factors [see Boxed Warning]. Therefore, it is important that the dosing recommendations be followed closely.

  The risk of nonserious rash may be increased when the recommended initial dose and/or the rate of dose escalation of lamotrigine tablets is exceeded and in patients with a history of allergy or rash to other AEDs.

  It is recommended that lamotrigine tablets not be restarted in patients who discontinued due to rash associated with prior treatment with lamotrigine, unless the potential benefits clearly outweigh the risks. If the decision is made to restart a patient who has discontinued lamotrigine, the need to restart with the initial dosing recommendations should be assessed. The greater the interval of time since the previous dose, the greater consideration should be given to restarting with the initial dosing recommendations. If a patient has discontinued lamotrigine for a period of more than 5 half-lives, it is recommended that initial dosing recommendations and guidelines be followed. The half-life of lamotrigine is affected by other concomitant medications [see Clinical Pharmacology (12.3)].

  Lamotrigine Added to Drugs Known to Induce or Inhibit Glucuronidation: Drugs other than those listed in the Clinical Pharmacology section [see Clinical Pharmacology (12.3)] have not been systematically evaluated in combination with lamotrigine. Because lamotrigine is metabolized predominantly by glucuronic acid conjugation, drugs that are known to induce or inhibit glucuronidation may affect the apparent clearance of lamotrigine and doses of lamotrigine tablets may require adjustment based on clinical response.

  Target Plasma Levels for Patients With Epilepsy or Bipolar Disorder: A therapeutic plasma concentration range has not been established for lamotrigine. Dosing of lamotrigine tablets should be based on therapeutic response [see Clinical Pharmacology (12.3)].

  Women Taking Estrogen-Containing Oral Contraceptives:  Starting Lamotrigine Tablets in Women Taking Estrogen-Containing Oral Contraceptives: Although estrogen-containing oral contraceptives have been shown to increase the clearance of lamotrigine [see Clinical Pharmacology (12.3)], no adjustments to the recommended dose-escalation guidelines for lamotrigine tablets should be necessary solely based on the use of estrogen-containing oral contraceptives. Therefore, dose escalation should follow the recommended guidelines for initiating adjunctive therapy with lamotrigine tablets based on the concomitant AED or other concomitant medications (see Table 1 or Table 5). See below for adjustments to maintenance doses of lamotrigine tablets in women taking estrogen-containing oral contraceptives.

  Adjustments to the Maintenance Dose of Lamotrigine Tablets in Women Taking Estrogen-Containing Oral Contraceptives:

  (1) Taking Estrogen-Containing Oral Contraceptives: For women not taking carbamazepine, phenytoin, phenobarbital, primidone, or rifampin, the maintenance dose of lamotrigine tablets will in most cases need to be increased, by as much as 2 fold over the recommended target maintenance dose, in order to maintain a consistent lamotrigine plasma level [see Clinical Pharmacology (12.3)].

  (2) Starting Estrogen-Containing Oral Contraceptives: In women taking a stable dose of lamotrigine tablets and not taking carbamazepine, phenytoin, phenobarbital, primidone, or rifampin, the maintenance dose will in most cases need to be increased by as much as 2 fold in order to maintain a consistent lamotrigine plasma level. The dose increases should begin at the same time that the oral contraceptive is introduced and continue, based on clinical response, no more rapidly than 50 to 100 mg/day every week. Dose increases should not exceed the recommended rate (seeTable 1 or Table 5) unless lamotrigine plasma levels or clinical response support larger increases. Gradual transient increases in lamotrigine plasma levels may occur during the week of inactive hormonal preparation (“pill-free” week), and these increases will be greater if dose increases are made in the days before or during the week of inactive hormonal preparation. Increased lamotrigine plasma levels could result in additional adverse reactions, such as dizziness, ataxia, and diplopia. If adverse reactions attributable to lamotrigine tablets consistently occur during the “pill-free” week, dose adjustments to the overall maintenance dose may be necessary. Dose adjustments limited to the “pill-free” week are not recommended. For women taking lamotrigine tablets in addition to carbamazepine, phenytoin, phenobarbital, primidone, or rifampin, no adjustment should be necessary to the dose of lamotrigine tablets.

  (3) Stopping Estrogen-Containing Oral Contraceptives: For women not taking carbamazepine, phenytoin, phenobarbital, primidone, or rifampin, the maintenance dose of lamotrigine tablets will in most cases need to be decreased by as much as 50% in order to maintain a consistent lamotrigine plasma level. The decrease in dose of lamotrigine tablets should not exceed 25% of the total daily dose per week over a 2 week period, unless clinical response or lamotrigine plasma levels indicate otherwise [see Clinical Pharmacology (12.3)]. For women taking lamotrigine tablets in addition to carbamazepine, phenytoin, phenobarbital, primidone, or rifampin, no adjustment to the dose of lamotrigine tablets should be necessary.

  Women and Other Hormonal Contraceptive Preparations or Hormone Replacement Therapy: The effect of other hormonal contraceptive preparations or hormone replacement therapy on the pharmacokinetics of lamotrigine has not been systematically evaluated. It has been reported that ethinylestradiol, not progestogens, increased the clearance of lamotrigine up to 2 fold, and the progestin-only pills had no effect on lamotrigine plasma levels. Therefore, adjustments to the dosage of lamotrigine tablets in the presence of progestogens alone will likely not be needed.

  Patients With Hepatic Impairment: Experience in patients with hepatic impairment is limited. Based on a clinical pharmacology study in 24 patients with mild, moderate, and severe liver impairment [see Use in Specific Populations (8.6), Clinical Pharmacology (12.3)], the following general recommendations can be made. No dosage adjustment is needed in patients with mild liver impairment. Initial, escalation, and maintenance doses should generally be reduced by approximately 25% in patients with moderate and severe liver impairment without ascites and 50% in patients with severe liver impairment with ascites. Escalation and maintenance doses may be adjusted according to clinical response.

  Patients With Renal Impairment: Initial doses of lamotrigine tablets should be based on patients' concomitant medications (see Tables 1 to 3 or Table 5); reduced maintenance doses may be effective for patients with significant renal impairment [see Use in Specific Populations (8.7), Clinical Pharmacology (12.3)]. Few patients with severe renal impairment have been evaluated during chronic treatment with lamotrigine tablets. Because there is inadequate experience in this population, lamotrigine tablets should be used with caution in these patients.

  Discontinuation Strategy:  Epilepsy: For patients receiving lamotrigine tablets in combination with other AEDs, a re-evaluation of all AEDs in the regimen should be considered if a change in seizure control or an appearance or worsening of adverse reactions is observed.

  If a decision is made to discontinue therapy with lamotrigine tablets, a step-wise reduction of dose over at least 2 weeks (approximately 50% per week) is recommended unless safety concerns require a more rapid withdrawal [see Warnings and Precautions (5.9)].

  Discontinuing carbamazepine, phenytoin, phenobarbital, or primidone should prolong the half-life of lamotrigine; discontinuing valproate should shorten the half-life of lamotrigine.

  Bipolar Disorder: In the controlled clinical trials, there was no increase in the incidence, type, or severity of adverse reactions following abrupt termination of lamotrigine tablets. In clinical trials in patients with Bipolar Disorder, 2 patients experienced seizures shortly after abrupt withdrawal of lamotrigine tablets. However, there were confounding factors that may have contributed to the occurrence of seizures in these bipolar patients. Discontinuation of lamotrigine tablets should involve a step-wise reduction of dose over at least 2 weeks (approximately 50% per week) unless safety concerns require a more rapid withdrawal [see Warnings and Precautions (5.9)].

  2.2 Epilepsy – Adjunctive Therapy

  This section provides specific dosing recommendations for patients greater than 12 years of age and patients 2 to 12 years of age. Within each of these age-groups, specific dosing recommendations are provided depending upon concomitant AED or other concomitant medications (Table 1 for patients greater than 12 years of age and Table 2 for patients 2 to 12 years of age). A weight-based dosing guide for patients 2 to 12 years of age on concomitant valproate is provided in Table 3.

  Patients Over 12 Years of Age: Recommended dosing guidelines are summarized in Table 1.

  Table 1. Escalation Regimen for Lamotrigine in Patients Over 12 Years of Age With Epilepsy  * Valproate has been shown to inhibit glucuronidation and decrease the apparent clearance of lamotrigine [ see Drug Interactions (7), Pharmacokinetics (12.3)] . † These drugs induce glucuronidation and increase clearance [ see Drug Interactions (7) Pharmacokinetics (12.3)]. Other drugs, which have similar effects include estrogen-containing oral contraceptives and rifampin [ see Drug Interactions (7), Pharmacokinetics (12.3)] . Dosing recommendations for oral contraceptives can be found in General Dosing Considerations [ see Dosage and Administration (2.1)] . Patients on rifampin should follow the same dosing titration/maintenance regimen used with drugs that induce glucuronidation and increase clearance. For Patients Taking Valproate* For Patients Taking AEDs Other Than Carbamazepine, Phenytoin, Phenobarbital, or Primidone†, and Not Taking Valproate For Patients Taking Carbamazepine, Phenytoin, Phenobarbital, or Primidone† and Not Taking Valproate Weeks 1 and 2 25 mg every other day 25 mg every day 50 mg/day Weeks 3 and 4 25 mg every day 50 mg/day 100 mg/day (in 2 divided doses) Weeks 5 onwards to maintenance Increase by 25 to 50 mg/day every 1 to 2 weeks Increase by 50 mg/day every 1 to 2 weeks Increase by 100 mg/day every 1 to 2 weeks Usual Maintenance Dose

  100 to 200 mg/day with valproate alone

  100 to 400 mg/day with valproate and other drugs that induce glucuronication

  (in 1 or 2 divided doses)

  225 to 375 mg/day (in 2 divided doses)

  300 to 500 mg/day

   (in 2 divided doses)

  Patients 2 to 12 Years of Age: Recommended dosing guidelines are summarized in Table 2.

  Smaller starting doses and slower dose escalations than those used in clinical trials are recommended because of the suggestion that the risk of rash may be decreased by smaller starting doses and slower dose escalations. Therefore, maintenance doses will take longer to reach in clinical practice than in clinical trials. It may take several weeks to months to achieve an individualized maintenance dose. Maintenance doses in patients weighing less than 30 kg, regardless of age or concomitant AED, may need to be increased as much as 50%, based on clinical response.

  Table 2. Escalation Regimen for Lamotrigine in Patients 2 to 12 Years of Age With Epilepsy For Patients Taking Valproate* For Patients Taking AEDs Other Than Carbamazepine, Phenytoin, Phenobarbital, or Primidone† , and Not Taking Valproate For Patients Taking Carbamazepine, Phenytoin, Phenobarbital, or Primidone† and Not Taking Valproate Weeks 1 and 2 0.15 mg/kg/day in 1 or 2 divided doses, rounded down to the nearest whole tablet (see Table 3 for weight based dosing guide) 0.3 mg/kg/day in 1 or 2 divided doses, rounded down to the nearest whole tablet 0.6 mg/kg/day in 2 divided doses, rounded down to the nearest whole tablet Weeks 3 and 4 0.3 mg/kg/day in 1 or 2 divided doses, rounded down to the nearest whole tablet (see Table 3for weight based dosing guide) 0.6 mg/kg/day in 2 divided doses, rounded down to the nearest whole tablet 1.2 mg/kg/day in 2 divided doses, rounded down to the nearest whole tablet Weeks 5 onwards to maintenance The dose should be increased every 1 to 2 weeks as follows: calculate 0.3 mg/kg/day, round this amount down to the nearest whole tablet, and add this amount to the previously administered daily dose The dose should be increased every 1 to 2 weeks as follows: calculate 0.6 mg/kg/day, round this amount down to the nearest whole tablet, and add this amount to the previously administered daily dose The dose should be increased every 1 to 2 weeks as follows: calculate 1.2 mg/kg/day, round this amount down to the nearest whole tablet, and add this amount to the previously administered daily dose Usual Maintenance Dose 1 to 5 mg/kg/day (maximum 200 mg/day in 1 or 2 divided doses).
  1 to 3 mg/kg/day with valproate alone 4.5 to 7.5 mg/kg/day (maximum 300 mg/day in 2 divided doses) 5 to 15 mg/kg/day (maximum 400 mg/day in 2 divided doses) Maintenance dose in patients less than 30 kg May need to be increased by as much as 50%, based on clinical response May need to be increased by as much as 50%, based on clinical response May need to be increased by as much as 50%, based on clinical response

  Note: Only whole tablets should be used for dosing .

  *  Valproate has been shown to inhibit glucuronidation and decrease the apparent clearance of lamotrigine [see Drug Interactions (7), Pharmacokinetics (12.3)].
  † These drugs induce glucuronidation and increase clearance [see Drug Interactions (7) Pharmacokinetics (12.3)]. Other drugs, which have similar effects include estrogen-containing oral contraceptives and rifampin [see Drug Interactions (7), Pharmacokinetics (12.3)]. Dosing recommendations for oral contraceptives can be found in General Dosing Considerations [see Dosage and Administration (2.1)]. Patients on rifampin should follow the same dosing titration/maintenance regimen used with drugs that induce glucuronidation.

  Table 3. The Initial Weight-Based Dosing Guide for Patients 2 to 12 Years Taking Valproate (Weeks 1 to 4) With Epilepsy If the patient’s weight is Give this daily dose, using the most appropriate combination of lamotrigine tablets, 2 mg and 5 mg Greater than And less than Weeks 1 and 2 Weeks 3 and 4 6.7 kg 14 kg 2 mg every other day 2 mg every day 14.1 kg 27 kg 2 mg every day 4 mg every day 27.1 kg 34 kg 4 mg every day 8 mg every day 34.1 kg 40 kg 5 mg every day 10 mg every day

  Usual Adjunctive Maintenance Dose for Epilepsy: The usual maintenance doses identified in Tables 1 and 2 are derived from dosing regimens employed in the placebo-controlled adjunctive studies in which the efficacy of lamotrigine tablets was established. In patients receiving multidrug regimens employing carbamazepine, phenytoin, phenobarbital, or primidone without valproate, maintenance doses of adjunctive lamotrigine tablets as high as 700 mg/day have been used. In patients receiving valproate alone, maintenance doses of adjunctive lamotrigine tablets as high as 200 mg/day have been used. The advantage of using doses above those recommended in Tables 1 through 4 has not been established in controlled trials.

  2.3 Epilepsy – Conversion From Adjunctive Therapy to Monotherapy

  The goal of the transition regimen is to effect the conversion to monotherapy with lamotrigine tablets under conditions that ensure adequate seizure control while mitigating the risk of serious rash associated with the rapid titration of lamotrigine tablets.

  The recommended maintenance dose of lamotrigine tablets as monotherapy is 500 mg/day given in 2 divided doses.

  To avoid an increased risk of rash, the recommended initial dose and subsequent dose escalations of lamotrigine tablets should not be exceeded [see Boxed Warning].

  Conversion From Adjunctive Therapy With Carbamazepine, Phenytoin, Phenobarbital, or Primidone to Monotherapy With Lamotrigine Tablets: After achieving a dose of 500 mg/day of lamotrigine tablets according to the guidelines in Table 1, the concomitant AED should be withdrawn by 20% decrements each week over a 4 week period. The regimen for the withdrawal of the concomitant AED is based on experience gained in the controlled monotherapy clinical trial.

  Conversion From Adjunctive Therapy With Valproate to Monotherapy With Lamotrigine Tablets: The conversion regimen involves 4 steps outlined in Table 4.

  Table 4. Conversion From Adjunctive Therapy With Valproate to Monotherapy With Lamotrigine in Patients ≥16 Years of Age with Epilepsy

   

  Lamotrigine

  Valproate

  Step 1

  Achieve a dose of 200 mg/day according to guidelines in Table 1 (if not already on 200 mg/day).

  Maintain previous stable dose.

  Step 2

  Maintain at 200 mg/day.

  Decrease to 500 mg/day by decrements no greater than 500 mg/day/week and then maintain the dose of 500 mg/day for 1 week.

  Step 3

  Increase to 300 mg/day and maintain for 1 week.

  Simultaneously decrease to 250 mg/day and maintain for 1 week.

  Step 4

  Increase by 100 mg/day every week to achieve maintenance dose of 500 mg/day.

  Discontinue.

  Conversion From Adjunctive Therapy With AEDs Other Than Carbamazepine, Phenytoin, Phenobarbital, Primidone, or Valproate to Monotherapy With Lamotrigine Tablets: No specific dosing guidelines can be provided for conversion to monotherapy with lamotrigine tablets with AEDs other than carbamazepine, phenobarbital, phenytoin, primidone, or valproate.

  2.4 Bipolar Disorder

  The goal of maintenance treatment with lamotrigine tablets is to delay the time to occurrence of mood episodes (depression, mania, hypomania, mixed episodes) in patients treated for acute mood episodes with standard therapy. The target dose of lamotrigine tablets is 200 mg/day (100 mg/day in patients taking valproate, which decreases the apparent clearance of lamotrigine, and 400 mg/day in patients not taking valproate and taking either carbamazepine, phenytoin, phenobarbital, primidone, or rifampin, which increase the apparent clearance of lamotrigine). In the clinical trials, doses up to 400 mg/day as monotherapy were evaluated; however, no additional benefit was seen at 400 mg/day compared with 200 mg/day [see Clinical Studies (14.2)]. Accordingly, doses above 200 mg/day are not recommended. Treatment with lamotrigine tablets is introduced, based on concurrent medications, according to the regimen outlined in Table 5. If other psychotropic medications are withdrawn following stabilization, the dose of lamotrigine tablets should be adjusted. For patients discontinuing valproate, the dose of lamotrigine tablets should be doubled over a 2 week period in equal weekly increments (see Table 6). For patients discontinuing carbamazepine, phenytoin, phenobarbital, primidone, or rifampin, the dose of lamotrigine tablets should remain constant for the first week and then should be decreased by half over a 2 week period in equal weekly decrements (see Table 6). The dose of lamotrigine tablets may then be further adjusted to the target dose (200 mg) as clinically indicated.

  If other drugs are subsequently introduced, the dose of lamotrigine tablets may need to be adjusted. In particular, the introduction of valproate requires reduction in the dose of lamotrigine tablets [see Drug Interactions (7), Clinical Pharmacology (12.3)].

  To avoid an increased risk of rash, the recommended initial dose and subsequent dose escalations of lamotrigine tablets should not be exceeded [see Boxed Warning].

   

  Table 5. Escalation Regimen for Lamotrigine for Patients With Bipolar Disorder* * See Drug Interactions (7) and Clinical Pharmacology (12.3) for a description of known drug interactions. † Valproate has been shown to decrease the apparent clearance of lamotrigine. ‡ Carbamazepine, phenytoin, phenobarbital, primidone, and rifampin have been shown to increase the apparent clearance of lamotrigine. For Patients Taking Valproate† For Patients Not Taking Carbamazepine, Phenytoin, Phenobarbital, Primidone, or Rifampin‡ and Not Taking Valproate† For Patients Taking Carbamazepine, Phenytoin, Phenobarbital, Primidone, or Rifampin‡ and Not Taking Valproate† Weeks 1 and 2 25 mg every other day 25 mg daily 50 mg daily Weeks 3 and 4 25 mg daily 50 mg daily 100 mg daily, in divided doses Week 5 50 mg daily 100 mg daily 200 mg daily, in divided doses Week 6 100 mg daily 200 mg daily 300 mg daily, in divided doses Week 7 100 mg daily 200 mg daily up to 400 mg daily, in divided doses Table 6. Dosage Adjustments to Lamotrigine for Patients With Bipolar Disorder Following Discontinuation of Psychotropic Medications* * See Drug Interactions (7) and Clinical Pharmacology (12.3) for a description of known drug interactions. † Carbamazepine, phenytoin, phenobarbital, primidone, and rifampin have been shown to increase the apparent clearance of lamotrigine. ‡ Valproate has been shown to decrease the apparent clearance of lamotrigine.   Discontinuation of Psychotropic Drugs (excluding Carbamazepine, Phenytoin, Phenobarbital, Primidone, Rifampin†, or Valproate‡) After Discontinuation of Valproate‡ After Discontinuation of Carbamazepine, Phenytoin, Phenobarbital, Primidone, or Rifampin† Current dose of Lamotrigine (mg/day) 100

  Current dose of Lamotrigine (mg/day)

  400

  Week 1 Maintain current dose of lamotrigine 150 400 Week 2 Maintain current dose of lamotrigine 200 300 Week 3 onward Maintain current dose of lamotrigine 200 200

  The benefit of continuing treatment in patients who had been stabilized in an 8 to 16 week open-label phase with lamotrigine tablets was established in 2 randomized, placebo-controlled clinical maintenance trials [see Clinical Studies (14.2)]. However, the optimal duration of treatment with lamotrigine tablets has not been established. Thus, patients should be periodically reassessed to determine the need for maintenance treatment.

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  Lamotrigine extended-release tablets are taken once daily, with or without food. Tablets must be swallowed whole and must not be chewed, crushed, or divided.

  2.1 General Dosing Considerations

  Rash: There are suggestions, yet to be proven, that the risk of severe, potentially life-threatening rash may be increased by (1) coadministration of lamotrigine extended-release tablets with valproate, (2) exceeding the recommended initial dose of lamotrigine extended-release tablets, or (3) exceeding the recommended dose escalation for lamotrigine extended-release tablets. However, cases have occurred in the absence of these factors [see Boxed Warning]. Therefore, it is important that the dosing recommendations be followed closely.

  The risk of nonserious rash may be increased when the recommended initial dose and/or the rate of dose escalation for lamotrigine extended-release tablet is exceeded and in patients with a history of allergy or rash to other AEDs.

  It is recommended that lamotrigine extended-release tablets not be restarted in patients who discontinued due to rash associated with prior treatment with lamotrigine, unless the potential benefits clearly outweigh the risks. If the decision is made to restart a patient who has discontinued lamotrigine extended-release tablets, the need to restart with the initial dosing recommendations should be assessed. The greater the interval of time since the previous dose, the greater consideration should be given to restarting with the initial dosing recommendations. If a patient has discontinued lamotrigine for a period of more than 5 half-lives, it is recommended that initial dosing recommendations and guidelines be followed. The half-life of lamotrigine is affected by other concomitant medications [see Clinical Pharmacology (12.3)].

  Lamotrigine Extended-Release Tablets Added to Drugs Known to Induce or Inhibit Glucuronidation: Drugs other than those listed in the Clinical Pharmacology section [see Clinical Pharmacology (12.3)] have not been systematically evaluated in combination with lamotrigine. Because lamotrigine is metabolized predominantly by glucuronic acid conjugation, drugs that are known to induce or inhibit glucuronidation may affect the apparent clearance of lamotrigine and doses of lamotrigine extended-release tablets may require adjustment based on clinical response.

  Target Plasma Levels: A therapeutic plasma concentration range has not been established for lamotrigine. Dosing of lamotrigine extended-release tablets should be based on therapeutic response [see Clinical Pharmacology (12.3)].

  Women Taking Estrogen-Containing Oral Contraceptives: Starting Lamotrigine Extended-Release Tablets in Women Taking Estrogen-Containing Oral Contraceptives: Although estrogen-containing oral contraceptives have been shown to increase the clearance of lamotrigine [see Clinical Pharmacology (12.3)], no adjustments to the recommended dose-escalation guidelines for lamotrigine extended-release tablets should be necessary solely based on the use of estrogen-containing oral contraceptives. Therefore, dose escalation should follow the recommended guidelines for initiating adjunctive therapy with lamotrigine extended-release tablets based on the concomitant AED or other concomitant medications (see Table 1). See below for adjustments to maintenance doses of lamotrigine extended-release tablets in women taking estrogen-containing oral contraceptives.

  Adjustments to the Maintenance Dose of Lamotrigine Extended-Release Tablets in Women Taking Estrogen-Containing Oral Contraceptives:

  (1) Taking Estrogen-Containing Oral Contraceptives: For women not taking carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin that induce lamotrigine glucuronidation [see Drug Interactions, (7), Clinical Pharmacology (12.3)], the maintenance dose of lamotrigine extended-release tablets will in most cases need to be increased by as much as 2-fold over the recommended target maintenance dose in order to maintain a consistent lamotrigine plasma level [see Clinical Pharmacology (12.3)].

  (2) Starting Estrogen-Containing Oral Contraceptives: In women taking a stable dose of lamotrigine extended-release tablets and not taking carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin that induce lamotrigine glucuronidation [see Drug Interactions (7), Clinical Pharmacology (12.3)], the maintenance dose will in most cases need to be increased by as much as 2-fold in order to maintain a consistent lamotrigine plasma level. The dose increases should begin at the same time that the oral contraceptive is introduced and continue, based on clinical response, no more rapidly than 50 to 100 mg/day every week. Dose increases should not exceed the recommended rate (see Table 1) unless lamotrigine plasma levels or clinical response support larger increases. Gradual transient increases in lamotrigine plasma levels may occur during the week of inactive hormonal preparation (pill-free week), and these increases will be greater if dose increases are made in the days before or during the week of inactive hormonal preparation. Increased lamotrigine plasma levels could result in additional adverse reactions, such as dizziness, ataxia, and diplopia. If adverse reactions attributable to lamotrigine extended-release tablets consistently occur during the pill-free week, dose adjustments to the overall maintenance dose may be necessary. Dose adjustments limited to the pill-free week are not recommended. For women taking lamotrigine extended-release tablets in addition to carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin that induce lamotrigine glucuronidation [see Drug Interactions (7), Clinical Pharmacology (12.3)], no adjustment to the dose of lamotrigine extended-release tablets should be necessary.

  (3) Stopping Estrogen-Containing Oral Contraceptives: For women not taking carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin that induce lamotrigine glucuronidation [see Drug Interactions (7), Clinical Pharmacology (12.3)], the maintenance dose of lamotrigine extended-release tablets will in most cases need to be decreased by as much as 50% in order to maintain a consistent lamotrigine plasma level. The decrease in dose of lamotrigine extended-release tablets should not exceed 25% of the total daily dose per week over a 2-week period, unless clinical response or lamotrigine plasma levels indicate otherwise [see Clinical Pharmacology (12.3)]. For women taking lamotrigine extended-release tablets in addition to carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin that induce lamotrigine glucuronidation [see Drug Interactions (7), Clinical Pharmacology (12.3)], no adjustment to the dose of lamotrigine extended-release tablets should be necessary.

  Women and Other Hormonal Contraceptive Preparations or Hormone Replacement Therapy: The effect of other hormonal contraceptive preparations or hormone replacement therapy on the pharmacokinetics of lamotrigine has not been systematically evaluated. It has been reported that ethinylestradiol, not progestogens, increased the clearance of lamotrigine up to 2-fold, and the progestin-only pills had no effect on lamotrigine plasma levels. Therefore, adjustments to the dosage of lamotrigine extended-release tablets in the presence of progestogens alone will likely not be needed.

  Patients With Hepatic Impairment: Experience in patients with hepatic impairment is limited. Based on a clinical pharmacology study in 24 patients with mild, moderate, and severe liver impairment [see Use in Specific Populations (8.6), Clinical Pharmacology (12.3)], the following general recommendations can be made. No dosage adjustment is needed in patients with mild liver impairment. Initial, escalation, and maintenance doses should generally be reduced by approximately 25% in patients with moderate and severe liver impairment without ascites and 50% in patients with severe liver impairment with ascites. Escalation and maintenance doses may be adjusted according to clinical response.

  Patients With Renal Impairment: Initial doses of lamotrigine extended-release tablets should be based on patients’ concomitant medications (see Table 1); reduced maintenance doses may be effective for patients with significant renal impairment [see Use in Specific Populations (8.7), Clinical Pharmacology (12.3)]. Few patients with severe renal impairment have been evaluated during chronic treatment with immediate-release lamotrigine. Because there is inadequate experience in this population, lamotrigine extended-release tablets should be used with caution in these patients.

  Discontinuation Strategy: For patients receiving lamotrigine extended-release tablets in combination with other AEDs, a re-evaluation of all AEDs in the regimen should be considered if a change in seizure control or an appearance or worsening of adverse reactions is observed.

  If a decision is made to discontinue therapy with lamotrigine extended-release tablets, a step-wise reduction of dose over at least 2 weeks (approximately 50% per week) is recommended unless safety concerns require a more rapid withdrawal [see Warnings and Precautions (5.8)].

  Discontinuing carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin that induce lamotrigine glucuronidation should prolong the half-life of lamotrigine; discontinuing valproate should shorten the half-life of lamotrigine.

  2.2 Adjunctive Therapy for Partial Onset Seizures

  This section provides specific dosing recommendations for patients ≥13 years of age. Specific dosing recommendations are provided depending upon concomitant AED or other concomitant medications.

  Table 1. Escalation Regimen for Lamotrigine Extended-Release Tablets in Patients ≥13 Years of Age

  a Valproate has been shown to inhibit glucuronidation and decrease the apparent
  

  clearance of lamotrigine [see Drug Interactions (7), Clinical Pharmacology (12.3)].

  b These drugs induce glucuronidation and increase clearance [see Drug Interactions (7),

  Clinical Pharmacology (12.3)]. Other drugs which have similar effects include estrogen-

  containing oral contraceptives [see Drug Interactions (7), Clinical Pharmacology (12.3)].

  Dosing recommendations for oral contraceptives can be found in General Dosing
  

  Considerations [see Dosage and Administration (2.1)]. Patients on rifampin, or other drugs

  that induce lamotrigine glucuronidation and increase clearance, should follow the same
  

  dosing titration/maintenance regimen as that used with anticonvulsants that have this
  

  effect.
  

  c Dose increases at week 8 or later should not exceed 100 mg daily at weekly intervals.

  
  For Patients TAKING 
  Valproatea
  For Patients NOT
  TAKING Carbamazepine,
  Phenytoin, Phenobarbital, 
  Primidoneb, or
  Valproatea
  For Patients TAKING 
  Carbamazepine,
  Phenytoin, 
  Phenobarbital, or 
  Primidoneb and NOT 
  TAKING Valproatea
  Weeks 1 and 2 
  25 mg every
  other day 
  25 mg every day 
  50 mg every day 
  Weeks 3 and 4 
  25 mg every day 
  50 mg every day 
  100 mg every day 
  Week 5 
  50 mg every day 
  100 mg every day 
  200 mg every day 
  Week 6 
  100 mg every day 
  150 mg every day 
  300 mg every day 
  Week 7 
  150 mg every day 
  200 mg every day 
  400 mg every day 
  Maintenance range 
  (week 8 and
  onward) 
  200 to 250 mg
  every dayc 
  300 to 400 mg
  every dayc 
  400 to 600 mg
  every dayc 
  2.3 2.3 2.4 Conversion From Immediate-Release Lamotrigine Tablets to Lamotrigine Extended-Release Tablets

  Patients may be converted directly from immediate-release lamotrigine to lamotrigine extended-release tablets. The initial dose of lamotrigine extended-release tablets should match the total daily dose of immediate-release lamotrigine. However, some subjects on concomitant enzyme-inducing agents may have lower plasma levels of lamotrigine on conversion and should be monitored [see Clinical Pharmacology (12.3)].

  Following conversion to lamotrigine extended-release tablets, all patients (but especially those on drugs that induce lamotrigine glucuronidation) should be closely monitored for seizure control [see Drug Interactions (7)]. Depending on the therapeutic response after conversion, the total daily dose may need to be adjusted within the recommended dosing instructions (Table 1).

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  Lamotrigine extended-release tablets are taken once daily, with or without food. Tablets must be swallowed whole and must not be chewed, crushed, or divided.

  2.1 General Dosing Considerations

  Rash: There are suggestions, yet to be proven, that the risk of severe, potentially life-threatening rash may be increased by (1) coadministration of lamotrigine extended-release tablets with valproate, (2) exceeding the recommended initial dose of lamotrigine extended-release tablets, or (3) exceeding the recommended dose escalation for lamotrigine extended-release tablets. However, cases have occurred in the absence of these factors [see Boxed Warning]. Therefore, it is important that the dosing recommendations be followed closely.

  The risk of nonserious rash may be increased when the recommended initial dose and/or the rate of dose escalation for lamotrigine extended-release tablet is exceeded and in patients with a history of allergy or rash to other AEDs.

  It is recommended that lamotrigine extended-release tablets not be restarted in patients who discontinued due to rash associated with prior treatment with lamotrigine, unless the potential benefits clearly outweigh the risks. If the decision is made to restart a patient who has discontinued lamotrigine extended-release tablets, the need to restart with the initial dosing recommendations should be assessed. The greater the interval of time since the previous dose, the greater consideration should be given to restarting with the initial dosing recommendations. If a patient has discontinued lamotrigine for a period of more than 5 half-lives, it is recommended that initial dosing recommendations and guidelines be followed. The half-life of lamotrigine is affected by other concomitant medications [see Clinical Pharmacology (12.3)].

  Lamotrigine Extended-Release Tablets Added to Drugs Known to Induce or Inhibit Glucuronidation: Drugs other than those listed in the Clinical Pharmacology section [see Clinical Pharmacology (12.3)] have not been systematically evaluated in combination with lamotrigine. Because lamotrigine is metabolized predominantly by glucuronic acid conjugation, drugs that are known to induce or inhibit glucuronidation may affect the apparent clearance of lamotrigine and doses of lamotrigine extended-release tablets may require adjustment based on clinical response.

  Target Plasma Levels: A therapeutic plasma concentration range has not been established for lamotrigine. Dosing of lamotrigine extended-release tablets should be based on therapeutic response [see Clinical Pharmacology (12.3)].

  Women Taking Estrogen-Containing Oral Contraceptives: Starting Lamotrigine Extended-Release Tablets in Women Taking Estrogen-Containing Oral Contraceptives: Although estrogen-containing oral contraceptives have been shown to increase the clearance of lamotrigine [see Clinical Pharmacology (12.3)], no adjustments to the recommended dose-escalation guidelines for lamotrigine extended-release tablets should be necessary solely based on the use of estrogen-containing oral contraceptives. Therefore, dose escalation should follow the recommended guidelines for initiating adjunctive therapy with lamotrigine extended-release tablets based on the concomitant AED or other concomitant medications (see Table 1). See below for adjustments to maintenance doses of lamotrigine extended-release tablets in women taking estrogen-containing oral contraceptives.

  Adjustments to the Maintenance Dose of Lamotrigine Extended-Release Tablets in Women Taking Estrogen-Containing Oral Contraceptives:

  (1) Taking Estrogen-Containing Oral Contraceptives: For women not taking carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin that induce lamotrigine glucuronidation [see Drug Interactions, (7), Clinical Pharmacology (12.3)], the maintenance dose of lamotrigine extended-release tablets will in most cases need to be increased by as much as 2-fold over the recommended target maintenance dose in order to maintain a consistent lamotrigine plasma level [see Clinical Pharmacology (12.3)].

  (2) Starting Estrogen-Containing Oral Contraceptives: In women taking a stable dose of lamotrigine extended-release tablets and not taking carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin that induce lamotrigine glucuronidation [see Drug Interactions (7), Clinical Pharmacology (12.3)], the maintenance dose will in most cases need to be increased by as much as 2-fold in order to maintain a consistent lamotrigine plasma level. The dose increases should begin at the same time that the oral contraceptive is introduced and continue, based on clinical response, no more rapidly than 50 to 100 mg/day every week. Dose increases should not exceed the recommended rate (see Table 1) unless lamotrigine plasma levels or clinical response support larger increases. Gradual transient increases in lamotrigine plasma levels may occur during the week of inactive hormonal preparation (pill-free week), and these increases will be greater if dose increases are made in the days before or during the week of inactive hormonal preparation. Increased lamotrigine plasma levels could result in additional adverse reactions, such as dizziness, ataxia, and diplopia. If adverse reactions attributable to lamotrigine extended-release tablets consistently occur during the pill-free week, dose adjustments to the overall maintenance dose may be necessary. Dose adjustments limited to the pill-free week are not recommended. For women taking lamotrigine extended-release tablets in addition to carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin that induce lamotrigine glucuronidation [see Drug Interactions (7), Clinical Pharmacology (12.3)], no adjustment to the dose of lamotrigine extended-release tablets should be necessary.

  (3) Stopping Estrogen-Containing Oral Contraceptives: For women not taking carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin that induce lamotrigine glucuronidation [see Drug Interactions (7), Clinical Pharmacology (12.3)], the maintenance dose of lamotrigine extended-release tablets will in most cases need to be decreased by as much as 50% in order to maintain a consistent lamotrigine plasma level. The decrease in dose of lamotrigine extended-release tablets should not exceed 25% of the total daily dose per week over a 2-week period, unless clinical response or lamotrigine plasma levels indicate otherwise [see Clinical Pharmacology (12.3)]. For women taking lamotrigine extended-release tablets in addition to carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin that induce lamotrigine glucuronidation [see Drug Interactions (7), Clinical Pharmacology (12.3)], no adjustment to the dose of lamotrigine extended-release tablets should be necessary.

  Women and Other Hormonal Contraceptive Preparations or Hormone Replacement Therapy: The effect of other hormonal contraceptive preparations or hormone replacement therapy on the pharmacokinetics of lamotrigine has not been systematically evaluated. It has been reported that ethinylestradiol, not progestogens, increased the clearance of lamotrigine up to 2-fold, and the progestin-only pills had no effect on lamotrigine plasma levels. Therefore, adjustments to the dosage of lamotrigine extended-release tablets in the presence of progestogens alone will likely not be needed.

  Patients With Hepatic Impairment: Experience in patients with hepatic impairment is limited. Based on a clinical pharmacology study in 24 patients with mild, moderate, and severe liver impairment [see Use in Specific Populations (8.6), Clinical Pharmacology (12.3)], the following general recommendations can be made. No dosage adjustment is needed in patients with mild liver impairment. Initial, escalation, and maintenance doses should generally be reduced by approximately 25% in patients with moderate and severe liver impairment without ascites and 50% in patients with severe liver impairment with ascites. Escalation and maintenance doses may be adjusted according to clinical response.

  Patients With Renal Impairment: Initial doses of lamotrigine extended-release tablets should be based on patients’ concomitant medications (see Table 1); reduced maintenance doses may be effective for patients with significant renal impairment [see Use in Specific Populations (8.7), Clinical Pharmacology (12.3)]. Few patients with severe renal impairment have been evaluated during chronic treatment with immediate-release lamotrigine. Because there is inadequate experience in this population, lamotrigine extended-release tablets should be used with caution in these patients.

  Discontinuation Strategy: For patients receiving lamotrigine extended-release tablets in combination with other AEDs, a re-evaluation of all AEDs in the regimen should be considered if a change in seizure control or an appearance or worsening of adverse reactions is observed.

  If a decision is made to discontinue therapy with lamotrigine extended-release tablets, a step-wise reduction of dose over at least 2 weeks (approximately 50% per week) is recommended unless safety concerns require a more rapid withdrawal [see Warnings and Precautions (5.8)].

  Discontinuing carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin that induce lamotrigine glucuronidation should prolong the half-life of lamotrigine; discontinuing valproate should shorten the half-life of lamotrigine.

  2.2 Adjunctive Therapy for Partial Onset Seizures

  This section provides specific dosing recommendations for patients ≥13 years of age. Specific dosing recommendations are provided depending upon concomitant AED or other concomitant medications.

  Table 1. Escalation Regimen for Lamotrigine Extended-Release Tablets in Patients ≥13 Years of Age

  a Valproate has been shown to inhibit glucuronidation and decrease the apparent
  

  clearance of lamotrigine [see Drug Interactions (7), Clinical Pharmacology (12.3)].

  b These drugs induce glucuronidation and increase clearance [see Drug Interactions (7),

  Clinical Pharmacology (12.3)]. Other drugs which have similar effects include estrogen-

  containing oral contraceptives [see Drug Interactions (7), Clinical Pharmacology (12.3)].

  Dosing recommendations for oral contraceptives can be found in General Dosing
  

  Considerations [see Dosage and Administration (2.1)]. Patients on rifampin, or other drugs

  that induce lamotrigine glucuronidation and increase clearance, should follow the same
  

  dosing titration/maintenance regimen as that used with anticonvulsants that have this
  

  effect.
  

  c Dose increases at week 8 or later should not exceed 100 mg daily at weekly intervals.

  
  For Patients TAKING 
  Valproatea
  For Patients NOT
  TAKING Carbamazepine,
  Phenytoin, Phenobarbital, 
  Primidoneb, or
  Valproatea
  For Patients TAKING 
  Carbamazepine,
  Phenytoin, 
  Phenobarbital, or 
  Primidoneb and NOT 
  TAKING Valproatea
  Weeks 1 and 2 
  25 mg every
  other day 
  25 mg every day 
  50 mg every day 
  Weeks 3 and 4 
  25 mg every day 
  50 mg every day 
  100 mg every day 
  Week 5 
  50 mg every day 
  100 mg every day 
  200 mg every day 
  Week 6 
  100 mg every day 
  150 mg every day 
  300 mg every day 
  Week 7 
  150 mg every day 
  200 mg every day 
  400 mg every day 
  Maintenance range 
  (week 8 and
  onward) 
  200 to 250 mg
  every dayc 
  300 to 400 mg
  every dayc 
  400 to 600 mg
  every dayc 
  2.3 2.3 2.4 Conversion From Immediate-Release Lamotrigine Tablets to Lamotrigine Extended-Release Tablets

  Patients may be converted directly from immediate-release lamotrigine to lamotrigine extended-release tablets. The initial dose of lamotrigine extended-release tablets should match the total daily dose of immediate-release lamotrigine. However, some subjects on concomitant enzyme-inducing agents may have lower plasma levels of lamotrigine on conversion and should be monitored [see Clinical Pharmacology (12.3)].

  Following conversion to lamotrigine extended-release tablets, all patients (but especially those on drugs that induce lamotrigine glucuronidation) should be closely monitored for seizure control [see Drug Interactions (7)]. Depending on the therapeutic response after conversion, the total daily dose may need to be adjusted within the recommended dosing instructions (Table 1).

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  Lamotrigine | Upsher-smith Laboratories, Inc.

  

  ---

  2.1 General Dosing Considerations

  Rash: There are suggestions, yet to be proven, that the risk of severe, potentially life-threatening rash may be increased by (1) coadministration of lamotrigine with valproate, (2) exceeding the recommended initial dose of lamotrigine, or (3) exceeding the recommended dose escalation for lamotrigine. However, cases have occurred in the absence of these factors [see Boxed Warning]. Therefore, it is important that the dosing recommendations be followed closely.

  The risk of nonserious rash may be increased when the recommended initial dose and/or the rate of dose escalation of Lamotrigine Tablets is exceeded and in patients with a history of allergy or rash to other AEDs.

  Lamotrigine Tablets Starter Kits provide Lamotrigine Tablets at doses consistent with the recommended titration schedule for the first 5 weeks of treatment, based upon concomitant medications for patients with epilepsy (>12 years of age) and Bipolar I Disorder (≥18 years of age) and are intended to help reduce the potential for rash. The use of Lamotrigine Tablets Starter Kits is recommended for appropriate patients who are starting or restarting Lamotrigine Tablets [see How Supplied/Storage and Handling (16)].

  It is recommended that Lamotrigine Tablets not be restarted in patients who discontinued due to rash associated with prior treatment with lamotrigine, unless the potential benefits clearly outweigh the risks. If the decision is made to restart a patient who has discontinued lamotrigine, the need to restart with the initial dosing recommendations should be assessed. The greater the interval of time since the previous dose, the greater consideration should be given to restarting with the initial dosing recommendations. If a patient has discontinued lamotrigine for a period of more than 5 half-lives, it is recommended that initial dosing recommendations and guidelines be followed. The half-life of lamotrigine is affected by other concomitant medications [see Clinical Pharmacology (12.3)].

  Lamotrigine Tablets Added to Drugs Known to Induce or Inhibit Glucuronidation: Drugs other than those listed in the Clinical Pharmacology section [see Clinical Pharmacology (12.3)] have not been systematically evaluated in combination with lamotrigine. Because lamotrigine is metabolized predominantly by glucuronic acid conjugation, drugs that are known to induce or inhibit glucuronidation may affect the apparent clearance of lamotrigine and doses of Lamotrigine Tablets may require adjustment based on clinical response.

  Target Plasma Levels for Patients With Epilepsy or Bipolar Disorder: A therapeutic plasma concentration range has not been established for lamotrigine. Dosing of Lamotrigine Tablets should be based on therapeutic response [see Clinical Pharmacology (12.3)].

  Women Taking Estrogen-Containing Oral Contraceptives: Starting Lamotrigine Tablets in Women Taking Estrogen-Containing Oral Contraceptives: Although estrogen-containing oral contraceptives have been shown to increase the clearance of lamotrigine [see Clinical Pharmacology (12.3)], no adjustments to the recommended dose-escalation guidelines for Lamotrigine Tablets should be necessary solely based on the use of estrogen-containing oral contraceptives. Therefore, dose escalation should follow the recommended guidelines for initiating adjunctive therapy with Lamotrigine Tablets based on the concomitant AED or other concomitant medications (see Table 1 or Table 5). See below for adjustments to maintenance doses of Lamotrigine Tablets in women taking estrogen-containing oral contraceptives.

  Adjustments to the Maintenance Dose of Lamotrigine Tablets in Women Taking Estrogen-Containing Oral Contraceptives:

  (1) Taking Estrogen-Containing Oral Contraceptives: For women not taking carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin that induce lamotrigine glucuronidation [see Drug Interactions (7), Clinical Pharmacology (12.3)], the maintenance dose of Lamotrigine Tablets will in most cases need to be increased, by as much as 2-fold over the recommended target maintenance dose, in order to maintain a consistent lamotrigine plasma level [see Clinical Pharmacology (12.3)].

  (2) Starting Estrogen-Containing Oral Contraceptives: In women taking a stable dose of Lamotrigine Tablets and not taking carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin that induce lamotrigine glucuronidation [see Drug Interactions (7), Clinical Pharmacology (12.3)], the maintenance dose will in most cases need to be increased by as much as 2-fold in order to maintain a consistent lamotrigine plasma level. The dose increases should begin at the same time that the oral contraceptive is introduced and continue, based on clinical response, no more rapidly than 50 to 100 mg/day every week. Dose increases should not exceed the recommended rate (see Table 1 or Table 5) unless lamotrigine plasma levels or clinical response support larger increases. Gradual transient increases in lamotrigine plasma levels may occur during the week of inactive hormonal preparation ("pill-free" week), and these increases will be greater if dose increases are made in the days before or during the week of inactive hormonal preparation. Increased lamotrigine plasma levels could result in additional adverse reactions, such as dizziness, ataxia, and diplopia. If adverse reactions attributable to Lamotrigine Tablets consistently occur during the "pill-free" week, dose adjustments to the overall maintenance dose may be necessary. Dose adjustments limited to the "pill-free" week are not recommended. For women taking Lamotrigine Tablets in addition to carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin that induce lamotrigine glucuronidation [see Drug Interactions (7), Clinical Pharmacology (12.3)], no adjustment to the dose of Lamotrigine Tablets should be necessary.

  (3) Stopping Estrogen-Containing Oral Contraceptives: For women not taking carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin that induce lamotrigine glucuronidation [see Drug Interactions (7), Clinical Pharmacology (12.3)], the maintenance dose of Lamotrigine Tablets will in most cases need to be decreased by as much as 50% in order to maintain a consistent lamotrigine plasma level. The decrease in dose of Lamotrigine Tablets should not exceed 25% of the total daily dose per week over a 2-week period, unless clinical response or lamotrigine plasma levels indicate otherwise [see Clinical Pharmacology (12.3)]. For women taking Lamotrigine Tablets in addition to carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin that induce lamotrigine glucuronidation [see Drug Interactions (7), Clinical Pharmacology (12.3)], no adjustment to the dose of Lamotrigine Tablets should be necessary.

  Women and Other Hormonal Contraceptive Preparations or Hormone Replacement Therapy: The effect of other hormonal contraceptive preparations or hormone replacement therapy on the pharmacokinetics of lamotrigine has not been systematically evaluated. It has been reported that ethinylestradiol, not progestogens, increased the clearance of lamotrigine up to 2-fold, and the progestin-only pills had no effect on lamotrigine plasma levels. Therefore, adjustments to the dosage of Lamotrigine Tablets in the presence of progestogens alone will likely not be needed.

  Patients With Hepatic Impairment: Experience in patients with hepatic impairment is limited. Based on a clinical pharmacology study in 24 patients with mild, moderate, and severe liver impairment [see Use in Specific Populations (8.6), Clinical Pharmacology (12.3)], the following general recommendations can be made. No dosage adjustment is needed in patients with mild liver impairment. Initial, escalation, and maintenance doses should generally be reduced by approximately 25% in patients with moderate and severe liver impairment without ascites and 50% in patients with severe liver impairment with ascites. Escalation and maintenance doses may be adjusted according to clinical response.

  Patients With Renal Impairment: Initial doses of Lamotrigine Tablets should be based on patients' concomitant medications (see Tables 1-3 or Table 5); reduced maintenance doses may be effective for patients with significant renal impairment [see Use in Specific Populations (8.7), Clinical Pharmacology (12.3)]. Few patients with severe renal impairment have been evaluated during chronic treatment with Lamotrigine Tablets. Because there is inadequate experience in this population, Lamotrigine Tablets should be used with caution in these patients.

  Discontinuation Strategy: Epilepsy: For patients receiving Lamotrigine Tablets in combination with other AEDs, a reevaluation of all AEDs in the regimen should be considered if a change in seizure control or an appearance or worsening of adverse reactions is observed.

  If a decision is made to discontinue therapy with Lamotrigine Tablets, a step-wise reduction of dose over at least 2 weeks (approximately 50% per week) is recommended unless safety concerns require a more rapid withdrawal [see Warnings and Precautions (5.9)].

  Discontinuing carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin that induce lamotrigine glucuronidation should prolong the half-life of lamotrigine; discontinuing valproate should shorten the half-life of lamotrigine.

  Bipolar Disorder: In the controlled clinical trials, there was no increase in the incidence, type, or severity of adverse reactions following abrupt termination of lamotrigine. In clinical trials in patients with Bipolar Disorder, 2 patients experienced seizures shortly after abrupt withdrawal of lamotrigine. However, there were confounding factors that may have contributed to the occurrence of seizures in these bipolar patients. Discontinuation of Lamotrigine Tablets should involve a step-wise reduction of dose over at least 2 weeks (approximately 50% per week) unless safety concerns require a more rapid withdrawal [see Warnings and Precautions (5.9)].

  2.2 Epilepsy – Adjunctive Therapy

  This section provides specific dosing recommendations for patients greater than 12 years of age and patients 2 to 12 years of age. Within each of these age-groups, specific dosing recommendations are provided depending upon concomitant AED or other concomitant medications (Table 1 for patients greater than 12 years of age and Table 2 for patients 2 to 12 years of age). A weight-based dosing guide for patients 2 to 12 years of age on concomitant valproate is provided in Table 3.

  Patients Over 12 Years of Age: Recommended dosing guidelines are summarized in Table 1.

  Table 1. Escalation Regimen for Lamotrigine Tablets in Patients Over 12 Years of Age With Epilepsy For Patients TAKING Valproate* For Patients NOT TAKING Carbamazepine, Phenytoin, Phenobarbital, Primidone†, or Valproate* For Patients TAKING Carbamazepine, Phenytoin, Phenobarbital, or Primidone† and NOT TAKING Valproate* * Valproate has been shown to inhibit glucuronidation and decrease the apparent clearance of lamotrigine [see Drug Interactions (7), Clinical Pharmacology (12.3)]. † These drugs induce lamotrigine glucuronidation and increase clearance [see Drug Interactions (7), Clinical Pharmacology (12.3)]. Other drugs that have similar effects include estrogen-containing oral contraceptives [see Drug Interactions (7), Clinical Pharmacology (12.3)]. Dosing recommendations for oral contraceptives can be found in General Dosing Considerations [ see Dosage and Administration (2.1)]. Patients on rifampin, or other drugs that induce lamotrigine glucuronidation and increase clearance, should follow the same dosing titration/maintenance regimen as that used with anticonvulsants that have this effect. Weeks 1 and 2 25 mg every other day 25 mg every day 50 mg/day Weeks 3 and 4 25 mg every day 50 mg/day 100 mg/day
  (in 2 divided doses) Week 5 onwards to maintenance Increase by 25 to 50 mg/day every 1 to 2 weeks Increase by 50 mg/day every 1 to 2 weeks Increase by 100 mg/day every 1 to 2 weeks Usual maintenance dose 100 to 200 mg/day with valproate alone
  
  100 to 400 mg/day with valproate and other drugs that induce glucuronidation (in 1 or 2 divided doses) 225 to 375 mg/day
  (in 2 divided doses) 300 to 500 mg/day
  (in 2 divided doses)

  Patients 2 to 12 Years of Age: Recommended dosing guidelines are summarized in Table 2.

  Smaller starting doses and slower dose escalations than those used in clinical trials are recommended because of the suggestion that the risk of rash may be decreased by smaller starting doses and slower dose escalations. Therefore, maintenance doses will take longer to reach in clinical practice than in clinical trials. It may take several weeks to months to achieve an individualized maintenance dose. Maintenance doses in patients weighing less than 30 kg, regardless of age or concomitant AED, may need to be increased as much as 50%, based on clinical response.

  Table 2. Escalation Regimen for Lamotrigine Tablets in Patients 2 to 12 Years of Age With Epilepsy For Patients TAKING Valproate*
  For Patients NOT TAKING Carbamazepine, Phenytoin, Phenobarbital, Primidone†, or Valproate* For Patients TAKING Carbamazepine, Phenytoin, Phenobarbital, or Primidone† and NOT TAKING Valproate* Note: Only whole tablets should be used for dosing. * Valproate has been shown to inhibit glucuronidation and decrease the apparent clearance of lamotrigine [see Drug Interactions (7), Clinical Pharmacology (12.3)]. † These drugs induce lamotrigine glucuronidation and increase clearance [see Drug Interactions (7), Clinical Pharmacology (12.3)]. Other drugs that have similar effects include estrogen-containing oral contraceptives [see Drug Interactions (7), Clinical Pharmacology (12.3)]. Dosing recommendations for oral contraceptives can be found in General Dosing Considerations [see Dosage and Administration (2.1)]. Patients on rifampin, or other drugs that induce lamotrigine glucuronidation and increase clearance, should follow the same dosing titration/maintenance regimen as that used with anticonvulsants that have this effect. Weeks 1 and 2 0.15 mg/kg/day in 1 or 2 divided doses, rounded down to the nearest whole tablet (see Table 3 for weight-based dosing guide) 0.3 mg/kg/day in 1 or 2 divided doses, rounded down to the nearest whole tablet 0.6 mg/kg/day in 2 divided doses, rounded down to the nearest whole tablet Weeks 3 and 4 0.3 mg/kg/day in 1 or 2 divided doses, rounded down to the nearest whole tablet (see Table 3 for weight-based dosing guide) 0.6 mg/kg/day in 2 divided doses, rounded down to the nearest whole tablet 1.2 mg/kg/day in 2 divided doses, rounded down to the nearest whole tablet Week 5 onwards to maintenance The dose should be increased every 1 to 2 weeks as follows: calculate 0.3 mg/kg/day, round this amount down to the nearest whole tablet, and add this amount to the previously administered daily dose The dose should be increased every 1 to 2 weeks as follows: calculate 0.6 mg/kg/day, round this amount down to the nearest whole tablet, and add this amount to the previously administered daily dose The dose should be increased every 1 to 2 weeks as follows: calculate 1.2 mg/kg/day, round this amount down to the nearest whole tablet, and add this amount to the previously administered daily dose Usual maintenance dose 1 to 5 mg/kg/day
  (maximum 200 mg/day in 1 or 2 divided doses)
  1 to 3 mg/kg/day with valproate alone 4.5 to 7.5 mg/kg/day
  (maximum 300 mg/day in 2 divided doses) 5 to 15 mg/kg/day
  (maximum 400 mg/day in 2 divided doses) Maintenance dose in patients less than 30 kg May need to be increased by as much as 50%, based on clinical response May need to be increased by as much as 50%, based on clinical response May need to be increased by as much as 50%, based on clinical response Table 3. The Initial Weight-Based Dosing Guide for Patients 2 to 12 Years of Age Taking Valproate (Weeks 1 to 4) With Epilepsy If the patient's weight is Give this daily dose, using the most appropriate combination of Lamotrigine Tablets 2 mg and 5 mg tablets Greater than And less than Weeks 1 and 2 Weeks 3 and 4 6.7 kg 14 kg 2 mg every other day 2 mg every day 14.1 kg 27 kg 2 mg every day 4 mg every day 27.1 kg 34 kg 4 mg every day 8 mg every day 34.1 kg 40 kg 5 mg every day 10 mg every day

  Usual Adjunctive Maintenance Dose for Epilepsy: The usual maintenance doses identified in Tables 1 and 2 are derived from dosing regimens employed in the placebo-controlled adjunctive studies in which the efficacy of lamotrigine was established. In patients receiving multidrug regimens employing carbamazepine, phenytoin, phenobarbital, or primidone without valproate, maintenance doses of adjunctive lamotrigine as high as 700 mg/day have been used. In patients receiving valproate alone, maintenance doses of adjunctive lamotrigine as high as 200 mg/day have been used. The advantage of using doses above those recommended in Tables 1 through 4 has not been established in controlled trials.

  2.3 Epilepsy – Conversion From Adjunctive Therapy to Monotherapy

  The goal of the transition regimen is to effect the conversion to monotherapy with Lamotrigine Tablets under conditions that ensure adequate seizure control while mitigating the risk of serious rash associated with the rapid titration of Lamotrigine Tablets.

  The recommended maintenance dose of Lamotrigine Tablets as monotherapy is 500 mg/day given in 2 divided doses.

  To avoid an increased risk of rash, the recommended initial dose and subsequent dose escalations of Lamotrigine Tablets should not be exceeded [see Boxed Warning].

  Conversion From Adjunctive Therapy With Carbamazepine, Phenytoin, Phenobarbital, or Primidone to Monotherapy With Lamotrigine Tablets: After achieving a dose of 500 mg/day of Lamotrigine Tablets according to the guidelines in Table 1, the concomitant AED should be withdrawn by 20% decrements each week over a 4-week period. The regimen for the withdrawal of the concomitant AED is based on experience gained in the controlled monotherapy clinical trial.

  Conversion From Adjunctive Therapy With Valproate to Monotherapy With Lamotrigine Tablets: The conversion regimen involves 4 steps outlined in Table 4.

  Table 4. Conversion From Adjunctive Therapy With Valproate to Monotherapy With Lamotrigine Tablets in Patients ≥16 Years of Age With Epilepsy Lamotrigine Tablets Valproate Step 1 Achieve a dose of 200 mg/day according to guidelines in Table 1 (if not already on 200 mg/day). Maintain previous stable dose. Step 2 Maintain at 200 mg/day. Decrease to 500 mg/day by decrements no greater than 500 mg/day/week and then maintain the dose of 500 mg/day for 1 week. Step 3 Increase to 300 mg/day and maintain for 1 week. Simultaneously decrease to 250 mg/day and maintain for 1 week. Step 4 Increase by 100 mg/day every week to achieve maintenance dose of 500 mg/day. Discontinue.

  Conversion From Adjunctive Therapy With Antiepileptic Drugs Other Than Carbamazepine, Phenytoin, Phenobarbital, Primidone, or Valproate to Monotherapy With Lamotrigine Tablets: No specific dosing guidelines can be provided for conversion to monotherapy with Lamotrigine Tablets with AEDs other than carbamazepine, phenobarbital, phenytoin, primidone, or valproate.

  2.4 Bipolar Disorder

  The goal of maintenance treatment with Lamotrigine Tablets is to delay the time to occurrence of mood episodes (depression, mania, hypomania, mixed episodes) in patients treated for acute mood episodes with standard therapy. The target dose of Lamotrigine Tablets is 200 mg/day (100 mg/day in patients taking valproate, which decreases the apparent clearance of lamotrigine, and 400 mg/day in patients not taking valproate and taking either carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin that increase the apparent clearance of lamotrigine). In the clinical trials, doses up to 400 mg/day as monotherapy were evaluated; however, no additional benefit was seen at 400 mg/day compared with 200 mg/day [see Clinical Studies (14.2)]. Accordingly, doses above 200 mg/day are not recommended. Treatment with Lamotrigine Tablets is introduced, based on concurrent medications, according to the regimen outlined in Table 5. If other psychotropic medications are withdrawn following stabilization, the dose of Lamotrigine Tablets should be adjusted. For patients discontinuing valproate, the dose of Lamotrigine Tablets should be doubled over a 2-week period in equal weekly increments (see Table 6). For patients discontinuing carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin that induce lamotrigine glucuronidation, the dose of Lamotrigine Tablets should remain constant for the first week and then should be decreased by half over a 2-week period in equal weekly decrements (see Table 6). The dose of Lamotrigine Tablets may then be further adjusted to the target dose (200 mg) as clinically indicated.

  If other drugs are subsequently introduced, the dose of Lamotrigine Tablets may need to be adjusted. In particular, the introduction of valproate requires reduction in the dose of Lamotrigine Tablets [see Drug Interactions (7), Clinical Pharmacology (12.3)].

  To avoid an increased risk of rash, the recommended initial dose and subsequent dose escalations of Lamotrigine Tablets should not be exceeded [see Boxed Warning].

  Table 5. Escalation Regimen for Lamotrigine Tablets for Patients With Bipolar Disorder For Patients TAKING Valproate* For Patients NOT TAKING Carbamazepine, Phenytoin, Phenobarbital, Primidone,† or Valproate* For Patients TAKING Carbamazepine, Phenytoin, Phenobarbital, or Primidone,† and NOT TAKING Valproate* * Valproate has been shown to inhibit glucuronidation and decrease the apparent clearance of lamotrigine [see Drug Interactions (7), Clinical Pharmacology (12.3)]. † These drugs induce lamotrigine glucuronidation and increase clearance [see Drug Interactions (7), Clinical Pharmacology (12.3)]. Other drugs that have similar effects include estrogen-containing oral contraceptives [see Drug Interactions (7), Clinical Pharmacology (12.3)]. Dosing recommendations for oral contraceptives can be found in General Dosing Considerations [see Dosage and Administration (2.1)]. Patients on rifampin, or other drugs that induce lamotrigine glucuronidation and increase clearance, should follow the same dosing titration/maintenance regimen as that used with anticonvulsants that have this effect. Weeks 1 and 2 25 mg every other day 25 mg daily 50 mg daily Weeks 3 and 4 25 mg daily 50 mg daily 100 mg daily, in divided doses Week 5 50 mg daily 100 mg daily 200 mg daily, in divided doses Week 6 100 mg daily 200 mg daily 300 mg daily, in divided doses Week 7 100 mg daily 200 mg daily up to 400 mg daily, in divided doses Table 6. Dosage Adjustments to Lamotrigine Tablets for Patients With Bipolar Disorder Following Discontinuation of Psychotropic Medications Discontinuation of Psychotropic Drugs (excluding Carbamazepine, Phenytoin, Phenobarbital, Primidone,* or Valproate†) After Discontinuation of Valproate† After Discontinuation of Carbamazepine, Phenytoin, Phenobarbital, or Primidone* Current dose of Lamotrigine Tablets (mg/day) 100 Current dose of Lamotrigine Tablets (mg/day) 400 * These drugs induce lamotrigine glucuronidation and increase clearance [see Drug Interactions (7), Clinical Pharmacology (12.3)]. Other drugs that have similar effects include estrogen-containing oral contraceptives [see Drug Interactions (7), Clinical Pharmacology (12.3)]. Dosing recommendations for oral contraceptives can be found in General Dosing Considerations [see Dosage and Administration (2.1)]. Patients on rifampin, or other drugs that induce lamotrigine glucuronidation and increase clearance, should follow the same dosing titration/maintenance regimen as that used with anticonvulsants that have this effect. † Valproate has been shown to inhibit glucuronidation and decrease the apparent clearance of lamotrigine [see Drug Interactions (7), Clinical Pharmacology (12.3)]. Week 1 Maintain current dose of Lamotrigine Tablets 150 400 Week 2 Maintain current dose of Lamotrigine Tablets 200 300 Week 3 onward Maintain current dose of Lamotrigine Tablets 200 200

  The benefit of continuing treatment in patients who had been stabilized in an 8- to 16-week open-label phase with lamotrigine was established in 2 randomized, placebo-controlled clinical maintenance trials [see Clinical Studies (14.2)]. However, the optimal duration of treatment with lamotrigine has not been established. Thus, patients should be periodically reassessed to determine the need for maintenance treatment.

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  2.1 General Dosing Considerations 

  Rash: There are suggestions, yet to be proven, that the risk of severe, potentially life-threatening rash may be increased by (1) coadministration of Lamotrigine with valproate, (2) exceeding the recommended initial dose of Lamotrigine, or (3) exceeding the recommended dose escalation for Lamotrigine. However, cases have occurred in the absence of these factors [see Boxed Warning]. Therefore, it is important that the dosing recommendations be followed closely.

  The risk of nonserious rash may be increased when the recommended initial dose and/or the rate of dose escalation of Lamotrigine is exceeded and in patients with a history of allergy or rash to other AEDs.

  It is recommended that Lamotrigine not be restarted in patients who discontinued due to rash associated with prior treatment with Lamotrigine, unless the potential benefits clearly outweigh the risks. If the decision is made to restart a patient who has discontinued Lamotrigine, the need to restart with the initial dosing recommendations should be assessed. The greater the interval of time since the previous dose, the greater consideration should be given to restarting with the initial dosing recommendations. If a patient has discontinued Lamotrigine for a period of more than 5 half-lives, it is recommended that initial dosing recommendations and guidelines be followed. The half-life of Lamotrigine is affected by other concomitant medications [see Clinical Pharmacology (12.3)].

  Lamotrigine Added to Drugs Known to Induce or Inhibit Glucuronidation: Drugs other than those listed in the Clinical Pharmacology section [see Clinical Pharmacology (12.3)] have not been systematically evaluated in combination with Lamotrigine. Because Lamotrigine is metabolized predominantly by glucuronic acid conjugation, drugs that are known to induce or inhibit glucuronidation may affect the apparent clearance of Lamotrigine and doses of Lamotrigine may require adjustment based on clinical response.

  Target Plasma Levels for Patients With Epilepsy or Bipolar Disorder: A therapeutic plasma concentration range has not been established for Lamotrigine. Dosing of Lamotrigine should be based on therapeutic response [see Clinical Pharmacology (12.3)].

  Women Taking Estrogen-Containing Oral Contraceptives:  Starting Lamotrigine in Women Taking Estrogen-Containing Oral Contraceptives: Although estrogen-containing oral contraceptives have been shown to increase the clearance of Lamotrigine [see Clinical Pharmacology (12.3)], no adjustments to the recommended dose-escalation guidelines for Lamotrigine should be necessary solely based on the use of estrogen-containing oral contraceptives. Therefore, dose escalation should follow the recommended guidelines for initiating adjunctive therapy with Lamotrigine based on the concomitant AED or other concomitant medications (see Table 1 or Table 5). See below for adjustments to maintenance doses of Lamotrigine in women taking estrogen-containing oral contraceptives.

  Adjustments to the Maintenance Dose of Lamotrigine in Women Taking Estrogen-Containing Oral Contraceptives:

  (1) Taking Estrogen-Containing Oral Contraceptives: For women not taking carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin that induce Lamotrigine glucuronidation [see Drug Interactions (7), Clinical Pharmacology (12.3)], the maintenance dose of Lamotrigine will in most cases need to be increased, by as much as 2-fold over the recommended target maintenance dose, in order to maintain a consistent Lamotrigine plasma level [see Clinical Pharmacology (12.3)].

  (2) Starting Estrogen-Containing Oral Contraceptives: In women taking a stable dose of Lamotrigine and not taking carbamazepine, phenytoin, phenobarbital, primidone, or  other drugs such as rifampin that induce Lamotrigine glucuronidation [see Drug Interactions (7), Clinical Pharmacology (12.3)], the maintenance dose will in most cases need to be increased by as much as 2-fold in order to maintain a consistent Lamotrigine plasma level. The dose increases should begin at the same time that the oral contraceptive is introduced and continue, based on clinical response, no more rapidly than 50 to 100 mg/day every week. Dose increases should not exceed the recommended rate (see Table 1 or Table 5) unless Lamotrigine plasma levels or clinical response support larger increases. Gradual transient increases in Lamotrigine plasma levels may occur during the week of inactive hormonal preparation (“pill-free” week), and these increases will be greater if dose increases are made in the days before or during the week of inactive hormonal preparation. Increased Lamotrigine plasma levels could result in additional adverse reactions, such as dizziness, ataxia, and diplopia. If adverse reactions attributable to Lamotrigine consistently occur during the “pill-free” week, dose adjustments to the overall maintenance dose may be necessary. Dose adjustments limited to the “pill-free” week are not recommended. For women taking Lamotrigine in addition to carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin that induce Lamotrigine glucuronidation [see Drug Interactions (7), Clinical Pharmacology (12.3)], no adjustment to the dose of Lamotrigine should be necessary.

  (3) Stopping Estrogen-Containing Oral Contraceptives: For women not taking carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin that induce Lamotrigine glucuronidation [see Drug Interactions (7), Clinical Pharmacology (12.3)], the maintenance dose of Lamotrigine will in most cases need to be decreased by as much as 50% in order to maintain a consistent Lamotrigine plasma level. The decrease in dose of Lamotrigine should not exceed 25% of the total daily dose per week over a 2-week period, unless clinical response or Lamotrigine plasma levels indicate otherwise [see Clinical Pharmacology (12.3)]. For women taking Lamotrigine in addition to carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin that induce Lamotrigine glucuronidation [see Drug Interactions (7), Clinical Pharmacology (12.3)], no adjustment to the dose of Lamotrigine should be necessary.

  Women and Other Hormonal Contraceptive Preparations or Hormone Replacement Therapy: The effect of other hormonal contraceptive preparations or hormone replacement therapy on the pharmacokinetics of Lamotrigine has not been systematically evaluated. It has been reported that ethinylestradiol, not progestogens, increased the clearance of Lamotrigine up to 2-fold, and the progestin-only pills had no effect on Lamotrigine plasma levels. Therefore, adjustments to the dosage of Lamotrigine in the presence of progestogens alone will likely not be needed.

  Patients With Hepatic Impairment: Experience in patients with hepatic impairment is limited. Based on a clinical pharmacology study in 24 patients with mild, moderate, and severe liver impairment [see Use in Specific Populations (8.6), Clinical Pharmacology (12.3)], the following general recommendations can be made. No dosage adjustment is needed in patients with mild liver impairment. Initial, escalation, and maintenance doses should generally be reduced by approximately 25% in patients with moderate and severe liver impairment without ascites and 50% in patients with severe liver impairment with ascites. Escalation and maintenance doses may be adjusted according to clinical response.

  Patients With Renal Impairment: Initial doses of Lamotrigine should be based on patients' concomitant medications (see Tables 1-3 or Table 5); reduced maintenance doses may be effective for patients with significant renal impairment [see Use in Specific Populations (8.7), Clinical Pharmacology (12.3)]. Few patients with severe renal impairment have been evaluated during chronic treatment with Lamotrigine. Because there is inadequate experience in this population, Lamotrigine should be used with caution in these patients.

  Discontinuation Strategy:  Epilepsy: For patients receiving Lamotrigine in combination with other AEDs, a re-evaluation of all AEDs in the regimen should be considered if a change in seizure control or an appearance or worsening of adverse experiences is observed.

  If a decision is made to discontinue therapy with Lamotrigine, a step-wise reduction of dose over at least 2 weeks (approximately 50% per week) is recommended unless safety concerns require a more rapid withdrawal [see Warnings and Precautions (5.9)].

  Discontinuing carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin that induce Lamotrigine glucuronidation should prolong the half-life of Lamotrigine; discontinuing valproate should shorten the half-life of Lamotrigine.

  Bipolar Disorder: In the controlled clinical trials, there was no increase in the incidence, type, or severity of adverse reactions following abrupt termination of Lamotrigine. In clinical trials in patients with Bipolar Disorder, 2 patients experienced seizures shortly after abrupt withdrawal of Lamotrigine. However, there were confounding factors that may have contributed to the occurrence of seizures in these bipolar patients. Discontinuation of Lamotrigine should involve a step-wise reduction of dose over at least 2 weeks (approximately 50% per week) unless safety concerns require a more rapid withdrawal [see Warnings and Precautions (5.9)].

  2.2 Epilepsy – Adjunctive Therapy

  This section provides specific dosing recommendations for patients greater than 12 years of age and patients 2 to 12 years of age. Within each of these age-groups, specific dosing recommendations are provided depending upon concomitant AED or other concomitant medications (Table 1 for patients greater than 12 years of age and Table 2 for patients 2 to 12 years of age). A weight-based dosing guide for patients 2 to 12 years of age on concomitant valproate is provided in Table 3.

  Patients Over 12 Years of Age: Recommended dosing guidelines are summarized in Table 1.

  Table 1. Escalation Regimen for Lamotrigine in Patients Over 12 Years of Age With Epilepsy  * Valproate has been shown to inhibit glucuronidation and decrease the apparent clearance of Lamotrigine [see Drug Interactions ( 7 ), Clinical Pharmacology  ( 12.3 )]. † These drugs induce Lamotrigine glucuronidation and increase clearance [see Drug Interactions ( 7 ) Clinical Pharmacology ( 12.3 )]. Other drugs, which have similar effects include estrogen-containing oral contraceptives [see Drug Interactions ( 7 ), Clinical Pharmacology  ( 12.3 )]. Dosing recommendations for oral contraceptives can be found in General Dosing Considerations [see Dosage and Administration ( 2.1 )]. Patients on rifampin, or other drugs that induce Lamotrigine glucuronidation and increase clearance, should follow the same dosing titration/maintenance regimen as that used with anticonvulsants that have this effect.   For Patients TAKING Valproate* For Patients NOT TAKING Carbamazepine, Phenytoin, Phenobarbital, Primidone†,or Valproate* For Patients TAKING Carbamazepine, Phenytoin, Phenobarbital, or Primidone† and NOT TAKING Valproate* Weeks 1 and 2 25 mg every other day 25 mg every day 50 mg/day Weeks 3 and 4 25 mg every day 50 mg/day 100 mg/day (in 2 divided doses) Weeks 5 onwards to maintenance Increase by 25 to 50 mg/day every 1 to 2 weeks Increase by 50 mg/day
  every 1 to 2 weeks Increase by 100 mg/day every 1 to 2 weeks Usual Maintenance Dose 100 to 200 mg/day with valproate alone
  
  100 to 400 mg/day with valproate and other drugs that induce glucuronication
  (in 1 or 2 divided doses) 225 to 375 mg/day
  (in 2 divided doses) 300 to 500 mg/day  (in 2 divided doses)

  Patients 2 to 12 Years of Age: Recommended dosing guidelines are summarized in Table 2.

  Smaller starting doses and slower dose escalations than those used in clinical trials are recommended because of the suggestion that the risk of rash may be decreased by smaller starting doses and slower dose escalations. Therefore, maintenance doses will take longer to reach in clinical practice than in clinical trials. It may take several weeks to months to achieve an individualized maintenance dose. Maintenance doses in patients weighing less than 30 kg, regardless of age or concomitant AED, may need to be increased as much as 50%, based on clinical response. 

  Table 2. Escalation Regimen for Lamotrigine in Patients 2 to 12 Years of Age With Epilepsy * Valproate has been shown to inhibit glucuronidation and decrease the apparent clearance of Lamotrigine [see Drug Interactions (7 ), Clinical Pharmacology  (12.3)]. † These drugs induce Lamotrigine glucuronidation and increase clearance [see Drug Interactions (7 ) Clinical Pharmacology  (12.3)]. Other drugs, which have similar effects include estrogen-containing oral contraceptives [see Drug Interactions (7 ) Clinical Pharmacology  (12.3)].
  Dosing recommendations for oral contraceptives can be found in General Dosing Considerations [see Dosage and Administration (2.1)]. Patients on rifampin, or other drugs that induce Lamotrigine glucuronidation and increase clearance, should follow the same dosing titration/maintenance regimen as that used with anticonvulsants that have this effect.   For Patients TAKING Valproate* For Patients NOT TAKING Carbamazepine,
  Phenytoin,
  Phenobarbital,  
  Primidone†  or
   Valproate* For Patients TAKING Carbamazepine, Phenytoin, Phenobarbital, or  Primidone† and NOT TAKING Valproate* Weeks 1 and 2 0.15 mg/kg/day
   in 1 or 2 divided doses, rounded down to the nearest whole tablet (see Table 3 for weight based dosing guide) 0.3 mg/kg/day
  in 1 or 2 divided doses, rounded down to the nearest whole tablet 0.6 mg/kg/day
  in 2 divided doses, rounded down to the nearest whole tablet Weeks 3 and 4 0.3 mg/kg/day
  in 1 or 2 divided doses, rounded down to the nearest whole tablet (see Table 3 for weight based dosing guide) 0.6 mg/kg/day
    in 2 divided doses, rounded down to the nearest whole tablet 1.2 mg/kg/day
    in 2 divided doses, rounded down to the nearest whole tablet Weeks 5 onwards to maintenance The dose should be increased every 1 to 2 weeks as follows: calculate 0.3 mg/kg/day, round this amount down to the nearest whole tablet, and add this amount to the previously administered daily dose The dose should be increased every 1 to 2 weeks as follows: calculate 0.6 mg/kg/day, round this amount down to the nearest whole tablet, and add this amount to the previously administered daily dose The dose should be increased every 1 to 2 weeks as follows: calculate 1.2 mg/kg/day, round this amount down to the nearest whole tablet, and add this amount to the previously administered daily dose Usual Maintenance Dose 1 to 5 mg/kg/day (maximum 200 mg/day in 1 or 2 divided doses).
  1 to 3 mg/kg/day with valproate alone 4.5 to 7.5 mg/kg/day
   (maximum 300 mg/day in 2 divided doses) 5 to 15 mg/kg/day
   (maximum 400 mg/day in 2 divided doses) Maintenance dose in patients less than 30 kg May need to be increased by as much as 50%, based on clinical response May need to be increased by as much as 50%, based on clinical response May need to be increased by as much as 50%, based on clinical response Note: Only whole tablets should be used for dosing. Table 3. The Initial Weight-Based Dosing Guide for Patients 2 to 12 Years Taking Valproate (Weeks 1 to 4) With Epilepsy If the patient’s weight is Give this daily dose, using the most appropriate combination of Lamotrigine 2-mg and 5-mg tablets Greater than And less than Weeks 1 and 2 Weeks 3 and 4 6.7 kg 14 kg 2 mg every other day 2 mg every day 14.1 kg 27 kg 2 mg every day 4 mg every day 27.1 kg 34 kg 4 mg every day 8 mg every day 34.1 kg 40 kg 5 mg every day 10 mg every day

  Usual Adjunctive Maintenance Dose for Epilepsy: The usual maintenance doses identified in Tables 1 and 2 are derived from dosing regimens employed in the placebo-controlled adjunctive studies in which the efficacy of Lamotrigine was established. In patients receiving multidrug regimens employing carbamazepine, phenytoin, phenobarbital, or primidone without valproate, maintenance doses of adjunctive Lamotrigine as high as 700 mg/day have been used. In patients receiving valproate alone, maintenance doses of adjunctive Lamotrigine as high as 200 mg/day have been used. The advantage of using doses above those recommended in Tables 1 through 4 has not been established in controlled trials.

  2.3 Epilepsy – Conversion From Adjunctive Therapy to Monotherapy

  The goal of the transition regimen is to effect the conversion to monotherapy with Lamotrigine under conditions that ensure adequate seizure control while mitigating the risk of serious rash associated with the rapid titration of Lamotrigine.

  The recommended maintenance dose of Lamotrigine as monotherapy is 500 mg/day given in 2 divided doses.

  To avoid an increased risk of rash, the recommended initial dose and subsequent dose escalations of Lamotrigine should not be exceeded [see Boxed Warning].

  Conversion From Adjunctive Therapy With Carbamazepine, Phenytoin, Phenobarbital, or Primidone to Monotherapy With Lamotrigine: After achieving a dose of 500 mg/day of Lamotrigine according to the guidelines in Table 1, the concomitant AED should be withdrawn by 20% decrements each week over a 4-week period. The regimen for the withdrawal of the concomitant AED is based on experience gained in the controlled monotherapy clinical trial. 

  Conversion from Adjunctive Therapy With Valproate to Monotherapy With Lamotrigine: The conversion regimen involves 4 steps outlined in Table 4.

  Table 4. Conversion From Adjunctive Therapy With Valproate to Monotherapy With Lamotrigine in Patients ≥16 Years of Age with Epilepsy

  Lamotrigine

  Valproate

  Step 1

  Achieve a dose of 200 mg/day according to guidelines in Table 1 (if not already on 200 mg/day).

  Maintain previous stable dose.

  Step 2

  Maintain at 200 mg/day.

  Decrease to 500 mg/day by decrements no greater than 500 mg/day/week and then maintain the dose of 500 mg/day for 1 week.

  Step 3

  Increase to 300 mg/day and maintain for 1 week.

  Simultaneously decrease to 250 mg/day and maintain for 1 week.

  Step 4

  Increase by 100 mg/day every week to achieve maintenance dose of 500 mg/day.

  Discontinue.

  
  Conversion from Adjunctive Therapy With AEDs Other Than Carbamazepine, Phenytoin, Phenobarbital, Primidone, or Valproate to Monotherapy With Lamotrigine: No specific dosing guidelines can be provided for conversion to monotherapy with Lamotrigine with AEDs other than carbamazepine, phenobarbital, phenytoin, primidone, or valproate.

  2.4 Bipolar Disorder

  The goal of maintenance treatment with Lamotrigine is to delay the time to occurrence of mood episodes (depression, mania, hypomania, mixed episodes) in patients treated for acute mood episodes with standard therapy. The target dose of Lamotrigine is 200 mg/day (100 mg/day in patients taking valproate, which decreases the apparent clearance of Lamotrigine, and 400 mg/day in patients not taking valproate and taking either carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin, that  increase the apparent clearance of Lamotrigine). In the clinical trials, doses up to 400 mg/day as monotherapy were evaluated; however, no additional benefit was seen at 400 mg/day compared with 200 mg/day [see Clinical Studies (14.2)]. Accordingly, doses above 200 mg/day are not recommended. Treatment with Lamotrigine is introduced, based on concurrent medications, according to the regimen outlined in Table 5. If other psychotropic medications are withdrawn following stabilization, the dose of Lamotrigine should be adjusted. For patients discontinuing valproate, the dose of Lamotrigine should be doubled over a 2-week period in equal weekly increments (see Table 6). For patients discontinuing carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin that induce Lamotrigine glucuronidation, the dose of Lamotrigine should remain constant for the first week and then should be decreased by half over a 2-week period in equal weekly decrements (see Table 6). The dose of Lamotrigine may then be further adjusted to the target dose (200 mg) as clinically indicated.

  If other drugs are subsequently introduced, the dose of Lamotrigine may need to be adjusted. In particular, the introduction of valproate requires reduction in the dose of Lamotrigine [see Drug Interactions (7), Clinical Pharmacology (12.3)].

  To avoid an increased risk of rash, the recommended initial dose and subsequent dose escalations of Lamotrigine should not be exceeded [see Boxed Warning].

   

  Table 5. Escalation Regimen for Lamotrigine for Patients With Bipolar Disorder * Valproate has been shown to inhibit glucuronidation and decrease the apparent clearance of Lamotrigine [see Drug Interactions (7 ), Clinical Pharmacology (12.3)]. † These drugs induce Lamotrigine glucuronidation and increase clearance [see Drug Interactions (7 ), Clinical Pharmacology (12.3)]. Other drugs which have similar effects include estrogen- containing oral contraceptives [see Drug Interactions (7), Clinical Pharmacology (12.3)].
  Dosing recommendations for oral contraceptives can be found in General Dosing Considerations [see Dosage and Administration (2.1)]. Patients on rifampin, or other drugs that induce Lamotrigine glucuronidation and increase clearance, should follow the same dosing titration/ maintenance regimen as that used with anticonvulsants that have this effect. For Patients TAKING Valproate* For Patients NOT TAKING Carbamazepine, Phenytoin, Phenobarbital, Primidone†, or Valproate* For Patients TAKING Carbamazepine, Phenytoin, Phenobarbital, or Primidone† and NOT TAKING Valproate* Weeks 1 and 2 25 mg every other day 25 mg daily 50 mg daily Weeks 3 and 4 25 mg daily 50 mg daily 100 mg daily, in divided doses Week 5 50 mg daily 100 mg daily 200 mg daily, in divided doses Week 6 100 mg daily 200 mg daily 300 mg daily, in divided doses Week 7 100 mg daily 200 mg daily up to 400 mg daily, in divided doses Table 6. Dosage Adjustments to Lamotrigine for Patients With Bipolar Disorder Following Discontinuation of Psychotropic Medications * These drugs induce Lamotrigine glucuronidation and increase clearance [see Drug Interactions (7 ), Clinical Pharmacology (12.3)]. Other drugs which have similar effects include estrogen-containing oral contraceptives [see Drug Interactions (7), Clinical Pharmacology (12.3)]. Dosing recommendations for oral contraceptives can be found in General Dosing Considerations [see Dosage and Administration (2.1)]. Patients on rifampin, or other drugs that induce Lamotrigine glucuronidation and increase clearance, should follow the same dosing titration/ maintenance regimen as that used with anticonvulsants that have this effect. † Valproate has been shown to inhibit glucuronidation and decrease the apparent clearance of Lamotrigine [see Drug Interactions (7), Clinical Pharmacology (12.3)].  

  Discontinuation of Psychotropic Drugs (excluding Carbamazepine, Phenytoin, Phenobarbital, Primidone*, or Valproate†)

  After Discontinuation of Valproate† After Discontinuation of Carbamazepine, Phenytoin, Phenobarbital, or Primidone* Current dose of Lamotrigine (mg/day) 100

  Current dose of Lamotrigine (mg/day) 400

  Week 1 Maintain current dose of Lamotrigine 150 400 Week 2 Maintain current dose of Lamotrigine 200 300 Week 3 onward Maintain current dose of Lamotrigine 200 200

  The benefit of continuing treatment in patients who had been stabilized in an 8- to 16-week open-label phase with Lamotrigine was established in 2 randomized, placebo-controlled clinical maintenance trials [see Clinical Studies (14.2)]. However, the optimal duration of treatment with Lamotrigine has not been established. Thus, patients should be periodically reassessed to determine the need for maintenance treatment.

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  Rash: There are suggestions, yet to be proven, that the risk of severe, potentially life-threatening rash may be increased by (1) coadministration of Lamotrigine with valproate, (2) exceeding the recommended initial dose of Lamotrigine, or (3) exceeding the recommended dose escalation for Lamotrigine. However, cases have occurred in the absence of these factors [see Boxed Warning]. Therefore, it is important that the dosing recommendations be followed closely.

  The risk of nonserious rash may be increased when the recommended initial dose and/or the rate of dose escalation of Lamotrigine is exceeded and in patients with a history of allergy or rash to other AEDs.

  It is recommended that Lamotrigine not be restarted in patients who discontinued due to rash associated with prior treatment with Lamotrigine, unless the potential benefits clearly outweigh the risks. If the decision is made to restart a patient who has discontinued Lamotrigine, the need to restart with the initial dosing recommendations should be assessed. The greater the interval of time since the previous dose, the greater consideration should be given to restarting with the initial dosing recommendations. If a patient has discontinued Lamotrigine for a period of more than 5 half-lives, it is recommended that initial dosing recommendations and guidelines be followed. The half-life of Lamotrigine is affected by other concomitant medications [see Clinical Pharmacology (12.3)].

  Lamotrigine Added to Drugs Known to Induce or Inhibit Glucuronidation: Drugs other than those listed in the Clinical Pharmacology section [see Clinical Pharmacology (12.3)] have not been systematically evaluated in combination with Lamotrigine. Because Lamotrigine is metabolized predominantly by glucuronic acid conjugation, drugs that are known to induce or inhibit glucuronidation may affect the apparent clearance of Lamotrigine and doses of Lamotrigine may require adjustment based on clinical response.

  Target Plasma Levels for Patients With Epilepsy or Bipolar Disorder: A therapeutic plasma concentration range has not been established for Lamotrigine. Dosing of Lamotrigine should be based on therapeutic response [see Clinical Pharmacology (12.3)].

  Women Taking Estrogen-Containing Oral Contraceptives:  Starting Lamotrigine in Women Taking Estrogen-Containing Oral Contraceptives: Although estrogen-containing oral contraceptives have been shown to increase the clearance of Lamotrigine [see Clinical Pharmacology (12.3)], no adjustments to the recommended dose-escalation guidelines for Lamotrigine should be necessary solely based on the use of estrogen-containing oral contraceptives. Therefore, dose escalation should follow the recommended guidelines for initiating adjunctive therapy with Lamotrigine based on the concomitant AED or other concomitant medications (see Table 1 or Table 5). See below for adjustments to maintenance doses of Lamotrigine in women taking estrogen-containing oral contraceptives.

  Adjustments to the Maintenance Dose of Lamotrigine in Women Taking Estrogen-Containing Oral Contraceptives:

  (1) Taking Estrogen-Containing Oral Contraceptives: For women not taking carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin that induce Lamotrigine glucuronidation [see Drug Interactions (7), Clinical Pharmacology (12.3)], the maintenance dose of Lamotrigine will in most cases need to be increased, by as much as 2-fold over the recommended target maintenance dose, in order to maintain a consistent Lamotrigine plasma level [see Clinical Pharmacology (12.3)].

  (2) Starting Estrogen-Containing Oral Contraceptives: In women taking a stable dose of Lamotrigine and not taking carbamazepine, phenytoin, phenobarbital, primidone, or  other drugs such as rifampin that induce Lamotrigine glucuronidation [see Drug Interactions (7), Clinical Pharmacology (12.3)], the maintenance dose will in most cases need to be increased by as much as 2-fold in order to maintain a consistent Lamotrigine plasma level. The dose increases should begin at the same time that the oral contraceptive is introduced and continue, based on clinical response, no more rapidly than 50 to 100 mg/day every week. Dose increases should not exceed the recommended rate (see Table 1 or Table 5) unless Lamotrigine plasma levels or clinical response support larger increases. Gradual transient increases in Lamotrigine plasma levels may occur during the week of inactive hormonal preparation (“pill-free” week), and these increases will be greater if dose increases are made in the days before or during the week of inactive hormonal preparation. Increased Lamotrigine plasma levels could result in additional adverse reactions, such as dizziness, ataxia, and diplopia. If adverse reactions attributable to Lamotrigine consistently occur during the “pill-free” week, dose adjustments to the overall maintenance dose may be necessary. Dose adjustments limited to the “pill-free” week are not recommended. For women taking Lamotrigine in addition to carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin that induce Lamotrigine glucuronidation [see Drug Interactions (7), Clinical Pharmacology (12.3)], no adjustment to the dose of Lamotrigine should be necessary.

  (3) Stopping Estrogen-Containing Oral Contraceptives: For women not taking carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin that induce Lamotrigine glucuronidation [see Drug Interactions (7), Clinical Pharmacology (12.3)], the maintenance dose of Lamotrigine will in most cases need to be decreased by as much as 50% in order to maintain a consistent Lamotrigine plasma level. The decrease in dose of Lamotrigine should not exceed 25% of the total daily dose per week over a 2-week period, unless clinical response or Lamotrigine plasma levels indicate otherwise [see Clinical Pharmacology (12.3)]. For women taking Lamotrigine in addition to carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin that induce Lamotrigine glucuronidation [see Drug Interactions (7), Clinical Pharmacology (12.3)], no adjustment to the dose of Lamotrigine should be necessary.

  Women and Other Hormonal Contraceptive Preparations or Hormone Replacement Therapy: The effect of other hormonal contraceptive preparations or hormone replacement therapy on the pharmacokinetics of Lamotrigine has not been systematically evaluated. It has been reported that ethinylestradiol, not progestogens, increased the clearance of Lamotrigine up to 2-fold, and the progestin-only pills had no effect on Lamotrigine plasma levels. Therefore, adjustments to the dosage of Lamotrigine in the presence of progestogens alone will likely not be needed.

  Patients With Hepatic Impairment: Experience in patients with hepatic impairment is limited. Based on a clinical pharmacology study in 24 patients with mild, moderate, and severe liver impairment [see Use in Specific Populations (8.6), Clinical Pharmacology (12.3)], the following general recommendations can be made. No dosage adjustment is needed in patients with mild liver impairment. Initial, escalation, and maintenance doses should generally be reduced by approximately 25% in patients with moderate and severe liver impairment without ascites and 50% in patients with severe liver impairment with ascites. Escalation and maintenance doses may be adjusted according to clinical response.

  Patients With Renal Impairment: Initial doses of Lamotrigine should be based on patients' concomitant medications (see Tables 1-3 or Table 5); reduced maintenance doses may be effective for patients with significant renal impairment [see Use in Specific Populations (8.7), Clinical Pharmacology (12.3)]. Few patients with severe renal impairment have been evaluated during chronic treatment with Lamotrigine. Because there is inadequate experience in this population, Lamotrigine should be used with caution in these patients.

  Discontinuation Strategy:  Epilepsy: For patients receiving Lamotrigine in combination with other AEDs, a re-evaluation of all AEDs in the regimen should be considered if a change in seizure control or an appearance or worsening of adverse experiences is observed.

  If a decision is made to discontinue therapy with Lamotrigine, a step-wise reduction of dose over at least 2 weeks (approximately 50% per week) is recommended unless safety concerns require a more rapid withdrawal [see Warnings and Precautions (5.9)].

  Discontinuing carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin that induce Lamotrigine glucuronidation should prolong the half-life of Lamotrigine; discontinuing valproate should shorten the half-life of Lamotrigine.

  Bipolar Disorder: In the controlled clinical trials, there was no increase in the incidence, type, or severity of adverse reactions following abrupt termination of Lamotrigine. In clinical trials in patients with Bipolar Disorder, 2 patients experienced seizures shortly after abrupt withdrawal of Lamotrigine. However, there were confounding factors that may have contributed to the occurrence of seizures in these bipolar patients. Discontinuation of Lamotrigine should involve a step-wise reduction of dose over at least 2 weeks (approximately 50% per week) unless safety concerns require a more rapid withdrawal [see Warnings and Precautions (5.9)].

   

  This section provides specific dosing recommendations for patients greater than 12 years of age and patients 2 to 12 years of age. Within each of these age-groups, specific dosing recommendations are provided depending upon concomitant AED or other concomitant medications (Table 1 for patients greater than 12 years of age and Table 2 for patients 2 to 12 years of age). A weight-based dosing guide for patients 2 to 12 years of age on concomitant valproate is provided in Table 3.

  Patients Over 12 Years of Age: Recommended dosing guidelines are summarized in Table 1.

  Table 1. Escalation Regimen for Lamotrigine in Patients Over 12 Years of Age With Epilepsy    For Patients TAKING Valproate* For Patients NOT TAKING Carbamazepine, Phenytoin, Phenobarbital, Primidone†,or Valproate1 For Patients TAKING Carbamazepine, Phenytoin, Phenobarbital, or Primidone2 and NOT TAKING Valproate1 Weeks 1 and 2 25 mg every other day 25 mg every day 50 mg/day Weeks 3 and 4 25 mg every day 50 mg/day 100 mg/day (in 2 divided doses) Weeks 5 onwards to maintenance Increase by 25 to 50 mg/day every 1 to 2 weeks Increase by 50 mg/day
  every 1 to 2 weeks Increase by 100 mg/day every 1 to 2 weeks Usual Maintenance Dose 100 to 200 mg/day with valproate alone
  
  100 to 400 mg/day with valproate and other drugs that induce glucuronication
  (in 1 or 2 divided doses) 225 to 375 mg/day
  (in 2 divided doses) 300 to 500 mg/day  (in 2 divided doses)
  

  Patients 2 to 12 Years of Age: Recommended dosing guidelines are summarized in Table 2.

  Smaller starting doses and slower dose escalations than those used in clinical trials are recommended because of the suggestion that the risk of rash may be decreased by smaller starting doses and slower dose escalations. Therefore, maintenance doses will take longer to reach in clinical practice than in clinical trials. It may take several weeks to months to achieve an individualized maintenance dose. Maintenance doses in patients weighing less than 30 kg, regardless of age or concomitant AED, may need to be increased as much as 50%, based on clinical response. 

  Table 2. Escalation Regimen for Lamotrigine in Patients 2 to 12 Years of Age With Epilepsy   For Patients TAKING Valproate* For Patients NOT TAKING Carbamazepine,
  Phenytoin,
  Phenobarbital,  
  Primidone†  or
   Valproate3 For Patients TAKING Carbamazepine, Phenytoin, Phenobarbital, or  Primidone4 and NOT TAKING Valproate3 Weeks 1 and 2 0.15 mg/kg/day
   in 1 or 2 divided doses, rounded down to the nearest whole tablet (see Table 3 for weight based dosing guide) 0.3 mg/kg/day
  in 1 or 2 divided doses, rounded down to the nearest whole tablet 0.6 mg/kg/day
  in 2 divided doses, rounded down to the nearest whole tablet Weeks 3 and 4 0.3 mg/kg/day
  in 1 or 2 divided doses, rounded down to the nearest whole tablet (see Table 3 for weight based dosing guide) 0.6 mg/kg/day
    in 2 divided doses, rounded down to the nearest whole tablet 1.2 mg/kg/day
    in 2 divided doses, rounded down to the nearest whole tablet Weeks 5 onwards to maintenance The dose should be increased every 1 to 2 weeks as follows: calculate 0.3 mg/kg/day, round this amount down to the nearest whole tablet, and add this amount to the previously administered daily dose The dose should be increased every 1 to 2 weeks as follows: calculate 0.6 mg/kg/day, round this amount down to the nearest whole tablet, and add this amount to the previously administered daily dose The dose should be increased every 1 to 2 weeks as follows: calculate 1.2 mg/kg/day, round this amount down to the nearest whole tablet, and add this amount to the previously administered daily dose Usual Maintenance Dose 1 to 5 mg/kg/day (maximum 200 mg/day in 1 or 2 divided doses).
  1 to 3 mg/kg/day with valproate alone 4.5 to 7.5 mg/kg/day
   (maximum 300 mg/day in 2 divided doses) 5 to 15 mg/kg/day
   (maximum 400 mg/day in 2 divided doses) Maintenance dose in patients less than 30 kg May need to be increased by as much as 50%, based on clinical response May need to be increased by as much as 50%, based on clinical response May need to be increased by as much as 50%, based on clinical response Note: Only whole tablets should be used for dosing.
  Table 3. The Initial Weight-Based Dosing Guide for Patients 2 to 12 Years Taking Valproate (Weeks 1 to 4) With Epilepsy If the patient’s weight is Give this daily dose, using the most appropriate combination of Lamotrigine 2-mg and 5-mg tablets Greater than And less than Weeks 1 and 2 Weeks 3 and 4 6.7 kg 14 kg 2 mg every other day 2 mg every day 14.1 kg 27 kg 2 mg every day 4 mg every day 27.1 kg 34 kg 4 mg every day 8 mg every day 34.1 kg 40 kg 5 mg every day 10 mg every day

  Usual Adjunctive Maintenance Dose for Epilepsy: The usual maintenance doses identified in Tables 1 and 2 are derived from dosing regimens employed in the placebo-controlled adjunctive studies in which the efficacy of Lamotrigine was established. In patients receiving multidrug regimens employing carbamazepine, phenytoin, phenobarbital, or primidone without valproate, maintenance doses of adjunctive Lamotrigine as high as 700 mg/day have been used. In patients receiving valproate alone, maintenance doses of adjunctive Lamotrigine as high as 200 mg/day have been used. The advantage of using doses above those recommended in Tables 1 through 4 has not been established in controlled trials.

   

  The goal of the transition regimen is to effect the conversion to monotherapy with Lamotrigine under conditions that ensure adequate seizure control while mitigating the risk of serious rash associated with the rapid titration of Lamotrigine.

  The recommended maintenance dose of Lamotrigine as monotherapy is 500 mg/day given in 2 divided doses.

  To avoid an increased risk of rash, the recommended initial dose and subsequent dose escalations of Lamotrigine should not be exceeded [see Boxed Warning].

  Conversion From Adjunctive Therapy With Carbamazepine, Phenytoin, Phenobarbital, or Primidone to Monotherapy With Lamotrigine: After achieving a dose of 500 mg/day of Lamotrigine according to the guidelines in Table 1, the concomitant AED should be withdrawn by 20% decrements each week over a 4-week period. The regimen for the withdrawal of the concomitant AED is based on experience gained in the controlled monotherapy clinical trial. 

  Conversion from Adjunctive Therapy With Valproate to Monotherapy With Lamotrigine: The conversion regimen involves 4 steps outlined in Table 4.

  Table 4. Conversion From Adjunctive Therapy With Valproate to Monotherapy With Lamotrigine in Patients ≥16 Years of Age with Epilepsy

  Lamotrigine

  Valproate

  Step 1

  Achieve a dose of 200 mg/day according to guidelines in Table 1 (if not already on 200 mg/day).

  Maintain previous stable dose.

  Step 2

  Maintain at 200 mg/day.

  Decrease to 500 mg/day by decrements no greater than 500 mg/day/week and then maintain the dose of 500 mg/day for 1 week.

  Step 3

  Increase to 300 mg/day and maintain for 1 week.

  Simultaneously decrease to 250 mg/day and maintain for 1 week.

  Step 4

  Increase by 100 mg/day every week to achieve maintenance dose of 500 mg/day.

  Discontinue.

  
  Conversion from Adjunctive Therapy With AEDs Other Than Carbamazepine, Phenytoin, Phenobarbital, Primidone, or Valproate to Monotherapy With Lamotrigine: No specific dosing guidelines can be provided for conversion to monotherapy with Lamotrigine with AEDs other than carbamazepine, phenobarbital, phenytoin, primidone, or valproate.

   

  The goal of maintenance treatment with Lamotrigine is to delay the time to occurrence of mood episodes (depression, mania, hypomania, mixed episodes) in patients treated for acute mood episodes with standard therapy. The target dose of Lamotrigine is 200 mg/day (100 mg/day in patients taking valproate, which decreases the apparent clearance of Lamotrigine, and 400 mg/day in patients not taking valproate and taking either carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin, that  increase the apparent clearance of Lamotrigine). In the clinical trials, doses up to 400 mg/day as monotherapy were evaluated; however, no additional benefit was seen at 400 mg/day compared with 200 mg/day [see Clinical Studies (14.2)]. Accordingly, doses above 200 mg/day are not recommended. Treatment with Lamotrigine is introduced, based on concurrent medications, according to the regimen outlined in Table 5. If other psychotropic medications are withdrawn following stabilization, the dose of Lamotrigine should be adjusted. For patients discontinuing valproate, the dose of Lamotrigine should be doubled over a 2-week period in equal weekly increments (see Table 6). For patients discontinuing carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin that induce Lamotrigine glucuronidation, the dose of Lamotrigine should remain constant for the first week and then should be decreased by half over a 2-week period in equal weekly decrements (see Table 6). The dose of Lamotrigine may then be further adjusted to the target dose (200 mg) as clinically indicated.

  If other drugs are subsequently introduced, the dose of Lamotrigine may need to be adjusted. In particular, the introduction of valproate requires reduction in the dose of Lamotrigine [see Drug Interactions (7), Clinical Pharmacology (12.3)].

  To avoid an increased risk of rash, the recommended initial dose and subsequent dose escalations of Lamotrigine should not be exceeded [see Boxed Warning].

   

  Table 5. Escalation Regimen for Lamotrigine for Patients With Bipolar Disorder For Patients TAKING Valproate* For Patients NOT TAKING Carbamazepine, Phenytoin, Phenobarbital, Primidone†, or Valproate5 For Patients TAKING Carbamazepine, Phenytoin, Phenobarbital, or Primidone6 and NOT TAKING Valproate5 Weeks 1 and 2 25 mg every other day 25 mg daily 50 mg daily Weeks 3 and 4 25 mg daily 50 mg daily 100 mg daily, in divided doses Week 5 50 mg daily 100 mg daily 200 mg daily, in divided doses Week 6 100 mg daily 200 mg daily 300 mg daily, in divided doses Week 7 100 mg daily 200 mg daily up to 400 mg daily, in divided doses
  Table 6. Dosage Adjustments to Lamotrigine for Patients With Bipolar Disorder Following Discontinuation of Psychotropic Medications  

  Discontinuation of Psychotropic Drugs (excluding Carbamazepine, Phenytoin, Phenobarbital, Primidone*, or Valproate†)

  After Discontinuation of Valproate8 After Discontinuation of Carbamazepine, Phenytoin, Phenobarbital, or Primidone7 Current dose of Lamotrigine (mg/day) 100

  Current dose of Lamotrigine (mg/day) 400

  Week 1 Maintain current dose of Lamotrigine 150 400 Week 2 Maintain current dose of Lamotrigine 200 300 Week 3 onward Maintain current dose of Lamotrigine 200 200
  

  The benefit of continuing treatment in patients who had been stabilized in an 8- to 16-week open-label phase with Lamotrigine was established in 2 randomized, placebo-controlled clinical maintenance trials [see Clinical Studies (14.2)]. However, the optimal duration of treatment with Lamotrigine has not been established. Thus, patients should be periodically reassessed to determine the need for maintenance treatment.

   

  1 Valproate has been shown to inhibit glucuronidation and decrease the apparent clearance of Lamotrigine 2 These drugs induce Lamotrigine glucuronidation and increase clearance 3 Valproate has been shown to inhibit glucuronidation and decrease the apparent clearance of Lamotrigine 4 These drugs induce Lamotrigine glucuronidation and increase clearance 5 Valproate has been shown to inhibit glucuronidation and decrease the apparent clearance of Lamotrigine 6 These drugs induce Lamotrigine glucuronidation and increase clearance 7 These drugs induce Lamotrigine glucuronidation and increase clearance 8 Valproate has been shown to inhibit glucuronidation and decrease the apparent clearance of Lamotrigine

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  Rash: There are suggestions, yet to be proven, that the risk of severe, potentially life-threatening rash may be increased by (1) coadministration of lamotrigine with valproate, (2) exceeding the recommended initial dose of lamotrigine, or (3) exceeding the recommended dose escalation for lamotrigine. However, cases have occurred in the absence of these factors [see Boxed Warning]. Therefore, it is important that the dosing recommendations be followed closely.

  The risk of nonserious rash may be increased when the recommended initial dose and/or the rate of dose escalation of lamotrigine is exceeded and in patients with a history of allergy or rash to other AEDs.

  Lamotrigine Starter Kits provide lamotrigine at doses consistent with the recommended titration schedule for the first 5 weeks of treatment, based upon concomitant medications for patients with epilepsy (>12 years of age) and Bipolar I Disorder (≥18 years of age) and are intended to help reduce the potential for rash. The use of Lamotrigine Starter Kits is recommended for appropriate patients who are starting or restarting lamotrigine [see How Supplied/Storage and Handling (16)].

  It is recommended that lamotrigine not be restarted in patients who discontinued due to rash associated with prior treatment with lamotrigine, unless the potential benefits clearly outweigh the risks. If the decision is made to restart a patient who has discontinued lamotrigine, the need to restart with the initial dosing recommendations should be assessed. The greater the interval of time since the previous dose, the greater consideration should be given to restarting with the initial dosing recommendations. If a patient has discontinued lamotrigine for a period of more than 5 half-lives, it is recommended that initial dosing recommendations and guidelines be followed. The half-life of lamotrigine is affected by other concomitant medications [see Clinical Pharmacology (12.3)].

   

  Lamotrigine Added to Drugs Known to Induce or Inhibit Glucuronidation: Drugs other than those listed in the Clinical Pharmacology section [see Clinical Pharmacology (12.3)] have not been systematically evaluated in combination with lamotrigine. Because lamotrigine is metabolized predominantly by glucuronic acid conjugation, drugs that are known to induce or inhibit glucuronidation may affect the apparent clearance of lamotrigine and doses of lamotrigine may require adjustment based on clinical response.

   

  Target Plasma Levels for Patients With Epilepsy or Bipolar Disorder: A therapeutic plasma concentration range has not been established for lamotrigine. Dosing of lamotrigine should be based on therapeutic response [see Clinical Pharmacology (12.3)].

   

  Women Taking Estrogen-Containing Oral Contraceptives: Starting Lamotrigine in Women Taking Estrogen-Containing Oral Contraceptives: Although estrogen-containing oral contraceptives have been shown to increase the clearance of lamotrigine [see Clinical Pharmacology (12.3)], no adjustments to the recommended dose-escalation guidelines for lamotrigine should be necessary solely based on the use of estrogen-containing oral contraceptives. Therefore, dose escalation should follow the recommended guidelines for initiating adjunctive therapy with lamotrigine based on the concomitant AED or other concomitant medications (see Table 1 or Table 5). See below for adjustments to maintenance doses of lamotrigine in women taking estrogen-containing oral contraceptives.

   

  Adjustments to the Maintenance Dose of Lamotrigine In Women Taking Estrogen-Containing Oral Contraceptives:

   

  (1) Taking Estrogen-Containing Oral Contraceptives: For women not taking carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin that induce lamotrigine glucuronidation [see Drug Interactions (7), Clinical Pharmacology (12.3)], the maintenance dose of lamotrigine will in most cases need to be increased, by as much as 2-fold over the recommended target maintenance dose, in order to maintain a consistent lamotrigine plasma level [see Clinical Pharmacology (12.3)].

   

  (2) Starting Estrogen-Containing Oral Contraceptives: In women taking a stable dose of lamotrigine and not taking carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin that induce lamotrigine glucuronidation [see Drug Interactions (7), Clinical Pharmacology (12.3)], the maintenance dose will in most cases need to be increased by as much as 2-fold in order to maintain a consistent lamotrigine plasma level. The dose increases should begin at the same time that the oral contraceptive is introduced and continue, based on clinical response, no more rapidly than 50 to 100 mg/day every week. Dose increases should not exceed the recommended rate (see Table 1 or Table 5) unless lamotrigine plasma levels or clinical response support larger increases. Gradual transient increases in lamotrigine plasma levels may occur during the week of inactive hormonal preparation ("pill-free" week), and these increases will be greater if dose increases are made in the days before or during the week of inactive hormonal preparation. Increased lamotrigine plasma levels could result in additional adverse reactions, such as dizziness, ataxia, and diplopia. If adverse reactions attributable to lamotrigine consistently occur during the "pill-free" week, dose adjustments to the overall maintenance dose may be necessary. Dose adjustments limited to the "pill-free" week are not recommended. For women taking lamotrigine in addition to carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin that induce lamotrigine glucuronidation [see Drug Interactions (7), Clinical Pharmacology (12.3)], no adjustment to the dose of lamotrigine should be necessary.

   

  (3) Stopping Estrogen-Containing Oral Contraceptives: For women not taking carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin that induce lamotrigine glucuronidation [see Drug Interactions (7), Clinical Pharmacology (12.3)], the maintenance dose of lamotrigine will in most cases need to be decreased by as much as 50% in order to maintain a consistent lamotrigine plasma level. The decrease in dose of lamotrigine should not exceed 25% of the total daily dose per week over a 2-week period, unless clinical response or lamotrigine plasma levels indicate otherwise [see Clinical Pharmacology (12.3)]. For women taking lamotrigine in addition to carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin that induce lamotrigine glucuronidation [see Drug Interactions (7), Clinical Pharmacology (12.3)], no adjustment to the dose of lamotrigine should be necessary.

   

  Women and Other Hormonal Contraceptive Preparations or Hormone Replacement Therapy: The effect of other hormonal contraceptive preparations or hormone replacement therapy on the pharmacokinetics of lamotrigine has not been systematically evaluated. It has been reported that ethinylestradiol, not progestogens, increased the clearance of lamotrigine up to 2-fold, and the progestin-only pills had no effect on lamotrigine plasma levels. Therefore, adjustments to the dosage of lamotrigine in the presence of progestogens alone will likely not be needed.

   

  Patients With Hepatic Impairment: Experience in patients with hepatic impairment is limited. Based on a clinical pharmacology study in 24 patients with mild, moderate, and severe liver impairment [see Use in Specific Populations (8.6), Clinical Pharmacology (12.3)], the following general recommendations can be made. No dosage adjustment is needed in patients with mild liver impairment. Initial, escalation, and maintenance doses should generally be reduced by approximately 25% in patients with moderate and severe liver impairment without ascites and 50% in patients with severe liver impairment with ascites. Escalation and maintenance doses may be adjusted according to clinical response.

   

  Patients With Renal Impairment: Initial doses of lamotrigine should be based on patients' concomitant medications (see Tables 1-3 or Table 5); reduced maintenance doses may be effective for patients with significant renal impairment [see Use in Specific Populations (8.7), Clinical Pharmacology (12.3)]. Few patients with severe renal impairment have been evaluated during chronic treatment with lamotrigine. Because there is inadequate experience in this population, lamotrigine should be used with caution in these patients.

   

  Discontinuation Strategy: Epilepsy: For patients receiving lamotrigine in combination with other AEDs, a reevaluation of all AEDs in the regimen should be considered if a change in seizure control or an appearance or worsening of adverse reactions is observed.

  If a decision is made to discontinue therapy with lamotrigine, a step-wise reduction of dose over at least 2 weeks (approximately 50% per week) is recommended unless safety concerns require a more rapid withdrawal [see Warnings and Precautions (5.9)].

  Discontinuing carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin that induce lamotrigine glucuronidation should prolong the half-life of lamotrigine; discontinuing valproate should shorten the half-life of lamotrigine.

   

  Bipolar Disorder: In the controlled clinical trials, there was no increase in the incidence, type, or severity of adverse reactions following abrupt termination of lamotrigine. In clinical trials in patients with Bipolar Disorder, 2 patients experienced seizures shortly after abrupt withdrawal of lamotrigine. However, there were confounding factors that may have contributed to the occurrence of seizures in these bipolar patients. Discontinuation of lamotrigine should involve a step-wise reduction of dose over at least 2 weeks (approximately 50% per week) unless safety concerns require a more rapid withdrawal [see Warnings and Precautions (5.9)].

   

  This section provides specific dosing recommendations for patients greater than 12 years of age and patients 2 to 12 years of age. Within each of these age-groups, specific dosing recommendations are provided depending upon concomitant AED or other concomitant medications (Table 1 for patients greater than 12 years of age and Table 2 for patients 2 to 12 years of age). A weight-based dosing guide for patients 2 to 12 years of age on concomitant valproate is provided in Table 3.

   

  Patients Over 12 Years of Age: Recommended dosing guidelines are summarized in Table 1.

  Table 1. Escalation Regimen for Lamotrigine in Patients Over 12 Years of Age With Epilepsy For Patients TAKING Valproate * For Patients NOT TAKING Carbamazepine, Phenytoin, Phenobarbital, Primidone†, or Valproate1 For Patients TAKING Carbamazepine, Phenytoin, Phenobarbital, or Primidone2 and NOT TAKING Valproate1 Weeks 1 and 2 25 mg every other day 25 mg every day 50 mg/day Weeks 3 and 4 25 mg every day 50 mg/day 100 mg/day
  (in 2 divided doses) Week 5 onwards to maintenance Increase by 25 to 50 mg/day every 1 to 2 weeks Increase by 50 mg/day every 1 to 2 weeks Increase by 100 mg/day every 1 to 2 weeks Usual maintenance dose 100 to 200 mg/day with valproate alone
  100 to 400 mg/day with valproate and other drugs that induce glucuronidation
  (in 1 or 2 divided doses) 225 to 375 mg/day
  (in 2 divided doses) 300 to 500 mg/day
  (in 2 divided doses)

  Dosing recommendations for oral contraceptives can be found in General Dosing Considerations [see Dosage and Administration (2.1)]. Patients on rifampin, or other drugs that induce lamotrigine glucuronidation and increase clearance, should follow the same dosing titration/maintenance regimen as that used with anticonvulsants that have this effect.

   

  Patients 2 to 12 Years of Age: Recommended dosing guidelines are summarized in Table 2.

  Smaller starting doses and slower dose escalations than those used in clinical trials are recommended because of the suggestion that the risk of rash may be decreased by smaller starting doses and slower dose escalations. Therefore, maintenance doses will take longer to reach in clinical practice than in clinical trials. It may take several weeks to months to achieve an individualized maintenance dose. Maintenance doses in patients weighing less than 30 kg, regardless of age or concomitant AED, may need to be increased as much as 50%, based on clinical response.

  Table 2. Escalation Regimen for Lamotrigine in Patients 2 to 12 Years of Age With Epilepsy For Patients TAKING Valproate * For Patients NOT TAKING Carbamazepine, Phenytoin, Phenobarbital, Primidone†, or Valproate3 For Patients TAKING Carbamazepine, Phenytoin, Phenobarbital, or Primidone4 and NOT TAKING Valproate3 Weeks 1 and 2 0.15 mg/kg/day
  in 1 or 2 divided doses, rounded down to the nearest whole tablet (see Table 3 for weight based dosing guide) 0.3 mg/kg/day
  in 1 or 2 divided doses, rounded down to the nearest whole tablet 0.6 mg/kg/day
  in 2 divided doses, rounded down to the nearest whole tablet Weeks 3 and 4 0.3 mg/kg/day
  in 1 or 2 divided doses, rounded down to the nearest whole tablet (see Table 3 for weight based dosing guide) 0.6 mg/kg/day
  in 2 divided doses, rounded down to the nearest whole tablet 1.2 mg/kg/day
  in 2 divided doses, rounded down to the nearest whole tablet Week 5 onwards to maintenance The dose should be increased every 1 to 2 weeks as follows: calculate 0.3 mg/kg/day, round this amount down to the nearest whole tablet, and add this amount to the previously administered daily dose The dose should be increased every 1 to 2 weeks as follows: calculate 0.6 mg/kg/day, round this amount down to the nearest whole tablet, and add this amount to the previously administered daily dose The dose should be increased every 1 to 2 weeks as follows: calculate 1.2 mg/kg/day, round this amount down to the nearest whole tablet, and add this amount to the previously administered daily dose Usual maintenance dose 1 to 5 mg/kg/day
  (maximum 200 mg/day in 1 or 2 divided doses)
  1 to 3 mg/kg/day with valproate alone 4.5 to 7.5 mg/kg/day
  (maximum 300 mg/day in 2 divided doses) 5 to 15 mg/kg/day
  (maximum 400 mg/day in 2 divided doses) Maintenance dose in patients less than 30 kg May need to be increased by as much as 50%, based on clinical response May need to be increased by as much as 50%, based on clinical response May need to be increased by as much as 50%, based on clinical response

  Dosing recommendations for oral contraceptives can be found in General Dosing Considerations [see Dosage and Administration (2.1)]. Patients on rifampin, or other drugs that induce lamotrigine glucuronidation and increase clearance, should follow the same dosing titration/maintenance regimen as that used with anticonvulsants that have this effect.

  Table 3. The Initial Weight-Based Dosing Guide for Patients 2 to 12 Years Taking Valproate (Weeks 1 to 4) With Epilepsy If the patient's weight is Give this daily dose, using the most appropriate combination of Lamotrigine 2-mg and 5-mg tablets Greater than And less than Weeks 1 and 2 Weeks 3 and 4 6.7 kg 14 kg 2 mg every other day 2 mg every day 14.1 kg 27 kg 2 mg every day 4 mg every day 27.1 kg 34 kg 4 mg every day 8 mg every day 34.1 kg 40 kg 5 mg every day 10 mg every day

   

  Usual Adjunctive Maintenance Dose for Epilepsy: The usual maintenance doses identified in Tables 1 and 2 are derived from dosing regimens employed in the placebo-controlled adjunctive studies in which the efficacy of lamotrigine was established. In patients receiving multidrug regimens employing carbamazepine, phenytoin, phenobarbital, or primidone without valproate, maintenance doses of adjunctive lamotrigine as high as 700 mg/day have been used. In patients receiving valproate alone, maintenance doses of adjunctive lamotrigine as high as 200 mg/day have been used. The advantage of using doses above those recommended in Tables 1 through 4 has not been established in controlled trials.

   

  The goal of the transition regimen is to effect the conversion to monotherapy with lamotrigine under conditions that ensure adequate seizure control while mitigating the risk of serious rash associated with the rapid titration of lamotrigine.

  The recommended maintenance dose of lamotrigine as monotherapy is 500 mg/day given in 2 divided doses.

  To avoid an increased risk of rash, the recommended initial dose and subsequent dose escalations of lamotrigine should not be exceeded [see Boxed Warning].

   

  Conversion From Adjunctive Therapy With Carbamazepine, Phenytoin, Phenobarbital, or Primidone to Monotherapy With Lamotrigine: After achieving a dose of 500 mg/day of lamotrigine according to the guidelines in Table 1, the concomitant AED should be withdrawn by 20% decrements each week over a 4-week period. The regimen for the withdrawal of the concomitant AED is based on experience gained in the controlled monotherapy clinical trial.

   

  Conversion From Adjunctive Therapy With Valproate to Monotherapy With Lamotrigine: The conversion regimen involves 4 steps outlined in Table 4.

  Table 4. Conversion From Adjunctive Therapy With Valproate to Monotherapy With Lamotrigine in Patients ≥16 Years of Age With Epilepsy Lamotrigine Valproate Step 1 Achieve a dose of 200 mg/day according to guidelines in Table 1 (if not already on 200 mg/day). Maintain previous stable dose. Step 2 Maintain at 200 mg/day. Decrease to 500 mg/day by decrements no greater than 500 mg/day/week and then maintain the dose of 500 mg/day for 1 week. Step 3 Increase to 300 mg/day and maintain for 1 week. Simultaneously decrease to 250 mg/day and maintain for 1 week. Step 4 Increase by 100 mg/day every week to achieve maintenance dose of 500 mg/day. Discontinue.

   

  Conversion From Adjunctive Therapy With Antiepileptic Drugs Other Than Carbamazepine, Phenytoin, Phenobarbital, Primidone, or Valproate to Monotherapy With Lamotrigine: No specific dosing guidelines can be provided for conversion to monotherapy with lamotrigine with AEDs other than carbamazepine, phenobarbital, phenytoin, primidone, or valproate.

   

  The goal of maintenance treatment with lamotrigine is to delay the time to occurrence of mood episodes (depression, mania, hypomania, mixed episodes) in patients treated for acute mood episodes with standard therapy. The target dose of lamotrigine is 200 mg/day (100 mg/day in patients taking valproate, which decreases the apparent clearance of lamotrigine, and 400 mg/day in patients not taking valproate and taking either carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin that increase the apparent clearance of lamotrigine). In the clinical trials, doses up to 400 mg/day as monotherapy were evaluated; however, no additional benefit was seen at 400 mg/day compared with 200 mg/day [see Clinical Studies (14.2)]. Accordingly, doses above 200 mg/day are not recommended. Treatment with lamotrigine is introduced, based on concurrent medications, according to the regimen outlined in Table 5. If other psychotropic medications are withdrawn following stabilization, the dose of lamotrigine should be adjusted. For patients discontinuing valproate, the dose of lamotrigine should be doubled over a 2-week period in equal weekly increments (see Table 6). For patients discontinuing carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin that induce lamotrigine glucuronidation, the dose of lamotrigine should remain constant for the first week and then should be decreased by half over a 2-week period in equal weekly decrements (see Table 6). The dose of lamotrigine may then be further adjusted to the target dose (200 mg) as clinically indicated.

  If other drugs are subsequently introduced, the dose of lamotrigine may need to be adjusted. In particular, the introduction of valproate requires reduction in the dose of lamotrigine [see Drug Interactions (7), Clinical Pharmacology (12.3)].

  To avoid an increased risk of rash, the recommended initial dose and subsequent dose escalations of lamotrigine should not be exceeded [see Boxed Warning].

  Table 5. Escalation Regimen for Lamotrigine for Patients With Bipolar Disorder For Patients TAKING Valproate* For Patients NOT TAKING Carbamazepine, Phenytoin, Phenobarbital, Primidone†, or Valproate5 For Patients TAKING Carbamazepine, Phenytoin, Phenobarbital, or Primidone6, and NOT TAKING Valproate5 Weeks 1 and 2 25 mg every other day 25 mg daily 50 mg daily Weeks 3 and 4 25 mg daily 50 mg daily 100 mg daily, in divided doses Week 5 50 mg daily 100 mg daily 200 mg daily, in divided doses Week 6 100 mg daily 200 mg daily 300 mg daily, in divided doses Week 7 100 mg daily 200 mg daily up to 400 mg daily, in divided doses Table 6. Dosage Adjustments to Lamotrigine for Patients With Bipolar Disorder Following Discontinuation of Psychotropic Medications Discontinuation of Psychotropic Drugs (excluding Carbamazepine, Phenytoin, Phenobarbital, Primidone*, or Valproate†) After Discontinuation of Valproate8 After Discontinuation of Carbamazepine, Phenytoin, Phenobarbital or Primidone7 Current dose of Lamotrigine (mg/day) 100 Current dose of Lamotrigine (mg/day) 400 Week 1 Maintain current dose of Lamotrigine 150 400 Week 2 Maintain current dose of Lamotrigine 200 300 Week 3 onward Maintain current dose of Lamotrigine 200 200

  The benefit of continuing treatment in patients who had been stabilized in an 8- to 16-week open-label phase with lamotrigine was established in 2 randomized, placebo-controlled clinical maintenance trials [see Clinical Studies (14.2)]. However, the optimal duration of treatment with lamotrigine has not been established. Thus, patients should be periodically reassessed to determine the need for maintenance treatment.

   

  1 Valproate has been shown to inhibit glucuronidation and decrease the apparent clearance of lamotrigine 2 These drugs induce lamotrigine glucuronidation and increase clearance 3 Valproate has been shown to inhibit glucuronidation and decrease the apparent clearance of lamotrigine 4 These drugs induce lamotrigine glucuronidation and increase clearance 5 Valproate has been shown to inhibit glucuronidation and decrease the apparent clearance of lamotrigine 6 These drugs induce lamotrigine glucuronidation and increase clearance 7 These drugs induce lamotrigine glucuronidation and increase clearance 8 Valproate has been shown to inhibit glucuronidation and decrease the apparent clearance of lamotrigine

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  Rash: There are suggestions, yet to be proven, that the risk of severe, potentially life-threatening rash may be increased by (1) coadministration of Lamotrigine with valproate, (2) exceeding the recommended initial dose of Lamotrigine, or (3) exceeding the recommended dose escalation for Lamotrigine. However, cases have occurred in the absence of these factors [see Boxed Warning]. Therefore, it is important that the dosing recommendations be followed closely.

  The risk of nonserious rash may be increased when the recommended initial dose and/or the rate of dose escalation of Lamotrigine is exceeded and in patients with a history of allergy or rash to other AEDs.

  It is recommended that Lamotrigine not be restarted in patients who discontinued due to rash associated with prior treatment with Lamotrigine, unless the potential benefits clearly outweigh the risks. If the decision is made to restart a patient who has discontinued Lamotrigine, the need to restart with the initial dosing recommendations should be assessed. The greater the interval of time since the previous dose, the greater consideration should be given to restarting with the initial dosing recommendations. If a patient has discontinued Lamotrigine for a period of more than 5 half-lives, it is recommended that initial dosing recommendations and guidelines be followed. The half-life of Lamotrigine is affected by other concomitant medications [see Clinical Pharmacology (12.3)].

  Lamotrigine Added to Drugs Known to Induce or Inhibit Glucuronidation: Drugs other than those listed in the Clinical Pharmacology section [see Clinical Pharmacology (12.3)] have not been systematically evaluated in combination with Lamotrigine. Because Lamotrigine is metabolized predominantly by glucuronic acid conjugation, drugs that are known to induce or inhibit glucuronidation may affect the apparent clearance of Lamotrigine and doses of Lamotrigine may require adjustment based on clinical response.

  Target Plasma Levels for Patients With Epilepsy or Bipolar Disorder: A therapeutic plasma concentration range has not been established for Lamotrigine. Dosing of Lamotrigine should be based on therapeutic response [see Clinical Pharmacology (12.3)].

  Women Taking Estrogen-Containing Oral Contraceptives:  Starting Lamotrigine in Women Taking Estrogen-Containing Oral Contraceptives: Although estrogen-containing oral contraceptives have been shown to increase the clearance of Lamotrigine [see Clinical Pharmacology (12.3)], no adjustments to the recommended dose-escalation guidelines for Lamotrigine should be necessary solely based on the use of estrogen-containing oral contraceptives. Therefore, dose escalation should follow the recommended guidelines for initiating adjunctive therapy with Lamotrigine based on the concomitant AED or other concomitant medications (see Table 1 or Table 5). See below for adjustments to maintenance doses of Lamotrigine in women taking estrogen-containing oral contraceptives.

  Adjustments to the Maintenance Dose of Lamotrigine in Women Taking Estrogen-Containing Oral Contraceptives:

  (1) Taking Estrogen-Containing Oral Contraceptives: For women not taking carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin that induce Lamotrigine glucuronidation [see Drug Interactions (7), Clinical Pharmacology (12.3)], the maintenance dose of Lamotrigine will in most cases need to be increased, by as much as 2-fold over the recommended target maintenance dose, in order to maintain a consistent Lamotrigine plasma level [see Clinical Pharmacology (12.3)].

  (2) Starting Estrogen-Containing Oral Contraceptives: In women taking a stable dose of Lamotrigine and not taking carbamazepine, phenytoin, phenobarbital, primidone, or  other drugs such as rifampin that induce Lamotrigine glucuronidation [see Drug Interactions (7), Clinical Pharmacology (12.3)], the maintenance dose will in most cases need to be increased by as much as 2-fold in order to maintain a consistent Lamotrigine plasma level. The dose increases should begin at the same time that the oral contraceptive is introduced and continue, based on clinical response, no more rapidly than 50 to 100 mg/day every week. Dose increases should not exceed the recommended rate (see Table 1 or Table 5) unless Lamotrigine plasma levels or clinical response support larger increases. Gradual transient increases in Lamotrigine plasma levels may occur during the week of inactive hormonal preparation (“pill-free” week), and these increases will be greater if dose increases are made in the days before or during the week of inactive hormonal preparation. Increased Lamotrigine plasma levels could result in additional adverse reactions, such as dizziness, ataxia, and diplopia. If adverse reactions attributable to Lamotrigine consistently occur during the “pill-free” week, dose adjustments to the overall maintenance dose may be necessary. Dose adjustments limited to the “pill-free” week are not recommended. For women taking Lamotrigine in addition to carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin that induce Lamotrigine glucuronidation [see Drug Interactions (7), Clinical Pharmacology (12.3)], no adjustment to the dose of Lamotrigine should be necessary.

  (3) Stopping Estrogen-Containing Oral Contraceptives: For women not taking carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin that induce Lamotrigine glucuronidation [see Drug Interactions (7), Clinical Pharmacology (12.3)], the maintenance dose of Lamotrigine will in most cases need to be decreased by as much as 50% in order to maintain a consistent Lamotrigine plasma level. The decrease in dose of Lamotrigine should not exceed 25% of the total daily dose per week over a 2-week period, unless clinical response or Lamotrigine plasma levels indicate otherwise [see Clinical Pharmacology (12.3)]. For women taking Lamotrigine in addition to carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin that induce Lamotrigine glucuronidation [see Drug Interactions (7), Clinical Pharmacology (12.3)], no adjustment to the dose of Lamotrigine should be necessary.

  Women and Other Hormonal Contraceptive Preparations or Hormone Replacement Therapy: The effect of other hormonal contraceptive preparations or hormone replacement therapy on the pharmacokinetics of Lamotrigine has not been systematically evaluated. It has been reported that ethinylestradiol, not progestogens, increased the clearance of Lamotrigine up to 2-fold, and the progestin-only pills had no effect on Lamotrigine plasma levels. Therefore, adjustments to the dosage of Lamotrigine in the presence of progestogens alone will likely not be needed.

  Patients With Hepatic Impairment: Experience in patients with hepatic impairment is limited. Based on a clinical pharmacology study in 24 patients with mild, moderate, and severe liver impairment [see Use in Specific Populations (8.6), Clinical Pharmacology (12.3)], the following general recommendations can be made. No dosage adjustment is needed in patients with mild liver impairment. Initial, escalation, and maintenance doses should generally be reduced by approximately 25% in patients with moderate and severe liver impairment without ascites and 50% in patients with severe liver impairment with ascites. Escalation and maintenance doses may be adjusted according to clinical response.

  Patients With Renal Impairment: Initial doses of Lamotrigine should be based on patients' concomitant medications (see Tables 1-3 or Table 5); reduced maintenance doses may be effective for patients with significant renal impairment [see Use in Specific Populations (8.7), Clinical Pharmacology (12.3)]. Few patients with severe renal impairment have been evaluated during chronic treatment with Lamotrigine. Because there is inadequate experience in this population, Lamotrigine should be used with caution in these patients.

  Discontinuation Strategy:  Epilepsy: For patients receiving Lamotrigine in combination with other AEDs, a re-evaluation of all AEDs in the regimen should be considered if a change in seizure control or an appearance or worsening of adverse experiences is observed.

  If a decision is made to discontinue therapy with Lamotrigine, a step-wise reduction of dose over at least 2 weeks (approximately 50% per week) is recommended unless safety concerns require a more rapid withdrawal [see Warnings and Precautions (5.9)].

  Discontinuing carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin that induce Lamotrigine glucuronidation should prolong the half-life of Lamotrigine; discontinuing valproate should shorten the half-life of Lamotrigine.

  Bipolar Disorder: In the controlled clinical trials, there was no increase in the incidence, type, or severity of adverse reactions following abrupt termination of Lamotrigine. In clinical trials in patients with Bipolar Disorder, 2 patients experienced seizures shortly after abrupt withdrawal of Lamotrigine. However, there were confounding factors that may have contributed to the occurrence of seizures in these bipolar patients. Discontinuation of Lamotrigine should involve a step-wise reduction of dose over at least 2 weeks (approximately 50% per week) unless safety concerns require a more rapid withdrawal [see Warnings and Precautions (5.9)].

   

  This section provides specific dosing recommendations for patients greater than 12 years of age and patients 2 to 12 years of age. Within each of these age-groups, specific dosing recommendations are provided depending upon concomitant AED or other concomitant medications (Table 1 for patients greater than 12 years of age and Table 2 for patients 2 to 12 years of age). A weight-based dosing guide for patients 2 to 12 years of age on concomitant valproate is provided in Table 3.

  Patients Over 12 Years of Age: Recommended dosing guidelines are summarized in Table 1.

  Table 1. Escalation Regimen for Lamotrigine in Patients Over 12 Years of Age With Epilepsy    For Patients TAKING Valproate* For Patients NOT TAKING Carbamazepine, Phenytoin, Phenobarbital, Primidone†,or Valproate1 For Patients TAKING Carbamazepine, Phenytoin, Phenobarbital, or Primidone2 and NOT TAKING Valproate1 Weeks 1 and 2 25 mg every other day 25 mg every day 50 mg/day Weeks 3 and 4 25 mg every day 50 mg/day 100 mg/day (in 2 divided doses) Weeks 5 onwards to maintenance Increase by 25 to 50 mg/day every 1 to 2 weeks Increase by 50 mg/day
  every 1 to 2 weeks Increase by 100 mg/day every 1 to 2 weeks Usual Maintenance Dose 100 to 200 mg/day with valproate alone
  
  100 to 400 mg/day with valproate and other drugs that induce glucuronication
  (in 1 or 2 divided doses) 225 to 375 mg/day
  (in 2 divided doses) 300 to 500 mg/day  (in 2 divided doses)
  

  Patients 2 to 12 Years of Age: Recommended dosing guidelines are summarized in Table 2.

  Smaller starting doses and slower dose escalations than those used in clinical trials are recommended because of the suggestion that the risk of rash may be decreased by smaller starting doses and slower dose escalations. Therefore, maintenance doses will take longer to reach in clinical practice than in clinical trials. It may take several weeks to months to achieve an individualized maintenance dose. Maintenance doses in patients weighing less than 30 kg, regardless of age or concomitant AED, may need to be increased as much as 50%, based on clinical response. 

  Table 2. Escalation Regimen for Lamotrigine in Patients 2 to 12 Years of Age With Epilepsy   For Patients TAKING Valproate* For Patients NOT TAKING Carbamazepine,
  Phenytoin,
  Phenobarbital,  
  Primidone†  or
   Valproate3 For Patients TAKING Carbamazepine, Phenytoin, Phenobarbital, or  Primidone4 and NOT TAKING Valproate3 Weeks 1 and 2 0.15 mg/kg/day
   in 1 or 2 divided doses, rounded down to the nearest whole tablet (see Table 3 for weight based dosing guide) 0.3 mg/kg/day
  in 1 or 2 divided doses, rounded down to the nearest whole tablet 0.6 mg/kg/day
  in 2 divided doses, rounded down to the nearest whole tablet Weeks 3 and 4 0.3 mg/kg/day
  in 1 or 2 divided doses, rounded down to the nearest whole tablet (see Table 3 for weight based dosing guide) 0.6 mg/kg/day
    in 2 divided doses, rounded down to the nearest whole tablet 1.2 mg/kg/day
    in 2 divided doses, rounded down to the nearest whole tablet Weeks 5 onwards to maintenance The dose should be increased every 1 to 2 weeks as follows: calculate 0.3 mg/kg/day, round this amount down to the nearest whole tablet, and add this amount to the previously administered daily dose The dose should be increased every 1 to 2 weeks as follows: calculate 0.6 mg/kg/day, round this amount down to the nearest whole tablet, and add this amount to the previously administered daily dose The dose should be increased every 1 to 2 weeks as follows: calculate 1.2 mg/kg/day, round this amount down to the nearest whole tablet, and add this amount to the previously administered daily dose Usual Maintenance Dose 1 to 5 mg/kg/day (maximum 200 mg/day in 1 or 2 divided doses).
  1 to 3 mg/kg/day with valproate alone 4.5 to 7.5 mg/kg/day
   (maximum 300 mg/day in 2 divided doses) 5 to 15 mg/kg/day
   (maximum 400 mg/day in 2 divided doses) Maintenance dose in patients less than 30 kg May need to be increased by as much as 50%, based on clinical response May need to be increased by as much as 50%, based on clinical response May need to be increased by as much as 50%, based on clinical response Note: Only whole tablets should be used for dosing.
  Table 3. The Initial Weight-Based Dosing Guide for Patients 2 to 12 Years Taking Valproate (Weeks 1 to 4) With Epilepsy If the patient’s weight is Give this daily dose, using the most appropriate combination of Lamotrigine 2-mg and 5-mg tablets Greater than And less than Weeks 1 and 2 Weeks 3 and 4 6.7 kg 14 kg 2 mg every other day 2 mg every day 14.1 kg 27 kg 2 mg every day 4 mg every day 27.1 kg 34 kg 4 mg every day 8 mg every day 34.1 kg 40 kg 5 mg every day 10 mg every day

  Usual Adjunctive Maintenance Dose for Epilepsy: The usual maintenance doses identified in Tables 1 and 2 are derived from dosing regimens employed in the placebo-controlled adjunctive studies in which the efficacy of Lamotrigine was established. In patients receiving multidrug regimens employing carbamazepine, phenytoin, phenobarbital, or primidone without valproate, maintenance doses of adjunctive Lamotrigine as high as 700 mg/day have been used. In patients receiving valproate alone, maintenance doses of adjunctive Lamotrigine as high as 200 mg/day have been used. The advantage of using doses above those recommended in Tables 1 through 4 has not been established in controlled trials.

   

  The goal of the transition regimen is to effect the conversion to monotherapy with Lamotrigine under conditions that ensure adequate seizure control while mitigating the risk of serious rash associated with the rapid titration of Lamotrigine.

  The recommended maintenance dose of Lamotrigine as monotherapy is 500 mg/day given in 2 divided doses.

  To avoid an increased risk of rash, the recommended initial dose and subsequent dose escalations of Lamotrigine should not be exceeded [see Boxed Warning].

  Conversion From Adjunctive Therapy With Carbamazepine, Phenytoin, Phenobarbital, or Primidone to Monotherapy With Lamotrigine: After achieving a dose of 500 mg/day of Lamotrigine according to the guidelines in Table 1, the concomitant AED should be withdrawn by 20% decrements each week over a 4-week period. The regimen for the withdrawal of the concomitant AED is based on experience gained in the controlled monotherapy clinical trial. 

  Conversion from Adjunctive Therapy With Valproate to Monotherapy With Lamotrigine: The conversion regimen involves 4 steps outlined in Table 4.

  Table 4. Conversion From Adjunctive Therapy With Valproate to Monotherapy With Lamotrigine in Patients ≥16 Years of Age with Epilepsy

  Lamotrigine

  Valproate

  Step 1

  Achieve a dose of 200 mg/day according to guidelines in Table 1 (if not already on 200 mg/day).

  Maintain previous stable dose.

  Step 2

  Maintain at 200 mg/day.

  Decrease to 500 mg/day by decrements no greater than 500 mg/day/week and then maintain the dose of 500 mg/day for 1 week.

  Step 3

  Increase to 300 mg/day and maintain for 1 week.

  Simultaneously decrease to 250 mg/day and maintain for 1 week.

  Step 4

  Increase by 100 mg/day every week to achieve maintenance dose of 500 mg/day.

  Discontinue.

  
  Conversion from Adjunctive Therapy With AEDs Other Than Carbamazepine, Phenytoin, Phenobarbital, Primidone, or Valproate to Monotherapy With Lamotrigine: No specific dosing guidelines can be provided for conversion to monotherapy with Lamotrigine with AEDs other than carbamazepine, phenobarbital, phenytoin, primidone, or valproate.

   

  The goal of maintenance treatment with Lamotrigine is to delay the time to occurrence of mood episodes (depression, mania, hypomania, mixed episodes) in patients treated for acute mood episodes with standard therapy. The target dose of Lamotrigine is 200 mg/day (100 mg/day in patients taking valproate, which decreases the apparent clearance of Lamotrigine, and 400 mg/day in patients not taking valproate and taking either carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin, that  increase the apparent clearance of Lamotrigine). In the clinical trials, doses up to 400 mg/day as monotherapy were evaluated; however, no additional benefit was seen at 400 mg/day compared with 200 mg/day [see Clinical Studies (14.2)]. Accordingly, doses above 200 mg/day are not recommended. Treatment with Lamotrigine is introduced, based on concurrent medications, according to the regimen outlined in Table 5. If other psychotropic medications are withdrawn following stabilization, the dose of Lamotrigine should be adjusted. For patients discontinuing valproate, the dose of Lamotrigine should be doubled over a 2-week period in equal weekly increments (see Table 6). For patients discontinuing carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin that induce Lamotrigine glucuronidation, the dose of Lamotrigine should remain constant for the first week and then should be decreased by half over a 2-week period in equal weekly decrements (see Table 6). The dose of Lamotrigine may then be further adjusted to the target dose (200 mg) as clinically indicated.

  If other drugs are subsequently introduced, the dose of Lamotrigine may need to be adjusted. In particular, the introduction of valproate requires reduction in the dose of Lamotrigine [see Drug Interactions (7), Clinical Pharmacology (12.3)].

  To avoid an increased risk of rash, the recommended initial dose and subsequent dose escalations of Lamotrigine should not be exceeded [see Boxed Warning].

   

  Table 5. Escalation Regimen for Lamotrigine for Patients With Bipolar Disorder For Patients TAKING Valproate* For Patients NOT TAKING Carbamazepine, Phenytoin, Phenobarbital, Primidone†, or Valproate5 For Patients TAKING Carbamazepine, Phenytoin, Phenobarbital, or Primidone6 and NOT TAKING Valproate5 Weeks 1 and 2 25 mg every other day 25 mg daily 50 mg daily Weeks 3 and 4 25 mg daily 50 mg daily 100 mg daily, in divided doses Week 5 50 mg daily 100 mg daily 200 mg daily, in divided doses Week 6 100 mg daily 200 mg daily 300 mg daily, in divided doses Week 7 100 mg daily 200 mg daily up to 400 mg daily, in divided doses
  Table 6. Dosage Adjustments to Lamotrigine for Patients With Bipolar Disorder Following Discontinuation of Psychotropic Medications  

  Discontinuation of Psychotropic Drugs (excluding Carbamazepine, Phenytoin, Phenobarbital, Primidone*, or Valproate†)

  After Discontinuation of Valproate8 After Discontinuation of Carbamazepine, Phenytoin, Phenobarbital, or Primidone7 Current dose of Lamotrigine (mg/day) 100

  Current dose of Lamotrigine (mg/day) 400

  Week 1 Maintain current dose of Lamotrigine 150 400 Week 2 Maintain current dose of Lamotrigine 200 300 Week 3 onward Maintain current dose of Lamotrigine 200 200
  

  The benefit of continuing treatment in patients who had been stabilized in an 8- to 16-week open-label phase with Lamotrigine was established in 2 randomized, placebo-controlled clinical maintenance trials [see Clinical Studies (14.2)]. However, the optimal duration of treatment with Lamotrigine has not been established. Thus, patients should be periodically reassessed to determine the need for maintenance treatment.

   

  1 Valproate has been shown to inhibit glucuronidation and decrease the apparent clearance of Lamotrigine 2 These drugs induce Lamotrigine glucuronidation and increase clearance 3 Valproate has been shown to inhibit glucuronidation and decrease the apparent clearance of Lamotrigine 4 These drugs induce Lamotrigine glucuronidation and increase clearance 5 Valproate has been shown to inhibit glucuronidation and decrease the apparent clearance of Lamotrigine 6 These drugs induce Lamotrigine glucuronidation and increase clearance 7 These drugs induce Lamotrigine glucuronidation and increase clearance 8 Valproate has been shown to inhibit glucuronidation and decrease the apparent clearance of Lamotrigine

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  Rash: There are suggestions, yet to be proven, that the risk of severe, potentially life-threatening rash may be increased by (1) coadministration of Lamotrigine with valproate, (2) exceeding the recommended initial dose of Lamotrigine, or (3) exceeding the recommended dose escalation for Lamotrigine. However, cases have occurred in the absence of these factors [see Boxed Warning]. Therefore, it is important that the dosing recommendations be followed closely.

  The risk of nonserious rash may be increased when the recommended initial dose and/or the rate of dose escalation of Lamotrigine is exceeded and in patients with a history of allergy or rash to other AEDs.

  It is recommended that Lamotrigine not be restarted in patients who discontinued due to rash associated with prior treatment with Lamotrigine, unless the potential benefits clearly outweigh the risks. If the decision is made to restart a patient who has discontinued Lamotrigine, the need to restart with the initial dosing recommendations should be assessed. The greater the interval of time since the previous dose, the greater consideration should be given to restarting with the initial dosing recommendations. If a patient has discontinued Lamotrigine for a period of more than 5 half-lives, it is recommended that initial dosing recommendations and guidelines be followed. The half-life of Lamotrigine is affected by other concomitant medications [see Clinical Pharmacology (12.3)].

  Lamotrigine Added to Drugs Known to Induce or Inhibit Glucuronidation: Drugs other than those listed in the Clinical Pharmacology section [see Clinical Pharmacology (12.3)] have not been systematically evaluated in combination with Lamotrigine. Because Lamotrigine is metabolized predominantly by glucuronic acid conjugation, drugs that are known to induce or inhibit glucuronidation may affect the apparent clearance of Lamotrigine and doses of Lamotrigine may require adjustment based on clinical response.

  Target Plasma Levels for Patients With Epilepsy or Bipolar Disorder: A therapeutic plasma concentration range has not been established for Lamotrigine. Dosing of Lamotrigine should be based on therapeutic response [see Clinical Pharmacology (12.3)].

  Women Taking Estrogen-Containing Oral Contraceptives:  Starting Lamotrigine in Women Taking Estrogen-Containing Oral Contraceptives: Although estrogen-containing oral contraceptives have been shown to increase the clearance of Lamotrigine [see Clinical Pharmacology (12.3)], no adjustments to the recommended dose-escalation guidelines for Lamotrigine should be necessary solely based on the use of estrogen-containing oral contraceptives. Therefore, dose escalation should follow the recommended guidelines for initiating adjunctive therapy with Lamotrigine based on the concomitant AED or other concomitant medications (see Table 1 or Table 5). See below for adjustments to maintenance doses of Lamotrigine in women taking estrogen-containing oral contraceptives.

  Adjustments to the Maintenance Dose of Lamotrigine in Women Taking Estrogen-Containing Oral Contraceptives:

  (1) Taking Estrogen-Containing Oral Contraceptives: For women not taking carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin that induce Lamotrigine glucuronidation [see Drug Interactions (7), Clinical Pharmacology (12.3)], the maintenance dose of Lamotrigine will in most cases need to be increased, by as much as 2-fold over the recommended target maintenance dose, in order to maintain a consistent Lamotrigine plasma level [see Clinical Pharmacology (12.3)].

  (2) Starting Estrogen-Containing Oral Contraceptives: In women taking a stable dose of Lamotrigine and not taking carbamazepine, phenytoin, phenobarbital, primidone, or  other drugs such as rifampin that induce Lamotrigine glucuronidation [see Drug Interactions (7), Clinical Pharmacology (12.3)], the maintenance dose will in most cases need to be increased by as much as 2-fold in order to maintain a consistent Lamotrigine plasma level. The dose increases should begin at the same time that the oral contraceptive is introduced and continue, based on clinical response, no more rapidly than 50 to 100 mg/day every week. Dose increases should not exceed the recommended rate (see Table 1 or Table 5) unless Lamotrigine plasma levels or clinical response support larger increases. Gradual transient increases in Lamotrigine plasma levels may occur during the week of inactive hormonal preparation (“pill-free” week), and these increases will be greater if dose increases are made in the days before or during the week of inactive hormonal preparation. Increased Lamotrigine plasma levels could result in additional adverse reactions, such as dizziness, ataxia, and diplopia. If adverse reactions attributable to Lamotrigine consistently occur during the “pill-free” week, dose adjustments to the overall maintenance dose may be necessary. Dose adjustments limited to the “pill-free” week are not recommended. For women taking Lamotrigine in addition to carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin that induce Lamotrigine glucuronidation [see Drug Interactions (7), Clinical Pharmacology (12.3)], no adjustment to the dose of Lamotrigine should be necessary.

  (3) Stopping Estrogen-Containing Oral Contraceptives: For women not taking carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin that induce Lamotrigine glucuronidation [see Drug Interactions (7), Clinical Pharmacology (12.3)], the maintenance dose of Lamotrigine will in most cases need to be decreased by as much as 50% in order to maintain a consistent Lamotrigine plasma level. The decrease in dose of Lamotrigine should not exceed 25% of the total daily dose per week over a 2-week period, unless clinical response or Lamotrigine plasma levels indicate otherwise [see Clinical Pharmacology (12.3)]. For women taking Lamotrigine in addition to carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin that induce Lamotrigine glucuronidation [see Drug Interactions (7), Clinical Pharmacology (12.3)], no adjustment to the dose of Lamotrigine should be necessary.

  Women and Other Hormonal Contraceptive Preparations or Hormone Replacement Therapy: The effect of other hormonal contraceptive preparations or hormone replacement therapy on the pharmacokinetics of Lamotrigine has not been systematically evaluated. It has been reported that ethinylestradiol, not progestogens, increased the clearance of Lamotrigine up to 2-fold, and the progestin-only pills had no effect on Lamotrigine plasma levels. Therefore, adjustments to the dosage of Lamotrigine in the presence of progestogens alone will likely not be needed.

  Patients With Hepatic Impairment: Experience in patients with hepatic impairment is limited. Based on a clinical pharmacology study in 24 patients with mild, moderate, and severe liver impairment [see Use in Specific Populations (8.6), Clinical Pharmacology (12.3)], the following general recommendations can be made. No dosage adjustment is needed in patients with mild liver impairment. Initial, escalation, and maintenance doses should generally be reduced by approximately 25% in patients with moderate and severe liver impairment without ascites and 50% in patients with severe liver impairment with ascites. Escalation and maintenance doses may be adjusted according to clinical response.

  Patients With Renal Impairment: Initial doses of Lamotrigine should be based on patients' concomitant medications (see Tables 1-3 or Table 5); reduced maintenance doses may be effective for patients with significant renal impairment [see Use in Specific Populations (8.7), Clinical Pharmacology (12.3)]. Few patients with severe renal impairment have been evaluated during chronic treatment with Lamotrigine. Because there is inadequate experience in this population, Lamotrigine should be used with caution in these patients.

  Discontinuation Strategy:  Epilepsy: For patients receiving Lamotrigine in combination with other AEDs, a re-evaluation of all AEDs in the regimen should be considered if a change in seizure control or an appearance or worsening of adverse experiences is observed.

  If a decision is made to discontinue therapy with Lamotrigine, a step-wise reduction of dose over at least 2 weeks (approximately 50% per week) is recommended unless safety concerns require a more rapid withdrawal [see Warnings and Precautions (5.9)].

  Discontinuing carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin that induce Lamotrigine glucuronidation should prolong the half-life of Lamotrigine; discontinuing valproate should shorten the half-life of Lamotrigine.

  Bipolar Disorder: In the controlled clinical trials, there was no increase in the incidence, type, or severity of adverse reactions following abrupt termination of Lamotrigine. In clinical trials in patients with Bipolar Disorder, 2 patients experienced seizures shortly after abrupt withdrawal of Lamotrigine. However, there were confounding factors that may have contributed to the occurrence of seizures in these bipolar patients. Discontinuation of Lamotrigine should involve a step-wise reduction of dose over at least 2 weeks (approximately 50% per week) unless safety concerns require a more rapid withdrawal [see Warnings and Precautions (5.9)].

   

  This section provides specific dosing recommendations for patients greater than 12 years of age and patients 2 to 12 years of age. Within each of these age-groups, specific dosing recommendations are provided depending upon concomitant AED or other concomitant medications (Table 1 for patients greater than 12 years of age and Table 2 for patients 2 to 12 years of age). A weight-based dosing guide for patients 2 to 12 years of age on concomitant valproate is provided in Table 3.

  Patients Over 12 Years of Age: Recommended dosing guidelines are summarized in Table 1.

  Table 1. Escalation Regimen for Lamotrigine in Patients Over 12 Years of Age With Epilepsy    For Patients TAKING Valproate* For Patients NOT TAKING Carbamazepine, Phenytoin, Phenobarbital, Primidone†,or Valproate1 For Patients TAKING Carbamazepine, Phenytoin, Phenobarbital, or Primidone2 and NOT TAKING Valproate1 Weeks 1 and 2 25 mg every other day 25 mg every day 50 mg/day Weeks 3 and 4 25 mg every day 50 mg/day 100 mg/day (in 2 divided doses) Weeks 5 onwards to maintenance Increase by 25 to 50 mg/day every 1 to 2 weeks Increase by 50 mg/day
  every 1 to 2 weeks Increase by 100 mg/day every 1 to 2 weeks Usual Maintenance Dose 100 to 200 mg/day with valproate alone
  
  100 to 400 mg/day with valproate and other drugs that induce glucuronication
  (in 1 or 2 divided doses) 225 to 375 mg/day
  (in 2 divided doses) 300 to 500 mg/day  (in 2 divided doses)
  

  Patients 2 to 12 Years of Age: Recommended dosing guidelines are summarized in Table 2.

  Smaller starting doses and slower dose escalations than those used in clinical trials are recommended because of the suggestion that the risk of rash may be decreased by smaller starting doses and slower dose escalations. Therefore, maintenance doses will take longer to reach in clinical practice than in clinical trials. It may take several weeks to months to achieve an individualized maintenance dose. Maintenance doses in patients weighing less than 30 kg, regardless of age or concomitant AED, may need to be increased as much as 50%, based on clinical response. 

  Table 2. Escalation Regimen for Lamotrigine in Patients 2 to 12 Years of Age With Epilepsy   For Patients TAKING Valproate* For Patients NOT TAKING Carbamazepine,
  Phenytoin,
  Phenobarbital,  
  Primidone†  or
   Valproate3 For Patients TAKING Carbamazepine, Phenytoin, Phenobarbital, or  Primidone4 and NOT TAKING Valproate3 Weeks 1 and 2 0.15 mg/kg/day
   in 1 or 2 divided doses, rounded down to the nearest whole tablet (see Table 3 for weight based dosing guide) 0.3 mg/kg/day
  in 1 or 2 divided doses, rounded down to the nearest whole tablet 0.6 mg/kg/day
  in 2 divided doses, rounded down to the nearest whole tablet Weeks 3 and 4 0.3 mg/kg/day
  in 1 or 2 divided doses, rounded down to the nearest whole tablet (see Table 3 for weight based dosing guide) 0.6 mg/kg/day
    in 2 divided doses, rounded down to the nearest whole tablet 1.2 mg/kg/day
    in 2 divided doses, rounded down to the nearest whole tablet Weeks 5 onwards to maintenance The dose should be increased every 1 to 2 weeks as follows: calculate 0.3 mg/kg/day, round this amount down to the nearest whole tablet, and add this amount to the previously administered daily dose The dose should be increased every 1 to 2 weeks as follows: calculate 0.6 mg/kg/day, round this amount down to the nearest whole tablet, and add this amount to the previously administered daily dose The dose should be increased every 1 to 2 weeks as follows: calculate 1.2 mg/kg/day, round this amount down to the nearest whole tablet, and add this amount to the previously administered daily dose Usual Maintenance Dose 1 to 5 mg/kg/day (maximum 200 mg/day in 1 or 2 divided doses).
  1 to 3 mg/kg/day with valproate alone 4.5 to 7.5 mg/kg/day
   (maximum 300 mg/day in 2 divided doses) 5 to 15 mg/kg/day
   (maximum 400 mg/day in 2 divided doses) Maintenance dose in patients less than 30 kg May need to be increased by as much as 50%, based on clinical response May need to be increased by as much as 50%, based on clinical response May need to be increased by as much as 50%, based on clinical response Note: Only whole tablets should be used for dosing.
  Table 3. The Initial Weight-Based Dosing Guide for Patients 2 to 12 Years Taking Valproate (Weeks 1 to 4) With Epilepsy If the patient’s weight is Give this daily dose, using the most appropriate combination of Lamotrigine 2-mg and 5-mg tablets Greater than And less than Weeks 1 and 2 Weeks 3 and 4 6.7 kg 14 kg 2 mg every other day 2 mg every day 14.1 kg 27 kg 2 mg every day 4 mg every day 27.1 kg 34 kg 4 mg every day 8 mg every day 34.1 kg 40 kg 5 mg every day 10 mg every day

  Usual Adjunctive Maintenance Dose for Epilepsy: The usual maintenance doses identified in Tables 1 and 2 are derived from dosing regimens employed in the placebo-controlled adjunctive studies in which the efficacy of Lamotrigine was established. In patients receiving multidrug regimens employing carbamazepine, phenytoin, phenobarbital, or primidone without valproate, maintenance doses of adjunctive Lamotrigine as high as 700 mg/day have been used. In patients receiving valproate alone, maintenance doses of adjunctive Lamotrigine as high as 200 mg/day have been used. The advantage of using doses above those recommended in Tables 1 through 4 has not been established in controlled trials.

   

  The goal of the transition regimen is to effect the conversion to monotherapy with Lamotrigine under conditions that ensure adequate seizure control while mitigating the risk of serious rash associated with the rapid titration of Lamotrigine.

  The recommended maintenance dose of Lamotrigine as monotherapy is 500 mg/day given in 2 divided doses.

  To avoid an increased risk of rash, the recommended initial dose and subsequent dose escalations of Lamotrigine should not be exceeded [see Boxed Warning].

  Conversion From Adjunctive Therapy With Carbamazepine, Phenytoin, Phenobarbital, or Primidone to Monotherapy With Lamotrigine: After achieving a dose of 500 mg/day of Lamotrigine according to the guidelines in Table 1, the concomitant AED should be withdrawn by 20% decrements each week over a 4-week period. The regimen for the withdrawal of the concomitant AED is based on experience gained in the controlled monotherapy clinical trial. 

  Conversion from Adjunctive Therapy With Valproate to Monotherapy With Lamotrigine: The conversion regimen involves 4 steps outlined in Table 4.

  Table 4. Conversion From Adjunctive Therapy With Valproate to Monotherapy With Lamotrigine in Patients ≥16 Years of Age with Epilepsy

  Lamotrigine

  Valproate

  Step 1

  Achieve a dose of 200 mg/day according to guidelines in Table 1 (if not already on 200 mg/day).

  Maintain previous stable dose.

  Step 2

  Maintain at 200 mg/day.

  Decrease to 500 mg/day by decrements no greater than 500 mg/day/week and then maintain the dose of 500 mg/day for 1 week.

  Step 3

  Increase to 300 mg/day and maintain for 1 week.

  Simultaneously decrease to 250 mg/day and maintain for 1 week.

  Step 4

  Increase by 100 mg/day every week to achieve maintenance dose of 500 mg/day.

  Discontinue.

  
  Conversion from Adjunctive Therapy With AEDs Other Than Carbamazepine, Phenytoin, Phenobarbital, Primidone, or Valproate to Monotherapy With Lamotrigine: No specific dosing guidelines can be provided for conversion to monotherapy with Lamotrigine with AEDs other than carbamazepine, phenobarbital, phenytoin, primidone, or valproate.

   

  The goal of maintenance treatment with Lamotrigine is to delay the time to occurrence of mood episodes (depression, mania, hypomania, mixed episodes) in patients treated for acute mood episodes with standard therapy. The target dose of Lamotrigine is 200 mg/day (100 mg/day in patients taking valproate, which decreases the apparent clearance of Lamotrigine, and 400 mg/day in patients not taking valproate and taking either carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin, that  increase the apparent clearance of Lamotrigine). In the clinical trials, doses up to 400 mg/day as monotherapy were evaluated; however, no additional benefit was seen at 400 mg/day compared with 200 mg/day [see Clinical Studies (14.2)]. Accordingly, doses above 200 mg/day are not recommended. Treatment with Lamotrigine is introduced, based on concurrent medications, according to the regimen outlined in Table 5. If other psychotropic medications are withdrawn following stabilization, the dose of Lamotrigine should be adjusted. For patients discontinuing valproate, the dose of Lamotrigine should be doubled over a 2-week period in equal weekly increments (see Table 6). For patients discontinuing carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin that induce Lamotrigine glucuronidation, the dose of Lamotrigine should remain constant for the first week and then should be decreased by half over a 2-week period in equal weekly decrements (see Table 6). The dose of Lamotrigine may then be further adjusted to the target dose (200 mg) as clinically indicated.

  If other drugs are subsequently introduced, the dose of Lamotrigine may need to be adjusted. In particular, the introduction of valproate requires reduction in the dose of Lamotrigine [see Drug Interactions (7), Clinical Pharmacology (12.3)].

  To avoid an increased risk of rash, the recommended initial dose and subsequent dose escalations of Lamotrigine should not be exceeded [see Boxed Warning].

   

  Table 5. Escalation Regimen for Lamotrigine for Patients With Bipolar Disorder For Patients TAKING Valproate* For Patients NOT TAKING Carbamazepine, Phenytoin, Phenobarbital, Primidone†, or Valproate5 For Patients TAKING Carbamazepine, Phenytoin, Phenobarbital, or Primidone6 and NOT TAKING Valproate5 Weeks 1 and 2 25 mg every other day 25 mg daily 50 mg daily Weeks 3 and 4 25 mg daily 50 mg daily 100 mg daily, in divided doses Week 5 50 mg daily 100 mg daily 200 mg daily, in divided doses Week 6 100 mg daily 200 mg daily 300 mg daily, in divided doses Week 7 100 mg daily 200 mg daily up to 400 mg daily, in divided doses
  Table 6. Dosage Adjustments to Lamotrigine for Patients With Bipolar Disorder Following Discontinuation of Psychotropic Medications  

  Discontinuation of Psychotropic Drugs (excluding Carbamazepine, Phenytoin, Phenobarbital, Primidone*, or Valproate†)

  After Discontinuation of Valproate8 After Discontinuation of Carbamazepine, Phenytoin, Phenobarbital, or Primidone7 Current dose of Lamotrigine (mg/day) 100

  Current dose of Lamotrigine (mg/day) 400

  Week 1 Maintain current dose of Lamotrigine 150 400 Week 2 Maintain current dose of Lamotrigine 200 300 Week 3 onward Maintain current dose of Lamotrigine 200 200
  

  The benefit of continuing treatment in patients who had been stabilized in an 8- to 16-week open-label phase with Lamotrigine was established in 2 randomized, placebo-controlled clinical maintenance trials [see Clinical Studies (14.2)]. However, the optimal duration of treatment with Lamotrigine has not been established. Thus, patients should be periodically reassessed to determine the need for maintenance treatment.

   

  1 Valproate has been shown to inhibit glucuronidation and decrease the apparent clearance of Lamotrigine 2 These drugs induce Lamotrigine glucuronidation and increase clearance 3 Valproate has been shown to inhibit glucuronidation and decrease the apparent clearance of Lamotrigine 4 These drugs induce Lamotrigine glucuronidation and increase clearance 5 Valproate has been shown to inhibit glucuronidation and decrease the apparent clearance of Lamotrigine 6 These drugs induce Lamotrigine glucuronidation and increase clearance 7 These drugs induce Lamotrigine glucuronidation and increase clearance 8 Valproate has been shown to inhibit glucuronidation and decrease the apparent clearance of Lamotrigine

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  Rash: There are suggestions, yet to be proven, that the risk of severe, potentially life-threatening rash may be increased by (1) coadministration of  lamotrigine tablets with valproate, (2) exceeding the recommended initial dose of lamotrigine tablets,  or (3) exceeding the recommended dose escalation for lamotrigine tablets. However, cases have occurred in the absence of these factors [see Boxed Warning]. Therefore, it is important that the dosing recommendations be followed closely. 

  The risk of nonserious rash may be increased when the recommended initial dose and/or the rate of dose escalation of lamotrigine tablets is exceeded and in patients with a history of allergy or rash to other AEDs. 

  It is recommended that lamotrigine tablets not be restarted in patients who discontinued due to rash associated with prior treatment with lamotrigine, unless the potential benefits clearly outweigh the risks. If the decision is made to restart a patient who has discontinued lamotrigine, the need to restart with the initial dosing recommendations should be assessed. The greater the interval of time since the previous dose, the greater consideration should be given to restarting with the initial dosing recommendations. If a patient has discontinued lamotrigine for a period of more than 5 half-lives, it is recommended that initial dosing recommendations and guidelines be followed. The half-life of lamotrigine is affected by other concomitant medications [see Clinical Pharmacology (12.3)].

  Lamotrigine Added to Drugs Known to Induce or Inhibit Glucuronidation: Drugs other than those listed in the Clinical Pharmacology section [see Clinical Pharmacology (12.3)] have not been systematically evaluated in combination with lamotrigine. Because lamotrigine is metabolized predominantly by glucuronic acid conjugation, drugs that are known to induce or inhibit glucuronidation may affect the apparent clearance of lamotrigine and doses of lamotrigine tablets may require adjustment based on clinical response.

  Target Plasma Levels for Patients with Epilepsy or Bipolar Disorder: A therapeutic plasma concentration range has not been established for lamotrigine. Dosing of lamotrigine tablets should be based on therapeutic response [see Clinical Pharmacology (12.3)]. 

  Women Taking Estrogen-Containing Oral Contraceptives: Starting Lamotrigine in Women Taking Estrogen-Containing Oral Contraceptives: Although estrogen-containing oral contraceptives have been shown to increase the clearance of lamotrigine [see Clinical Pharmacology (12.3)], no adjustments to the recommended dose-escalation guidelines for lamotrigine tablets should be necessary solely based on the use of estrogen-containing oral contraceptives. Therefore, dose escalation should follow the recommended guidelines for initiating adjunctive therapy with lamotrigine tablets based on the concomitant AED or other concomitant medications (see Table 1 or Table 5). See below for adjustments to maintenance doses of lamotrigine tablets in women taking estrogen-containing oral contraceptives. 

  Adjustments to the Maintenance Dose of Lamotrigine in Women Taking Estrogen-Containing Oral Contraceptives:(1) Taking Estrogen-Containing Oral Contraceptives: For women not taking carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin that induce lamotrigine glucuronidation [see Drug Interactions (7), Clinical Pharmacology (12.3)],   the maintenance dose of lamotrigine tablets  will in most cases need to be increased, by as much as 2-fold over the recommended target maintenance dose, in order to maintain a consistent lamotrigine plasma level [see Clinical Pharmacology (12.3)].

  (2) Starting Estrogen-Containing Oral Contraceptives: In women taking a stable dose of lamotrigine tablets and not taking carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin that induce lamotrigine glucuronidation [see Drug Interactions (7), Clinical Pharmacology (12.3)],   the maintenance dose will in most cases need to be increased by as much as 2-fold in order to maintain a consistent lamotrigine plasma level. The dose increases should begin at the same time that the oral contraceptive is introduced and continue, based on clinical response, no more rapidly than 50 to 100 mg/day every week. Dose increases should not exceed the recommended rate (see Table 1 or Table 5) unless lamotrigine plasma levels or clinical response support larger increases. Gradual transient increases in lamotrigine plasma levels may occur during the week of inactive hormonal preparation (“pill-free” week), and these increases will be greater if dose increases are made in the days before or during the week of inactive hormonal preparation. Increased lamotrigine plasma levels could result in additional adverse reactions, such as dizziness, ataxia, and diplopia. If adverse reactions attributable to lamotrigine tablets consistently occur during the “pill-free” week, dose adjustments to the overall maintenance dose may be necessary. Dose adjustments limited to the “pill-free” week are not recommended. For women taking lamotrigine tablets in addition to carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin that induce lamotrigine glucuronidation [see Drug Interactions (7), Clinical Pharmacology (12.3)],  no adjustment to the dose of lamotrigine tablets should be necessary.

  (3) Stopping Estrogen-Containing Oral Contraceptives: For women not taking carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin that induce lamotrigine glucuronidation [see Drug Interactions (7), Clinical Pharmacology (12.3)], the maintenance dose of lamotrigine tablets will in most cases need to be decreased by as much as 50% in order to maintain a consistent lamotrigine plasma level. The decrease in dose of lamotrigine tablets should not exceed 25% of the total daily dose per week over a 2-week period, unless clinical response or lamotrigine plasma levels indicate otherwise [see Clinical Pharmacology (12.3)]. For women taking lamotrigine tablets in addition to carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin that induce lamotrigine glucuronidation [see Drug Interactions (7), Clinical Pharmacology (12.3)], no adjustment to the dose of lamotrigine tablets should be necessary. 

  Women and Other Hormonal Contraceptive Preparations or Hormone Replacement Therapy: The effect of other hormonal contraceptive preparations or hormone replacement therapy on the pharmacokinetics of lamotrigine has not been systematically evaluated. It has been reported that ethinylestradiol, not progestogens, increased the clearance of lamotrigine up to 2-fold, and the progestin-only pills had no effect on lamotrigine plasma levels. Therefore, adjustments to the dosage of lamotrigine tablets in the presence of progestogens alone will likely not be needed. 

  Patients with Hepatic Impairment: Experience in patients with hepatic impairment is limited. Based on a clinical pharmacology study in 24 patients with mild, moderate, and severe liver impairment [see Use in Specific Populations (8.6), Clinical Pharmacology (12.3)], the following general recommendations can be made. No dosage adjustment is needed in patients with mild liver impairment. Initial, escalation, and maintenance doses should generally be reduced by approximately 25% in patients with moderate and severe liver impairment without ascites and 50% in patients with severe liver impairment with ascites. Escalation and maintenance doses may be adjusted according to clinical response. 

  Patients with Renal Impairment: Initial doses of lamotrigine tablets should be based on patients' concomitant medications (see Tables 1-3 or Table 5); reduced maintenance doses may be effective for patients with significant renal impairment [see Use in Specific Populations (8.7), Clinical Pharmacology (12.3)]. Few patients with severe renal impairment have been evaluated during chronic treatment with lamotrigine tablets. Because there is inadequate experience in this population, lamotrigine tablets should be used with caution in these patients. 

  Discontinuation Strategy: Epilepsy: For patients receiving lamotrigine tablets in combination with other AEDs, a re-evaluation of all AEDs in the regimen should be considered if a change in seizure control or an appearance or worsening of adverse reactions is observed. 

  If a decision is made to discontinue therapy with lamotrigine tablets, a step-wise reduction of dose over at least 2 weeks (approximately 50% per week) is recommended unless safety concerns require a more rapid withdrawal [see Warnings and Precautions (5.9)].

  Discontinuing carbamazepine, phenytoin, phenobarbital, primidone or other drugs such as rifampin that induce lamotrigine glucuronidation should prolong the half-life of lamotrigine; discontinuing valproate should shorten the half-life of lamotrigine. 

  Bipolar Disorder: In the controlled clinical trials, there was no increase in the incidence, type, or severity of adverse reactions following abrupt termination of lamotrigine tablets. In clinical trials in patients with Bipolar Disorder, 2 patients experienced seizures shortly after abrupt withdrawal of lamotrigine tablets. However, there were confounding factors that may have contributed to the occurrence of seizures in these bipolar patients. Discontinuation of lamotrigine tablets should involve a step-wise reduction of dose over at least 2 weeks (approximately 50% per week) unless safety concerns require a more rapid withdrawal [see Warnings and Precautions (5.9)].

   

  This section provides specific dosing recommendations for patients greater than 12 years of age and patients 2 to 12 years of age. Within each of these age-groups, specific dosing recommendations are provided depending upon concomitant AED or other concomitant medications (Table 1 for patients greater than 12 years of age and Table 2 for patients 2 to 12 years of age). A weight-based dosing guide for patients 2 to 12 years of age on concomitant valproate is provided in Table 3. 

  Patients Over 12 Years of Age: Recommended dosing guidelines are summarized in Table 1. 

  Table 1. Escalation Regimen for Lamotrigine in Patients Over 12 Years of Age With Epilepsy

         For Patients TAKING Valproate a For Patients NOT TAKING Carbamazepine, Phenytoin, Phenobarbital, Primidoneb, or Valproatea For Patients TAKING Carbamazepine, Phenytoin, Phenobarbital, or Primidoneb and NOT TAKING Valproatea Weeks 1 and 2 25 mg every other day 25 mg every day 50 mg/day  Weeks 3 and 4 25 mg every day 50 mg/day 100 mg/day
  (in 2 divided doses) Weeks 5 onwards to maintenance Increase by 25 to 50 mg/day every 1 to 2 weeks Increase by 50 mg/day every 1 to 2 weeks  Increase by 100 mg/day every 1 to 2 weeks. Usual maintenance dose  100 to 200 mg/day with valproate alone 100 to 400 mg/day with valproate and other drugs that induceglucuronication 
  (in 1 or 2 divided doses) 225 to 375 mg/day
  (in 2 divided doses)  300 to 500 mg/day
  (in 2 divided doses) 

  a Valproate has been shown to inhibit glucuronidation and decrease the apparent clearance of    lamotrigine [see Drug Interactions (7), Clinical Pharmacology (12.3)].

  b   These drugs induce glucuronidation and increase clearance [see Drug Interactions (7) Clinical Pharmacology (12.3)]. Other drugs, that have similar effects include estrogen-containing oral contraceptives [see Drug Interactions (7),Clinical Pharmacology (12.3)].

  Dosing recommendations for oral contraceptives can be found in General Dosing Considerations [see Dosage and Administration (2.1)]. Patients on rifampin or other drugs that induce lamotrigine glucuronidation and increase clearance, should follow the same dosing titration/maintenance regimen as that used with anticonvulsants that have this effect..                                               

  Patients 2 to 12 Years of Age: Recommended dosing guidelines are summarized in Table 2.  Smaller starting doses and slower dose escalations than those used in clinical trials are recommended because of the suggestion that the risk of rash may be decreased by smaller starting doses and slower dose escalations. Therefore, maintenance doses will take longer to reach in clinical practice than in clinical trials. It may take several weeks to months to achieve an individualized maintenance dose. Maintenance doses in patients weighing less than 30 kg, regardless of age or concomitant AED, may need to be increased as much as 50%, based on clinical response.

  Table 2. Escalation Regimen for Lamotrigine in Patients 2 to 12 Years of Age With Epilepsy

    For Patients TAKING Valproatea For Patients NOT TAKING Carbamazepine, Phenytoin, Phenobarbital, Primidoneb, or Valproatea For Patients TAKING Carbamazepine, Phenytoin, Phenobarbital, or Primidoneb and NOT TAKING Valproatea Weeks 1 and 2 0.15 mg/kg/day
  in 1 or 2 divided doses, rounded down to the nearest whole tablet (see Table 3 for weight-based dosing guide) 0.3 mg/kg/day
  in 1 or 2 divided doses, rounded down to the nearest whole tablet 0.6 mg/kg/day
  in 2 divided doses, rounded down to the nearest whole tablet Weeks 3 and 4 0.3 mg/kg/day
  in 1 or 2 divided doses, rounded down to the nearest whole tablet (see Table 3 for weight-based dosing guide) 0.6 mg/kg/day
  in 2 divided doses, rounded down to the nearest whole tablet 1.2 mg/kg/day
  in 2 divided doses, rounded down to the nearest whole tablet Weeks 5 onwards to maintenance The dose should be increased every 1 to 2 weeks as follows: calculate 0.3 mg/kg/day, round this amount down to the nearest whole tablet, and add this amount to the previously administered daily dose The dose should be increased every 1 to 2 weeks as follows: calculate 0.6 mg/kg/day, round this amount down to the nearest whole tablet, and add this amount to the previously administered daily dose The dose should be increased every 1 to 2 weeks as follows: calculate 1.2 mg/kg/day, round this amount down to the nearest whole tablet, and add this amount to the previously administered daily dose Usual maintenance dose 1 to 5 mg/kg/day
  (maximum 200 mg/day in 1 or 2 divided doses).
  1 to 3 mg/kg/day with valproate alone 4.5 to 7.5 mg/kg/day
  (maximum 300 mg/day in 2 divided doses) 5 to 15 mg/kg/day
  (maximum 400 mg/day in 2 divided doses) Maintenance dose in patients less than 30 kg May need to be increased by as such much as 50%, based on clinical response May need to be increased by as much as 50%, based on clinical response May need to be increased by as much as 50%, based on clinical response

  Note: Only whole tablets should be used for dosing.

  a    Valproate has been shown to inhibit glucuronidation and decrease the apparent clearance of lamotrigine [see Drug Interactions (7), Clinical Pharmacology (12.3)].

   b    These drugs induce glucuronidation and increase clearance [see Drug Interactions (7)Clinical Pharmacology (12.3)]. Other drugs, that have similar effects include estrogen-containing oral contraceptives and rifampin [see Drug Interactions (7),Clinical Pharmacology Pharmacokinetics (12.3)]. Dosing recommendations for oral contraceptives can be found in General Dosing Considerations [see Dosage and Administration (2.1)]. Patients on rifampin or other drugs that induce lamotrigine glucuronidation and increase clearance, should follow the same dosing titration/maintenance regimen as that used with anticonvulsants that have this effect..                                               

  Table 3. The Initial Weight-Based Dosing Guide for Patients 2 to 12 Years Taking Valproate (Weeks 1 to 4) With Epilepsy 

  If the patient’s weight is Give this daily dose, using the most appropriate combination of lamotrigine 2 mg and 5 mg tablets Greater than And less than Weeks 1 and 2 Weeks 3 and 4 6.7 kg 14 kg 2 mg every other day 2 mg every day 14.1 kg 27 kg 2 mg every day 4 mg every day 27.1 kg 34 kg 4 mg every day 8 mg every day 34.1 kg 40 kg 5 mg every day 10 mg every day

  Usual Adjunctive Maintenance Dose for Epilepsy: The usual maintenance doses identified in Tables 1 and 2 are derived from dosing regimens employed in the placebo-controlled adjunctive studies in which the efficacy of lamotrigine tablets was established. In patients receiving multidrug regimens employing carbamazepine, phenytoin, phenobarbital, or primidone without valproate, maintenance doses of adjunctive lamotrigine tablets as high as 700 mg/day have been used. In patients receiving valproate alone, maintenance doses of adjunctive lamotrigine tablets as high as 200 mg/day have been used. The advantage of using doses above those recommended in Tables 1 through 4 has not been established in controlled trials.

   

  The goal of the transition regimen is to effect the conversion to monotherapy with lamotrigine tablets under conditions that ensure adequate seizure control while mitigating the risk of serious rash associated with the rapid titration of lamotrigine tablets.  

  The recommended maintenance dose of lamotrigine tablets as monotherapy is 500 mg/day given in 2 divided doses.

   To avoid an increased risk of rash, the recommended initial dose and subsequent dose escalations of lamotrigine tablets should not be exceeded [see Boxed Warning].

  Conversion from Adjunctive Therapy with Carbamazepine, Phenytoin, Phenobarbital, or Primidone to Monotherapy with Lamotrigine: After achieving a dose of 500 mg/day of lamotrigine tablets according to the guidelines in Table 1, the concomitant AED should be withdrawn by 20% decrements each week over a 4-week period. The regimen for the withdrawal of the concomitant AED is based on experience gained in the controlled monotherapy clinical trial.  

  Conversion from Adjunctive Therapy with Valproate to Monotherapy with Lamotrigine: The conversion regimen involves 4 steps outlined in Table 4. 

  Table 4. Conversion From Adjunctive Therapy With Valproate to Monotherapy With Lamotrigine in Patients ≥16 Years of Age with Epilepsy

    Lamotrigine Valproate Step 1 Achieve a dose of 200 mg/day according to guidelines in Table 1 (if not already on 200 mg/day). Maintain previous stable dose. Step 2 Maintain at 200 mg/day. Decrease to 500 mg/day by decrements no greater than 500 mg/day/week and then maintain the dose of 500 mg/day for 1 week. Step 3 Increase to 300 mg/day and maintain for 1 week. Simultaneously decrease to 250 mg/day and maintain for 1 week. Step 4 Increase by 100 mg/day every week to achieve maintenance dose of
  500 mg/day. Discontinue.

  Conversion from Adjunctive Therapy with Antiepileptic Drugs other than Carbamazepine, Phenytoin, Phenobarbital, Primidone, or Valproate to Monotherapy with Lamotrigine: No specific  dosing guidelines can be provided for conversion to monotherapy with lamotrigine tablets with AEDs other than carbamazepine, phenobarbital, phenytoin, primidone, or valproate.  

   

  The goal of maintenance treatment with lamotrigine tablets is to delay the time to occurrence of mood episodes (depression, mania, hypomania, mixed episodes) in patients treated for acute mood episodes with standard therapy. The target dose of lamotrigine tablets  is 200 mg/day (100 mg/day in patients taking valproate, which decreases the apparent clearance of lamotrigine, and 400 mg/day in patients not taking valproate and taking either carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin that increase the apparent clearance of lamotrigine). In the clinical trials, doses up to 400 mg/day as monotherapy were evaluated; however, no additional benefit was seen at 400 mg/day compared with 200 mg/day [see Clinical Studies (14.2)]. Accordingly, doses above 200 mg/day are not recommended. Treatment with lamotrigine tablets is introduced, based on concurrent medications, according to the regimen outlined in Table 5. If other psychotropic medications are withdrawn following stabilization, the dose of lamotrigine tablets should be adjusted. For patients discontinuing valproate, the dose of lamotrigine tablets should be doubled over a 2-week period in equal weekly increments (see Table 6). For patients discontinuing carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin that induce lamotrigine glucuronidation, the dose of lamotrigine tablets should remain constant for the first week and then should be decreased by half over a 2-week period in equal weekly decrements (see Table 6). The dose of lamotrigine tablets may then be further adjusted to the target dose (200 mg) as clinically indicated.

  If other drugs are subsequently introduced, the dose of lamotrigine tablets may need to be adjusted. In particular, the introduction of valproate requires reduction in the dose of lamotrigine tablets [see Drug Interactions (7), Clinical Pharmacology (12.3)].  

  To avoid an increased risk of rash, the recommended initial dose and subsequent dose escalations of lamotrigine tablets should not be exceeded [see Boxed Warning].

  Table 5. Escalation Regimen for Lamotrigine for Patients with Bipolar Disorder

    For Patients TAKING Valproatea For Patients NOT TAKING Carbamazepine, Phenytoin, Phenobarbital, Primidoneb, Valproatea For Patients TAKING Carbamazepine, Phenytoin, Phenobarbital, or Primidoneb, and NOT TAKING Valproatea Weeks 1 and 2 25 mg every other day 25 mg daily 50 mg daily Weeks 3 and 4 25 mg daily 50 mg daily 100 mg daily, in divided doses Week 5 50 mg daily 100 mg daily 200 mg daily, in divided doses Week 6 100 mg daily 200 mg daily 300 mg daily, in divided doses Week 7 100 mg daily 200 mg daily up to 400 mg daily, in divided doses

  a Valproate has been shown to inhibit glucuronidation and decrease the apparent clearance of  lamotrigine [see Drug Interactions (7), Clinical Pharmacology (12.3)].  

  b These drugs induce lamotrigine glucuronidation and increase clearance [see Drug Interactions  (7), Clinical Pharmacology (12.3)]. Other drugs that have similar effects include estrogen containing oral contraceptives [see Drug Interactions (7), Clinical Pharmacology (12.3)].  Dosing recommendations for oral contraceptives can be found in General Dosing  Considerations [see Dosage and Administration (2.1)]. Patients on rifampin, or other drugs  that induce lamotrigine glucuronidation and increase clearance, should follow the same dosing  titration/maintenance regimen as that used with anticonvulsants that have this effect.

  Table 6. Dosage Adjustments to Lamotrigine for Patients with Bipolar Disorder Following Discontinuation of Psychotropic Medications 

    Discontinuation of Psychotropic Drugs (excluding Carbamazepine, Phenytoin, Phenobarbital, Primidoneb, or Valproatea) After Discontinuation of Valproatea After Discontinuation of Valproatea Current dose of lamotrigine (mg/day) 100 Current dose of lamotrigine  (mg/day) 400 Week 1 Maintain current dose of lamotrigine 150 400 Week 2 Maintain current dose of lamotrigine 200 300 Week 3 onward Maintain current dose of lamotrigine 200 200

  a Valproate has been shown to inhibit glucuronidation and decrease the apparent clearance of  lamotrigine [see Drug Interactions (7), Clinical Pharmacology (12.3)].  

  b These drugs induce lamotrigine glucuronidation and increase clearance [see Drug Interactions  (7), Clinical Pharmacology (12.3)]. Other drugs that have similar effects include estrogen containing oral contraceptives [see Drug Interactions (7), Clinical Pharmacology (12.3)].  Dosing recommendations for oral contraceptives can be found in General Dosing  Considerations [see Dosage and Administration (2.1)]. Patients on rifampin, or other drugs  that induce lamotrigine glucuronidation and increase clearance, should follow the same dosing  titration/maintenance regimen as that used with anticonvulsants that have this effect.

   The benefit of continuing treatment in patients who had been stabilized in an 8- to 16-week open-label phase with lamotrigine tablets was established in 2 randomized, placebo-controlled clinical maintenance trials [see Clinical Studies (14.2)]. However, the optimal duration of treatment with lamotrigine tablets has not been established. Thus, patients should be periodically reassessed to determine the need for maintenance treatment.

   

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  Dosing is based on concomitant medications, indication, and patient age. (2.2, 2.4) To avoid an increased risk of rash, the recommended initial dose and subsequent dose escalations should not be exceeded. (2.1, 16) Do not restart Lamotrigine in patients who discontinued due to rash unless the potential benefits clearly outweigh the risks. (2.1) Adjustments to maintenance doses will in most cases be required in patients starting or stopping estrogen-containing oral contraceptives. (2.1, 5.8) Lamotrigine should be discontinued over a period of at least 2 weeks (approximately 50% reduction per week). (2.1, 5.9)

  Epilepsy

  Adjunctive therapy—See Table 1 for patients >12 years of age and Tables 2 and 3 for patients 2 to 12 years. (2.2) Conversion to monotherapy—See Table 4. (2.3)

  Bipolar Disorder: See Tables 5 and 6 (2.4)

   

  Rash: There are suggestions, yet to be proven, that the risk of severe, potentially life-threatening rash may be increased by (1) coadministration of Lamotrigine with valproate, (2) exceeding the recommended initial dose of Lamotrigine, or (3) exceeding the recommended dose escalation for Lamotrigine. However, cases have occurred in the absence of these factors [see Boxed Warning]. Therefore, it is important that the dosing recommendations be followed closely.

  The risk of nonserious rash may be increased when the recommended initial dose and/or the rate of dose escalation of Lamotrigine is exceeded and in patients with a history of allergy or rash to other AEDs.

  It is recommended that Lamotrigine not be restarted in patients who discontinued due to rash associated with prior treatment with Lamotrigine, unless the potential benefits clearly outweigh the risks. If the decision is made to restart a patient who has discontinued Lamotrigine, the need to restart with the initial dosing recommendations should be assessed. The greater the interval of time since the previous dose, the greater consideration should be given to restarting with the initial dosing recommendations. If a patient has discontinued Lamotrigine for a period of more than 5 half-lives, it is recommended that initial dosing recommendations and guidelines be followed. The half-life of Lamotrigine is affected by other concomitant medications [see Clinical Pharmacology (12.3)].

  Lamotrigine Added to Drugs Known to Induce or Inhibit Glucuronidation: Drugs other than those listed in the Clinical Pharmacology section [see Clinical Pharmacology (12.3)] have not been systematically evaluated in combination with Lamotrigine. Because Lamotrigine is metabolized predominantly by glucuronic acid conjugation, drugs that are known to induce or inhibit glucuronidation may affect the apparent clearance of Lamotrigine and doses of Lamotrigine may require adjustment based on clinical response.

  Target Plasma Levels for Patients With Epilepsy or Bipolar Disorder: A therapeutic plasma concentration range has not been established for Lamotrigine. Dosing of Lamotrigine should be based on therapeutic response [see Clinical Pharmacology (12.3)].

  Women Taking Estrogen-Containing Oral Contraceptives:  Starting Lamotrigine in Women Taking Estrogen-Containing Oral Contraceptives: Although estrogen-containing oral contraceptives have been shown to increase the clearance of Lamotrigine [see Clinical Pharmacology (12.3)], no adjustments to the recommended dose-escalation guidelines for Lamotrigine should be necessary solely based on the use of estrogen-containing oral contraceptives. Therefore, dose escalation should follow the recommended guidelines for initiating adjunctive therapy with Lamotrigine based on the concomitant AED or other concomitant medications (see Table 1 or Table 5). See below for adjustments to maintenance doses of Lamotrigine in women taking estrogen-containing oral contraceptives.

  Adjustments to the Maintenance Dose of Lamotrigine in Women Taking Estrogen-Containing Oral Contraceptives:

  (1) Taking Estrogen-Containing Oral Contraceptives: For women not taking carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin that induce Lamotrigine glucuronidation [see Drug Interactions (7), Clinical Pharmacology (12.3)], the maintenance dose of Lamotrigine will in most cases need to be increased, by as much as 2-fold over the recommended target maintenance dose, in order to maintain a consistent Lamotrigine plasma level [see Clinical Pharmacology (12.3)].

  (2) Starting Estrogen-Containing Oral Contraceptives: In women taking a stable dose of Lamotrigine and not taking carbamazepine, phenytoin, phenobarbital, primidone, or  other drugs such as rifampin that induce Lamotrigine glucuronidation [see Drug Interactions (7), Clinical Pharmacology (12.3)], the maintenance dose will in most cases need to be increased by as much as 2-fold in order to maintain a consistent Lamotrigine plasma level. The dose increases should begin at the same time that the oral contraceptive is introduced and continue, based on clinical response, no more rapidly than 50 to 100 mg/day every week. Dose increases should not exceed the recommended rate (see Table 1 or Table 5) unless Lamotrigine plasma levels or clinical response support larger increases. Gradual transient increases in Lamotrigine plasma levels may occur during the week of inactive hormonal preparation (“pill-free” week), and these increases will be greater if dose increases are made in the days before or during the week of inactive hormonal preparation. Increased Lamotrigine plasma levels could result in additional adverse reactions, such as dizziness, ataxia, and diplopia. If adverse reactions attributable to Lamotrigine consistently occur during the “pill-free” week, dose adjustments to the overall maintenance dose may be necessary. Dose adjustments limited to the “pill-free” week are not recommended. For women taking Lamotrigine in addition to carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin that induce Lamotrigine glucuronidation [see Drug Interactions (7), Clinical Pharmacology (12.3)], no adjustment to the dose of Lamotrigine should be necessary.

  (3) Stopping Estrogen-Containing Oral Contraceptives: For women not taking carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin that induce Lamotrigine glucuronidation [see Drug Interactions (7), Clinical Pharmacology (12.3)], the maintenance dose of Lamotrigine will in most cases need to be decreased by as much as 50% in order to maintain a consistent Lamotrigine plasma level. The decrease in dose of Lamotrigine should not exceed 25% of the total daily dose per week over a 2-week period, unless clinical response or Lamotrigine plasma levels indicate otherwise [see Clinical Pharmacology (12.3)]. For women taking Lamotrigine in addition to carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin that induce Lamotrigine glucuronidation [see Drug Interactions (7), Clinical Pharmacology (12.3)], no adjustment to the dose of Lamotrigine should be necessary.

  Women and Other Hormonal Contraceptive Preparations or Hormone Replacement Therapy: The effect of other hormonal contraceptive preparations or hormone replacement therapy on the pharmacokinetics of Lamotrigine has not been systematically evaluated. It has been reported that ethinylestradiol, not progestogens, increased the clearance of Lamotrigine up to 2-fold, and the progestin-only pills had no effect on Lamotrigine plasma levels. Therefore, adjustments to the dosage of Lamotrigine in the presence of progestogens alone will likely not be needed.

  Patients With Hepatic Impairment: Experience in patients with hepatic impairment is limited. Based on a clinical pharmacology study in 24 patients with mild, moderate, and severe liver impairment [see Use in Specific Populations (8.6), Clinical Pharmacology (12.3)], the following general recommendations can be made. No dosage adjustment is needed in patients with mild liver impairment. Initial, escalation, and maintenance doses should generally be reduced by approximately 25% in patients with moderate and severe liver impairment without ascites and 50% in patients with severe liver impairment with ascites. Escalation and maintenance doses may be adjusted according to clinical response.

  Patients With Renal Impairment: Initial doses of Lamotrigine should be based on patients' concomitant medications (see Tables 1-3 or Table 5); reduced maintenance doses may be effective for patients with significant renal impairment [see Use in Specific Populations (8.7), Clinical Pharmacology (12.3)]. Few patients with severe renal impairment have been evaluated during chronic treatment with Lamotrigine. Because there is inadequate experience in this population, Lamotrigine should be used with caution in these patients.

  Discontinuation Strategy:  Epilepsy: For patients receiving Lamotrigine in combination with other AEDs, a re-evaluation of all AEDs in the regimen should be considered if a change in seizure control or an appearance or worsening of adverse experiences is observed.

  If a decision is made to discontinue therapy with Lamotrigine, a step-wise reduction of dose over at least 2 weeks (approximately 50% per week) is recommended unless safety concerns require a more rapid withdrawal [see Warnings and Precautions (5.9)].

  Discontinuing carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin that induce Lamotrigine glucuronidation should prolong the half-life of Lamotrigine; discontinuing valproate should shorten the half-life of Lamotrigine.

  Bipolar Disorder: In the controlled clinical trials, there was no increase in the incidence, type, or severity of adverse reactions following abrupt termination of Lamotrigine. In clinical trials in patients with Bipolar Disorder, 2 patients experienced seizures shortly after abrupt withdrawal of Lamotrigine. However, there were confounding factors that may have contributed to the occurrence of seizures in these bipolar patients. Discontinuation of Lamotrigine should involve a step-wise reduction of dose over at least 2 weeks (approximately 50% per week) unless safety concerns require a more rapid withdrawal [see Warnings and Precautions (5.9)].

   

  This section provides specific dosing recommendations for patients greater than 12 years of age and patients 2 to 12 years of age. Within each of these age-groups, specific dosing recommendations are provided depending upon concomitant AED or other concomitant medications (Table 1 for patients greater than 12 years of age and Table 2 for patients 2 to 12 years of age). A weight-based dosing guide for patients 2 to 12 years of age on concomitant valproate is provided in Table 3.

  Patients Over 12 Years of Age: Recommended dosing guidelines are summarized in Table 1.

  Table 1. Escalation Regimen for Lamotrigine in Patients Over 12 Years of Age With Epilepsy    For Patients TAKING Valproate* For Patients NOT TAKING Carbamazepine, Phenytoin, Phenobarbital, Primidone†,or Valproate1 For Patients TAKING Carbamazepine, Phenytoin, Phenobarbital, or Primidone2 and NOT TAKING Valproate1 Weeks 1 and 2 25 mg every other day 25 mg every day 50 mg/day Weeks 3 and 4 25 mg every day 50 mg/day 100 mg/day (in 2 divided doses) Weeks 5 onwards to maintenance Increase by 25 to 50 mg/day every 1 to 2 weeks Increase by 50 mg/day
  every 1 to 2 weeks Increase by 100 mg/day every 1 to 2 weeks Usual Maintenance Dose 100 to 200 mg/day with valproate alone
  
  100 to 400 mg/day with valproate and other drugs that induce glucuronication
  (in 1 or 2 divided doses) 225 to 375 mg/day
  (in 2 divided doses) 300 to 500 mg/day  (in 2 divided doses)
  

  Patients 2 to 12 Years of Age: Recommended dosing guidelines are summarized in Table 2.

  Smaller starting doses and slower dose escalations than those used in clinical trials are recommended because of the suggestion that the risk of rash may be decreased by smaller starting doses and slower dose escalations. Therefore, maintenance doses will take longer to reach in clinical practice than in clinical trials. It may take several weeks to months to achieve an individualized maintenance dose. Maintenance doses in patients weighing less than 30 kg, regardless of age or concomitant AED, may need to be increased as much as 50%, based on clinical response. 

  Table 2. Escalation Regimen for Lamotrigine in Patients 2 to 12 Years of Age With Epilepsy   For Patients TAKING Valproate* For Patients NOT TAKING Carbamazepine,
  Phenytoin,
  Phenobarbital,  
  Primidone†  or
   Valproate3 For Patients TAKING Carbamazepine, Phenytoin, Phenobarbital, or  Primidone4 and NOT TAKING Valproate3 Weeks 1 and 2 0.15 mg/kg/day
   in 1 or 2 divided doses, rounded down to the nearest whole tablet (see Table 3 for weight based dosing guide) 0.3 mg/kg/day
  in 1 or 2 divided doses, rounded down to the nearest whole tablet 0.6 mg/kg/day
  in 2 divided doses, rounded down to the nearest whole tablet Weeks 3 and 4 0.3 mg/kg/day
  in 1 or 2 divided doses, rounded down to the nearest whole tablet (see Table 3 for weight based dosing guide) 0.6 mg/kg/day
    in 2 divided doses, rounded down to the nearest whole tablet 1.2 mg/kg/day
    in 2 divided doses, rounded down to the nearest whole tablet Weeks 5 onwards to maintenance The dose should be increased every 1 to 2 weeks as follows: calculate 0.3 mg/kg/day, round this amount down to the nearest whole tablet, and add this amount to the previously administered daily dose The dose should be increased every 1 to 2 weeks as follows: calculate 0.6 mg/kg/day, round this amount down to the nearest whole tablet, and add this amount to the previously administered daily dose The dose should be increased every 1 to 2 weeks as follows: calculate 1.2 mg/kg/day, round this amount down to the nearest whole tablet, and add this amount to the previously administered daily dose Usual Maintenance Dose 1 to 5 mg/kg/day (maximum 200 mg/day in 1 or 2 divided doses).
  1 to 3 mg/kg/day with valproate alone 4.5 to 7.5 mg/kg/day
   (maximum 300 mg/day in 2 divided doses) 5 to 15 mg/kg/day
   (maximum 400 mg/day in 2 divided doses) Maintenance dose in patients less than 30 kg May need to be increased by as much as 50%, based on clinical response May need to be increased by as much as 50%, based on clinical response May need to be increased by as much as 50%, based on clinical response Note: Only whole tablets should be used for dosing.
  Table 3. The Initial Weight-Based Dosing Guide for Patients 2 to 12 Years Taking Valproate (Weeks 1 to 4) With Epilepsy If the patient’s weight is Give this daily dose, using the most appropriate combination of Lamotrigine 2-mg and 5-mg tablets Greater than And less than Weeks 1 and 2 Weeks 3 and 4 6.7 kg 14 kg 2 mg every other day 2 mg every day 14.1 kg 27 kg 2 mg every day 4 mg every day 27.1 kg 34 kg 4 mg every day 8 mg every day 34.1 kg 40 kg 5 mg every day 10 mg every day

  Usual Adjunctive Maintenance Dose for Epilepsy: The usual maintenance doses identified in Tables 1 and 2 are derived from dosing regimens employed in the placebo-controlled adjunctive studies in which the efficacy of Lamotrigine was established. In patients receiving multidrug regimens employing carbamazepine, phenytoin, phenobarbital, or primidone without valproate, maintenance doses of adjunctive Lamotrigine as high as 700 mg/day have been used. In patients receiving valproate alone, maintenance doses of adjunctive Lamotrigine as high as 200 mg/day have been used. The advantage of using doses above those recommended in Tables 1 through 4 has not been established in controlled trials.

   

  The goal of the transition regimen is to effect the conversion to monotherapy with Lamotrigine under conditions that ensure adequate seizure control while mitigating the risk of serious rash associated with the rapid titration of Lamotrigine.

  The recommended maintenance dose of Lamotrigine as monotherapy is 500 mg/day given in 2 divided doses.

  To avoid an increased risk of rash, the recommended initial dose and subsequent dose escalations of Lamotrigine should not be exceeded [see Boxed Warning].

  Conversion From Adjunctive Therapy With Carbamazepine, Phenytoin, Phenobarbital, or Primidone to Monotherapy With Lamotrigine: After achieving a dose of 500 mg/day of Lamotrigine according to the guidelines in Table 1, the concomitant AED should be withdrawn by 20% decrements each week over a 4-week period. The regimen for the withdrawal of the concomitant AED is based on experience gained in the controlled monotherapy clinical trial. 

  Conversion from Adjunctive Therapy With Valproate to Monotherapy With Lamotrigine: The conversion regimen involves 4 steps outlined in Table 4.

  Table 4. Conversion From Adjunctive Therapy With Valproate to Monotherapy With Lamotrigine in Patients ≥16 Years of Age with Epilepsy

  Lamotrigine

  Valproate

  Step 1

  Achieve a dose of 200 mg/day according to guidelines in Table 1 (if not already on 200 mg/day).

  Maintain previous stable dose.

  Step 2

  Maintain at 200 mg/day.

  Decrease to 500 mg/day by decrements no greater than 500 mg/day/week and then maintain the dose of 500 mg/day for 1 week.

  Step 3

  Increase to 300 mg/day and maintain for 1 week.

  Simultaneously decrease to 250 mg/day and maintain for 1 week.

  Step 4

  Increase by 100 mg/day every week to achieve maintenance dose of 500 mg/day.

  Discontinue.

  
  Conversion from Adjunctive Therapy With AEDs Other Than Carbamazepine, Phenytoin, Phenobarbital, Primidone, or Valproate to Monotherapy With Lamotrigine: No specific dosing guidelines can be provided for conversion to monotherapy with Lamotrigine with AEDs other than carbamazepine, phenobarbital, phenytoin, primidone, or valproate.

   

  The goal of maintenance treatment with Lamotrigine is to delay the time to occurrence of mood episodes (depression, mania, hypomania, mixed episodes) in patients treated for acute mood episodes with standard therapy. The target dose of Lamotrigine is 200 mg/day (100 mg/day in patients taking valproate, which decreases the apparent clearance of Lamotrigine, and 400 mg/day in patients not taking valproate and taking either carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin, that  increase the apparent clearance of Lamotrigine). In the clinical trials, doses up to 400 mg/day as monotherapy were evaluated; however, no additional benefit was seen at 400 mg/day compared with 200 mg/day [see Clinical Studies (14.2)]. Accordingly, doses above 200 mg/day are not recommended. Treatment with Lamotrigine is introduced, based on concurrent medications, according to the regimen outlined in Table 5. If other psychotropic medications are withdrawn following stabilization, the dose of Lamotrigine should be adjusted. For patients discontinuing valproate, the dose of Lamotrigine should be doubled over a 2-week period in equal weekly increments (see Table 6). For patients discontinuing carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin that induce Lamotrigine glucuronidation, the dose of Lamotrigine should remain constant for the first week and then should be decreased by half over a 2-week period in equal weekly decrements (see Table 6). The dose of Lamotrigine may then be further adjusted to the target dose (200 mg) as clinically indicated.

  If other drugs are subsequently introduced, the dose of Lamotrigine may need to be adjusted. In particular, the introduction of valproate requires reduction in the dose of Lamotrigine [see Drug Interactions (7), Clinical Pharmacology (12.3)].

  To avoid an increased risk of rash, the recommended initial dose and subsequent dose escalations of Lamotrigine should not be exceeded [see Boxed Warning].

   

  Table 5. Escalation Regimen for Lamotrigine for Patients With Bipolar Disorder For Patients TAKING Valproate* For Patients NOT TAKING Carbamazepine, Phenytoin, Phenobarbital, Primidone†, or Valproate5 For Patients TAKING Carbamazepine, Phenytoin, Phenobarbital, or Primidone6 and NOT TAKING Valproate5 Weeks 1 and 2 25 mg every other day 25 mg daily 50 mg daily Weeks 3 and 4 25 mg daily 50 mg daily 100 mg daily, in divided doses Week 5 50 mg daily 100 mg daily 200 mg daily, in divided doses Week 6 100 mg daily 200 mg daily 300 mg daily, in divided doses Week 7 100 mg daily 200 mg daily up to 400 mg daily, in divided doses
  Table 6. Dosage Adjustments to Lamotrigine for Patients With Bipolar Disorder Following Discontinuation of Psychotropic Medications  

  Discontinuation of Psychotropic Drugs (excluding Carbamazepine, Phenytoin, Phenobarbital, Primidone*, or Valproate†)

  After Discontinuation of Valproate8 After Discontinuation of Carbamazepine, Phenytoin, Phenobarbital, or Primidone7 Current dose of Lamotrigine (mg/day) 100

  Current dose of Lamotrigine (mg/day) 400

  Week 1 Maintain current dose of Lamotrigine 150 400 Week 2 Maintain current dose of Lamotrigine 200 300 Week 3 onward Maintain current dose of Lamotrigine 200 200
  

  The benefit of continuing treatment in patients who had been stabilized in an 8- to 16-week open-label phase with Lamotrigine was established in 2 randomized, placebo-controlled clinical maintenance trials [see Clinical Studies (14.2)]. However, the optimal duration of treatment with Lamotrigine has not been established. Thus, patients should be periodically reassessed to determine the need for maintenance treatment.

   

  1 Valproate has been shown to inhibit glucuronidation and decrease the apparent clearance of Lamotrigine 2 These drugs induce Lamotrigine glucuronidation and increase clearance 3 Valproate has been shown to inhibit glucuronidation and decrease the apparent clearance of Lamotrigine 4 These drugs induce Lamotrigine glucuronidation and increase clearance 5 Valproate has been shown to inhibit glucuronidation and decrease the apparent clearance of Lamotrigine 6 These drugs induce Lamotrigine glucuronidation and increase clearance 7 These drugs induce Lamotrigine glucuronidation and increase clearance 8 Valproate has been shown to inhibit glucuronidation and decrease the apparent clearance of Lamotrigine

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  Adult use only: Shake well. Apply (spray) onto affected area not more than 3-4 times daily.
  

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  Dosing is based on concomitant medications, indication, and patient age. (2.2, 2.4) To avoid an increased risk of rash, the recommended initial dose and subsequent dose escalations should not be exceeded. Lamotrigine Starter Kits are available for the first 5 weeks of treatment. (2.1, 16) Do not restart lamotrigine tablets, USP in patients who discontinued due to rash unless the potential benefits clearly outweigh the risks. (2.1) Adjustments to maintenance doses will in most cases be required in patients starting or stopping estrogen-containing oral contraceptives. (2.1, 5.9) Lamotrigine tablets, USP should be discontinued over a period of at least 2 weeks (approximately 50% reduction per week). (2.1, 5.10)

  Epilepsy

  Adjunctive therapy—See Table 1 for patients >12 years of age and Tables 2 and 3 for patients 2 to 12 years. (2.2) Conversion to monotherapy—See Table 4. (2.3)

  Bipolar Disorder: See Tables 5 and 6. (2.4)

   

  Rash: There are suggestions, yet to be proven, that the risk of severe, potentially life-threatening rash may be increased by (1) coadministration of lamotrigine with valproate, (2) exceeding the recommended initial dose of lamotrigine, or (3) exceeding the recommended dose escalation for lamotrigine. However, cases have occurred in the absence of these factors [see Boxed Warning]. Therefore, it is important that the dosing recommendations be followed closely.

  The risk of nonserious rash may be increased when the recommended initial dose and/or the rate of dose escalation of lamotrigine is exceeded and in patients with a history of allergy or rash to other AEDs.

  Lamotrigine Starter Kits provide lamotrigine at doses consistent with the recommended titration schedule for the first 5 weeks of treatment, based upon concomitant medications for patients with epilepsy (>12 years of age) and Bipolar I Disorder (≥18 years of age) and are intended to help reduce the potential for rash. The use of lamotrigine Starter Kits is recommended for appropriate patients who are starting or restarting lamotrigine [see How Supplied/Storage and Handling (16)].

  It is recommended that lamotrigine tablets, USP not be restarted in patients who discontinued due to rash associated with prior treatment with lamotrigine, unless the potential benefits clearly outweigh the risks. If the decision is made to restart a patient who has discontinued lamotrigine, the need to restart with the initial dosing recommendations should be assessed. The greater the interval of time since the previous dose, the greater consideration should be given to restarting with the initial dosing recommendations. If a patient has discontinued lamotrigine for a period of more than 5 half-lives, it is recommended that initial dosing recommendations and guidelines be followed. The half-life of lamotrigine is affected by other concomitant medications [see Clinical Pharmacology (12.3)].

  Lamotrigine Added to Drugs Known to Induce or Inhibit Glucuronidation: Drugs other than those listed in the Clinical Pharmacology section [see Clinical Pharmacology (12.3)] have not been systematically evaluated in combination with lamotrigine. Because lamotrigine is metabolized predominantly by glucuronic acid conjugation, drugs that are known to induce or inhibit glucuronidation may affect the apparent clearance of lamotrigine and doses of lamotrigine may require adjustment based on clinical response.

  Target Plasma Levels for Patients With Epilepsy or Bipolar Disorder: A therapeutic plasma concentration range has not been established for lamotrigine. Dosing of lamotrigine should be based on therapeutic response [see Clinical Pharmacology (12.3)].

  Women Taking Estrogen-Containing Oral Contraceptives: Starting Lamotrigine in Women Taking Estrogen-Containing Oral Contraceptives: Although estrogen-containing oral contraceptives have been shown to increase the clearance of lamotrigine [see Clinical Pharmacology (12.3)], no adjustments to the recommended dose-escalation guidelines for lamotrigine should be necessary solely based on the use of estrogen-containing oral contraceptives. Therefore, dose escalation should follow the recommended guidelines for initiating adjunctive therapy with lamotrigine based on the concomitant AED or other concomitant medications (see Table 1 or Table 5). See below for adjustments to maintenance doses of lamotrigine in women taking estrogen-containing oral contraceptives.

  Adjustments to the Maintenance Dose of Lamotrigine In Women Taking Estrogen-Containing Oral Contraceptives:

  (1) Taking Estrogen-Containing Oral Contraceptives: For women not taking carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin that induce lamotrigine glucuronidation [see Drug Interactions (7), Clinical Pharmacology (12.3)], the maintenance dose of lamotrigine will in most cases need to be increased, by as much as 2-fold over the recommended target maintenance dose, in order to maintain a consistent lamotrigine plasma level [see Clinical Pharmacology (12.3)].

  (2) Starting Estrogen-Containing Oral Contraceptives: In women taking a stable dose of lamotrigine and not taking carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin that induce lamotrigine glucuronidation [see Drug Interactions (7), Clinical Pharmacology (12.3)], the maintenance dose will in most cases need to be increased by as much as 2-fold in order to maintain a consistent lamotrigine plasma level. The dose increases should begin at the same time that the oral contraceptive is introduced and continue, based on clinical response, no more rapidly than 50 to 100 mg/day every week. Dose increases should not exceed the recommended rate (see Table 1 or Table 5) unless lamotrigine plasma levels or clinical response support larger increases. Gradual transient increases in lamotrigine plasma levels may occur during the week of inactive hormonal preparation ("pill-free" week), and these increases will be greater if dose increases are made in the days before or during the week of inactive hormonal preparation. Increased lamotrigine plasma levels could result in additional adverse reactions, such as dizziness, ataxia, and diplopia. If adverse reactions attributable to lamotrigine consistently occur during the "pill-free" week, dose adjustments to the overall maintenance dose may be necessary. Dose adjustments limited to the "pill-free" week are not recommended. For women taking lamotrigine in addition to carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin that induce lamotrigine glucuronidation [see Drug Interactions (7), Clinical Pharmacology (12.3)], no adjustment to the dose of lamotrigine should be necessary.  

  (3) Stopping Estrogen-Containing Oral Contraceptives: For women not taking carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin that induce lamotrigine glucuronidation [see Drug Interactions (7), Clinical Pharmacology (12.3)], the maintenance dose of lamotrigine will in most cases need to be decreased by as much as 50% in order to maintain a consistent lamotrigine plasma level. The decrease in dose of lamotrigine should not exceed 25% of the total daily dose per week over a 2-week period, unless clinical response or lamotrigine plasma levels indicate otherwise [see Clinical Pharmacology (12.3)]. For women taking lamotrigine in addition to carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin that induce lamotrigine glucuronidation [see Drug Interactions (7), Clinical Pharmacology (12.3)], no adjustment to the dose of lamotrigine should be necessary.

  Women and Other Hormonal Contraceptive Preparations or Hormone Replacement Therapy: The effect of other hormonal contraceptive preparations or hormone replacement therapy on the pharmacokinetics of lamotrigine has not been systematically evaluated. It has been reported that ethinylestradiol, not progestogens, increased the clearance of lamotrigine up to 2-fold, and the progestin-only pills had no effect on lamotrigine plasma levels. Therefore, adjustments to the dosage of lamotrigine in the presence of progestogens alone will likely not be needed.

  Patients With Hepatic Impairment: Experience in patients with hepatic impairment is limited. Based on a clinical pharmacology study in 24 patients with mild, moderate, and severe liver impairment [see Use in Specific Populations (8.6), Clinical Pharmacology (12.3)], the following general recommendations can be made. No dosage adjustment is needed in patients with mild liver impairment. Initial, escalation, and maintenance doses should generally be reduced by approximately 25% in patients with moderate and severe liver impairment without ascites and 50% in patients with severe liver impairment with ascites. Escalation and maintenance doses may be adjusted according to clinical response.

  Patients With Renal Impairment: Initial doses of lamotrigine should be based on patients' concomitant medications (see Tables 1-3 or Table 5); reduced maintenance doses may be effective for patients with significant renal impairment [see Use in Specific Populations (8.7), Clinical Pharmacology (12.3)]. Few patients with severe renal impairment have been evaluated during chronic treatment with lamotrigine. Because there is inadequate experience in this population, lamotrigine should be used with caution in these patients.

  Discontinuation Strategy: Epilepsy: For patients receiving lamotrigine in combination with other AEDs, a reevaluation of all AEDs in the regimen should be considered if a change in seizure control or an appearance or worsening of adverse reactions is observed.

  If a decision is made to discontinue therapy with lamotrigine, a step-wise reduction of dose over at least 2 weeks (approximately 50% per week) is recommended unless safety concerns require a more rapid withdrawal [see Warnings and Precautions (5.10)].

  Discontinuing carbamazepine, phenytoin, phenobarbital, primidone or other drugs such as rifampin that induce lamotrigine glucuronidation should prolong the half-life of lamotrigine; discontinuing valproate should shorten the half-life of lamotrigine.

  Bipolar Disorder: In the controlled clinical trials, there was no increase in the incidence, type, or severity of adverse reactions following abrupt termination of lamotrigine. In clinical trials in patients with Bipolar Disorder, 2 patients experienced seizures shortly after abrupt withdrawal of lamotrigine. However, there were confounding factors that may have contributed to the occurrence of seizures in these bipolar patients. Discontinuation of lamotrigine should involve a step-wise reduction of dose over at least 2 weeks (approximately 50% per week) unless safety concerns require a more rapid withdrawal [see Warnings and Precautions (5.10)].

   

  This section provides specific dosing recommendations for patients greater than 12 years of age and patients 2 to 12 years of age. Within each of these age-groups, specific dosing recommendations are provided depending upon concomitant AED or other concomitant medications (Table 1 for patients greater than 12 years of age and Table 2 for patients 2 to 12 years of age). A weight-based dosing guide for patients 2 to 12 years of age on concomitant valproate is provided in Table 3.

  Patients Over 12 Years of Age: Recommended dosing guidelines are summarized in Table 1.

  Table 1. Escalation Regimen for Lamotrigine in Patients Over 12 Years of Age With Epilepsy
  For Patients TAKING
   Valproatea
  For Patients NOT 
  TAKING 
  Carbamazepine, 
  Phenytoin, 
  Phenobarbital,
   Primidoneb, or 
  Valproatea
  For Patients 
  TAKING 
  Carbamazepine, 
  Phenytoin, 
  Phenobarbital, or 
  Primidoneb and 
  NOT TAKING Valproatea
  Weeks 1 and 2
  25 mg every other day
  25 mg every day
  50 mg/day
  Weeks 3 and 4
  25 mg every day
  50 mg/day
  100 mg/day 
  (in 2 divided doses)
  Week 5
  onwards to
  maintenance
  Increase by 25 to 50
  mg/day every 1 to
  2 weeks
  Increase by 50
  mg/day every 1 to
  2 weeks
  Increase by 100
  mg/day every 1 to
  2 weeks.
  Usual
  Maintenance
  Dose
  100 to 200 mg/day
  with valproate 
  alone 
  100 to 400 mg/day 
  with valproate and 
  other drugs that 
  induce 
  glucuronidation 
  (in 1 or 2 divided 
  doses)
  225 to 375 mg/day 
  (in 2 divided doses)
  300 to 500 mg/day 
  (in 2 divided doses)
  

  a Valproate has been shown to inhibit glucuronidation and decrease the apparent clearance of lamotrigine [see Drug Interactions (7), Clinical Pharmacology (12.3)].

  b These drugs induce lamotrigine glucuronidation and increase clearance [see Drug Interactions (7), Clinical Pharmacology (12.3)]. Other drugs which have similar effects include estrogen-containing oral contraceptives [see Drug Interactions (7), Clinical Pharmacology (12.3)]. Dosing recommendations for oral contraceptives can be found in General Dosing Considerations [see Dosage and Administration (2.1)]. Patients on rifampin, or other drugs that induce lamotrigine glucuronidation and increase clearance, should follow the same dosing titration/maintenance regimen as that used with anticonvulsants that have this effect.

  Patients 2 to 12 Years of Age: Recommended dosing guidelines are summarized in Table 2.

  Smaller starting doses and slower dose escalations than those used in clinical trials are recommended because of the suggestion that the risk of rash may be decreased by smaller starting doses and slower dose escalations. Therefore, maintenance doses will take longer to reach in clinical practice than in clinical trials. It may take several weeks to months to achieve an individualized maintenance dose. Maintenance doses in patients weighing less than 30 kg, regardless of age or concomitant AED, may need to be increased as much as 50%, based on clinical response.

  The smallest available strength of lamotrigine tablets is 25 mg, and only whole tablets should be administered. If the calculated dose cannot be achieved using whole tablets, the dose should be rounded down to the nearest whole tablet [see How Supplied/Storage and Handling (16) and Medication Guide].

  Table 2. Escalation Regimen for Lamotrigine in Patients 2 to 12 Years of Age With Epilepsy
  For Patients 
  TAKING Valproatea
  For Patients NOT
   TAKING 
  Carbamazepine, 
  Phenytoin, 
  Phenobarbital, 
  Primidoneb, or 
  Valproatea
  For Patients TAKING
   Carbamazepine, 
  Phenytoin, 
  Phenobarbital, or 
  Primidoneb and NOT
  TAKING Valproatea
  Weeks 1 
  and 2 
  0.15 mg/kg/day 
  in 1 or 2 divided 
  doses, rounded 
  down to the nearest
  whole tablet (see 
  Table 3 for weight 
  based dosing guide)
  0.3 mg/kg/day 
  in 1 or 2 divided 
  doses, rounded down 
  to the nearest whole 
  tablet
  0.6 mg/kg/day 
  in 2 divided doses,
   rounded down to the
   nearest whole tablet
  Weeks 3 
  and 4 
  0.3 mg/kg/day 
  in 1 or 2 divided 
  doses, rounded 
  down to the nearest
  whole tablet (see
  Table 3 for weight
  based dosing guide)
  0.6 mg/kg/day 
  in 2 divided doses, 
  rounded down to the 
  nearest whole tablet
  1.2 mg/kg/day 
  in 2 divided doses,
   rounded down to the
   nearest whole tablet
  Week 5 
  onwards to 
  maintenance
  The dose should be 
  increased every 1 to 
  2 weeks as follows:
  calculate 0.3 mg/kg/day, 
  round this amount
  down to the nearest
  whole tablet, and
  add this amount to
  the previously 
  administered daily
  dose
  The dose should be increased every 1 to 
  2 weeks as follows: calculate 
  0.6 mg/kg/day, round 
  this amount down to 
  the nearest whole 
  tablet, and add this 
  amount to the 
  previously 
  administered daily
   dose
  The dose should be increased every 1 to 
  2 weeks as follows: calculate 
  1.2 mg/kg/day, round
   this amount down to
   the nearest whole
   tablet, and add this
   amount to the
   previously
   administered daily
   dose
  Usual 
  Maintenance 
  Dose 
  1 to 5 mg/kg/day
   (maximum 
  200 mg/day in 1 or 2
   divided doses). 
  1 to 3 mg/kg/day 
  with valproate alone
  4.5 to 7.5 mg/kg/day
   (maximum 300 
  mg/day in 2 divided
  doses)
  5 to 15 mg/kg/day
   (maximum 400 
  mg/day in 2 divided
   doses)
  Maintenance 
  dose in 
  patients less 
  than 30 kg 
  May need to be 
  increased by as 
  much as 50%, based 
  on clinical response
  May need to be
   increased by as much
   as 50%, based on 
  clinical response
  May need to be 
  increased by as much
   as 50%, based on 
  clinical response
  

  Note: Only whole tablets should be used for dosing.
  

  aValproate has been shown to inhibit glucuronidation and decrease the apparent clearance of lamotrigine [see Drug Interactions (7),
  Clinical Pharmacology (12.3)].
  

  bThese drugs induce lamotrigine glucuronidation and increase clearance [see Drug Interactions (7), Clinical Pharmacology (12.3)].
  Other drugs which have similar effects include estrogen-containing oral contraceptives [see Drug Interactions (7), Clinical Pharmacology (12.3)]. Dosing recommendations for oral contraceptives can be found in General Dosing Considerations [see 
  Dosage and Administration (2.1)]. Patients on rifampin, or other drugs that induce lamotrigine glucuronidation and increase clearance, should follow the same dosing titration/maintenance regimen as that used with anticonvulsants that have this effect.
  

  Table 3. The Initial Weight-Based Dosing Guide for Patients 2 to 12 Years Taking Valproate (Weeks 1 to 4) With Epilepsy If the patient’s weight is
  Give this daily dose, using the most appropriate combination of lamotrigine
  2-mg and 5-mg tablets 
  Greater than 
  And less than 
  Weeks 1 and 2
  Weeks 3 and 4
  6.7 kg 
  14 kg 
  2 mg every other day
  2 mg every day
  14.1 kg 
  27 kg 
  2 mg every day
  4 mg every day
  27.1 kg 
  34 kg 
  4 mg every day
  8 mg every day
  34.1 kg 
  40 kg 
  5 mg every day
  10 mg every day
  

  Usual Adjunctive Maintenance Dose for Epilepsy: The usual maintenance doses identified in Tables 1 and 2 are derived from dosing regimens employed in the placebo-controlled adjunctive studies in which the efficacy of lamotrigine was established. In patients receiving multidrug regimens employing carbamazepine, phenytoin, phenobarbital, or primidone without valproate, maintenance doses of adjunctive lamotrigine as high as 700 mg/day have been used. In patients receiving valproate alone, maintenance doses of adjunctive lamotrigine as high as 200 mg/day have been used. The advantage of using doses above those recommended in Tables 1 through 4 has not been established in controlled trials.

   

  The goal of the transition regimen is to effect the conversion to monotherapy with lamotrigine under conditions that ensure adequate seizure control while mitigating the risk of serious rash associated with the rapid titration of lamotrigine.

  The recommended maintenance dose of lamotrigine as monotherapy is 500 mg/day given in 2 divided doses.

  To avoid an increased risk of rash, the recommended initial dose and subsequent dose escalations of lamotrigine should not be exceeded [see Boxed Warning].

  Conversion From Adjunctive Therapy With Carbamazepine, Phenytoin, Phenobarbital, or Primidone to Monotherapy With Lamotrigine: After achieving a dose of 500 mg/day of lamotrigine according to the guidelines in Table 1, the concomitant AED should be withdrawn by 20% decrements each week over a 4-week period. The regimen for the withdrawal of the concomitant AED is based on experience gained in the controlled monotherapy clinical trial.

  Conversion From Adjunctive Therapy With Valproate to Monotherapy With Lamotrigine: The conversion regimen involves 4 steps outlined in Table 4.

  Table 4. Conversion From Adjunctive Therapy With Valproate to Monotherapy With Lamotrigine in Patients ≥16 Years of Age With Epilepsy
  Lamotrigine
  Valproate
  Step 1 
  Achieve a dose of 200 mg/day according to 
  guidelines in Table 1 (if not already on 
  200 mg/day).
  Maintain previous stable dose.
  Step 2 
  Maintain at 200 mg/day.
  Decrease to 500 mg/day by 
  decrements no greater than 
  500 mg/day/week and then 
  maintain the dose of 
  500 mg/day for 1 week.
  Step 3 
  Increase to 300 mg/day and maintain for 1 
  week.
  Simultaneously decrease to 
  250 mg/day and maintain for 1 week.
  Step 4 
  Increase by 100 mg/day every week to achieve 
  maintenance dose of 500 mg/day.
  Discontinue.
  

  Conversion From Adjunctive Therapy With AEDs Other Than Carbamazepine, Phenytoin, Phenobarbital, Primidone, or Valproate to Monotherapy With Lamotrigine: No specific dosing guidelines can be provided for conversion to monotherapy with lamotrigine with AEDs other than carbamazepine, phenobarbital, phenytoin, primidone, or valproate.

   

  The goal of maintenance treatment with lamotrigine is to delay the time to occurrence of mood episodes (depression, mania, hypomania, mixed episodes) in patients treated for acute mood episodes with standard therapy. The target dose of lamotrigine is 200 mg/day (100 mg/day in patients taking valproate, which decreases the apparent clearance of lamotrigine, and 400 mg/day in patients not taking valproate and taking either carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin that increase the apparent clearance of lamotrigine). In the clinical trials, doses up to 400 mg/day as monotherapy were evaluated; however, no additional benefit was seen at 400 mg/day compared with 200 mg/day [see Clinical Studies (14.2)]. Accordingly, doses above 200 mg/day are not recommended. Treatment with lamotrigine is introduced, based on concurrent medications, according to the regimen outlined in Table 5. If other psychotropic medications are withdrawn following stabilization, the dose of lamotrigine should be adjusted. For patients discontinuing valproate, the dose of lamotrigine should be doubled over a 2-week period in equal weekly increments (see Table 6). For patients discontinuing carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin that induce lamotrigine glucuronidation, the dose of lamotrigine should remain constant for the first week and then should be decreased by half over a 2-week period in equal weekly decrements (see Table 6). The dose of lamotrigine may then be further adjusted to the target dose (200 mg) as clinically indicated.

  If other drugs are subsequently introduced, the dose of lamotrigine may need to be adjusted. In particular, the introduction of valproate requires reduction in the dose of lamotrigine [see Drug Interactions (7), Clinical Pharmacology (12.3)].

  To avoid an increased risk of rash, the recommended initial dose and subsequent dose escalations of lamotrigine should not be exceeded [see Boxed Warning].

  Table 5. Escalation Regimen for Lamotrigine for Patients With Bipolar Disorder
  For Patients TAKING Valproatea
  For Patients NOT TAKING
  Carbamazepine, Phenytoin, 
  Phenobarbital, Primidoneb, or
   Valproatea
  For Patients TAKING
   Carbamazepine, Phenytoin, Phenobarbital,
  or Primidoneb and 
  NOT TAKING Valproatea
  Weeks 1 and 2 
  25 mg every other day
  25 mg daily
  50 mg daily
  Weeks 3 and 4 
  25 mg daily
  50 mg daily
  100 mg daily, in divided doses
  Week 5 
  50 mg daily
  100 mg daily
  200 mg daily, in divided doses
  Week 6 
  100 mg daily
  200 mg daily
  300 mg daily, in divided doses
  Week 7 
  100 mg daily
  200 mg daily
  up to 400 mg daily, in
  divided doses
  

  a Valproate has been shown to inhibit glucuronidation and decrease the apparent clearance of lamotrigine [see Drug Interactions (7), Clinical Pharmacology (12.3)].

  b These drugs induce lamotrigine glucuronidation and increase clearance [see Drug Interactions (7), Clinical Pharmacology (12.3)]. Other drugs which have similar effects include estrogen-containing oral contraceptives [see Drug Interactions (7), Clinical Pharmacology (12.3)]. Dosing recommendations for oral contraceptives can be found in General Dosing Considerations [see Dosage and Administration (2.1)]. Patients on rifampin, or other drugs that induce lamotrigine glucuronidation and increase clearance, should follow the same dosing titration/maintenance regimen as that used with anticonvulsants that have this effect.

  Table 6. Dosage Adjustments to Lamotrigine for Patients With Bipolar Disorder Following Discontinuation of Psychotropic Medications
  Discontinuation of Psychotropic Drugs 
  (excluding Carbamazepine, Phenytoin, 
  After Discontinuation of Valproatea
  After Discontinuation of Carbamazepine, 
  Phenytoin, Phenobarbital,or
   Primidoneb
  
  Phenobarbital, Primidoneb, or Valproatea)
  Current dose of Lamotrigine (mg/day) 
  100
  Current dose of Lamotrigine (mg/day) 
  400
  Week 1 
  Maintain current dose of Lamotrigine
  150
  400
  Week 2 
  Maintain current dose of Lamotrigine
  200
  300
  Week 3 onward 
  Maintain current dose of Lamotrigine
  200
  200
  

  a Valproate has been shown to inhibit glucuronidation and decrease the apparent clearance of lamotrigine [see Drug Interactions (7), Clinical Pharmacology (12.3)].

  b These drugs induce lamotrigine glucuronidation and increase clearance [see Drug Interactions (7), Clinical Pharmacology (12.3)]. Other drugs which have similar effects include estrogen-containing oral contraceptives [see Drug Interactions (7), Clinical Pharmacology (12.3)]. Dosing recommendations for oral contraceptives can be found in General Dosing Considerations [see Dosage and Administration (2.1)]. Patients on rifampin, or other drugs that induce lamotrigine glucuronidation and increase clearance, should follow the same dosing titration/maintenance regimen as that used with anticonvulsants that have this effect.

  The benefit of continuing treatment in patients who had been stabilized in an 8- to 16-week open-label phase with lamotrigine was established in 2 randomized, placebo-controlled clinical maintenance trials [see Clinical Studies (14.2)]. However, the optimal duration of treatment with lamotrigine has not been established. Thus, patients should be periodically reassessed to determine the need for maintenance treatment.

   

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  Dosing is based on concomitant medications, indication, and patient age. (2.2, 2.4) To avoid an increased risk of rash, the recommended initial dose and subsequent dose escalations should not be exceeded. (2.1) Do not restart lamotrigine tablets in patients who discontinued due to rash unless the potential benefits clearly outweigh the risks. (2.1) Adjustments to maintenance doses will in most cases be required in patients starting or stopping estrogen-containing oral contraceptives. (2.1, 5.8) Lamotrigine tablets should be discontinued over a period of at least 2 weeks (approximately 50% reduction per week). (2.1, 5.9)

  Epilepsy

  Adjunctive therapy—See Table 1 for patients > 12 years of age and Tables 2and 3 for patients 2 to 12 years. (2.2) Conversion to monotherapy—See Table 4. (2.3)

  Bipolar Disorder: See Tables 5 and6. (2.4)

   

  Rash: There are suggestions, yet to be proven, that the risk of severe, potentially life-threatening rash may be increased by (1) coadministration of lamotrigine tablets with valproate, (2) exceeding the recommended initial dose of lamotrigine tablets, or (3) exceeding the recommended dose escalation for lamotrigine tablets. However, cases have occurred in the absence of these factors [see Boxed Warning]. Therefore, it is important that the dosing recommendations be followed closely.

  The risk of nonserious rash may be increased when the recommended initial dose and/or the rate of dose escalation of lamotrigine tablets is exceeded and in patients with a history of allergy or rash to other AEDs.

  It is recommended that lamotrigine tablets not be restarted in patients who discontinued due to rash associated with prior treatment with lamotrigine, unless the potential benefits clearly outweigh the risks. If the decision is made to restart a patient who has discontinued lamotrigine, the need to restart with the initial dosing recommendations should be assessed. The greater the interval of time since the previous dose, the greater consideration should be given to restarting with the initial dosing recommendations. If a patient has discontinued lamotrigine for a period of more than 5 half-lives, it is recommended that initial dosing recommendations and guidelines be followed. The half-life of lamotrigine is affected by other concomitant medications [see Clinical Pharmacology (12.3)].

  Lamotrigine Added to Drugs Known to Induce or Inhibit Glucuronidation: Drugs other than those listed in the Clinical Pharmacology section [see Clinical Pharmacology (12.3)] have not been systematically evaluated in combination with lamotrigine. Because lamotrigine is metabolized predominantly by glucuronic acid conjugation, drugs that are known to induce or inhibit glucuronidation may affect the apparent clearance of lamotrigine and doses of lamotrigine tablets may require adjustment based on clinical response.

  Target Plasma Levels for Patients With Epilepsy or Bipolar Disorder: A therapeutic plasma concentration range has not been established for lamotrigine. Dosing of lamotrigine tablets should be based on therapeutic response [see Clinical Pharmacology (12.3)].

  Women Taking Estrogen-Containing Oral Contraceptives:  Starting Lamotrigine Tablets in Women Taking Estrogen-Containing Oral Contraceptives: Although estrogen-containing oral contraceptives have been shown to increase the clearance of lamotrigine [see Clinical Pharmacology (12.3)], no adjustments to the recommended dose-escalation guidelines for lamotrigine tablets should be necessary solely based on the use of estrogen-containing oral contraceptives. Therefore, dose escalation should follow the recommended guidelines for initiating adjunctive therapy with lamotrigine tablets based on the concomitant AED or other concomitant medications (see Table 1 or Table 5). See below for adjustments to maintenance doses of lamotrigine tablets in women taking estrogen-containing oral contraceptives.

  Adjustments to the Maintenance Dose of Lamotrigine Tablets in Women Taking Estrogen-Containing Oral Contraceptives:

  (1) Taking Estrogen-Containing Oral Contraceptives: For women not taking carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin that induce lamotrigine glucuronidation [see Drug Interactions (7), Clinical Pharmacology (12.3)], the maintenance dose of lamotrigine tablets will in most cases need to be increased, by as much as 2 fold over the recommended target maintenance dose, in order to maintain a consistent lamotrigine plasma level [see Clinical Pharmacology (12.3)].

  (2) Starting Estrogen-Containing Oral Contraceptives: In women taking a stable dose of lamotrigine tablets and not taking carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin that induce lamotrigine glucuronidation [see Drug Interactions (7), Clinical Pharmacology (12.3)], the maintenance dose will in most cases need to be increased by as much as 2 fold in order to maintain a consistent lamotrigine plasma level. The dose increases should begin at the same time that the oral contraceptive is introduced and continue, based on clinical response, no more rapidly than 50 to 100 mg/day every week. Dose increases should not exceed the recommended rate (seeTable 1 orTable 5) unless lamotrigine plasma levels or clinical response support larger increases. Gradual transient increases in lamotrigine plasma levels may occur during the week of inactive hormonal preparation (“pill-free” week), and these increases will be greater if dose increases are made in the days before or during the week of inactive hormonal preparation. Increased lamotrigine plasma levels could result in additional adverse reactions, such as dizziness, ataxia, and diplopia. If adverse reactions attributable to lamotrigine tablets consistently occur during the “pill-free” week, dose adjustments to the overall maintenance dose may be necessary. Dose adjustments limited to the “pill-free” week are not recommended. For women taking lamotrigine tablets in addition to carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin that induce lamotrigine glucuronidation [see Drug Interactions (7), Clinical Pharmacology (12.3)], no adjustment to the dose of lamotrigine tablets should be necessary.

  (3) Stopping Estrogen-Containing Oral Contraceptives: For women not taking carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin that induce lamotrigine glucuronidation [see Drug Interactions (7), Clinical Pharmacology (12.3)], the maintenance dose of lamotrigine tablets will in most cases need to be decreased by as much as 50% in order to maintain a consistent lamotrigine plasma level. The decrease in dose of lamotrigine tablets should not exceed 25% of the total daily dose per week over a 2 week period, unless clinical response or lamotrigine plasma levels indicate otherwise [see Clinical Pharmacology (12.3)]. For women taking lamotrigine tablets in addition to carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin that induce lamotrigine glucuronidation [see Drug Interactions (7), Clinical Pharmacology (12.3)], no adjustment to the dose of lamotrigine tablets should be necessary.

  Women and Other Hormonal Contraceptive Preparations or Hormone Replacement Therapy: The effect of other hormonal contraceptive preparations or hormone replacement therapy on the pharmacokinetics of lamotrigine has not been systematically evaluated. It has been reported that ethinylestradiol, not progestogens, increased the clearance of lamotrigine up to 2 fold, and the progestin-only pills had no effect on lamotrigine plasma levels. Therefore, adjustments to the dosage of lamotrigine tablets in the presence of progestogens alone will likely not be needed.

  Patients With Hepatic Impairment: Experience in patients with hepatic impairment is limited. Based on a clinical pharmacology study in 24 patients with mild, moderate, and severe liver impairment [see Use in Specific Populations (8.6), Clinical Pharmacology (12.3)], the following general recommendations can be made. No dosage adjustment is needed in patients with mild liver impairment. Initial, escalation, and maintenance doses should generally be reduced by approximately 25% in patients with moderate and severe liver impairment without ascites and 50% in patients with severe liver impairment with ascites. Escalation and maintenance doses may be adjusted according to clinical response.

  Patients With Renal Impairment: Initial doses of lamotrigine tablets should be based on patients' concomitant medications (see Tables 1to3 or Table 5); reduced maintenance doses may be effective for patients with significant renal impairment [see Use in Specific Populations (8.7), Clinical Pharmacology (12.3)]. Few patients with severe renal impairment have been evaluated during chronic treatment with lamotrigine tablets. Because there is inadequate experience in this population, lamotrigine tablets should be used with caution in these patients.

  Discontinuation Strategy:  Epilepsy: For patients receiving lamotrigine tablets in combination with other AEDs, a reevaluation of all AEDs in the regimen should be considered if a change in seizure control or an appearance or worsening of adverse reactions is observed.

  If a decision is made to discontinue therapy with lamotrigine tablets, a step-wise reduction of dose over at least 2 weeks (approximately 50% per week) is recommended unless safety concerns require a more rapid withdrawal [see Warnings and Precautions (5.9)].

  Discontinuing carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin that induce lamotrigine glucuronidation should prolong the half-life of lamotrigine; discontinuing valproate should shorten the half-life of lamotrigine.

  Bipolar Disorder: In the controlled clinical trials, there was no increase in the incidence, type, or severity of adverse reactions following abrupt termination of lamotrigine tablets. In clinical trials in patients with Bipolar Disorder, 2 patients experienced seizures shortly after abrupt withdrawal of lamotrigine tablets. However, there were confounding factors that may have contributed to the occurrence of seizures in these bipolar patients. Discontinuation of lamotrigine tablets should involve a step-wise reduction of dose over at least 2 weeks (approximately 50% per week) unless safety concerns require a more rapid withdrawal [see Warnings and Precautions (5.9)].

   

  This section provides specific dosing recommendations for patients greater than 12 years of age and patients 2 to 12 years of age. Within each of these age-groups, specific dosing recommendations are provided depending upon concomitant AED or other concomitant medications (Table 1 for patients greater than 12 years of age and Table 2 for patients 2 to 12 years of age). A weight-based dosing guide for patients 2 to 12 years of age on concomitant valproate is provided in Table 3.

  Patients Over 12 Years of Age: Recommended dosing guidelines are summarized in Table 1.

  Table 1. Escalation Regimen for Lamotrigine in Patients Over 12 Years of Age With Epilepsy  For Patients TAKING Valproate* For Patients NOT TAKING Carbamazepine, Phenytoin, Phenobarbital, Primidone,† or Valproate1 For Patients TAKING Carbamazepine, Phenytoin, Phenobarbital, or Primidone2 and NOT TAKING Valproate1 Weeks 1 and 2 25 mg every other day 25 mg every day 50 mg/day Weeks 3 and 4 25 mg every day 50 mg/day 100 mg/day (in 2 divided doses) Week 5 onwards to maintenance Increase by 25 to 50 mg/day every 1 to 2 weeks Increase by 50 mg/day every 1 to 2 weeks Increase by 100 mg/day every 1 to 2 weeks Usual Maintenance Dose

  100 to 200 mg/day with valproate alone

  100 to 400 mg/day with valproate and other drugs that induce glucuronidation

  (in 1 or 2 divided doses)

  225 to 375 mg/day (in 2 divided doses)

  300 to 500 mg/day

   (in 2 divided doses)

  
  

  1

  2

  Patients 2 to 12 Years of Age: Recommended dosing guidelines are summarized in Table 2.

  Smaller starting doses and slower dose escalations than those used in clinical trials are recommended because of the suggestion that the risk of rash may be decreased by smaller starting doses and slower dose escalations. Therefore, maintenance doses will take longer to reach in clinical practice than in clinical trials. It may take several weeks to months to achieve an individualized maintenance dose. Maintenance doses in patients weighing less than 30 kg, regardless of age or concomitant AED, may need to be increased as much as 50%, based on clinical response.

  Table 2. Escalation Regimen for Lamotrigine in Patients 2 to 12 Years of Age With Epilepsy For Patients TAKING Valproate* For Patients NOT TAKING Carbamazepine, Phenytoin, Phenobarbital, Primidone,† or Valproate3 For Patients TAKING Carbamazepine, Phenytoin, Phenobarbital, or Primidone4 and NOT TAKING Valproate3 Weeks 1 and 2 0.15 mg/kg/day in 1 or 2 divided doses, rounded down to the nearest whole tablet (see Table 3 for weight based dosing guide) 0.3 mg/kg/day in 1 or 2 divided doses, rounded down to the nearest whole tablet 0.6 mg/kg/day in 2 divided doses, rounded down to the nearest whole tablet Weeks 3 and 4 0.3 mg/kg/day in 1 or 2 divided doses, rounded down to the nearest whole tablet (see Table 3for weight based dosing guide) 0.6 mg/kg/day in 2 divided doses, rounded down to the nearest whole tablet 1.2 mg/kg/day in 2 divided doses, rounded down to the nearest whole tablet Week 5 onwards to maintenance The dose should be increased every 1 to 2 weeks as follows: calculate 0.3 mg/kg/day, round this amount down to the nearest whole tablet, and add this amount to the previously administered daily dose The dose should be increased every 1 to 2 weeks as follows: calculate 0.6 mg/kg/day, round this amount down to the nearest whole tablet, and add this amount to the previously administered daily dose The dose should be increased every 1 to 2 weeks as follows: calculate 1.2 mg/kg/day, round this amount down to the nearest whole tablet, and add this amount to the previously administered daily dose Usual Maintenance Dose 1 to 5 mg/kg/day (maximum 200 mg/day in 1 or 2 divided doses)
  1 to 3 mg/kg/day with valproate alone 4.5 to 7.5 mg/kg/day (maximum 300 mg/day in 2 divided doses) 5 to 15 mg/kg/day (maximum 400 mg/day in 2 divided doses) Maintenance dose in patients less than 30 kg May need to be increased by as much as 50%, based on clinical response May need to be increased by as much as 50%, based on clinical response May need to be increased by as much as 50%, based on clinical response

  Note: Only whole tablets should be used for dosing.

  
  

  3

  4

  Table 3. The Initial Weight-Based Dosing Guide for Patients 2 to 12 Years of Age Taking Valproate (Weeks 1 to 4) With Epilepsy If the patient’s weight is Give this daily dose, using the most appropriate combination of lamotrigine tablets, 2 mg and 5 mg Greater than And less than Weeks 1 and 2 Weeks 3 and 4 6.7 kg 14 kg 2 mg every other day 2 mg every day 14.1 kg 27 kg 2 mg every day 4 mg every day 27.1 kg 34 kg 4 mg every day 8 mg every day 34.1 kg 40 kg 5 mg every day 10 mg every day

  Usual Adjunctive Maintenance Dose for Epilepsy: The usual maintenance doses identified in Tables 1 and 2 are derived from dosing regimens employed in the placebo-controlled adjunctive studies in which the efficacy of lamotrigine tablets was established. In patients receiving multidrug regimens employing carbamazepine, phenytoin, phenobarbital, or primidone without valproate, maintenance doses of adjunctive lamotrigine tablets as high as 700 mg/day have been used. In patients receiving valproate alone, maintenance doses of adjunctive lamotrigine tablets as high as 200 mg/day have been used. The advantage of using doses above those recommended in Tables 1 through 4 has not been established in controlled trials.

   

  The goal of the transition regimen is to effect the conversion to monotherapy with lamotrigine tablets under conditions that ensure adequate seizure control while mitigating the risk of serious rash associated with the rapid titration of lamotrigine tablets.

  The recommended maintenance dose of lamotrigine tablets as monotherapy is 500 mg/day given in 2 divided doses.

  To avoid an increased risk of rash, the recommended initial dose and subsequent dose escalations of lamotrigine tablets should not be exceeded [see Boxed Warning].

  Conversion From Adjunctive Therapy With Carbamazepine, Phenytoin, Phenobarbital, or Primidone to Monotherapy With Lamotrigine Tablets: After achieving a dose of 500 mg/day of lamotrigine tablets according to the guidelines in Table 1, the concomitant AED should be withdrawn by 20% decrements each week over a 4 week period. The regimen for the withdrawal of the concomitant AED is based on experience gained in the controlled monotherapy clinical trial.

  Conversion From Adjunctive Therapy With Valproate to Monotherapy With Lamotrigine Tablets: The conversion regimen involves 4 steps outlined in Table 4.

  Table 4. Conversion From Adjunctive Therapy With Valproate to Monotherapy With Lamotrigine in Patients ≥ 16 Years of Age With Epilepsy   Lamotrigine Valproate Step 1 Achieve a dose of 200 mg/day according to guidelines in Table 1 (if not already on 200 mg/day). Maintain previous stable dose. Step 2 Maintain at 200 mg/day. Decrease to 500 mg/day by decrements no greater than 500 mg/day/week and then maintain the dose of 500 mg/day for 1 week. Step 3 Increase to 300 mg/day and maintain for 1 week. Simultaneously decrease to 250 mg/day and maintain for 1 week. Step 4 Increase by 100 mg/day every week to achieve maintenance dose of 500 mg/day. Discontinue.

  Conversion From Adjunctive Therapy With Antiepileptic Drugs Other Than Carbamazepine, Phenytoin, Phenobarbital, Primidone, or Valproate to Monotherapy With Lamotrigine Tablets: No specific dosing guidelines can be provided for conversion to monotherapy with lamotrigine tablets with AEDs other than carbamazepine, phenobarbital, phenytoin, primidone, or valproate.

   

  The goal of maintenance treatment with lamotrigine tablets is to delay the time to occurrence of mood episodes (depression, mania, hypomania, mixed episodes) in patients treated for acute mood episodes with standard therapy. The target dose of lamotrigine tablets is 200 mg/day (100 mg/day in patients taking valproate, which decreases the apparent clearance of lamotrigine, and 400 mg/day in patients not taking valproate and taking either carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin that increase the apparent clearance of lamotrigine). In the clinical trials, doses up to 400 mg/day as monotherapy were evaluated; however, no additional benefit was seen at 400 mg/day compared with 200 mg/day [see Clinical Studies (14.2)]. Accordingly, doses above 200 mg/day are not recommended. Treatment with lamotrigine tablets is introduced, based on concurrent medications, according to the regimen outlined in Table 5. If other psychotropic medications are withdrawn following stabilization, the dose of lamotrigine tablets should be adjusted. For patients discontinuing valproate, the dose of lamotrigine tablets should be doubled over a 2 week period in equal weekly increments (see Table 6). For patients discontinuing carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin that induce lamotrigine glucuronidation, the dose of lamotrigine tablets should remain constant for the first week and then should be decreased by half over a 2 week period in equal weekly decrements (see Table 6). The dose of lamotrigine tablets may then be further adjusted to the target dose (200 mg) as clinically indicated.

  If other drugs are subsequently introduced, the dose of lamotrigine tablets may need to be adjusted. In particular, the introduction of valproate requires reduction in the dose of lamotrigine tablets [see Drug Interactions (7), Clinical Pharmacology (12.3)].

  To avoid an increased risk of rash, the recommended initial dose and subsequent dose escalations of lamotrigine tablets should not be exceeded [see Boxed Warning].

   

  Table 5. Escalation Regimen for Lamotrigine for Patients With Bipolar Disorder For Patients TAKING Valproate* For Patients NOT TAKING Carbamazepine, Phenytoin, Phenobarbital, Primidone,† or Valproate5 For Patients TAKING Carbamazepine, Phenytoin, Phenobarbital, or Primidone6 and NOT TAKING Valproate5 Weeks 1 and 2 25 mg every other day 25 mg daily 50 mg daily Weeks 3 and 4 25 mg daily 50 mg daily 100 mg daily, in divided doses Week 5 50 mg daily 100 mg daily 200 mg daily, in divided doses Week 6 100 mg daily 200 mg daily 300 mg daily, in divided doses Week 7 100 mg daily 200 mg daily up to 400 mg daily, in divided doses
  

  5

  6

  Table 6. Dosage Adjustments to Lamotrigine for Patients With Bipolar Disorder Following Discontinuation of Psychotropic Medications   Discontinuation of Psychotropic Drugs (excluding Carbamazepine, Phenytoin, Phenobarbital, Primidone,* or Valproate†) After Discontinuation of Valproate8 After Discontinuation of Carbamazepine, Phenytoin, Phenobarbital, or Primidone7 Current dose of Lamotrigine (mg/day) 100

  Current dose of Lamotrigine (mg/day)

  400

  Week 1 Maintain current dose of lamotrigine 150 400 Week 2 Maintain current dose of lamotrigine 200 300 Week 3 onward Maintain current dose of lamotrigine 200 200
  

  7

  8

  The benefit of continuing treatment in patients who had been stabilized in an 8 to 16 week open-label phase with lamotrigine tablets was established in 2 randomized, placebo-controlled clinical maintenance trials [see Clinical Studies (14.2)]. However, the optimal duration of treatment with lamotrigine tablets has not been established. Thus, patients should be periodically reassessed to determine the need for maintenance treatment.

   

  1 Valproate has been shown to inhibit glucuronidation and decrease the apparent clearance of lamotrigine [ 2 These drugs induce lamotrigine glucuronidation and increase clearance [ 3 Valproate has been shown to inhibit glucuronidation and decrease the apparent clearance of lamotrigine [ 4 These drugs induce lamotrigine glucuronidation and increase clearance [ 5 Valproate has been shown to inhibit glucuronidation and decrease the apparent clearance of lamotrigine [ 6 These drugs induce lamotrigine glucuronidation and increase clearance [ 7 These drugs induce lamotrigine glucuronidation and increase clearance [ 8 Valproate has been shown to inhibit glucuronidation and decrease the apparent clearance of lamotrigine [

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  Dosing is based on concomitant medications, indication, and patient age. (2.2, 2.4) To avoid an increased risk of rash, the recommended initial dose and subsequent dose escalations should not be exceeded. Lamotrigine Starter Kits are available for the first 5 weeks of treatment. (2.1, 16) Do not restart lamotrigine tablets, USP in patients who discontinued due to rash unless the potential benefits clearly outweigh the risks. (2.1) Adjustments to maintenance doses will in most cases be required in patients starting or stopping estrogen-containing oral contraceptives. (2.1, 5.9) Lamotrigine tablets, USP should be discontinued over a period of at least 2 weeks (approximately 50% reduction per week). (2.1, 5.10)

  Epilepsy

  Adjunctive therapy—See Table 1 for patients >12 years of age and Tables 2 and 3 for patients 2 to 12 years. (2.2) Conversion to monotherapy—See Table 4. (2.3)

  Bipolar Disorder: See Tables 5 and 6. (2.4)

   

  Rash: There are suggestions, yet to be proven, that the risk of severe, potentially life-threatening rash may be increased by (1) coadministration of lamotrigine with valproate, (2) exceeding the recommended initial dose of lamotrigine, or (3) exceeding the recommended dose escalation for lamotrigine. However, cases have occurred in the absence of these factors [see Boxed Warning]. Therefore, it is important that the dosing recommendations be followed closely.

  The risk of nonserious rash may be increased when the recommended initial dose and/or the rate of dose escalation of lamotrigine is exceeded and in patients with a history of allergy or rash to other AEDs.

  Lamotrigine Starter Kits provide lamotrigine at doses consistent with the recommended titration schedule for the first 5 weeks of treatment, based upon concomitant medications for patients with epilepsy (>12 years of age) and Bipolar I Disorder (≥18 years of age) and are intended to help reduce the potential for rash. The use of lamotrigine Starter Kits is recommended for appropriate patients who are starting or restarting lamotrigine [see How Supplied/Storage and Handling (16)].

  It is recommended that lamotrigine tablets, USP not be restarted in patients who discontinued due to rash associated with prior treatment with lamotrigine, unless the potential benefits clearly outweigh the risks. If the decision is made to restart a patient who has discontinued lamotrigine, the need to restart with the initial dosing recommendations should be assessed. The greater the interval of time since the previous dose, the greater consideration should be given to restarting with the initial dosing recommendations. If a patient has discontinued lamotrigine for a period of more than 5 half-lives, it is recommended that initial dosing recommendations and guidelines be followed. The half-life of lamotrigine is affected by other concomitant medications [see Clinical Pharmacology (12.3)].

  Lamotrigine Added to Drugs Known to Induce or Inhibit Glucuronidation: Drugs other than those listed in the Clinical Pharmacology section [see Clinical Pharmacology (12.3)] have not been systematically evaluated in combination with lamotrigine. Because lamotrigine is metabolized predominantly by glucuronic acid conjugation, drugs that are known to induce or inhibit glucuronidation may affect the apparent clearance of lamotrigine and doses of lamotrigine may require adjustment based on clinical response.

  Target Plasma Levels for Patients With Epilepsy or Bipolar Disorder: A therapeutic plasma concentration range has not been established for lamotrigine. Dosing of lamotrigine should be based on therapeutic response [see Clinical Pharmacology (12.3)].

  Women Taking Estrogen-Containing Oral Contraceptives: Starting Lamotrigine in Women Taking Estrogen-Containing Oral Contraceptives: Although estrogen-containing oral contraceptives have been shown to increase the clearance of lamotrigine [see Clinical Pharmacology (12.3)], no adjustments to the recommended dose-escalation guidelines for lamotrigine should be necessary solely based on the use of estrogen-containing oral contraceptives. Therefore, dose escalation should follow the recommended guidelines for initiating adjunctive therapy with lamotrigine based on the concomitant AED or other concomitant medications (see Table 1 or Table 5). See below for adjustments to maintenance doses of lamotrigine in women taking estrogen-containing oral contraceptives.

  Adjustments to the Maintenance Dose of Lamotrigine In Women Taking Estrogen-Containing Oral Contraceptives:

  (1) Taking Estrogen-Containing Oral Contraceptives: For women not taking carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin that induce lamotrigine glucuronidation [see Drug Interactions (7), Clinical Pharmacology (12.3)], the maintenance dose of lamotrigine will in most cases need to be increased, by as much as 2-fold over the recommended target maintenance dose, in order to maintain a consistent lamotrigine plasma level [see Clinical Pharmacology (12.3)].

  (2) Starting Estrogen-Containing Oral Contraceptives: In women taking a stable dose of lamotrigine and not taking carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin that induce lamotrigine glucuronidation [see Drug Interactions (7), Clinical Pharmacology (12.3)], the maintenance dose will in most cases need to be increased by as much as 2-fold in order to maintain a consistent lamotrigine plasma level. The dose increases should begin at the same time that the oral contraceptive is introduced and continue, based on clinical response, no more rapidly than 50 to 100 mg/day every week. Dose increases should not exceed the recommended rate (see Table 1 or Table 5) unless lamotrigine plasma levels or clinical response support larger increases. Gradual transient increases in lamotrigine plasma levels may occur during the week of inactive hormonal preparation ("pill-free" week), and these increases will be greater if dose increases are made in the days before or during the week of inactive hormonal preparation. Increased lamotrigine plasma levels could result in additional adverse reactions, such as dizziness, ataxia, and diplopia. If adverse reactions attributable to lamotrigine consistently occur during the "pill-free" week, dose adjustments to the overall maintenance dose may be necessary. Dose adjustments limited to the "pill-free" week are not recommended. For women taking lamotrigine in addition to carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin that induce lamotrigine glucuronidation [see Drug Interactions (7), Clinical Pharmacology (12.3)], no adjustment to the dose of lamotrigine should be necessary.  

  (3) Stopping Estrogen-Containing Oral Contraceptives: For women not taking carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin that induce lamotrigine glucuronidation [see Drug Interactions (7), Clinical Pharmacology (12.3)], the maintenance dose of lamotrigine will in most cases need to be decreased by as much as 50% in order to maintain a consistent lamotrigine plasma level. The decrease in dose of lamotrigine should not exceed 25% of the total daily dose per week over a 2-week period, unless clinical response or lamotrigine plasma levels indicate otherwise [see Clinical Pharmacology (12.3)]. For women taking lamotrigine in addition to carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin that induce lamotrigine glucuronidation [see Drug Interactions (7), Clinical Pharmacology (12.3)], no adjustment to the dose of lamotrigine should be necessary.

  Women and Other Hormonal Contraceptive Preparations or Hormone Replacement Therapy: The effect of other hormonal contraceptive preparations or hormone replacement therapy on the pharmacokinetics of lamotrigine has not been systematically evaluated. It has been reported that ethinylestradiol, not progestogens, increased the clearance of lamotrigine up to 2-fold, and the progestin-only pills had no effect on lamotrigine plasma levels. Therefore, adjustments to the dosage of lamotrigine in the presence of progestogens alone will likely not be needed.

  Patients With Hepatic Impairment: Experience in patients with hepatic impairment is limited. Based on a clinical pharmacology study in 24 patients with mild, moderate, and severe liver impairment [see Use in Specific Populations (8.6), Clinical Pharmacology (12.3)], the following general recommendations can be made. No dosage adjustment is needed in patients with mild liver impairment. Initial, escalation, and maintenance doses should generally be reduced by approximately 25% in patients with moderate and severe liver impairment without ascites and 50% in patients with severe liver impairment with ascites. Escalation and maintenance doses may be adjusted according to clinical response.

  Patients With Renal Impairment: Initial doses of lamotrigine should be based on patients' concomitant medications (see Tables 1-3 or Table 5); reduced maintenance doses may be effective for patients with significant renal impairment [see Use in Specific Populations (8.7), Clinical Pharmacology (12.3)]. Few patients with severe renal impairment have been evaluated during chronic treatment with lamotrigine. Because there is inadequate experience in this population, lamotrigine should be used with caution in these patients.

  Discontinuation Strategy: Epilepsy: For patients receiving lamotrigine in combination with other AEDs, a reevaluation of all AEDs in the regimen should be considered if a change in seizure control or an appearance or worsening of adverse reactions is observed.

  If a decision is made to discontinue therapy with lamotrigine, a step-wise reduction of dose over at least 2 weeks (approximately 50% per week) is recommended unless safety concerns require a more rapid withdrawal [see Warnings and Precautions (5.10)].

  Discontinuing carbamazepine, phenytoin, phenobarbital, primidone or other drugs such as rifampin that induce lamotrigine glucuronidation should prolong the half-life of lamotrigine; discontinuing valproate should shorten the half-life of lamotrigine.

  Bipolar Disorder: In the controlled clinical trials, there was no increase in the incidence, type, or severity of adverse reactions following abrupt termination of lamotrigine. In clinical trials in patients with Bipolar Disorder, 2 patients experienced seizures shortly after abrupt withdrawal of lamotrigine. However, there were confounding factors that may have contributed to the occurrence of seizures in these bipolar patients. Discontinuation of lamotrigine should involve a step-wise reduction of dose over at least 2 weeks (approximately 50% per week) unless safety concerns require a more rapid withdrawal [see Warnings and Precautions (5.10)].

   

  This section provides specific dosing recommendations for patients greater than 12 years of age and patients 2 to 12 years of age. Within each of these age-groups, specific dosing recommendations are provided depending upon concomitant AED or other concomitant medications (Table 1 for patients greater than 12 years of age and Table 2 for patients 2 to 12 years of age). A weight-based dosing guide for patients 2 to 12 years of age on concomitant valproate is provided in Table 3.

  Patients Over 12 Years of Age: Recommended dosing guidelines are summarized in Table 1.

  Table 1. Escalation Regimen for Lamotrigine in Patients Over 12 Years of Age With Epilepsy
  For Patients TAKING
   Valproatea
  For Patients NOT 
  TAKING 
  Carbamazepine, 
  Phenytoin, 
  Phenobarbital,
   Primidoneb, or 
  Valproatea
  For Patients 
  TAKING 
  Carbamazepine, 
  Phenytoin, 
  Phenobarbital, or 
  Primidoneb and 
  NOT TAKING Valproatea
  Weeks 1 and 2
  25 mg every other day
  25 mg every day
  50 mg/day
  Weeks 3 and 4
  25 mg every day
  50 mg/day
  100 mg/day 
  (in 2 divided doses)
  Week 5
  onwards to
  maintenance
  Increase by 25 to 50
  mg/day every 1 to
  2 weeks
  Increase by 50
  mg/day every 1 to
  2 weeks
  Increase by 100
  mg/day every 1 to
  2 weeks.
  Usual
  Maintenance
  Dose
  100 to 200 mg/day
  with valproate 
  alone 
  100 to 400 mg/day 
  with valproate and 
  other drugs that 
  induce 
  glucuronidation 
  (in 1 or 2 divided 
  doses)
  225 to 375 mg/day 
  (in 2 divided doses)
  300 to 500 mg/day 
  (in 2 divided doses)
  

  a Valproate has been shown to inhibit glucuronidation and decrease the apparent clearance of lamotrigine [see Drug Interactions (7), Clinical Pharmacology (12.3)].

  b These drugs induce lamotrigine glucuronidation and increase clearance [see Drug Interactions (7), Clinical Pharmacology (12.3)]. Other drugs which have similar effects include estrogen-containing oral contraceptives [see Drug Interactions (7), Clinical Pharmacology (12.3)]. Dosing recommendations for oral contraceptives can be found in General Dosing Considerations [see Dosage and Administration (2.1)]. Patients on rifampin, or other drugs that induce lamotrigine glucuronidation and increase clearance, should follow the same dosing titration/maintenance regimen as that used with anticonvulsants that have this effect.

  Patients 2 to 12 Years of Age: Recommended dosing guidelines are summarized in Table 2.

  Smaller starting doses and slower dose escalations than those used in clinical trials are recommended because of the suggestion that the risk of rash may be decreased by smaller starting doses and slower dose escalations. Therefore, maintenance doses will take longer to reach in clinical practice than in clinical trials. It may take several weeks to months to achieve an individualized maintenance dose. Maintenance doses in patients weighing less than 30 kg, regardless of age or concomitant AED, may need to be increased as much as 50%, based on clinical response.

  The smallest available strength of lamotrigine tablets is 25 mg, and only whole tablets should be administered. If the calculated dose cannot be achieved using whole tablets, the dose should be rounded down to the nearest whole tablet [see How Supplied/Storage and Handling (16) and Medication Guide].

  Table 2. Escalation Regimen for Lamotrigine in Patients 2 to 12 Years of Age With Epilepsy
  For Patients 
  TAKING Valproatea
  For Patients NOT
   TAKING 
  Carbamazepine, 
  Phenytoin, 
  Phenobarbital, 
  Primidoneb, or 
  Valproatea
  For Patients TAKING
   Carbamazepine, 
  Phenytoin, 
  Phenobarbital, or 
  Primidoneb and NOT
  TAKING Valproatea
  Weeks 1 
  and 2 
  0.15 mg/kg/day 
  in 1 or 2 divided 
  doses, rounded 
  down to the nearest
  whole tablet (see 
  Table 3 for weight 
  based dosing guide)
  0.3 mg/kg/day 
  in 1 or 2 divided 
  doses, rounded down 
  to the nearest whole 
  tablet
  0.6 mg/kg/day 
  in 2 divided doses,
   rounded down to the
   nearest whole tablet
  Weeks 3 
  and 4 
  0.3 mg/kg/day 
  in 1 or 2 divided 
  doses, rounded 
  down to the nearest
  whole tablet (see
  Table 3 for weight
  based dosing guide)
  0.6 mg/kg/day 
  in 2 divided doses, 
  rounded down to the 
  nearest whole tablet
  1.2 mg/kg/day 
  in 2 divided doses,
   rounded down to the
   nearest whole tablet
  Week 5 
  onwards to 
  maintenance
  The dose should be 
  increased every 1 to 
  2 weeks as follows:
  calculate 0.3 mg/kg/day, 
  round this amount
  down to the nearest
  whole tablet, and
  add this amount to
  the previously 
  administered daily
  dose
  The dose should be increased every 1 to 
  2 weeks as follows: calculate 
  0.6 mg/kg/day, round 
  this amount down to 
  the nearest whole 
  tablet, and add this 
  amount to the 
  previously 
  administered daily
   dose
  The dose should be increased every 1 to 
  2 weeks as follows: calculate 
  1.2 mg/kg/day, round
   this amount down to
   the nearest whole
   tablet, and add this
   amount to the
   previously
   administered daily
   dose
  Usual 
  Maintenance 
  Dose 
  1 to 5 mg/kg/day
   (maximum 
  200 mg/day in 1 or 2
   divided doses). 
  1 to 3 mg/kg/day 
  with valproate alone
  4.5 to 7.5 mg/kg/day
   (maximum 300 
  mg/day in 2 divided
  doses)
  5 to 15 mg/kg/day
   (maximum 400 
  mg/day in 2 divided
   doses)
  Maintenance 
  dose in 
  patients less 
  than 30 kg 
  May need to be 
  increased by as 
  much as 50%, based 
  on clinical response
  May need to be
   increased by as much
   as 50%, based on 
  clinical response
  May need to be 
  increased by as much
   as 50%, based on 
  clinical response
  

  Note: Only whole tablets should be used for dosing.
  

  aValproate has been shown to inhibit glucuronidation and decrease the apparent clearance of lamotrigine [see Drug Interactions (7),
  Clinical Pharmacology (12.3)].
  

  bThese drugs induce lamotrigine glucuronidation and increase clearance [see Drug Interactions (7), Clinical Pharmacology (12.3)].
  Other drugs which have similar effects include estrogen-containing oral contraceptives [see Drug Interactions (7), Clinical Pharmacology (12.3)]. Dosing recommendations for oral contraceptives can be found in General Dosing Considerations [see 
  Dosage and Administration (2.1)]. Patients on rifampin, or other drugs that induce lamotrigine glucuronidation and increase clearance, should follow the same dosing titration/maintenance regimen as that used with anticonvulsants that have this effect.
  

  Table 3. The Initial Weight-Based Dosing Guide for Patients 2 to 12 Years Taking Valproate (Weeks 1 to 4) With Epilepsy If the patient’s weight is
  Give this daily dose, using the most appropriate combination of lamotrigine
  2-mg and 5-mg tablets 
  Greater than 
  And less than 
  Weeks 1 and 2
  Weeks 3 and 4
  6.7 kg 
  14 kg 
  2 mg every other day
  2 mg every day
  14.1 kg 
  27 kg 
  2 mg every day
  4 mg every day
  27.1 kg 
  34 kg 
  4 mg every day
  8 mg every day
  34.1 kg 
  40 kg 
  5 mg every day
  10 mg every day
  

  Usual Adjunctive Maintenance Dose for Epilepsy: The usual maintenance doses identified in Tables 1 and 2 are derived from dosing regimens employed in the placebo-controlled adjunctive studies in which the efficacy of lamotrigine was established. In patients receiving multidrug regimens employing carbamazepine, phenytoin, phenobarbital, or primidone without valproate, maintenance doses of adjunctive lamotrigine as high as 700 mg/day have been used. In patients receiving valproate alone, maintenance doses of adjunctive lamotrigine as high as 200 mg/day have been used. The advantage of using doses above those recommended in Tables 1 through 4 has not been established in controlled trials.

   

  The goal of the transition regimen is to effect the conversion to monotherapy with lamotrigine under conditions that ensure adequate seizure control while mitigating the risk of serious rash associated with the rapid titration of lamotrigine.

  The recommended maintenance dose of lamotrigine as monotherapy is 500 mg/day given in 2 divided doses.

  To avoid an increased risk of rash, the recommended initial dose and subsequent dose escalations of lamotrigine should not be exceeded [see Boxed Warning].

  Conversion From Adjunctive Therapy With Carbamazepine, Phenytoin, Phenobarbital, or Primidone to Monotherapy With Lamotrigine: After achieving a dose of 500 mg/day of lamotrigine according to the guidelines in Table 1, the concomitant AED should be withdrawn by 20% decrements each week over a 4-week period. The regimen for the withdrawal of the concomitant AED is based on experience gained in the controlled monotherapy clinical trial.

  Conversion From Adjunctive Therapy With Valproate to Monotherapy With Lamotrigine: The conversion regimen involves 4 steps outlined in Table 4.

  Table 4. Conversion From Adjunctive Therapy With Valproate to Monotherapy With Lamotrigine in Patients ≥16 Years of Age With Epilepsy
  Lamotrigine
  Valproate
  Step 1 
  Achieve a dose of 200 mg/day according to 
  guidelines in Table 1 (if not already on 
  200 mg/day).
  Maintain previous stable dose.
  Step 2 
  Maintain at 200 mg/day.
  Decrease to 500 mg/day by 
  decrements no greater than 
  500 mg/day/week and then 
  maintain the dose of 
  500 mg/day for 1 week.
  Step 3 
  Increase to 300 mg/day and maintain for 1 
  week.
  Simultaneously decrease to 
  250 mg/day and maintain for 1 week.
  Step 4 
  Increase by 100 mg/day every week to achieve 
  maintenance dose of 500 mg/day.
  Discontinue.
  

  Conversion From Adjunctive Therapy With AEDs Other Than Carbamazepine, Phenytoin, Phenobarbital, Primidone, or Valproate to Monotherapy With Lamotrigine: No specific dosing guidelines can be provided for conversion to monotherapy with lamotrigine with AEDs other than carbamazepine, phenobarbital, phenytoin, primidone, or valproate.

   

  The goal of maintenance treatment with lamotrigine is to delay the time to occurrence of mood episodes (depression, mania, hypomania, mixed episodes) in patients treated for acute mood episodes with standard therapy. The target dose of lamotrigine is 200 mg/day (100 mg/day in patients taking valproate, which decreases the apparent clearance of lamotrigine, and 400 mg/day in patients not taking valproate and taking either carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin that increase the apparent clearance of lamotrigine). In the clinical trials, doses up to 400 mg/day as monotherapy were evaluated; however, no additional benefit was seen at 400 mg/day compared with 200 mg/day [see Clinical Studies (14.2)]. Accordingly, doses above 200 mg/day are not recommended. Treatment with lamotrigine is introduced, based on concurrent medications, according to the regimen outlined in Table 5. If other psychotropic medications are withdrawn following stabilization, the dose of lamotrigine should be adjusted. For patients discontinuing valproate, the dose of lamotrigine should be doubled over a 2-week period in equal weekly increments (see Table 6). For patients discontinuing carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin that induce lamotrigine glucuronidation, the dose of lamotrigine should remain constant for the first week and then should be decreased by half over a 2-week period in equal weekly decrements (see Table 6). The dose of lamotrigine may then be further adjusted to the target dose (200 mg) as clinically indicated.

  If other drugs are subsequently introduced, the dose of lamotrigine may need to be adjusted. In particular, the introduction of valproate requires reduction in the dose of lamotrigine [see Drug Interactions (7), Clinical Pharmacology (12.3)].

  To avoid an increased risk of rash, the recommended initial dose and subsequent dose escalations of lamotrigine should not be exceeded [see Boxed Warning].

  Table 5. Escalation Regimen for Lamotrigine for Patients With Bipolar Disorder
  For Patients TAKING Valproatea
  For Patients NOT TAKING
  Carbamazepine, Phenytoin, 
  Phenobarbital, Primidoneb, or
   Valproatea
  For Patients TAKING
   Carbamazepine, Phenytoin, Phenobarbital,
  or Primidoneb and 
  NOT TAKING Valproatea
  Weeks 1 and 2 
  25 mg every other day
  25 mg daily
  50 mg daily
  Weeks 3 and 4 
  25 mg daily
  50 mg daily
  100 mg daily, in divided doses
  Week 5 
  50 mg daily
  100 mg daily
  200 mg daily, in divided doses
  Week 6 
  100 mg daily
  200 mg daily
  300 mg daily, in divided doses
  Week 7 
  100 mg daily
  200 mg daily
  up to 400 mg daily, in
  divided doses
  

  a Valproate has been shown to inhibit glucuronidation and decrease the apparent clearance of lamotrigine [see Drug Interactions (7), Clinical Pharmacology (12.3)].

  b These drugs induce lamotrigine glucuronidation and increase clearance [see Drug Interactions (7), Clinical Pharmacology (12.3)]. Other drugs which have similar effects include estrogen-containing oral contraceptives [see Drug Interactions (7), Clinical Pharmacology (12.3)]. Dosing recommendations for oral contraceptives can be found in General Dosing Considerations [see Dosage and Administration (2.1)]. Patients on rifampin, or other drugs that induce lamotrigine glucuronidation and increase clearance, should follow the same dosing titration/maintenance regimen as that used with anticonvulsants that have this effect.

  Table 6. Dosage Adjustments to Lamotrigine for Patients With Bipolar Disorder Following Discontinuation of Psychotropic Medications
  Discontinuation of Psychotropic Drugs 
  (excluding Carbamazepine, Phenytoin, 
  After Discontinuation of Valproatea
  After Discontinuation of Carbamazepine, 
  Phenytoin, Phenobarbital,or
   Primidoneb
  
  Phenobarbital, Primidoneb, or Valproatea)
  Current dose of Lamotrigine (mg/day) 
  100
  Current dose of Lamotrigine (mg/day) 
  400
  Week 1 
  Maintain current dose of Lamotrigine
  150
  400
  Week 2 
  Maintain current dose of Lamotrigine
  200
  300
  Week 3 onward 
  Maintain current dose of Lamotrigine
  200
  200
  

  a Valproate has been shown to inhibit glucuronidation and decrease the apparent clearance of lamotrigine [see Drug Interactions (7), Clinical Pharmacology (12.3)].

  b These drugs induce lamotrigine glucuronidation and increase clearance [see Drug Interactions (7), Clinical Pharmacology (12.3)]. Other drugs which have similar effects include estrogen-containing oral contraceptives [see Drug Interactions (7), Clinical Pharmacology (12.3)]. Dosing recommendations for oral contraceptives can be found in General Dosing Considerations [see Dosage and Administration (2.1)]. Patients on rifampin, or other drugs that induce lamotrigine glucuronidation and increase clearance, should follow the same dosing titration/maintenance regimen as that used with anticonvulsants that have this effect.

  The benefit of continuing treatment in patients who had been stabilized in an 8- to 16-week open-label phase with lamotrigine was established in 2 randomized, placebo-controlled clinical maintenance trials [see Clinical Studies (14.2)]. However, the optimal duration of treatment with lamotrigine has not been established. Thus, patients should be periodically reassessed to determine the need for maintenance treatment.

   

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  Topical corticosteroids are generally applied to the affected area as a thin film from two to four times daily depending on the severity of the condition. In hairy sites, the hair should be parted to allow direct contact with the lesion.
  
  Occlusive dressings may be used for the management of psoriasis or recalcitrant conditions. Some plastic films may be flammable and due care should be exercised in their use. Similarly, caution should be employed when such films are used on children or left in their proximity, to avoid the possibility of accidental suffocation.
  
  If an infection develops, the use of occlusive dressings should be discontinued and appropriate antimicrobial therapy instituted.

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  Dosing is based on concomitant medications, indication, and patient age. (2.2, 2.4) To avoid an increased risk of rash, the recommended initial dose and subsequent dose escalations should not be exceeded. Lamotrigine Starter Kits are available for the first 5 weeks of treatment. (2.1, 16) Do not restart lamotrigine tablets, USP in patients who discontinued due to rash unless the potential benefits clearly outweigh the risks. (2.1) Adjustments to maintenance doses will in most cases be required in patients starting or stopping estrogen-containing oral contraceptives. (2.1, 5.9) Lamotrigine tablets, USP should be discontinued over a period of at least 2 weeks (approximately 50% reduction per week). (2.1, 5.10)

  Epilepsy

  Adjunctive therapy—See Table 1 for patients >12 years of age and Tables 2 and 3 for patients 2 to 12 years. (2.2) Conversion to monotherapy—See Table 4. (2.3)

  Bipolar Disorder: See Tables 5 and 6. (2.4)

   

  Rash: There are suggestions, yet to be proven, that the risk of severe, potentially life-threatening rash may be increased by (1) coadministration of lamotrigine with valproate, (2) exceeding the recommended initial dose of lamotrigine, or (3) exceeding the recommended dose escalation for lamotrigine. However, cases have occurred in the absence of these factors [see Boxed Warning]. Therefore, it is important that the dosing recommendations be followed closely.

  The risk of nonserious rash may be increased when the recommended initial dose and/or the rate of dose escalation of lamotrigine is exceeded and in patients with a history of allergy or rash to other AEDs.

  Lamotrigine Starter Kits provide lamotrigine at doses consistent with the recommended titration schedule for the first 5 weeks of treatment, based upon concomitant medications for patients with epilepsy (>12 years of age) and Bipolar I Disorder (≥18 years of age) and are intended to help reduce the potential for rash. The use of lamotrigine Starter Kits is recommended for appropriate patients who are starting or restarting lamotrigine [see How Supplied/Storage and Handling (16)].

  It is recommended that lamotrigine tablets, USP not be restarted in patients who discontinued due to rash associated with prior treatment with lamotrigine, unless the potential benefits clearly outweigh the risks. If the decision is made to restart a patient who has discontinued lamotrigine, the need to restart with the initial dosing recommendations should be assessed. The greater the interval of time since the previous dose, the greater consideration should be given to restarting with the initial dosing recommendations. If a patient has discontinued lamotrigine for a period of more than 5 half-lives, it is recommended that initial dosing recommendations and guidelines be followed. The half-life of lamotrigine is affected by other concomitant medications [see Clinical Pharmacology (12.3)].

  Lamotrigine Added to Drugs Known to Induce or Inhibit Glucuronidation: Drugs other than those listed in the Clinical Pharmacology section [see Clinical Pharmacology (12.3)] have not been systematically evaluated in combination with lamotrigine. Because lamotrigine is metabolized predominantly by glucuronic acid conjugation, drugs that are known to induce or inhibit glucuronidation may affect the apparent clearance of lamotrigine and doses of lamotrigine may require adjustment based on clinical response.

  Target Plasma Levels for Patients With Epilepsy or Bipolar Disorder: A therapeutic plasma concentration range has not been established for lamotrigine. Dosing of lamotrigine should be based on therapeutic response [see Clinical Pharmacology (12.3)].

  Women Taking Estrogen-Containing Oral Contraceptives: Starting Lamotrigine in Women Taking Estrogen-Containing Oral Contraceptives: Although estrogen-containing oral contraceptives have been shown to increase the clearance of lamotrigine [see Clinical Pharmacology (12.3)], no adjustments to the recommended dose-escalation guidelines for lamotrigine should be necessary solely based on the use of estrogen-containing oral contraceptives. Therefore, dose escalation should follow the recommended guidelines for initiating adjunctive therapy with lamotrigine based on the concomitant AED or other concomitant medications (see Table 1 or Table 5). See below for adjustments to maintenance doses of lamotrigine in women taking estrogen-containing oral contraceptives.

  Adjustments to the Maintenance Dose of Lamotrigine In Women Taking Estrogen-Containing Oral Contraceptives:

  (1) Taking Estrogen-Containing Oral Contraceptives: For women not taking carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin that induce lamotrigine glucuronidation [see Drug Interactions (7), Clinical Pharmacology (12.3)], the maintenance dose of lamotrigine will in most cases need to be increased, by as much as 2-fold over the recommended target maintenance dose, in order to maintain a consistent lamotrigine plasma level [see Clinical Pharmacology (12.3)].

  (2) Starting Estrogen-Containing Oral Contraceptives: In women taking a stable dose of lamotrigine and not taking carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin that induce lamotrigine glucuronidation [see Drug Interactions (7), Clinical Pharmacology (12.3)], the maintenance dose will in most cases need to be increased by as much as 2-fold in order to maintain a consistent lamotrigine plasma level. The dose increases should begin at the same time that the oral contraceptive is introduced and continue, based on clinical response, no more rapidly than 50 to 100 mg/day every week. Dose increases should not exceed the recommended rate (see Table 1 or Table 5) unless lamotrigine plasma levels or clinical response support larger increases. Gradual transient increases in lamotrigine plasma levels may occur during the week of inactive hormonal preparation ("pill-free" week), and these increases will be greater if dose increases are made in the days before or during the week of inactive hormonal preparation. Increased lamotrigine plasma levels could result in additional adverse reactions, such as dizziness, ataxia, and diplopia. If adverse reactions attributable to lamotrigine consistently occur during the "pill-free" week, dose adjustments to the overall maintenance dose may be necessary. Dose adjustments limited to the "pill-free" week are not recommended. For women taking lamotrigine in addition to carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin that induce lamotrigine glucuronidation [see Drug Interactions (7), Clinical Pharmacology (12.3)], no adjustment to the dose of lamotrigine should be necessary.  

  (3) Stopping Estrogen-Containing Oral Contraceptives: For women not taking carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin that induce lamotrigine glucuronidation [see Drug Interactions (7), Clinical Pharmacology (12.3)], the maintenance dose of lamotrigine will in most cases need to be decreased by as much as 50% in order to maintain a consistent lamotrigine plasma level. The decrease in dose of lamotrigine should not exceed 25% of the total daily dose per week over a 2-week period, unless clinical response or lamotrigine plasma levels indicate otherwise [see Clinical Pharmacology (12.3)]. For women taking lamotrigine in addition to carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin that induce lamotrigine glucuronidation [see Drug Interactions (7), Clinical Pharmacology (12.3)], no adjustment to the dose of lamotrigine should be necessary.

  Women and Other Hormonal Contraceptive Preparations or Hormone Replacement Therapy: The effect of other hormonal contraceptive preparations or hormone replacement therapy on the pharmacokinetics of lamotrigine has not been systematically evaluated. It has been reported that ethinylestradiol, not progestogens, increased the clearance of lamotrigine up to 2-fold, and the progestin-only pills had no effect on lamotrigine plasma levels. Therefore, adjustments to the dosage of lamotrigine in the presence of progestogens alone will likely not be needed.

  Patients With Hepatic Impairment: Experience in patients with hepatic impairment is limited. Based on a clinical pharmacology study in 24 patients with mild, moderate, and severe liver impairment [see Use in Specific Populations (8.6), Clinical Pharmacology (12.3)], the following general recommendations can be made. No dosage adjustment is needed in patients with mild liver impairment. Initial, escalation, and maintenance doses should generally be reduced by approximately 25% in patients with moderate and severe liver impairment without ascites and 50% in patients with severe liver impairment with ascites. Escalation and maintenance doses may be adjusted according to clinical response.

  Patients With Renal Impairment: Initial doses of lamotrigine should be based on patients' concomitant medications (see Tables 1-3 or Table 5); reduced maintenance doses may be effective for patients with significant renal impairment [see Use in Specific Populations (8.7), Clinical Pharmacology (12.3)]. Few patients with severe renal impairment have been evaluated during chronic treatment with lamotrigine. Because there is inadequate experience in this population, lamotrigine should be used with caution in these patients.

  Discontinuation Strategy: Epilepsy: For patients receiving lamotrigine in combination with other AEDs, a reevaluation of all AEDs in the regimen should be considered if a change in seizure control or an appearance or worsening of adverse reactions is observed.

  If a decision is made to discontinue therapy with lamotrigine, a step-wise reduction of dose over at least 2 weeks (approximately 50% per week) is recommended unless safety concerns require a more rapid withdrawal [see Warnings and Precautions (5.10)].

  Discontinuing carbamazepine, phenytoin, phenobarbital, primidone or other drugs such as rifampin that induce lamotrigine glucuronidation should prolong the half-life of lamotrigine; discontinuing valproate should shorten the half-life of lamotrigine.

  Bipolar Disorder: In the controlled clinical trials, there was no increase in the incidence, type, or severity of adverse reactions following abrupt termination of lamotrigine. In clinical trials in patients with Bipolar Disorder, 2 patients experienced seizures shortly after abrupt withdrawal of lamotrigine. However, there were confounding factors that may have contributed to the occurrence of seizures in these bipolar patients. Discontinuation of lamotrigine should involve a step-wise reduction of dose over at least 2 weeks (approximately 50% per week) unless safety concerns require a more rapid withdrawal [see Warnings and Precautions (5.10)].

   

  This section provides specific dosing recommendations for patients greater than 12 years of age and patients 2 to 12 years of age. Within each of these age-groups, specific dosing recommendations are provided depending upon concomitant AED or other concomitant medications (Table 1 for patients greater than 12 years of age and Table 2 for patients 2 to 12 years of age). A weight-based dosing guide for patients 2 to 12 years of age on concomitant valproate is provided in Table 3.

  Patients Over 12 Years of Age: Recommended dosing guidelines are summarized in Table 1.

  Table 1. Escalation Regimen for Lamotrigine in Patients Over 12 Years of Age With Epilepsy
  For Patients TAKING
   Valproatea
  For Patients NOT 
  TAKING 
  Carbamazepine, 
  Phenytoin, 
  Phenobarbital,
   Primidoneb, or 
  Valproatea
  For Patients 
  TAKING 
  Carbamazepine, 
  Phenytoin, 
  Phenobarbital, or 
  Primidoneb and 
  NOT TAKING Valproatea
  Weeks 1 and 2
  25 mg every other day
  25 mg every day
  50 mg/day
  Weeks 3 and 4
  25 mg every day
  50 mg/day
  100 mg/day 
  (in 2 divided doses)
  Week 5
  onwards to
  maintenance
  Increase by 25 to 50
  mg/day every 1 to
  2 weeks
  Increase by 50
  mg/day every 1 to
  2 weeks
  Increase by 100
  mg/day every 1 to
  2 weeks.
  Usual
  Maintenance
  Dose
  100 to 200 mg/day
  with valproate 
  alone 
  100 to 400 mg/day 
  with valproate and 
  other drugs that 
  induce 
  glucuronidation 
  (in 1 or 2 divided 
  doses)
  225 to 375 mg/day 
  (in 2 divided doses)
  300 to 500 mg/day 
  (in 2 divided doses)
  

  a Valproate has been shown to inhibit glucuronidation and decrease the apparent clearance of lamotrigine [see Drug Interactions (7), Clinical Pharmacology (12.3)].

  b These drugs induce lamotrigine glucuronidation and increase clearance [see Drug Interactions (7), Clinical Pharmacology (12.3)]. Other drugs which have similar effects include estrogen-containing oral contraceptives [see Drug Interactions (7), Clinical Pharmacology (12.3)]. Dosing recommendations for oral contraceptives can be found in General Dosing Considerations [see Dosage and Administration (2.1)]. Patients on rifampin, or other drugs that induce lamotrigine glucuronidation and increase clearance, should follow the same dosing titration/maintenance regimen as that used with anticonvulsants that have this effect.

  Patients 2 to 12 Years of Age: Recommended dosing guidelines are summarized in Table 2.

  Smaller starting doses and slower dose escalations than those used in clinical trials are recommended because of the suggestion that the risk of rash may be decreased by smaller starting doses and slower dose escalations. Therefore, maintenance doses will take longer to reach in clinical practice than in clinical trials. It may take several weeks to months to achieve an individualized maintenance dose. Maintenance doses in patients weighing less than 30 kg, regardless of age or concomitant AED, may need to be increased as much as 50%, based on clinical response.

  The smallest available strength of lamotrigine tablets is 25 mg, and only whole tablets should be administered. If the calculated dose cannot be achieved using whole tablets, the dose should be rounded down to the nearest whole tablet [see How Supplied/Storage and Handling (16) and Medication Guide].

  Table 2. Escalation Regimen for Lamotrigine in Patients 2 to 12 Years of Age With Epilepsy
  For Patients 
  TAKING Valproatea
  For Patients NOT
   TAKING 
  Carbamazepine, 
  Phenytoin, 
  Phenobarbital, 
  Primidoneb, or 
  Valproatea
  For Patients TAKING
   Carbamazepine, 
  Phenytoin, 
  Phenobarbital, or 
  Primidoneb and NOT
  TAKING Valproatea
  Weeks 1 
  and 2 
  0.15 mg/kg/day 
  in 1 or 2 divided 
  doses, rounded 
  down to the nearest
  whole tablet (see 
  Table 3 for weight 
  based dosing guide)
  0.3 mg/kg/day 
  in 1 or 2 divided 
  doses, rounded down 
  to the nearest whole 
  tablet
  0.6 mg/kg/day 
  in 2 divided doses,
   rounded down to the
   nearest whole tablet
  Weeks 3 
  and 4 
  0.3 mg/kg/day 
  in 1 or 2 divided 
  doses, rounded 
  down to the nearest
  whole tablet (see
  Table 3 for weight
  based dosing guide)
  0.6 mg/kg/day 
  in 2 divided doses, 
  rounded down to the 
  nearest whole tablet
  1.2 mg/kg/day 
  in 2 divided doses,
   rounded down to the
   nearest whole tablet
  Week 5 
  onwards to 
  maintenance
  The dose should be 
  increased every 1 to 
  2 weeks as follows:
  calculate 0.3 mg/kg/day, 
  round this amount
  down to the nearest
  whole tablet, and
  add this amount to
  the previously 
  administered daily
  dose
  The dose should be increased every 1 to 
  2 weeks as follows: calculate 
  0.6 mg/kg/day, round 
  this amount down to 
  the nearest whole 
  tablet, and add this 
  amount to the 
  previously 
  administered daily
   dose
  The dose should be increased every 1 to 
  2 weeks as follows: calculate 
  1.2 mg/kg/day, round
   this amount down to
   the nearest whole
   tablet, and add this
   amount to the
   previously
   administered daily
   dose
  Usual 
  Maintenance 
  Dose 
  1 to 5 mg/kg/day
   (maximum 
  200 mg/day in 1 or 2
   divided doses). 
  1 to 3 mg/kg/day 
  with valproate alone
  4.5 to 7.5 mg/kg/day
   (maximum 300 
  mg/day in 2 divided
  doses)
  5 to 15 mg/kg/day
   (maximum 400 
  mg/day in 2 divided
   doses)
  Maintenance 
  dose in 
  patients less 
  than 30 kg 
  May need to be 
  increased by as 
  much as 50%, based 
  on clinical response
  May need to be
   increased by as much
   as 50%, based on 
  clinical response
  May need to be 
  increased by as much
   as 50%, based on 
  clinical response
  

  Note: Only whole tablets should be used for dosing.
  

  aValproate has been shown to inhibit glucuronidation and decrease the apparent clearance of lamotrigine [see Drug Interactions (7),
  Clinical Pharmacology (12.3)].
  

  bThese drugs induce lamotrigine glucuronidation and increase clearance [see Drug Interactions (7), Clinical Pharmacology (12.3)].
  Other drugs which have similar effects include estrogen-containing oral contraceptives [see Drug Interactions (7), Clinical Pharmacology (12.3)]. Dosing recommendations for oral contraceptives can be found in General Dosing Considerations [see 
  Dosage and Administration (2.1)]. Patients on rifampin, or other drugs that induce lamotrigine glucuronidation and increase clearance, should follow the same dosing titration/maintenance regimen as that used with anticonvulsants that have this effect.
  

  Table 3. The Initial Weight-Based Dosing Guide for Patients 2 to 12 Years Taking Valproate (Weeks 1 to 4) With Epilepsy If the patient’s weight is
  Give this daily dose, using the most appropriate combination of lamotrigine
  2-mg and 5-mg tablets 
  Greater than 
  And less than 
  Weeks 1 and 2
  Weeks 3 and 4
  6.7 kg 
  14 kg 
  2 mg every other day
  2 mg every day
  14.1 kg 
  27 kg 
  2 mg every day
  4 mg every day
  27.1 kg 
  34 kg 
  4 mg every day
  8 mg every day
  34.1 kg 
  40 kg 
  5 mg every day
  10 mg every day
  

  Usual Adjunctive Maintenance Dose for Epilepsy: The usual maintenance doses identified in Tables 1 and 2 are derived from dosing regimens employed in the placebo-controlled adjunctive studies in which the efficacy of lamotrigine was established. In patients receiving multidrug regimens employing carbamazepine, phenytoin, phenobarbital, or primidone without valproate, maintenance doses of adjunctive lamotrigine as high as 700 mg/day have been used. In patients receiving valproate alone, maintenance doses of adjunctive lamotrigine as high as 200 mg/day have been used. The advantage of using doses above those recommended in Tables 1 through 4 has not been established in controlled trials.

   

  The goal of the transition regimen is to effect the conversion to monotherapy with lamotrigine under conditions that ensure adequate seizure control while mitigating the risk of serious rash associated with the rapid titration of lamotrigine.

  The recommended maintenance dose of lamotrigine as monotherapy is 500 mg/day given in 2 divided doses.

  To avoid an increased risk of rash, the recommended initial dose and subsequent dose escalations of lamotrigine should not be exceeded [see Boxed Warning].

  Conversion From Adjunctive Therapy With Carbamazepine, Phenytoin, Phenobarbital, or Primidone to Monotherapy With Lamotrigine: After achieving a dose of 500 mg/day of lamotrigine according to the guidelines in Table 1, the concomitant AED should be withdrawn by 20% decrements each week over a 4-week period. The regimen for the withdrawal of the concomitant AED is based on experience gained in the controlled monotherapy clinical trial.

  Conversion From Adjunctive Therapy With Valproate to Monotherapy With Lamotrigine: The conversion regimen involves 4 steps outlined in Table 4.

  Table 4. Conversion From Adjunctive Therapy With Valproate to Monotherapy With Lamotrigine in Patients ≥16 Years of Age With Epilepsy
  Lamotrigine
  Valproate
  Step 1 
  Achieve a dose of 200 mg/day according to 
  guidelines in Table 1 (if not already on 
  200 mg/day).
  Maintain previous stable dose.
  Step 2 
  Maintain at 200 mg/day.
  Decrease to 500 mg/day by 
  decrements no greater than 
  500 mg/day/week and then 
  maintain the dose of 
  500 mg/day for 1 week.
  Step 3 
  Increase to 300 mg/day and maintain for 1 
  week.
  Simultaneously decrease to 
  250 mg/day and maintain for 1 week.
  Step 4 
  Increase by 100 mg/day every week to achieve 
  maintenance dose of 500 mg/day.
  Discontinue.
  

  Conversion From Adjunctive Therapy With AEDs Other Than Carbamazepine, Phenytoin, Phenobarbital, Primidone, or Valproate to Monotherapy With Lamotrigine: No specific dosing guidelines can be provided for conversion to monotherapy with lamotrigine with AEDs other than carbamazepine, phenobarbital, phenytoin, primidone, or valproate.

   

  The goal of maintenance treatment with lamotrigine is to delay the time to occurrence of mood episodes (depression, mania, hypomania, mixed episodes) in patients treated for acute mood episodes with standard therapy. The target dose of lamotrigine is 200 mg/day (100 mg/day in patients taking valproate, which decreases the apparent clearance of lamotrigine, and 400 mg/day in patients not taking valproate and taking either carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin that increase the apparent clearance of lamotrigine). In the clinical trials, doses up to 400 mg/day as monotherapy were evaluated; however, no additional benefit was seen at 400 mg/day compared with 200 mg/day [see Clinical Studies (14.2)]. Accordingly, doses above 200 mg/day are not recommended. Treatment with lamotrigine is introduced, based on concurrent medications, according to the regimen outlined in Table 5. If other psychotropic medications are withdrawn following stabilization, the dose of lamotrigine should be adjusted. For patients discontinuing valproate, the dose of lamotrigine should be doubled over a 2-week period in equal weekly increments (see Table 6). For patients discontinuing carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin that induce lamotrigine glucuronidation, the dose of lamotrigine should remain constant for the first week and then should be decreased by half over a 2-week period in equal weekly decrements (see Table 6). The dose of lamotrigine may then be further adjusted to the target dose (200 mg) as clinically indicated.

  If other drugs are subsequently introduced, the dose of lamotrigine may need to be adjusted. In particular, the introduction of valproate requires reduction in the dose of lamotrigine [see Drug Interactions (7), Clinical Pharmacology (12.3)].

  To avoid an increased risk of rash, the recommended initial dose and subsequent dose escalations of lamotrigine should not be exceeded [see Boxed Warning].

  Table 5. Escalation Regimen for Lamotrigine for Patients With Bipolar Disorder
  For Patients TAKING Valproatea
  For Patients NOT TAKING
  Carbamazepine, Phenytoin, 
  Phenobarbital, Primidoneb, or
   Valproatea
  For Patients TAKING
   Carbamazepine, Phenytoin, Phenobarbital,
  or Primidoneb and 
  NOT TAKING Valproatea
  Weeks 1 and 2 
  25 mg every other day
  25 mg daily
  50 mg daily
  Weeks 3 and 4 
  25 mg daily
  50 mg daily
  100 mg daily, in divided doses
  Week 5 
  50 mg daily
  100 mg daily
  200 mg daily, in divided doses
  Week 6 
  100 mg daily
  200 mg daily
  300 mg daily, in divided doses
  Week 7 
  100 mg daily
  200 mg daily
  up to 400 mg daily, in
  divided doses
  

  a Valproate has been shown to inhibit glucuronidation and decrease the apparent clearance of lamotrigine [see Drug Interactions (7), Clinical Pharmacology (12.3)].

  b These drugs induce lamotrigine glucuronidation and increase clearance [see Drug Interactions (7), Clinical Pharmacology (12.3)]. Other drugs which have similar effects include estrogen-containing oral contraceptives [see Drug Interactions (7), Clinical Pharmacology (12.3)]. Dosing recommendations for oral contraceptives can be found in General Dosing Considerations [see Dosage and Administration (2.1)]. Patients on rifampin, or other drugs that induce lamotrigine glucuronidation and increase clearance, should follow the same dosing titration/maintenance regimen as that used with anticonvulsants that have this effect.

  Table 6. Dosage Adjustments to Lamotrigine for Patients With Bipolar Disorder Following Discontinuation of Psychotropic Medications
  Discontinuation of Psychotropic Drugs 
  (excluding Carbamazepine, Phenytoin, 
  After Discontinuation of Valproatea
  After Discontinuation of Carbamazepine, 
  Phenytoin, Phenobarbital,or
   Primidoneb
  
  Phenobarbital, Primidoneb, or Valproatea)
  Current dose of Lamotrigine (mg/day) 
  100
  Current dose of Lamotrigine (mg/day) 
  400
  Week 1 
  Maintain current dose of Lamotrigine
  150
  400
  Week 2 
  Maintain current dose of Lamotrigine
  200
  300
  Week 3 onward 
  Maintain current dose of Lamotrigine
  200
  200
  

  a Valproate has been shown to inhibit glucuronidation and decrease the apparent clearance of lamotrigine [see Drug Interactions (7), Clinical Pharmacology (12.3)].

  b These drugs induce lamotrigine glucuronidation and increase clearance [see Drug Interactions (7), Clinical Pharmacology (12.3)]. Other drugs which have similar effects include estrogen-containing oral contraceptives [see Drug Interactions (7), Clinical Pharmacology (12.3)]. Dosing recommendations for oral contraceptives can be found in General Dosing Considerations [see Dosage and Administration (2.1)]. Patients on rifampin, or other drugs that induce lamotrigine glucuronidation and increase clearance, should follow the same dosing titration/maintenance regimen as that used with anticonvulsants that have this effect.

  The benefit of continuing treatment in patients who had been stabilized in an 8- to 16-week open-label phase with lamotrigine was established in 2 randomized, placebo-controlled clinical maintenance trials [see Clinical Studies (14.2)]. However, the optimal duration of treatment with lamotrigine has not been established. Thus, patients should be periodically reassessed to determine the need for maintenance treatment.

   

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  Dosing is based on concomitant medications, indication, and patient age. (2.2, 2.4) To avoid an increased risk of rash, the recommended initial dose and subsequent dose escalations should not be exceeded. Lamotrigine Starter Kits are available for the first 5 weeks of treatment. (2.1, 16) Do not restart lamotrigine tablets, USP in patients who discontinued due to rash unless the potential benefits clearly outweigh the risks. (2.1) Adjustments to maintenance doses will in most cases be required in patients starting or stopping estrogen-containing oral contraceptives. (2.1, 5.9) Lamotrigine tablets, USP should be discontinued over a period of at least 2 weeks (approximately 50% reduction per week). (2.1, 5.10)

  Epilepsy

  Adjunctive therapy—See Table 1 for patients >12 years of age and Tables 2 and 3 for patients 2 to 12 years. (2.2) Conversion to monotherapy—See Table 4. (2.3)

  Bipolar Disorder: See Tables 5 and 6. (2.4)

   

  Rash: There are suggestions, yet to be proven, that the risk of severe, potentially life-threatening rash may be increased by (1) coadministration of lamotrigine with valproate, (2) exceeding the recommended initial dose of lamotrigine, or (3) exceeding the recommended dose escalation for lamotrigine. However, cases have occurred in the absence of these factors [see Boxed Warning]. Therefore, it is important that the dosing recommendations be followed closely.

  The risk of nonserious rash may be increased when the recommended initial dose and/or the rate of dose escalation of lamotrigine is exceeded and in patients with a history of allergy or rash to other AEDs.

  Lamotrigine Starter Kits provide lamotrigine at doses consistent with the recommended titration schedule for the first 5 weeks of treatment, based upon concomitant medications for patients with epilepsy (>12 years of age) and Bipolar I Disorder (≥18 years of age) and are intended to help reduce the potential for rash. The use of lamotrigine Starter Kits is recommended for appropriate patients who are starting or restarting lamotrigine [see How Supplied/Storage and Handling (16)].

  It is recommended that lamotrigine tablets, USP not be restarted in patients who discontinued due to rash associated with prior treatment with lamotrigine, unless the potential benefits clearly outweigh the risks. If the decision is made to restart a patient who has discontinued lamotrigine, the need to restart with the initial dosing recommendations should be assessed. The greater the interval of time since the previous dose, the greater consideration should be given to restarting with the initial dosing recommendations. If a patient has discontinued lamotrigine for a period of more than 5 half-lives, it is recommended that initial dosing recommendations and guidelines be followed. The half-life of lamotrigine is affected by other concomitant medications [see Clinical Pharmacology (12.3)].

  Lamotrigine Added to Drugs Known to Induce or Inhibit Glucuronidation: Drugs other than those listed in the Clinical Pharmacology section [see Clinical Pharmacology (12.3)] have not been systematically evaluated in combination with lamotrigine. Because lamotrigine is metabolized predominantly by glucuronic acid conjugation, drugs that are known to induce or inhibit glucuronidation may affect the apparent clearance of lamotrigine and doses of lamotrigine may require adjustment based on clinical response.

  Target Plasma Levels for Patients With Epilepsy or Bipolar Disorder: A therapeutic plasma concentration range has not been established for lamotrigine. Dosing of lamotrigine should be based on therapeutic response [see Clinical Pharmacology (12.3)].

  Women Taking Estrogen-Containing Oral Contraceptives: Starting Lamotrigine in Women Taking Estrogen-Containing Oral Contraceptives: Although estrogen-containing oral contraceptives have been shown to increase the clearance of lamotrigine [see Clinical Pharmacology (12.3)], no adjustments to the recommended dose-escalation guidelines for lamotrigine should be necessary solely based on the use of estrogen-containing oral contraceptives. Therefore, dose escalation should follow the recommended guidelines for initiating adjunctive therapy with lamotrigine based on the concomitant AED or other concomitant medications (see Table 1 or Table 5). See below for adjustments to maintenance doses of lamotrigine in women taking estrogen-containing oral contraceptives.

  Adjustments to the Maintenance Dose of Lamotrigine In Women Taking Estrogen-Containing Oral Contraceptives:

  (1) Taking Estrogen-Containing Oral Contraceptives: For women not taking carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin that induce lamotrigine glucuronidation [see Drug Interactions (7), Clinical Pharmacology (12.3)], the maintenance dose of lamotrigine will in most cases need to be increased, by as much as 2-fold over the recommended target maintenance dose, in order to maintain a consistent lamotrigine plasma level [see Clinical Pharmacology (12.3)].

  (2) Starting Estrogen-Containing Oral Contraceptives: In women taking a stable dose of lamotrigine and not taking carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin that induce lamotrigine glucuronidation [see Drug Interactions (7), Clinical Pharmacology (12.3)], the maintenance dose will in most cases need to be increased by as much as 2-fold in order to maintain a consistent lamotrigine plasma level. The dose increases should begin at the same time that the oral contraceptive is introduced and continue, based on clinical response, no more rapidly than 50 to 100 mg/day every week. Dose increases should not exceed the recommended rate (see Table 1 or Table 5) unless lamotrigine plasma levels or clinical response support larger increases. Gradual transient increases in lamotrigine plasma levels may occur during the week of inactive hormonal preparation ("pill-free" week), and these increases will be greater if dose increases are made in the days before or during the week of inactive hormonal preparation. Increased lamotrigine plasma levels could result in additional adverse reactions, such as dizziness, ataxia, and diplopia. If adverse reactions attributable to lamotrigine consistently occur during the "pill-free" week, dose adjustments to the overall maintenance dose may be necessary. Dose adjustments limited to the "pill-free" week are not recommended. For women taking lamotrigine in addition to carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin that induce lamotrigine glucuronidation [see Drug Interactions (7), Clinical Pharmacology (12.3)], no adjustment to the dose of lamotrigine should be necessary.  

  (3) Stopping Estrogen-Containing Oral Contraceptives: For women not taking carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin that induce lamotrigine glucuronidation [see Drug Interactions (7), Clinical Pharmacology (12.3)], the maintenance dose of lamotrigine will in most cases need to be decreased by as much as 50% in order to maintain a consistent lamotrigine plasma level. The decrease in dose of lamotrigine should not exceed 25% of the total daily dose per week over a 2-week period, unless clinical response or lamotrigine plasma levels indicate otherwise [see Clinical Pharmacology (12.3)]. For women taking lamotrigine in addition to carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin that induce lamotrigine glucuronidation [see Drug Interactions (7), Clinical Pharmacology (12.3)], no adjustment to the dose of lamotrigine should be necessary.

  Women and Other Hormonal Contraceptive Preparations or Hormone Replacement Therapy: The effect of other hormonal contraceptive preparations or hormone replacement therapy on the pharmacokinetics of lamotrigine has not been systematically evaluated. It has been reported that ethinylestradiol, not progestogens, increased the clearance of lamotrigine up to 2-fold, and the progestin-only pills had no effect on lamotrigine plasma levels. Therefore, adjustments to the dosage of lamotrigine in the presence of progestogens alone will likely not be needed.

  Patients With Hepatic Impairment: Experience in patients with hepatic impairment is limited. Based on a clinical pharmacology study in 24 patients with mild, moderate, and severe liver impairment [see Use in Specific Populations (8.6), Clinical Pharmacology (12.3)], the following general recommendations can be made. No dosage adjustment is needed in patients with mild liver impairment. Initial, escalation, and maintenance doses should generally be reduced by approximately 25% in patients with moderate and severe liver impairment without ascites and 50% in patients with severe liver impairment with ascites. Escalation and maintenance doses may be adjusted according to clinical response.

  Patients With Renal Impairment: Initial doses of lamotrigine should be based on patients' concomitant medications (see Tables 1-3 or Table 5); reduced maintenance doses may be effective for patients with significant renal impairment [see Use in Specific Populations (8.7), Clinical Pharmacology (12.3)]. Few patients with severe renal impairment have been evaluated during chronic treatment with lamotrigine. Because there is inadequate experience in this population, lamotrigine should be used with caution in these patients.

  Discontinuation Strategy: Epilepsy: For patients receiving lamotrigine in combination with other AEDs, a reevaluation of all AEDs in the regimen should be considered if a change in seizure control or an appearance or worsening of adverse reactions is observed.

  If a decision is made to discontinue therapy with lamotrigine, a step-wise reduction of dose over at least 2 weeks (approximately 50% per week) is recommended unless safety concerns require a more rapid withdrawal [see Warnings and Precautions (5.10)].

  Discontinuing carbamazepine, phenytoin, phenobarbital, primidone or other drugs such as rifampin that induce lamotrigine glucuronidation should prolong the half-life of lamotrigine; discontinuing valproate should shorten the half-life of lamotrigine.

  Bipolar Disorder: In the controlled clinical trials, there was no increase in the incidence, type, or severity of adverse reactions following abrupt termination of lamotrigine. In clinical trials in patients with Bipolar Disorder, 2 patients experienced seizures shortly after abrupt withdrawal of lamotrigine. However, there were confounding factors that may have contributed to the occurrence of seizures in these bipolar patients. Discontinuation of lamotrigine should involve a step-wise reduction of dose over at least 2 weeks (approximately 50% per week) unless safety concerns require a more rapid withdrawal [see Warnings and Precautions (5.10)].

   

  This section provides specific dosing recommendations for patients greater than 12 years of age and patients 2 to 12 years of age. Within each of these age-groups, specific dosing recommendations are provided depending upon concomitant AED or other concomitant medications (Table 1 for patients greater than 12 years of age and Table 2 for patients 2 to 12 years of age). A weight-based dosing guide for patients 2 to 12 years of age on concomitant valproate is provided in Table 3.

  Patients Over 12 Years of Age: Recommended dosing guidelines are summarized in Table 1.

  Table 1. Escalation Regimen for Lamotrigine in Patients Over 12 Years of Age With Epilepsy
  For Patients TAKING
   Valproatea
  For Patients NOT 
  TAKING 
  Carbamazepine, 
  Phenytoin, 
  Phenobarbital,
   Primidoneb, or 
  Valproatea
  For Patients 
  TAKING 
  Carbamazepine, 
  Phenytoin, 
  Phenobarbital, or 
  Primidoneb and 
  NOT TAKING Valproatea
  Weeks 1 and 2
  25 mg every other day
  25 mg every day
  50 mg/day
  Weeks 3 and 4
  25 mg every day
  50 mg/day
  100 mg/day 
  (in 2 divided doses)
  Week 5
  onwards to
  maintenance
  Increase by 25 to 50
  mg/day every 1 to
  2 weeks
  Increase by 50
  mg/day every 1 to
  2 weeks
  Increase by 100
  mg/day every 1 to
  2 weeks.
  Usual
  Maintenance
  Dose
  100 to 200 mg/day
  with valproate 
  alone 
  100 to 400 mg/day 
  with valproate and 
  other drugs that 
  induce 
  glucuronidation 
  (in 1 or 2 divided 
  doses)
  225 to 375 mg/day 
  (in 2 divided doses)
  300 to 500 mg/day 
  (in 2 divided doses)
  

  a Valproate has been shown to inhibit glucuronidation and decrease the apparent clearance of lamotrigine [see Drug Interactions (7), Clinical Pharmacology (12.3)].

  b These drugs induce lamotrigine glucuronidation and increase clearance [see Drug Interactions (7), Clinical Pharmacology (12.3)]. Other drugs which have similar effects include estrogen-containing oral contraceptives [see Drug Interactions (7), Clinical Pharmacology (12.3)]. Dosing recommendations for oral contraceptives can be found in General Dosing Considerations [see Dosage and Administration (2.1)]. Patients on rifampin, or other drugs that induce lamotrigine glucuronidation and increase clearance, should follow the same dosing titration/maintenance regimen as that used with anticonvulsants that have this effect.

  Patients 2 to 12 Years of Age: Recommended dosing guidelines are summarized in Table 2.

  Smaller starting doses and slower dose escalations than those used in clinical trials are recommended because of the suggestion that the risk of rash may be decreased by smaller starting doses and slower dose escalations. Therefore, maintenance doses will take longer to reach in clinical practice than in clinical trials. It may take several weeks to months to achieve an individualized maintenance dose. Maintenance doses in patients weighing less than 30 kg, regardless of age or concomitant AED, may need to be increased as much as 50%, based on clinical response.

  The smallest available strength of lamotrigine tablets is 25 mg, and only whole tablets should be administered. If the calculated dose cannot be achieved using whole tablets, the dose should be rounded down to the nearest whole tablet [see How Supplied/Storage and Handling (16) and Medication Guide].

  Table 2. Escalation Regimen for Lamotrigine in Patients 2 to 12 Years of Age With Epilepsy
  For Patients 
  TAKING Valproatea
  For Patients NOT
   TAKING 
  Carbamazepine, 
  Phenytoin, 
  Phenobarbital, 
  Primidoneb, or 
  Valproatea
  For Patients TAKING
   Carbamazepine, 
  Phenytoin, 
  Phenobarbital, or 
  Primidoneb and NOT
  TAKING Valproatea
  Weeks 1 
  and 2 
  0.15 mg/kg/day 
  in 1 or 2 divided 
  doses, rounded 
  down to the nearest
  whole tablet (see 
  Table 3 for weight 
  based dosing guide)
  0.3 mg/kg/day 
  in 1 or 2 divided 
  doses, rounded down 
  to the nearest whole 
  tablet
  0.6 mg/kg/day 
  in 2 divided doses,
   rounded down to the
   nearest whole tablet
  Weeks 3 
  and 4 
  0.3 mg/kg/day 
  in 1 or 2 divided 
  doses, rounded 
  down to the nearest
  whole tablet (see
  Table 3 for weight
  based dosing guide)
  0.6 mg/kg/day 
  in 2 divided doses, 
  rounded down to the 
  nearest whole tablet
  1.2 mg/kg/day 
  in 2 divided doses,
   rounded down to the
   nearest whole tablet
  Week 5 
  onwards to 
  maintenance
  The dose should be 
  increased every 1 to 
  2 weeks as follows:
  calculate 0.3 mg/kg/day, 
  round this amount
  down to the nearest
  whole tablet, and
  add this amount to
  the previously 
  administered daily
  dose
  The dose should be increased every 1 to 
  2 weeks as follows: calculate 
  0.6 mg/kg/day, round 
  this amount down to 
  the nearest whole 
  tablet, and add this 
  amount to the 
  previously 
  administered daily
   dose
  The dose should be increased every 1 to 
  2 weeks as follows: calculate 
  1.2 mg/kg/day, round
   this amount down to
   the nearest whole
   tablet, and add this
   amount to the
   previously
   administered daily
   dose
  Usual 
  Maintenance 
  Dose 
  1 to 5 mg/kg/day
   (maximum 
  200 mg/day in 1 or 2
   divided doses). 
  1 to 3 mg/kg/day 
  with valproate alone
  4.5 to 7.5 mg/kg/day
   (maximum 300 
  mg/day in 2 divided
  doses)
  5 to 15 mg/kg/day
   (maximum 400 
  mg/day in 2 divided
   doses)
  Maintenance 
  dose in 
  patients less 
  than 30 kg 
  May need to be 
  increased by as 
  much as 50%, based 
  on clinical response
  May need to be
   increased by as much
   as 50%, based on 
  clinical response
  May need to be 
  increased by as much
   as 50%, based on 
  clinical response
  

  Note: Only whole tablets should be used for dosing.
  

  aValproate has been shown to inhibit glucuronidation and decrease the apparent clearance of lamotrigine [see Drug Interactions (7),
  Clinical Pharmacology (12.3)].
  

  bThese drugs induce lamotrigine glucuronidation and increase clearance [see Drug Interactions (7), Clinical Pharmacology (12.3)].
  Other drugs which have similar effects include estrogen-containing oral contraceptives [see Drug Interactions (7), Clinical Pharmacology (12.3)]. Dosing recommendations for oral contraceptives can be found in General Dosing Considerations [see 
  Dosage and Administration (2.1)]. Patients on rifampin, or other drugs that induce lamotrigine glucuronidation and increase clearance, should follow the same dosing titration/maintenance regimen as that used with anticonvulsants that have this effect.
  

  Table 3. The Initial Weight-Based Dosing Guide for Patients 2 to 12 Years Taking Valproate (Weeks 1 to 4) With Epilepsy If the patient’s weight is
  Give this daily dose, using the most appropriate combination of lamotrigine
  2-mg and 5-mg tablets 
  Greater than 
  And less than 
  Weeks 1 and 2
  Weeks 3 and 4
  6.7 kg 
  14 kg 
  2 mg every other day
  2 mg every day
  14.1 kg 
  27 kg 
  2 mg every day
  4 mg every day
  27.1 kg 
  34 kg 
  4 mg every day
  8 mg every day
  34.1 kg 
  40 kg 
  5 mg every day
  10 mg every day
  

  Usual Adjunctive Maintenance Dose for Epilepsy: The usual maintenance doses identified in Tables 1 and 2 are derived from dosing regimens employed in the placebo-controlled adjunctive studies in which the efficacy of lamotrigine was established. In patients receiving multidrug regimens employing carbamazepine, phenytoin, phenobarbital, or primidone without valproate, maintenance doses of adjunctive lamotrigine as high as 700 mg/day have been used. In patients receiving valproate alone, maintenance doses of adjunctive lamotrigine as high as 200 mg/day have been used. The advantage of using doses above those recommended in Tables 1 through 4 has not been established in controlled trials.

   

  The goal of the transition regimen is to effect the conversion to monotherapy with lamotrigine under conditions that ensure adequate seizure control while mitigating the risk of serious rash associated with the rapid titration of lamotrigine.

  The recommended maintenance dose of lamotrigine as monotherapy is 500 mg/day given in 2 divided doses.

  To avoid an increased risk of rash, the recommended initial dose and subsequent dose escalations of lamotrigine should not be exceeded [see Boxed Warning].

  Conversion From Adjunctive Therapy With Carbamazepine, Phenytoin, Phenobarbital, or Primidone to Monotherapy With Lamotrigine: After achieving a dose of 500 mg/day of lamotrigine according to the guidelines in Table 1, the concomitant AED should be withdrawn by 20% decrements each week over a 4-week period. The regimen for the withdrawal of the concomitant AED is based on experience gained in the controlled monotherapy clinical trial.

  Conversion From Adjunctive Therapy With Valproate to Monotherapy With Lamotrigine: The conversion regimen involves 4 steps outlined in Table 4.

  Table 4. Conversion From Adjunctive Therapy With Valproate to Monotherapy With Lamotrigine in Patients ≥16 Years of Age With Epilepsy
  Lamotrigine
  Valproate
  Step 1 
  Achieve a dose of 200 mg/day according to 
  guidelines in Table 1 (if not already on 
  200 mg/day).
  Maintain previous stable dose.
  Step 2 
  Maintain at 200 mg/day.
  Decrease to 500 mg/day by 
  decrements no greater than 
  500 mg/day/week and then 
  maintain the dose of 
  500 mg/day for 1 week.
  Step 3 
  Increase to 300 mg/day and maintain for 1 
  week.
  Simultaneously decrease to 
  250 mg/day and maintain for 1 week.
  Step 4 
  Increase by 100 mg/day every week to achieve 
  maintenance dose of 500 mg/day.
  Discontinue.
  

  Conversion From Adjunctive Therapy With AEDs Other Than Carbamazepine, Phenytoin, Phenobarbital, Primidone, or Valproate to Monotherapy With Lamotrigine: No specific dosing guidelines can be provided for conversion to monotherapy with lamotrigine with AEDs other than carbamazepine, phenobarbital, phenytoin, primidone, or valproate.

   

  The goal of maintenance treatment with lamotrigine is to delay the time to occurrence of mood episodes (depression, mania, hypomania, mixed episodes) in patients treated for acute mood episodes with standard therapy. The target dose of lamotrigine is 200 mg/day (100 mg/day in patients taking valproate, which decreases the apparent clearance of lamotrigine, and 400 mg/day in patients not taking valproate and taking either carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin that increase the apparent clearance of lamotrigine). In the clinical trials, doses up to 400 mg/day as monotherapy were evaluated; however, no additional benefit was seen at 400 mg/day compared with 200 mg/day [see Clinical Studies (14.2)]. Accordingly, doses above 200 mg/day are not recommended. Treatment with lamotrigine is introduced, based on concurrent medications, according to the regimen outlined in Table 5. If other psychotropic medications are withdrawn following stabilization, the dose of lamotrigine should be adjusted. For patients discontinuing valproate, the dose of lamotrigine should be doubled over a 2-week period in equal weekly increments (see Table 6). For patients discontinuing carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin that induce lamotrigine glucuronidation, the dose of lamotrigine should remain constant for the first week and then should be decreased by half over a 2-week period in equal weekly decrements (see Table 6). The dose of lamotrigine may then be further adjusted to the target dose (200 mg) as clinically indicated.

  If other drugs are subsequently introduced, the dose of lamotrigine may need to be adjusted. In particular, the introduction of valproate requires reduction in the dose of lamotrigine [see Drug Interactions (7), Clinical Pharmacology (12.3)].

  To avoid an increased risk of rash, the recommended initial dose and subsequent dose escalations of lamotrigine should not be exceeded [see Boxed Warning].

  Table 5. Escalation Regimen for Lamotrigine for Patients With Bipolar Disorder
  For Patients TAKING Valproatea
  For Patients NOT TAKING
  Carbamazepine, Phenytoin, 
  Phenobarbital, Primidoneb, or
   Valproatea
  For Patients TAKING
   Carbamazepine, Phenytoin, Phenobarbital,
  or Primidoneb and 
  NOT TAKING Valproatea
  Weeks 1 and 2 
  25 mg every other day
  25 mg daily
  50 mg daily
  Weeks 3 and 4 
  25 mg daily
  50 mg daily
  100 mg daily, in divided doses
  Week 5 
  50 mg daily
  100 mg daily
  200 mg daily, in divided doses
  Week 6 
  100 mg daily
  200 mg daily
  300 mg daily, in divided doses
  Week 7 
  100 mg daily
  200 mg daily
  up to 400 mg daily, in
  divided doses
  

  a Valproate has been shown to inhibit glucuronidation and decrease the apparent clearance of lamotrigine [see Drug Interactions (7), Clinical Pharmacology (12.3)].

  b These drugs induce lamotrigine glucuronidation and increase clearance [see Drug Interactions (7), Clinical Pharmacology (12.3)]. Other drugs which have similar effects include estrogen-containing oral contraceptives [see Drug Interactions (7), Clinical Pharmacology (12.3)]. Dosing recommendations for oral contraceptives can be found in General Dosing Considerations [see Dosage and Administration (2.1)]. Patients on rifampin, or other drugs that induce lamotrigine glucuronidation and increase clearance, should follow the same dosing titration/maintenance regimen as that used with anticonvulsants that have this effect.

  Table 6. Dosage Adjustments to Lamotrigine for Patients With Bipolar Disorder Following Discontinuation of Psychotropic Medications
  Discontinuation of Psychotropic Drugs 
  (excluding Carbamazepine, Phenytoin, 
  After Discontinuation of Valproatea
  After Discontinuation of Carbamazepine, 
  Phenytoin, Phenobarbital,or
   Primidoneb
  
  Phenobarbital, Primidoneb, or Valproatea)
  Current dose of Lamotrigine (mg/day) 
  100
  Current dose of Lamotrigine (mg/day) 
  400
  Week 1 
  Maintain current dose of Lamotrigine
  150
  400
  Week 2 
  Maintain current dose of Lamotrigine
  200
  300
  Week 3 onward 
  Maintain current dose of Lamotrigine
  200
  200
  

  a Valproate has been shown to inhibit glucuronidation and decrease the apparent clearance of lamotrigine [see Drug Interactions (7), Clinical Pharmacology (12.3)].

  b These drugs induce lamotrigine glucuronidation and increase clearance [see Drug Interactions (7), Clinical Pharmacology (12.3)]. Other drugs which have similar effects include estrogen-containing oral contraceptives [see Drug Interactions (7), Clinical Pharmacology (12.3)]. Dosing recommendations for oral contraceptives can be found in General Dosing Considerations [see Dosage and Administration (2.1)]. Patients on rifampin, or other drugs that induce lamotrigine glucuronidation and increase clearance, should follow the same dosing titration/maintenance regimen as that used with anticonvulsants that have this effect.

  The benefit of continuing treatment in patients who had been stabilized in an 8- to 16-week open-label phase with lamotrigine was established in 2 randomized, placebo-controlled clinical maintenance trials [see Clinical Studies (14.2)]. However, the optimal duration of treatment with lamotrigine has not been established. Thus, patients should be periodically reassessed to determine the need for maintenance treatment.

   

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  Dosing is based on concomitant medications, indication, and patient age. (2.2, 2.4) To avoid an increased risk of rash, the recommended initial dose and subsequent dose escalations should not be exceeded. (2.1, 16) Do not restart Lamotrigine in patients who discontinued due to rash unless the potential benefits clearly outweigh the risks. (2.1) Adjustments to maintenance doses will in most cases be required in patients starting or stopping estrogen-containing oral contraceptives. (2.1, 5.8) Lamotrigine should be discontinued over a period of at least 2 weeks (approximately 50% reduction per week). (2.1, 5.9)

  Epilepsy

  Adjunctive therapy—See Table 1 for patients >12 years of age and Tables 2 and 3 for patients 2 to 12 years. (2.2) Conversion to monotherapy—See Table 4. (2.3)

  Bipolar Disorder: See Tables 5 and 6 (2.4)

   

  Rash: There are suggestions, yet to be proven, that the risk of severe, potentially life-threatening rash may be increased by (1) coadministration of Lamotrigine with valproate, (2) exceeding the recommended initial dose of Lamotrigine, or (3) exceeding the recommended dose escalation for Lamotrigine. However, cases have occurred in the absence of these factors [see Boxed Warning]. Therefore, it is important that the dosing recommendations be followed closely.

  The risk of nonserious rash may be increased when the recommended initial dose and/or the rate of dose escalation of Lamotrigine is exceeded and in patients with a history of allergy or rash to other AEDs.

  It is recommended that Lamotrigine not be restarted in patients who discontinued due to rash associated with prior treatment with Lamotrigine, unless the potential benefits clearly outweigh the risks. If the decision is made to restart a patient who has discontinued Lamotrigine, the need to restart with the initial dosing recommendations should be assessed. The greater the interval of time since the previous dose, the greater consideration should be given to restarting with the initial dosing recommendations. If a patient has discontinued Lamotrigine for a period of more than 5 half-lives, it is recommended that initial dosing recommendations and guidelines be followed. The half-life of Lamotrigine is affected by other concomitant medications [see Clinical Pharmacology (12.3)].

  Lamotrigine Added to Drugs Known to Induce or Inhibit Glucuronidation: Drugs other than those listed in the Clinical Pharmacology section [see Clinical Pharmacology (12.3)] have not been systematically evaluated in combination with Lamotrigine. Because Lamotrigine is metabolized predominantly by glucuronic acid conjugation, drugs that are known to induce or inhibit glucuronidation may affect the apparent clearance of Lamotrigine and doses of Lamotrigine may require adjustment based on clinical response.

  Target Plasma Levels for Patients With Epilepsy or Bipolar Disorder: A therapeutic plasma concentration range has not been established for Lamotrigine. Dosing of Lamotrigine should be based on therapeutic response [see Clinical Pharmacology (12.3)].

  Women Taking Estrogen-Containing Oral Contraceptives:  Starting Lamotrigine in Women Taking Estrogen-Containing Oral Contraceptives: Although estrogen-containing oral contraceptives have been shown to increase the clearance of Lamotrigine [see Clinical Pharmacology (12.3)], no adjustments to the recommended dose-escalation guidelines for Lamotrigine should be necessary solely based on the use of estrogen-containing oral contraceptives. Therefore, dose escalation should follow the recommended guidelines for initiating adjunctive therapy with Lamotrigine based on the concomitant AED or other concomitant medications (see Table 1 or Table 5). See below for adjustments to maintenance doses of Lamotrigine in women taking estrogen-containing oral contraceptives.

  Adjustments to the Maintenance Dose of Lamotrigine in Women Taking Estrogen-Containing Oral Contraceptives:

  (1) Taking Estrogen-Containing Oral Contraceptives: For women not taking carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin that induce Lamotrigine glucuronidation [see Drug Interactions (7), Clinical Pharmacology (12.3)], the maintenance dose of Lamotrigine will in most cases need to be increased, by as much as 2-fold over the recommended target maintenance dose, in order to maintain a consistent Lamotrigine plasma level [see Clinical Pharmacology (12.3)].

  (2) Starting Estrogen-Containing Oral Contraceptives: In women taking a stable dose of Lamotrigine and not taking carbamazepine, phenytoin, phenobarbital, primidone, or  other drugs such as rifampin that induce Lamotrigine glucuronidation [see Drug Interactions (7), Clinical Pharmacology (12.3)], the maintenance dose will in most cases need to be increased by as much as 2-fold in order to maintain a consistent Lamotrigine plasma level. The dose increases should begin at the same time that the oral contraceptive is introduced and continue, based on clinical response, no more rapidly than 50 to 100 mg/day every week. Dose increases should not exceed the recommended rate (see Table 1 or Table 5) unless Lamotrigine plasma levels or clinical response support larger increases. Gradual transient increases in Lamotrigine plasma levels may occur during the week of inactive hormonal preparation (“pill-free” week), and these increases will be greater if dose increases are made in the days before or during the week of inactive hormonal preparation. Increased Lamotrigine plasma levels could result in additional adverse reactions, such as dizziness, ataxia, and diplopia. If adverse reactions attributable to Lamotrigine consistently occur during the “pill-free” week, dose adjustments to the overall maintenance dose may be necessary. Dose adjustments limited to the “pill-free” week are not recommended. For women taking Lamotrigine in addition to carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin that induce Lamotrigine glucuronidation [see Drug Interactions (7), Clinical Pharmacology (12.3)], no adjustment to the dose of Lamotrigine should be necessary.

  (3) Stopping Estrogen-Containing Oral Contraceptives: For women not taking carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin that induce Lamotrigine glucuronidation [see Drug Interactions (7), Clinical Pharmacology (12.3)], the maintenance dose of Lamotrigine will in most cases need to be decreased by as much as 50% in order to maintain a consistent Lamotrigine plasma level. The decrease in dose of Lamotrigine should not exceed 25% of the total daily dose per week over a 2-week period, unless clinical response or Lamotrigine plasma levels indicate otherwise [see Clinical Pharmacology (12.3)]. For women taking Lamotrigine in addition to carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin that induce Lamotrigine glucuronidation [see Drug Interactions (7), Clinical Pharmacology (12.3)], no adjustment to the dose of Lamotrigine should be necessary.

  Women and Other Hormonal Contraceptive Preparations or Hormone Replacement Therapy: The effect of other hormonal contraceptive preparations or hormone replacement therapy on the pharmacokinetics of Lamotrigine has not been systematically evaluated. It has been reported that ethinylestradiol, not progestogens, increased the clearance of Lamotrigine up to 2-fold, and the progestin-only pills had no effect on Lamotrigine plasma levels. Therefore, adjustments to the dosage of Lamotrigine in the presence of progestogens alone will likely not be needed.

  Patients With Hepatic Impairment: Experience in patients with hepatic impairment is limited. Based on a clinical pharmacology study in 24 patients with mild, moderate, and severe liver impairment [see Use in Specific Populations (8.6), Clinical Pharmacology (12.3)], the following general recommendations can be made. No dosage adjustment is needed in patients with mild liver impairment. Initial, escalation, and maintenance doses should generally be reduced by approximately 25% in patients with moderate and severe liver impairment without ascites and 50% in patients with severe liver impairment with ascites. Escalation and maintenance doses may be adjusted according to clinical response.

  Patients With Renal Impairment: Initial doses of Lamotrigine should be based on patients' concomitant medications (see Tables 1-3 or Table 5); reduced maintenance doses may be effective for patients with significant renal impairment [see Use in Specific Populations (8.7), Clinical Pharmacology (12.3)]. Few patients with severe renal impairment have been evaluated during chronic treatment with Lamotrigine. Because there is inadequate experience in this population, Lamotrigine should be used with caution in these patients.

  Discontinuation Strategy:  Epilepsy: For patients receiving Lamotrigine in combination with other AEDs, a re-evaluation of all AEDs in the regimen should be considered if a change in seizure control or an appearance or worsening of adverse experiences is observed.

  If a decision is made to discontinue therapy with Lamotrigine, a step-wise reduction of dose over at least 2 weeks (approximately 50% per week) is recommended unless safety concerns require a more rapid withdrawal [see Warnings and Precautions (5.9)].

  Discontinuing carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin that induce Lamotrigine glucuronidation should prolong the half-life of Lamotrigine; discontinuing valproate should shorten the half-life of Lamotrigine.

  Bipolar Disorder: In the controlled clinical trials, there was no increase in the incidence, type, or severity of adverse reactions following abrupt termination of Lamotrigine. In clinical trials in patients with Bipolar Disorder, 2 patients experienced seizures shortly after abrupt withdrawal of Lamotrigine. However, there were confounding factors that may have contributed to the occurrence of seizures in these bipolar patients. Discontinuation of Lamotrigine should involve a step-wise reduction of dose over at least 2 weeks (approximately 50% per week) unless safety concerns require a more rapid withdrawal [see Warnings and Precautions (5.9)].

   

  This section provides specific dosing recommendations for patients greater than 12 years of age and patients 2 to 12 years of age. Within each of these age-groups, specific dosing recommendations are provided depending upon concomitant AED or other concomitant medications (Table 1 for patients greater than 12 years of age and Table 2 for patients 2 to 12 years of age). A weight-based dosing guide for patients 2 to 12 years of age on concomitant valproate is provided in Table 3.

  Patients Over 12 Years of Age: Recommended dosing guidelines are summarized in Table 1.

  Table 1. Escalation Regimen for Lamotrigine in Patients Over 12 Years of Age With Epilepsy    For Patients TAKING Valproate* For Patients NOT TAKING Carbamazepine, Phenytoin, Phenobarbital, Primidone†,or Valproate1 For Patients TAKING Carbamazepine, Phenytoin, Phenobarbital, or Primidone2 and NOT TAKING Valproate1 Weeks 1 and 2 25 mg every other day 25 mg every day 50 mg/day Weeks 3 and 4 25 mg every day 50 mg/day 100 mg/day (in 2 divided doses) Weeks 5 onwards to maintenance Increase by 25 to 50 mg/day every 1 to 2 weeks Increase by 50 mg/day
  every 1 to 2 weeks Increase by 100 mg/day every 1 to 2 weeks Usual Maintenance Dose 100 to 200 mg/day with valproate alone
  
  100 to 400 mg/day with valproate and other drugs that induce glucuronication
  (in 1 or 2 divided doses) 225 to 375 mg/day
  (in 2 divided doses) 300 to 500 mg/day  (in 2 divided doses)
  

  1

  2

  Patients 2 to 12 Years of Age: Recommended dosing guidelines are summarized in Table 2.

  Smaller starting doses and slower dose escalations than those used in clinical trials are recommended because of the suggestion that the risk of rash may be decreased by smaller starting doses and slower dose escalations. Therefore, maintenance doses will take longer to reach in clinical practice than in clinical trials. It may take several weeks to months to achieve an individualized maintenance dose. Maintenance doses in patients weighing less than 30 kg, regardless of age or concomitant AED, may need to be increased as much as 50%, based on clinical response. 

  Table 2. Escalation Regimen for Lamotrigine in Patients 2 to 12 Years of Age With Epilepsy   For Patients TAKING Valproate* For Patients NOT TAKING Carbamazepine,
  Phenytoin,
  Phenobarbital,  
  Primidone†  or
   Valproate3 For Patients TAKING Carbamazepine, Phenytoin, Phenobarbital, or  Primidone4 and NOT TAKING Valproate3 Weeks 1 and 2 0.15 mg/kg/day
   in 1 or 2 divided doses, rounded down to the nearest whole tablet (see Table 3 for weight based dosing guide) 0.3 mg/kg/day
  in 1 or 2 divided doses, rounded down to the nearest whole tablet 0.6 mg/kg/day
  in 2 divided doses, rounded down to the nearest whole tablet Weeks 3 and 4 0.3 mg/kg/day
  in 1 or 2 divided doses, rounded down to the nearest whole tablet (see Table 3 for weight based dosing guide) 0.6 mg/kg/day
    in 2 divided doses, rounded down to the nearest whole tablet 1.2 mg/kg/day
    in 2 divided doses, rounded down to the nearest whole tablet Weeks 5 onwards to maintenance The dose should be increased every 1 to 2 weeks as follows: calculate 0.3 mg/kg/day, round this amount down to the nearest whole tablet, and add this amount to the previously administered daily dose The dose should be increased every 1 to 2 weeks as follows: calculate 0.6 mg/kg/day, round this amount down to the nearest whole tablet, and add this amount to the previously administered daily dose The dose should be increased every 1 to 2 weeks as follows: calculate 1.2 mg/kg/day, round this amount down to the nearest whole tablet, and add this amount to the previously administered daily dose Usual Maintenance Dose 1 to 5 mg/kg/day (maximum 200 mg/day in 1 or 2 divided doses).
  1 to 3 mg/kg/day with valproate alone 4.5 to 7.5 mg/kg/day
   (maximum 300 mg/day in 2 divided doses) 5 to 15 mg/kg/day
   (maximum 400 mg/day in 2 divided doses) Maintenance dose in patients less than 30 kg May need to be increased by as much as 50%, based on clinical response May need to be increased by as much as 50%, based on clinical response May need to be increased by as much as 50%, based on clinical response Note: Only whole tablets should be used for dosing.
  

  3

  4

  Table 3. The Initial Weight-Based Dosing Guide for Patients 2 to 12 Years Taking Valproate (Weeks 1 to 4) With Epilepsy If the patient’s weight is Give this daily dose, using the most appropriate combination of Lamotrigine 2-mg and 5-mg tablets Greater than And less than Weeks 1 and 2 Weeks 3 and 4 6.7 kg 14 kg 2 mg every other day 2 mg every day 14.1 kg 27 kg 2 mg every day 4 mg every day 27.1 kg 34 kg 4 mg every day 8 mg every day 34.1 kg 40 kg 5 mg every day 10 mg every day

  Usual Adjunctive Maintenance Dose for Epilepsy: The usual maintenance doses identified in Tables 1 and 2 are derived from dosing regimens employed in the placebo-controlled adjunctive studies in which the efficacy of Lamotrigine was established. In patients receiving multidrug regimens employing carbamazepine, phenytoin, phenobarbital, or primidone without valproate, maintenance doses of adjunctive Lamotrigine as high as 700 mg/day have been used. In patients receiving valproate alone, maintenance doses of adjunctive Lamotrigine as high as 200 mg/day have been used. The advantage of using doses above those recommended in Tables 1 through 4 has not been established in controlled trials.

   

  The goal of the transition regimen is to effect the conversion to monotherapy with Lamotrigine under conditions that ensure adequate seizure control while mitigating the risk of serious rash associated with the rapid titration of Lamotrigine.

  The recommended maintenance dose of Lamotrigine as monotherapy is 500 mg/day given in 2 divided doses.

  To avoid an increased risk of rash, the recommended initial dose and subsequent dose escalations of Lamotrigine should not be exceeded [see Boxed Warning].

  Conversion From Adjunctive Therapy With Carbamazepine, Phenytoin, Phenobarbital, or Primidone to Monotherapy With Lamotrigine: After achieving a dose of 500 mg/day of Lamotrigine according to the guidelines in Table 1, the concomitant AED should be withdrawn by 20% decrements each week over a 4-week period. The regimen for the withdrawal of the concomitant AED is based on experience gained in the controlled monotherapy clinical trial. 

  Conversion from Adjunctive Therapy With Valproate to Monotherapy With Lamotrigine: The conversion regimen involves 4 steps outlined in Table 4.

  Table 4. Conversion From Adjunctive Therapy With Valproate to Monotherapy With Lamotrigine in Patients ≥16 Years of Age with Epilepsy

  Lamotrigine

  Valproate

  Step 1

  Achieve a dose of 200 mg/day according to guidelines in Table 1 (if not already on 200 mg/day).

  Maintain previous stable dose.

  Step 2

  Maintain at 200 mg/day.

  Decrease to 500 mg/day by decrements no greater than 500 mg/day/week and then maintain the dose of 500 mg/day for 1 week.

  Step 3

  Increase to 300 mg/day and maintain for 1 week.

  Simultaneously decrease to 250 mg/day and maintain for 1 week.

  Step 4

  Increase by 100 mg/day every week to achieve maintenance dose of 500 mg/day.

  Discontinue.

  
  Conversion from Adjunctive Therapy With AEDs Other Than Carbamazepine, Phenytoin, Phenobarbital, Primidone, or Valproate to Monotherapy With Lamotrigine: No specific dosing guidelines can be provided for conversion to monotherapy with Lamotrigine with AEDs other than carbamazepine, phenobarbital, phenytoin, primidone, or valproate.

   

  The goal of maintenance treatment with Lamotrigine is to delay the time to occurrence of mood episodes (depression, mania, hypomania, mixed episodes) in patients treated for acute mood episodes with standard therapy. The target dose of Lamotrigine is 200 mg/day (100 mg/day in patients taking valproate, which decreases the apparent clearance of Lamotrigine, and 400 mg/day in patients not taking valproate and taking either carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin, that  increase the apparent clearance of Lamotrigine). In the clinical trials, doses up to 400 mg/day as monotherapy were evaluated; however, no additional benefit was seen at 400 mg/day compared with 200 mg/day [see Clinical Studies (14.2)]. Accordingly, doses above 200 mg/day are not recommended. Treatment with Lamotrigine is introduced, based on concurrent medications, according to the regimen outlined in Table 5. If other psychotropic medications are withdrawn following stabilization, the dose of Lamotrigine should be adjusted. For patients discontinuing valproate, the dose of Lamotrigine should be doubled over a 2-week period in equal weekly increments (see Table 6). For patients discontinuing carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin that induce Lamotrigine glucuronidation, the dose of Lamotrigine should remain constant for the first week and then should be decreased by half over a 2-week period in equal weekly decrements (see Table 6). The dose of Lamotrigine may then be further adjusted to the target dose (200 mg) as clinically indicated.

  If other drugs are subsequently introduced, the dose of Lamotrigine may need to be adjusted. In particular, the introduction of valproate requires reduction in the dose of Lamotrigine [see Drug Interactions (7), Clinical Pharmacology (12.3)].

  To avoid an increased risk of rash, the recommended initial dose and subsequent dose escalations of Lamotrigine should not be exceeded [see Boxed Warning].

   

  Table 5. Escalation Regimen for Lamotrigine for Patients With Bipolar Disorder For Patients TAKING Valproate* For Patients NOT TAKING Carbamazepine, Phenytoin, Phenobarbital, Primidone†, or Valproate5 For Patients TAKING Carbamazepine, Phenytoin, Phenobarbital, or Primidone6 and NOT TAKING Valproate5 Weeks 1 and 2 25 mg every other day 25 mg daily 50 mg daily Weeks 3 and 4 25 mg daily 50 mg daily 100 mg daily, in divided doses Week 5 50 mg daily 100 mg daily 200 mg daily, in divided doses Week 6 100 mg daily 200 mg daily 300 mg daily, in divided doses Week 7 100 mg daily 200 mg daily up to 400 mg daily, in divided doses
  

  5

  6

  Table 6. Dosage Adjustments to Lamotrigine for Patients With Bipolar Disorder Following Discontinuation of Psychotropic Medications  

  Discontinuation of Psychotropic Drugs (excluding Carbamazepine, Phenytoin, Phenobarbital, Primidone*, or Valproate†)

  After Discontinuation of Valproate8 After Discontinuation of Carbamazepine, Phenytoin, Phenobarbital, or Primidone7 Current dose of Lamotrigine (mg/day) 100

  Current dose of Lamotrigine (mg/day) 400

  Week 1 Maintain current dose of Lamotrigine 150 400 Week 2 Maintain current dose of Lamotrigine 200 300 Week 3 onward Maintain current dose of Lamotrigine 200 200
  

  7

  8

  The benefit of continuing treatment in patients who had been stabilized in an 8- to 16-week open-label phase with Lamotrigine was established in 2 randomized, placebo-controlled clinical maintenance trials [see Clinical Studies (14.2)]. However, the optimal duration of treatment with Lamotrigine has not been established. Thus, patients should be periodically reassessed to determine the need for maintenance treatment.

   

  1 Valproate has been shown to inhibit glucuronidation and decrease the apparent clearance of Lamotrigine 2 These drugs induce Lamotrigine glucuronidation and increase clearance 3 Valproate has been shown to inhibit glucuronidation and decrease the apparent clearance of Lamotrigine 4 These drugs induce Lamotrigine glucuronidation and increase clearance 5 Valproate has been shown to inhibit glucuronidation and decrease the apparent clearance of Lamotrigine 6 These drugs induce Lamotrigine glucuronidation and increase clearance 7 These drugs induce Lamotrigine glucuronidation and increase clearance 8 Valproate has been shown to inhibit glucuronidation and decrease the apparent clearance of Lamotrigine

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  2.1 General Dosing Considerations 

  Rash: There are suggestions, yet to be proven, that the risk of severe, potentially life-threatening rash may be increased by (1) coadministration of lamotrigine tablets with valproate, (2) exceeding the recommended initial dose of lamotrigine tablets, or (3) exceeding the recommended dose escalation for lamotrigine tablets. However, cases have occurred in the absence of these factors [see Boxed Warning ]. Therefore, it is important that the dosing recommendations be followed closely.

  The risk of nonserious rash may be increased when the recommended initial dose and/or the rate of dose escalation of lamotrigine tablets is exceeded and in patients with a history of allergy or rash to other AEDs.

  It is recommended that lamotrigine tablets not be restarted in patients who discontinued due to rash associated with prior treatment with lamotrigine, unless the potential benefits clearly outweigh the risks. If the decision is made to restart a patient who has discontinued lamotrigine, the need to restart with the initial dosing recommendations should be assessed. The greater the interval of time since the previous dose, the greater consideration should be given to restarting with the initial dosing recommendations. If a patient has discontinued lamotrigine for a period of more than 5 half-lives, it is recommended that initial dosing recommendations and guidelines be followed. The half-life of lamotrigine is affected by other concomitant medications [see Clinical Pharmacology (12.3)].

  Lamotrigine Added to Drugs Known to Induce or Inhibit Glucuronidation: Drugs other than those listed in the Clinical Pharmacology section [see Clinical Pharmacology (12.3)] have not been systematically evaluated in combination with lamotrigine. Because lamotrigine is metabolized predominantly by glucuronic acid conjugation, drugs that are known to induce or inhibit glucuronidation may affect the apparent clearance of lamotrigine and doses of lamotrigine tablets may require adjustment based on clinical response.

  Target Plasma Levels for Patients With Epilepsy or Bipolar Disorder: A therapeutic plasma concentration range has not been established for lamotrigine. Dosing of lamotrigine tablets should be based on therapeutic response [see Clinical Pharmacology (12.3)].

  Women Taking Estrogen-Containing Oral Contraceptives:  Starting Lamotrigine Tablets in Women Taking Estrogen-Containing Oral Contraceptives: Although estrogen-containing oral contraceptives have been shown to increase the clearance of lamotrigine [see Clinical Pharmacology (12.3)], no adjustments to the recommended dose-escalation guidelines for lamotrigine tablets should be necessary solely based on the use of estrogen-containing oral contraceptives. Therefore, dose escalation should follow the recommended guidelines for initiating adjunctive therapy with lamotrigine tablets based on the concomitant AED or other concomitant medications (see Table 1 or Table 5). See below for adjustments to maintenance doses of lamotrigine tablets in women taking estrogen-containing oral contraceptives.

  Adjustments to the Maintenance Dose of Lamotrigine Tablets in Women Taking Estrogen-Containing Oral Contraceptives:

  (1) Taking Estrogen-Containing Oral Contraceptives: For women not taking carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin that induce lamotrigine glucuronidation [see Drug Interactions (7), Clinical Pharmacology (12.3)], the maintenance dose of lamotrigine tablets will in most cases need to be increased, by as much as 2 fold over the recommended target maintenance dose, in order to maintain a consistent lamotrigine plasma level [see Clinical Pharmacology (12.3)].

  (2) Starting Estrogen-Containing Oral Contraceptives: In women taking a stable dose of lamotrigine tablets and not taking carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin that induce lamotrigine glucuronidation [see Drug Interactions (7), Clinical Pharmacology (12.3)], the maintenance dose will in most cases need to be increased by as much as 2 fold in order to maintain a consistent lamotrigine plasma level. The dose increases should begin at the same time that the oral contraceptive is introduced and continue, based on clinical response, no more rapidly than 50 to 100 mg/day every week. Dose increases should not exceed the recommended rate (seeTable 1 orTable 5) unless lamotrigine plasma levels or clinical response support larger increases. Gradual transient increases in lamotrigine plasma levels may occur during the week of inactive hormonal preparation (“pill-free” week), and these increases will be greater if dose increases are made in the days before or during the week of inactive hormonal preparation. Increased lamotrigine plasma levels could result in additional adverse reactions, such as dizziness, ataxia, and diplopia. If adverse reactions attributable to lamotrigine tablets consistently occur during the “pill-free” week, dose adjustments to the overall maintenance dose may be necessary. Dose adjustments limited to the “pill-free” week are not recommended. For women taking lamotrigine tablets in addition to carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin that induce lamotrigine glucuronidation [see Drug Interactions (7), Clinical Pharmacology (12.3)], no adjustment to the dose of lamotrigine tablets should be necessary.

  (3) Stopping Estrogen-Containing Oral Contraceptives: For women not taking carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin that induce lamotrigine glucuronidation [see Drug Interactions (7), Clinical Pharmacology (12.3)], the maintenance dose of lamotrigine tablets will in most cases need to be decreased by as much as 50% in order to maintain a consistent lamotrigine plasma level. The decrease in dose of lamotrigine tablets should not exceed 25% of the total daily dose per week over a 2 week period, unless clinical response or lamotrigine plasma levels indicate otherwise [see Clinical Pharmacology (12.3)]. For women taking lamotrigine tablets in addition to carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin that induce lamotrigine glucuronidation [see Drug Interactions (7), Clinical Pharmacology (12.3)], no adjustment to the dose of lamotrigine tablets should be necessary.

  Women and Other Hormonal Contraceptive Preparations or Hormone Replacement Therapy: The effect of other hormonal contraceptive preparations or hormone replacement therapy on the pharmacokinetics of lamotrigine has not been systematically evaluated. It has been reported that ethinylestradiol, not progestogens, increased the clearance of lamotrigine up to 2 fold, and the progestin-only pills had no effect on lamotrigine plasma levels. Therefore, adjustments to the dosage of lamotrigine tablets in the presence of progestogens alone will likely not be needed.

  Patients With Hepatic Impairment: Experience in patients with hepatic impairment is limited. Based on a clinical pharmacology study in 24 patients with mild, moderate, and severe liver impairment [see Use in Specific Populations (8.6), Clinical Pharmacology (12.3)], the following general recommendations can be made. No dosage adjustment is needed in patients with mild liver impairment. Initial, escalation, and maintenance doses should generally be reduced by approximately 25% in patients with moderate and severe liver impairment without ascites and 50% in patients with severe liver impairment with ascites. Escalation and maintenance doses may be adjusted according to clinical response.

  Patients With Renal Impairment: Initial doses of lamotrigine tablets should be based on patients' concomitant medications (see Tables 1to3 or Table 5); reduced maintenance doses may be effective for patients with significant renal impairment [see Use in Specific Populations (8.7), Clinical Pharmacology (12.3)]. Few patients with severe renal impairment have been evaluated during chronic treatment with lamotrigine tablets. Because there is inadequate experience in this population, lamotrigine tablets should be used with caution in these patients.

  Discontinuation Strategy:  Epilepsy: For patients receiving lamotrigine tablets in combination with other AEDs, a reevaluation of all AEDs in the regimen should be considered if a change in seizure control or an appearance or worsening of adverse reactions is observed.

  If a decision is made to discontinue therapy with lamotrigine tablets, a step-wise reduction of dose over at least 2 weeks (approximately 50% per week) is recommended unless safety concerns require a more rapid withdrawal [see Warnings and Precautions (5.9)].

  Discontinuing carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin that induce lamotrigine glucuronidation should prolong the half-life of lamotrigine; discontinuing valproate should shorten the half-life of lamotrigine.

  Bipolar Disorder: In the controlled clinical trials, there was no increase in the incidence, type, or severity of adverse reactions following abrupt termination of lamotrigine tablets. In clinical trials in patients with Bipolar Disorder, 2 patients experienced seizures shortly after abrupt withdrawal of lamotrigine tablets. However, there were confounding factors that may have contributed to the occurrence of seizures in these bipolar patients. Discontinuation of lamotrigine tablets should involve a step-wise reduction of dose over at least 2 weeks (approximately 50% per week) unless safety concerns require a more rapid withdrawal [see Warnings and Precautions (5.9)].

  2.2 Epilepsy – Adjunctive Therapy

  This section provides specific dosing recommendations for patients greater than 12 years of age and patients 2 to 12 years of age. Within each of these age-groups, specific dosing recommendations are provided depending upon concomitant AED or other concomitant medications (Table 1 for patients greater than 12 years of age and Table 2 for patients 2 to 12 years of age). A weight-based dosing guide for patients 2 to 12 years of age on concomitant valproate is provided in Table 3.

  Patients Over 12 Years of Age: Recommended dosing guidelines are summarized in Table 1.

  Table 1. Escalation Regimen for Lamotrigine in Patients Over 12 Years of Age With Epilepsy  * Valproate has been shown to inhibit glucuronidation and decrease the apparent clearance of lamotrigine [ see Drug Interactions (7), Clinical Pharmacology (12.3)] . † These drugs induce lamotrigine glucuronidation and increase clearance [ see Drug Interactions (7) Clinical Pharmacology (12.3)]. Other drugs which have similar effects include estrogen-containing oral contraceptives [ see Drug Interactions (7), Clinical Pharmacology (12.3)] . Dosing recommendations for oral contraceptives can be found in General Dosing Considerations [ see Dosage and Administration (2.1)] . Patients on rifampin, or other drugs that induce lamotrigine glucuronidation and increase clearance, should follow the same dosing titration/maintenance regimen as that used with anticonvulsants that have this effect. For Patients TAKING Valproate* For Patients NOT TAKING Carbamazepine, Phenytoin, Phenobarbital, Primidone,† or Valproate* For Patients TAKING Carbamazepine, Phenytoin, Phenobarbital, or Primidone† and NOT TAKING Valproate* Weeks 1 and 2 25 mg every other day 25 mg every day 50 mg/day Weeks 3 and 4 25 mg every day 50 mg/day 100 mg/day (in 2 divided doses) Week 5 onwards to maintenance Increase by 25 to 50 mg/day every 1 to 2 weeks Increase by 50 mg/day every 1 to 2 weeks Increase by 100 mg/day every 1 to 2 weeks Usual Maintenance Dose

  100 to 200 mg/day with valproate alone

  100 to 400 mg/day with valproate and other drugs that induce glucuronidation

  (in 1 or 2 divided doses)

  225 to 375 mg/day (in 2 divided doses)

  300 to 500 mg/day

   (in 2 divided doses)

  Patients 2 to 12 Years of Age: Recommended dosing guidelines are summarized in Table 2.

  Smaller starting doses and slower dose escalations than those used in clinical trials are recommended because of the suggestion that the risk of rash may be decreased by smaller starting doses and slower dose escalations. Therefore, maintenance doses will take longer to reach in clinical practice than in clinical trials. It may take several weeks to months to achieve an individualized maintenance dose. Maintenance doses in patients weighing less than 30 kg, regardless of age or concomitant AED, may need to be increased as much as 50%, based on clinical response.

  Table 2. Escalation Regimen for Lamotrigine in Patients 2 to 12 Years of Age With Epilepsy * Valproate has been shown to inhibit glucuronidation and decrease the apparent clearance of lamotrigine [ see Drug Interactions (7), Clinical Pharmacology (12.3)] . † These drugs induce lamotrigine glucuronidation and increase clearance [ see Drug Interactions (7), Clinical Pharmacology (12.3)]. Other drugs which have similar effects include estrogen-containing oral contraceptives [ see Drug Interactions (7), Clinical Pharmacology (12.3)] . Dosing recommendations for oral contraceptives can be found in General Dosing Considerations  [ see Dosage and Administration (2.1)] . Patients on rifampin, or other drugs that induce lamotrigine glucuronidation and increase clearance, should follow the same dosing titration/maintenance regimen as that used with anticonvulsants that have this effect. For Patients TAKING Valproate* For Patients NOT TAKING Carbamazepine, Phenytoin, Phenobarbital, Primidone,† or Valproate* For Patients TAKING Carbamazepine, Phenytoin, Phenobarbital, or Primidone† and NOT TAKING Valproate* Weeks 1 and 2 0.15 mg/kg/day in 1 or 2 divided doses, rounded down to the nearest whole tablet (see Table 3 for weight based dosing guide) 0.3 mg/kg/day in 1 or 2 divided doses, rounded down to the nearest whole tablet 0.6 mg/kg/day in 2 divided doses, rounded down to the nearest whole tablet Weeks 3 and 4 0.3 mg/kg/day in 1 or 2 divided doses, rounded down to the nearest whole tablet (see Table 3for weight based dosing guide) 0.6 mg/kg/day in 2 divided doses, rounded down to the nearest whole tablet 1.2 mg/kg/day in 2 divided doses, rounded down to the nearest whole tablet Week 5 onwards to maintenance The dose should be increased every 1 to 2 weeks as follows: calculate 0.3 mg/kg/day, round this amount down to the nearest whole tablet, and add this amount to the previously administered daily dose The dose should be increased every 1 to 2 weeks as follows: calculate 0.6 mg/kg/day, round this amount down to the nearest whole tablet, and add this amount to the previously administered daily dose The dose should be increased every 1 to 2 weeks as follows: calculate 1.2 mg/kg/day, round this amount down to the nearest whole tablet, and add this amount to the previously administered daily dose Usual Maintenance Dose 1 to 5 mg/kg/day (maximum 200 mg/day in 1 or 2 divided doses).
  1 to 3 mg/kg/day with valproate alone 4.5 to 7.5 mg/kg/day (maximum 300 mg/day in 2 divided doses) 5 to 15 mg/kg/day (maximum 400 mg/day in 2 divided doses) Maintenance dose in patients less than 30 kg May need to be increased by as much as 50%, based on clinical response May need to be increased by as much as 50%, based on clinical response May need to be increased by as much as 50%, based on clinical response

  Note: Only whole tablets should be used for dosing.

  Table 3. The Initial Weight-Based Dosing Guide for Patients 2 to 12 Years Taking Valproate (Weeks 1 to 4) With Epilepsy If the patient’s weight is Give this daily dose, using the most appropriate combination of lamotrigine tablets, 2 mg and 5 mg Greater than And less than Weeks 1 and 2 Weeks 3 and 4 6.7 kg 14 kg 2 mg every other day 2 mg every day 14.1 kg 27 kg 2 mg every day 4 mg every day 27.1 kg 34 kg 4 mg every day 8 mg every day 34.1 kg 40 kg 5 mg every day 10 mg every day

  Usual Adjunctive Maintenance Dose for Epilepsy: The usual maintenance doses identified in Tables 1 and 2 are derived from dosing regimens employed in the placebo-controlled adjunctive studies in which the efficacy of lamotrigine tablets was established. In patients receiving multidrug regimens employing carbamazepine, phenytoin, phenobarbital, or primidone without valproate, maintenance doses of adjunctive lamotrigine tablets as high as 700 mg/day have been used. In patients receiving valproate alone, maintenance doses of adjunctive lamotrigine tablets as high as 200 mg/day have been used. The advantage of using doses above those recommended in Tables 1 through 4 has not been established in controlled trials.

  2.3 Epilepsy – Conversion From Adjunctive Therapy to Monotherapy

  The goal of the transition regimen is to effect the conversion to monotherapy with lamotrigine tablets under conditions that ensure adequate seizure control while mitigating the risk of serious rash associated with the rapid titration of lamotrigine tablets.

  The recommended maintenance dose of lamotrigine tablets as monotherapy is 500 mg/day given in 2 divided doses.

  To avoid an increased risk of rash, the recommended initial dose and subsequent dose escalations of lamotrigine tablets should not be exceeded [see Boxed Warning ].

  Conversion From Adjunctive Therapy With Carbamazepine, Phenytoin, Phenobarbital, or Primidone to Monotherapy With Lamotrigine Tablets: After achieving a dose of 500 mg/day of lamotrigine tablets according to the guidelines in Table 1, the concomitant AED should be withdrawn by 20% decrements each week over a 4 week period. The regimen for the withdrawal of the concomitant AED is based on experience gained in the controlled monotherapy clinical trial.

  Conversion From Adjunctive Therapy With Valproate to Monotherapy With Lamotrigine Tablets: The conversion regimen involves 4 steps outlined in Table 4.

  Table 4. Conversion From Adjunctive Therapy With Valproate to Monotherapy With Lamotrigine in Patients ≥ 16 Years of Age With Epilepsy   Lamotrigine Valproate Step 1 Achieve a dose of 200 mg/day according to guidelines in Table 1 (if not already on 200 mg/day). Maintain previous stable dose. Step 2 Maintain at 200 mg/day. Decrease to 500 mg/day by decrements no greater than 500 mg/day/week and then maintain the dose of 500 mg/day for 1 week. Step 3 Increase to 300 mg/day and maintain for 1 week. Simultaneously decrease to 250 mg/day and maintain for 1 week. Step 4 Increase by 100 mg/day every week to achieve maintenance dose of 500 mg/day. Discontinue.

  Conversion From Adjunctive Therapy With AEDs Other Than Carbamazepine, Phenytoin, Phenobarbital, Primidone, or Valproate to Monotherapy With Lamotrigine Tablets: No specific dosing guidelines can be provided for conversion to monotherapy with lamotrigine tablets with AEDs other than carbamazepine, phenobarbital, phenytoin, primidone, or valproate.

  2.4 Bipolar Disorder

  The goal of maintenance treatment with lamotrigine tablets is to delay the time to occurrence of mood episodes (depression, mania, hypomania, mixed episodes) in patients treated for acute mood episodes with standard therapy. The target dose of lamotrigine tablets is 200 mg/day (100 mg/day in patients taking valproate, which decreases the apparent clearance of lamotrigine, and 400 mg/day in patients not taking valproate and taking either carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin that increase the apparent clearance of lamotrigine). In the clinical trials, doses up to 400 mg/day as monotherapy were evaluated; however, no additional benefit was seen at 400 mg/day compared with 200 mg/day [see Clinical Studies (14.2)]. Accordingly, doses above 200 mg/day are not recommended. Treatment with lamotrigine tablets is introduced, based on concurrent medications, according to the regimen outlined in Table 5. If other psychotropic medications are withdrawn following stabilization, the dose of lamotrigine tablets should be adjusted. For patients discontinuing valproate, the dose of lamotrigine tablets should be doubled over a 2 week period in equal weekly increments (see Table 6). For patients discontinuing carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin that induce lamotrigine glucuronidation, the dose of lamotrigine tablets should remain constant for the first week and then should be decreased by half over a 2 week period in equal weekly decrements (see Table 6). The dose of lamotrigine tablets may then be further adjusted to the target dose (200 mg) as clinically indicated.

  If other drugs are subsequently introduced, the dose of lamotrigine tablets may need to be adjusted. In particular, the introduction of valproate requires reduction in the dose of lamotrigine tablets [see Drug Interactions (7), Clinical Pharmacology (12.3)].

  To avoid an increased risk of rash, the recommended initial dose and subsequent dose escalations of lamotrigine tablets should not be exceeded [see Boxed Warning ].

   

  Table 5. Escalation Regimen for Lamotrigine for Patients With Bipolar Disorder * Valproate has been shown to inhibit glucuronidation and decrease the apparent clearance of lamotrigine [ see Drug Interactions (7), Clinical Pharmacology (12.3)]. † These drugs induce lamotrigine glucuronidation and increase clearance [ see Drug Interactions (7), Clinical Pharmacology (12.3)]. Other drugs which have similar effects include estrogen-containing oral contraceptives [ see Drug Interactions (7), Clinical Pharmacology (12.3)]. Dosing recommendations for oral contraceptives can be found in General Dosing Considerations [ see Dosage and Administration (2.1)]. Patients on rifampin, or other drugs that induce lamotrigine glucuronidation and increase clearance, should follow the same dosing titration/maintenance regimen as that used with anticonvulsants that have this effect. For Patients TAKING Valproate* For Patients NOT TAKING Carbamazepine, Phenytoin, Phenobarbital, Primidone,† or Valproate* For Patients TAKING Carbamazepine, Phenytoin, Phenobarbital, or Primidone† and NOT TAKING Valproate* Weeks 1 and 2 25 mg every other day 25 mg daily 50 mg daily Weeks 3 and 4 25 mg daily 50 mg daily 100 mg daily, in divided doses Week 5 50 mg daily 100 mg daily 200 mg daily, in divided doses Week 6 100 mg daily 200 mg daily 300 mg daily, in divided doses Week 7 100 mg daily 200 mg daily up to 400 mg daily, in divided doses Table 6. Dosage Adjustments to Lamotrigine for Patients With Bipolar Disorder Following Discontinuation of Psychotropic Medications * These drugs induce lamotrigine glucuronidation and increase clearance [ see Drug Interactions (7), Clinical Pharmacology (12.3)]. Other drugs which have similar effects include estrogen-containing oral contraceptives [ see Drug Interactions (7), Clinical Pharmacology (12.3)]. Dosing recommendations for oral contraceptives can be found in General Dosing Considerations [ see Dosage and Administration (2.1)]. Patients on rifampin, or other drugs that induce lamotrigine glucuronidation and increase clearance, should follow the same dosing titration/maintenance regimen as that used with anticonvulsants that have this effect. † Valproate has been shown to inhibit glucuronidation and decrease the apparent clearance of lamotrigine [ see Drug Interactions (7), Clinical Pharmacology (12.3)].   Discontinuation of Psychotropic Drugs (excluding Carbamazepine, Phenytoin, Phenobarbital, Primidone,* or Valproate†) After Discontinuation of Valproate† After Discontinuation of Carbamazepine, Phenytoin, Phenobarbital, or Primidone* Current dose of Lamotrigine (mg/day) 100

  Current dose of Lamotrigine (mg/day)

  400

  Week 1 Maintain current dose of lamotrigine 150 400 Week 2 Maintain current dose of lamotrigine 200 300 Week 3 onward Maintain current dose of lamotrigine 200 200

  The benefit of continuing treatment in patients who had been stabilized in an 8 to 16 week open-label phase with lamotrigine tablets was established in 2 randomized, placebo-controlled clinical maintenance trials [see Clinical Studies (14.2)]. However, the optimal duration of treatment with lamotrigine tablets has not been established. Thus, patients should be periodically reassessed to determine the need for maintenance treatment.

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  2.1 General Dosing Considerations

  Rash: There are suggestions, yet to be proven, that the risk of severe, potentially life-threatening rash may be increased by (1) coadministration of lamotrigine with valproate, (2) exceeding the recommended initial dose of lamotrigine, or (3) exceeding the recommended dose escalation for lamotrigine. However, cases have occurred in the absence of these factors [see Boxed Warning]. Therefore, it is important that the dosing recommendations be followed closely.

  The risk of nonserious rash may be increased when the recommended initial dose and/or the rate of dose escalation of lamotrigine is exceeded and in patients with a history of allergy or rash to other AEDs.

  Lamotrigine Starter Kits provide lamotrigine at doses consistent with the recommended titration schedule for the first 5 weeks of treatment, based upon concomitant medications for patients with epilepsy (>12 years of age) and Bipolar I Disorder (≥18 years of age) and are intended to help reduce the potential for rash. The use of Lamotrigine Starter Kits is recommended for appropriate patients who are starting or restarting lamotrigine [see How Supplied/Storage and Handling (16)].

  It is recommended that lamotrigine not be restarted in patients who discontinued due to rash associated with prior treatment with lamotrigine, unless the potential benefits clearly outweigh the risks. If the decision is made to restart a patient who has discontinued lamotrigine, the need to restart with the initial dosing recommendations should be assessed. The greater the interval of time since the previous dose, the greater consideration should be given to restarting with the initial dosing recommendations. If a patient has discontinued lamotrigine for a period of more than 5 half-lives, it is recommended that initial dosing recommendations and guidelines be followed. The half-life of lamotrigine is affected by other concomitant medications [see Clinical Pharmacology (12.3)].

  Lamotrigine Added to Drugs Known to Induce or Inhibit Glucuronidation: Drugs other than those listed in the Clinical Pharmacology section [see Clinical Pharmacology (12.3)] have not been systematically evaluated in combination with lamotrigine. Because lamotrigine is metabolized predominantly by glucuronic acid conjugation, drugs that are known to induce or inhibit glucuronidation may affect the apparent clearance of lamotrigine and doses of lamotrigine may require adjustment based on clinical response.

  Target Plasma Levels for Patients With Epilepsy or Bipolar Disorder: A therapeutic plasma concentration range has not been established for lamotrigine. Dosing of lamotrigine should be based on therapeutic response [see Clinical Pharmacology (12.3)].

  Women Taking Estrogen-Containing Oral Contraceptives: Starting Lamotrigine in Women Taking Estrogen-Containing Oral Contraceptives: Although estrogen-containing oral contraceptives have been shown to increase the clearance of lamotrigine [see Clinical Pharmacology (12.3)], no adjustments to the recommended dose-escalation guidelines for lamotrigine should be necessary solely based on the use of estrogen-containing oral contraceptives. Therefore, dose escalation should follow the recommended guidelines for initiating adjunctive therapy with lamotrigine based on the concomitant AED or other concomitant medications (see Table 1 or Table 5). See below for adjustments to maintenance doses of lamotrigine in women taking estrogen-containing oral contraceptives.

  Adjustments to the Maintenance Dose of Lamotrigine In Women Taking Estrogen-Containing Oral Contraceptives:

  (1) Taking Estrogen-Containing Oral Contraceptives: For women not taking carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin that induce lamotrigine glucuronidation [see Drug Interactions (7), Clinical Pharmacology (12.3)], the maintenance dose of lamotrigine will in most cases need to be increased, by as much as 2-fold over the recommended target maintenance dose, in order to maintain a consistent lamotrigine plasma level [see Clinical Pharmacology (12.3)].

  (2) Starting Estrogen-Containing Oral Contraceptives: In women taking a stable dose of lamotrigine and not taking carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin that induce lamotrigine glucuronidation [see Drug Interactions (7), Clinical Pharmacology (12.3)], the maintenance dose will in most cases need to be increased by as much as 2-fold in order to maintain a consistent lamotrigine plasma level. The dose increases should begin at the same time that the oral contraceptive is introduced and continue, based on clinical response, no more rapidly than 50 to 100 mg/day every week. Dose increases should not exceed the recommended rate (see Table 1 or Table 5) unless lamotrigine plasma levels or clinical response support larger increases. Gradual transient increases in lamotrigine plasma levels may occur during the week of inactive hormonal preparation ("pill-free" week), and these increases will be greater if dose increases are made in the days before or during the week of inactive hormonal preparation. Increased lamotrigine plasma levels could result in additional adverse reactions, such as dizziness, ataxia, and diplopia. If adverse reactions attributable to lamotrigine consistently occur during the "pill-free" week, dose adjustments to the overall maintenance dose may be necessary. Dose adjustments limited to the "pill-free" week are not recommended. For women taking lamotrigine in addition to carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin that induce lamotrigine glucuronidation [see Drug Interactions (7), Clinical Pharmacology (12.3)], no adjustment to the dose of lamotrigine should be necessary.

  (3) Stopping Estrogen-Containing Oral Contraceptives: For women not taking carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin that induce lamotrigine glucuronidation [see Drug Interactions (7), Clinical Pharmacology (12.3)], the maintenance dose of lamotrigine will in most cases need to be decreased by as much as 50% in order to maintain a consistent lamotrigine plasma level. The decrease in dose of lamotrigine should not exceed 25% of the total daily dose per week over a 2-week period, unless clinical response or lamotrigine plasma levels indicate otherwise [see Clinical Pharmacology (12.3)]. For women taking lamotrigine in addition to carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin that induce lamotrigine glucuronidation [see Drug Interactions (7), Clinical Pharmacology (12.3)], no adjustment to the dose of lamotrigine should be necessary.

  Women and Other Hormonal Contraceptive Preparations or Hormone Replacement Therapy: The effect of other hormonal contraceptive preparations or hormone replacement therapy on the pharmacokinetics of lamotrigine has not been systematically evaluated. It has been reported that ethinylestradiol, not progestogens, increased the clearance of lamotrigine up to 2-fold, and the progestin-only pills had no effect on lamotrigine plasma levels. Therefore, adjustments to the dosage of lamotrigine in the presence of progestogens alone will likely not be needed.

  Patients With Hepatic Impairment: Experience in patients with hepatic impairment is limited. Based on a clinical pharmacology study in 24 patients with mild, moderate, and severe liver impairment [see Use in Specific Populations (8.6), Clinical Pharmacology (12.3)], the following general recommendations can be made. No dosage adjustment is needed in patients with mild liver impairment. Initial, escalation, and maintenance doses should generally be reduced by approximately 25% in patients with moderate and severe liver impairment without ascites and 50% in patients with severe liver impairment with ascites. Escalation and maintenance doses may be adjusted according to clinical response.

  Patients With Renal Impairment: Initial doses of lamotrigine should be based on patients' concomitant medications (see Tables 1-3 or Table 5); reduced maintenance doses may be effective for patients with significant renal impairment [see Use in Specific Populations (8.7), Clinical Pharmacology (12.3)]. Few patients with severe renal impairment have been evaluated during chronic treatment with lamotrigine. Because there is inadequate experience in this population, lamotrigine should be used with caution in these patients.

  Discontinuation Strategy: Epilepsy: For patients receiving lamotrigine in combination with other AEDs, a reevaluation of all AEDs in the regimen should be considered if a change in seizure control or an appearance or worsening of adverse reactions is observed.

  If a decision is made to discontinue therapy with lamotrigine, a step-wise reduction of dose over at least 2 weeks (approximately 50% per week) is recommended unless safety concerns require a more rapid withdrawal [see Warnings and Precautions (5.9)].

  Discontinuing carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin that induce lamotrigine glucuronidation should prolong the half-life of lamotrigine; discontinuing valproate should shorten the half-life of lamotrigine.

  Bipolar Disorder: In the controlled clinical trials, there was no increase in the incidence, type, or severity of adverse reactions following abrupt termination of lamotrigine. In clinical trials in patients with Bipolar Disorder, 2 patients experienced seizures shortly after abrupt withdrawal of lamotrigine. However, there were confounding factors that may have contributed to the occurrence of seizures in these bipolar patients. Discontinuation of lamotrigine should involve a step-wise reduction of dose over at least 2 weeks (approximately 50% per week) unless safety concerns require a more rapid withdrawal [see Warnings and Precautions (5.9)].

  2.2 Epilepsy – Adjunctive Therapy

  This section provides specific dosing recommendations for patients greater than 12 years of age and patients 2 to 12 years of age. Within each of these age-groups, specific dosing recommendations are provided depending upon concomitant AED or other concomitant medications (Table 1 for patients greater than 12 years of age and Table 2 for patients 2 to 12 years of age). A weight-based dosing guide for patients 2 to 12 years of age on concomitant valproate is provided in Table 3.

  Patients Over 12 Years of Age: Recommended dosing guidelines are summarized in Table 1.

  Table 1. Escalation Regimen for Lamotrigine in Patients Over 12 Years of Age With Epilepsy For Patients TAKING Valproate * For Patients NOT TAKING Carbamazepine, Phenytoin, Phenobarbital, Primidone†, or Valproate* For Patients TAKING Carbamazepine, Phenytoin, Phenobarbital, or Primidone† and NOT TAKING Valproate* * Valproate has been shown to inhibit glucuronidation and decrease the apparent clearance of lamotrigine [see Drug Interactions (7), Clinical Pharmacology (12.3)]. † These drugs induce lamotrigine glucuronidation and increase clearance [see Drug Interactions (7), Clinical Pharmacology (12.3)]. Other drugs that have similar effects include estrogen-containing oral contraceptives [see Drug Interactions (7), Clinical Pharmacology (12.3)]. Weeks 1 and 2 25 mg every other day 25 mg every day 50 mg/day Weeks 3 and 4 25 mg every day 50 mg/day 100 mg/day
  (in 2 divided doses) Week 5 onwards to maintenance Increase by 25 to 50 mg/day every 1 to 2 weeks Increase by 50 mg/day every 1 to 2 weeks Increase by 100 mg/day every 1 to 2 weeks Usual maintenance dose 100 to 200 mg/day with valproate alone
  100 to 400 mg/day with valproate and other drugs that induce glucuronidation
  (in 1 or 2 divided doses) 225 to 375 mg/day
  (in 2 divided doses) 300 to 500 mg/day
  (in 2 divided doses)

  Dosing recommendations for oral contraceptives can be found in General Dosing Considerations [see Dosage and Administration (2.1)]. Patients on rifampin, or other drugs that induce lamotrigine glucuronidation and increase clearance, should follow the same dosing titration/maintenance regimen as that used with anticonvulsants that have this effect.

  Patients 2 to 12 Years of Age: Recommended dosing guidelines are summarized in Table 2.

  Smaller starting doses and slower dose escalations than those used in clinical trials are recommended because of the suggestion that the risk of rash may be decreased by smaller starting doses and slower dose escalations. Therefore, maintenance doses will take longer to reach in clinical practice than in clinical trials. It may take several weeks to months to achieve an individualized maintenance dose. Maintenance doses in patients weighing less than 30 kg, regardless of age or concomitant AED, may need to be increased as much as 50%, based on clinical response.

  Table 2. Escalation Regimen for Lamotrigine in Patients 2 to 12 Years of Age With Epilepsy For Patients TAKING Valproate * For Patients NOT TAKING Carbamazepine, Phenytoin, Phenobarbital, Primidone†, or Valproate* For Patients TAKING Carbamazepine, Phenytoin, Phenobarbital, or Primidone† and NOT TAKING Valproate* Note: Only whole tablets should be used for dosing. * Valproate has been shown to inhibit glucuronidation and decrease the apparent clearance of lamotrigine [see Drug Interactions (7), Clinical Pharmacology (12.3)]. † These drugs induce lamotrigine glucuronidation and increase clearance [see Drug Interactions (7), Clinical Pharmacology (12.3)]. Other drugs that have similar effects include estrogen-containing oral contraceptives [see Drug Interactions (7), Clinical Pharmacology (12.3)]. Weeks 1 and 2 0.15 mg/kg/day
  in 1 or 2 divided doses, rounded down to the nearest whole tablet (see Table 3 for weight based dosing guide) 0.3 mg/kg/day
  in 1 or 2 divided doses, rounded down to the nearest whole tablet 0.6 mg/kg/day
  in 2 divided doses, rounded down to the nearest whole tablet Weeks 3 and 4 0.3 mg/kg/day
  in 1 or 2 divided doses, rounded down to the nearest whole tablet (see Table 3 for weight based dosing guide) 0.6 mg/kg/day
  in 2 divided doses, rounded down to the nearest whole tablet 1.2 mg/kg/day
  in 2 divided doses, rounded down to the nearest whole tablet Week 5 onwards to maintenance The dose should be increased every 1 to 2 weeks as follows: calculate 0.3 mg/kg/day, round this amount down to the nearest whole tablet, and add this amount to the previously administered daily dose The dose should be increased every 1 to 2 weeks as follows: calculate 0.6 mg/kg/day, round this amount down to the nearest whole tablet, and add this amount to the previously administered daily dose The dose should be increased every 1 to 2 weeks as follows: calculate 1.2 mg/kg/day, round this amount down to the nearest whole tablet, and add this amount to the previously administered daily dose Usual maintenance dose 1 to 5 mg/kg/day
  (maximum 200 mg/day in 1 or 2 divided doses)
  1 to 3 mg/kg/day with valproate alone 4.5 to 7.5 mg/kg/day
  (maximum 300 mg/day in 2 divided doses) 5 to 15 mg/kg/day
  (maximum 400 mg/day in 2 divided doses) Maintenance dose in patients less than 30 kg May need to be increased by as much as 50%, based on clinical response May need to be increased by as much as 50%, based on clinical response May need to be increased by as much as 50%, based on clinical response

  Dosing recommendations for oral contraceptives can be found in General Dosing Considerations [see Dosage and Administration (2.1)]. Patients on rifampin, or other drugs that induce lamotrigine glucuronidation and increase clearance, should follow the same dosing titration/maintenance regimen as that used with anticonvulsants that have this effect.

  Table 3. The Initial Weight-Based Dosing Guide for Patients 2 to 12 Years Taking Valproate (Weeks 1 to 4) With Epilepsy If the patient's weight is Give this daily dose, using the most appropriate combination of Lamotrigine 2-mg and 5-mg tablets Greater than And less than Weeks 1 and 2 Weeks 3 and 4 6.7 kg 14 kg 2 mg every other day 2 mg every day 14.1 kg 27 kg 2 mg every day 4 mg every day 27.1 kg 34 kg 4 mg every day 8 mg every day 34.1 kg 40 kg 5 mg every day 10 mg every day

  Usual Adjunctive Maintenance Dose for Epilepsy: The usual maintenance doses identified in Tables 1 and 2 are derived from dosing regimens employed in the placebo-controlled adjunctive studies in which the efficacy of lamotrigine was established. In patients receiving multidrug regimens employing carbamazepine, phenytoin, phenobarbital, or primidone without valproate, maintenance doses of adjunctive lamotrigine as high as 700 mg/day have been used. In patients receiving valproate alone, maintenance doses of adjunctive lamotrigine as high as 200 mg/day have been used. The advantage of using doses above those recommended in Tables 1 through 4 has not been established in controlled trials.

  2.3 Epilepsy – Conversion From Adjunctive Therapy to Monotherapy

  The goal of the transition regimen is to effect the conversion to monotherapy with lamotrigine under conditions that ensure adequate seizure control while mitigating the risk of serious rash associated with the rapid titration of lamotrigine.

  The recommended maintenance dose of lamotrigine as monotherapy is 500 mg/day given in 2 divided doses.

  To avoid an increased risk of rash, the recommended initial dose and subsequent dose escalations of lamotrigine should not be exceeded [see Boxed Warning].

  Conversion From Adjunctive Therapy With Carbamazepine, Phenytoin, Phenobarbital, or Primidone to Monotherapy With Lamotrigine: After achieving a dose of 500 mg/day of lamotrigine according to the guidelines in Table 1, the concomitant AED should be withdrawn by 20% decrements each week over a 4-week period. The regimen for the withdrawal of the concomitant AED is based on experience gained in the controlled monotherapy clinical trial.

  Conversion From Adjunctive Therapy With Valproate to Monotherapy With Lamotrigine: The conversion regimen involves 4 steps outlined in Table 4.

  Table 4. Conversion From Adjunctive Therapy With Valproate to Monotherapy With Lamotrigine in Patients ≥16 Years of Age With Epilepsy Lamotrigine Valproate Step 1 Achieve a dose of 200 mg/day according to guidelines in Table 1 (if not already on 200 mg/day). Maintain previous stable dose. Step 2 Maintain at 200 mg/day. Decrease to 500 mg/day by decrements no greater than 500 mg/day/week and then maintain the dose of 500 mg/day for 1 week. Step 3 Increase to 300 mg/day and maintain for 1 week. Simultaneously decrease to 250 mg/day and maintain for 1 week. Step 4 Increase by 100 mg/day every week to achieve maintenance dose of 500 mg/day. Discontinue.

  Conversion From Adjunctive Therapy With Antiepileptic Drugs Other Than Carbamazepine, Phenytoin, Phenobarbital, Primidone, or Valproate to Monotherapy With Lamotrigine: No specific dosing guidelines can be provided for conversion to monotherapy with lamotrigine with AEDs other than carbamazepine, phenobarbital, phenytoin, primidone, or valproate.

  2.4 Bipolar Disorder

  The goal of maintenance treatment with lamotrigine is to delay the time to occurrence of mood episodes (depression, mania, hypomania, mixed episodes) in patients treated for acute mood episodes with standard therapy. The target dose of lamotrigine is 200 mg/day (100 mg/day in patients taking valproate, which decreases the apparent clearance of lamotrigine, and 400 mg/day in patients not taking valproate and taking either carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin that increase the apparent clearance of lamotrigine). In the clinical trials, doses up to 400 mg/day as monotherapy were evaluated; however, no additional benefit was seen at 400 mg/day compared with 200 mg/day [see Clinical Studies (14.2)]. Accordingly, doses above 200 mg/day are not recommended. Treatment with lamotrigine is introduced, based on concurrent medications, according to the regimen outlined in Table 5. If other psychotropic medications are withdrawn following stabilization, the dose of lamotrigine should be adjusted. For patients discontinuing valproate, the dose of lamotrigine should be doubled over a 2-week period in equal weekly increments (see Table 6). For patients discontinuing carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin that induce lamotrigine glucuronidation, the dose of lamotrigine should remain constant for the first week and then should be decreased by half over a 2-week period in equal weekly decrements (see Table 6). The dose of lamotrigine may then be further adjusted to the target dose (200 mg) as clinically indicated.

  If other drugs are subsequently introduced, the dose of lamotrigine may need to be adjusted. In particular, the introduction of valproate requires reduction in the dose of lamotrigine [see Drug Interactions (7), Clinical Pharmacology (12.3)].

  To avoid an increased risk of rash, the recommended initial dose and subsequent dose escalations of lamotrigine should not be exceeded [see Boxed Warning].

  Table 5. Escalation Regimen for Lamotrigine for Patients With Bipolar Disorder For Patients TAKING Valproate* For Patients NOT TAKING Carbamazepine, Phenytoin, Phenobarbital, Primidone†, or Valproate* For Patients TAKING Carbamazepine, Phenytoin, Phenobarbital, or Primidone†, and NOT TAKING Valproate* * Valproate has been shown to inhibit glucuronidation and decrease the apparent clearance of lamotrigine [see Drug Interactions (7), Clinical Pharmacology (12.3)]. † These drugs induce lamotrigine glucuronidation and increase clearance [see Drug Interactions (7), Clinical Pharmacology (12.3)]. Other drugs which have similar effects include estrogen-containing oral contraceptives [see Drug Interactions (7), Clinical Pharmacology (12.3)]. Dosing recommendations for oral contraceptives can be found in General Dosing Considerations [see Dosage and Administration (2.1)]. Patients on rifampin, or other drugs that induce lamotrigine glucuronidation and increase clearance, should follow the same dosing titration/maintenance regimen as that used with anticonvulsants that have this effect. Weeks 1 and 2 25 mg every other day 25 mg daily 50 mg daily Weeks 3 and 4 25 mg daily 50 mg daily 100 mg daily, in divided doses Week 5 50 mg daily 100 mg daily 200 mg daily, in divided doses Week 6 100 mg daily 200 mg daily 300 mg daily, in divided doses Week 7 100 mg daily 200 mg daily up to 400 mg daily, in divided doses Table 6. Dosage Adjustments to Lamotrigine for Patients With Bipolar Disorder Following Discontinuation of Psychotropic Medications Discontinuation of Psychotropic Drugs (excluding Carbamazepine, Phenytoin, Phenobarbital, Primidone*, or Valproate†) After Discontinuation of Valproate† After Discontinuation of Carbamazepine, Phenytoin, Phenobarbital or Primidone* Current dose of Lamotrigine (mg/day) 100 Current dose of Lamotrigine (mg/day) 400 * These drugs induce lamotrigine glucuronidation and increase clearance [see Drug Interactions (7), Clinical Pharmacology (12.3)]. Other drugs which have similar effects include estrogen-containing oral contraceptives [see Drug Interactions (7), Clinical Pharmacology (12.3)]. Dosing recommendations for oral contraceptives can be found in General Dosing Considerations [see Dosage and Administration (2.1)]. Patients on rifampin, or other drugs that induce lamotrigine glucuronidation and increase clearance, should follow the same dosing titration/maintenance regimen as that used with anticonvulsants that have this effect. † Valproate has been shown to inhibit glucuronidation and decrease the apparent clearance of lamotrigine [see Drug Interactions (7), Clinical Pharmacology (12.3)]. Week 1 Maintain current dose of Lamotrigine 150 400 Week 2 Maintain current dose of Lamotrigine 200 300 Week 3 onward Maintain current dose of Lamotrigine 200 200

  The benefit of continuing treatment in patients who had been stabilized in an 8- to 16-week open-label phase with lamotrigine was established in 2 randomized, placebo-controlled clinical maintenance trials [see Clinical Studies (14.2)]. However, the optimal duration of treatment with lamotrigine has not been established. Thus, patients should be periodically reassessed to determine the need for maintenance treatment.

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  2.1 General Dosing Considerations

  Rash: There are suggestions, yet to be proven, that the risk of severe, potentially life-threatening rash may be increased by (1) coadministration of lamotrigine tablets, USP with valproate, (2) exceeding the recommended initial dose of lamotrigine tablets, or (3) exceeding the recommended dose escalation for lamotrigine tablets, USP. However, cases have occurred in the absence of these factors [see Boxed Warning]. Therefore, it is important that the dosing recommendations be followed closely.

  The risk of nonserious rash may be increased when the recommended initial dose and/or the rate of dose escalation of lamotrigine tablets, USP are exceeded and in patients with a history of allergy or rash to other AEDs.

  It is recommended that lamotrigine tablets, USP not be restarted in patients who discontinued due to rash associated with prior treatment with lamotrigine, unless the potential benefits clearly outweigh the risks. If the decision is made to restart a patient who has discontinued lamotrigine, the need to restart with the initial dosing recommendations should be assessed. The greater the interval of time since the previous dose, the greater consideration should be given to restarting with the initial dosing recommendations. If a patient has discontinued lamotrigine for a period of more than 5 half-lives, it is recommended that initial dosing recommendations and guidelines be followed. The half-life of lamotrigine is affected by other concomitant medications [see Clinical Pharmacology (12.3)].

  Lamotrigine tablets, USP Added to Drugs Known to Induce or Inhibit Glucuronidation: Drugs other than those listed in the Clinical Pharmacology section [see Clinical Pharmacology (12.3)] have not been systematically evaluated in combination with lamotrigine. Because lamotrigine is metabolized predominantly by glucuronic acid conjugation, drugs that are known to induce or inhibit glucuronidation may affect the apparent clearance of lamotrigine and doses of lamotrigine tablets, USP may require adjustment based on clinical response.

  Target Plasma Levels for Patients With Epilepsy or Bipolar Disorder: A therapeutic plasma concentration range has not been established for lamotrigine. Dosing of lamotrigine tablets, USP should be based on therapeutic response [see Clinical Pharmacology (12.3)].

  Women Taking Estrogen-Containing Oral Contraceptives:Starting lamotrigine tablets, USP in Women Taking Estrogen-Containing Oral Contraceptives: Although estrogen-containing oral contraceptives have been shown to increase the clearance of lamotrigine [see Clinical Pharmacology (12.3)], no adjustments to the recommended dose-escalation guidelines for lamotrigine tablets, USP should be necessary solely based on the use of estrogen-containing oral contraceptives. Therefore, dose escalation should follow the recommended guidelines for initiating adjunctive therapy with lamotrigine tablets, USP based on the concomitant AED or other concomitant medications (see Table 1 or Table 5). See below for adjustments to maintenance doses of lamotrigine tablets, USP in women taking estrogen-containing oral contraceptives.

  Adjustments to the Maintenance Dose of lamotrigine tablets, USP In Women Taking Estrogen-Containing Oral Contraceptives:

  (1)Taking Estrogen-Containing Oral Contraceptives: For women not taking carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin that induce lamotrigine glucuronidation [see Drug Interactions (7), Clinical Pharmacology (12.3)], the maintenance dose of lamotrigine tablets, USP will in most cases need to be increased, by as much as 2-fold over the recommended target maintenance dose, in order to maintain a consistent lamotrigine plasma level [see Clinical Pharmacology (12.3)].

  (2) Starting Estrogen-Containing Oral Contraceptives: In women taking a stable dose of lamotrigine tablets, USP and not taking carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin that induce lamotrigine glucuronidation [see Drug Interactions (7), Clinical Pharmacology (12.3)], the maintenance dose will in most cases need to be increased by as much as 2-fold in order to maintain a consistent lamotrigine plasma level. The dose increases should begin at the same time that the oral contraceptive is introduced and continue, based on clinical response, no more rapidly than 50 to 100 mg/day every week. Dose increases should not exceed the recommended rate (see Table 1 or Table 5) unless lamotrigine plasma levels or clinical response support larger increases. Gradual transient increases in lamotrigine plasma levels may occur during the week of inactive hormonal preparation (“pill-free” week), and these increases will be greater if dose increases are made in the days before or during the week of inactive hormonal preparation. Increased lamotrigine plasma levels could result in additional adverse reactions, such as dizziness, ataxia, and diplopia. If adverse reactions attributable to lamotrigine tablets, USP consistently occur during the “pill-free” week, dose adjustments to the overall maintenance dose may be necessary. Dose adjustments limited to the “pill-free” week are not recommended. For women taking lamotrigine tablets, USP in addition to carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin that induce lamotrigine glucuronidation [see Drug Interactions (7), Clinical Pharmacology (12.3)], no adjustment to the dose of lamotrigine tablets, USP should be necessary. 

  (3) Stopping Estrogen-Containing Oral Contraceptives: For women not taking carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin that induce lamotrigine glucuronidation [see Drug Interactions (7), Clinical Pharmacology (12.3)], the maintenance dose of lamotrigine tablets, USP will in most cases need to be decreased by as much as 50% in order to maintain a consistent lamotrigine plasma level. The decrease in dose of lamotrigine tablets, USP should not exceed 25% of the total daily dose per week over a 2-week period, unless clinical response or lamotrigine plasma levels indicate otherwise [see Clinical Pharmacology (12.3)]. For women taking lamotrigine tablets, USP in addition to carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin that induce lamotrigine glucuronidation [see Drug Interactions (7), Clinical Pharmacology (12.3)], no adjustment to the dose of lamotrigine tablets, USP should be necessary.

  Women and Other Hormonal Contraceptive Preparations or Hormone Replacement Therapy: The effect of other hormonal contraceptive preparations or hormone replacement therapy on the pharmacokinetics of lamotrigine has not been systematically evaluated. It has been reported that ethinylestradiol, not progestogens, increased the clearance of lamotrigine up to 2-fold, and the progestin-only pills had no effect on lamotrigine plasma levels. Therefore, adjustments to the dosage of lamotrigine tablets, USP in the presence of progestogens alone will likely not be needed.

  Patients With Hepatic Impairment: Experience in patients with hepatic impairment is limited. Based on a clinical pharmacology study in 24 patients with mild, moderate, and severe liver impairment [see Use in Specific Populations (8.6), Clinical Pharmacology (12.3)], the following general recommendations can be made. No dosage adjustment is needed in patients with mild liver impairment. Initial, escalation, and maintenance doses should generally be reduced by approximately 25% in patients with moderate and severe liver impairment without ascites and 50% in patients with severe liver impairment with ascites. Escalation and maintenance doses may be adjusted according to clinical response.

  Patients With Renal Impairment: Initial doses of lamotrigine tablets, USP should be based on patients' concomitant medications (see Tables 1-3 or Table 5); reduced maintenance doses may be effective for patients with significant renal impairment [see Use in Specific Populations (8.7), Clinical Pharmacology (12.3)]. Few patients with severe renal impairment have been evaluated during chronic treatment with lamotrigine tablets, USP. Because there is inadequate experience in this population, lamotrigine tablets, USP should be used with caution in these patients.

  Discontinuation Strategy:Epilepsy: For patients receiving lamotrigine tablets, USP in combination with other AEDs, a re-evaluation of all AEDs in the regimen should be considered if a change in seizure control or an appearance or worsening of adverse experiences is observed.

  If a decision is made to discontinue therapy with lamotrigine tablets, USP, a step-wise reduction of dose over at least 2 weeks (approximately 50% per week) is recommended unless safety concerns require a more rapid withdrawal [see Warnings and Precautions (5.9)].

  Discontinuing carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin that induce lamotrigine glucuronidation should prolong the half-life of lamotrigine; discontinuing valproate should shorten the half-life of lamotrigine.

  Bipolar Disorder: In the controlled clinical trials, there was no increase in the incidence, type, or severity of adverse reactions following abrupt termination of lamotrigine tablets, USP. In clinical trials in patients with Bipolar Disorder, 2 patients experienced seizures shortly after abrupt withdrawal of lamotrigine tablets, USP. However, there were confounding factors that may have contributed to the occurrence of seizures in these bipolar patients. Discontinuation of lamotrigine tablets, USP should involve a step-wise reduction of dose over at least 2 weeks (approximately 50% per week) unless safety concerns require a more rapid withdrawal [see Warnings and Precautions (5.9)].

  2.2 Epilepsy – Adjunctive Therapy

  This section provides specific dosing recommendations for patients greater than 12 years of age and patients 2 to 12 years of age. Within each of these age-groups, specific dosing recommendations are provided depending upon concomitant AED or other concomitant medications (Table 1 for patients greater than 12 years of age and Table 2 for patients 2 to 12 years of age). A weight-based dosing guide for patients 2 to 12 years of age on concomitant valproate is provided in Table 3.

  Patients Over 12 Years of Age: Recommended dosing guidelines are summarized in Table 1.

  Table 1. Escalation Regimen for Lamotrigine Tablets, USP in Patients Over 12 Years of Age With Epilepsy b These drugs induce lamotrigine glucuronidation and increase clearance [see Drug Interactions (7), Clinical Pharmacology (12.3)]. Other drugs which have similar effects include estrogen-containing oral contraceptives [see Drug Interactions (7), Clinical Pharmacology (12.3)]. Dosing recommendations for oral contraceptives can be found in General Dosing Considerations [see Dosage and Administration (2.1)]. Patients on rifampin, or other drugs that induce lamotrigine glucuronidation and increase clearance, should follow the same dosing titration/maintenance regimen as that used with anticonvulsants that have this effect.
   
  For Patients TAKING Valproatea
  For Patients NOT TAKING Carbamazepine, Phenytoin, Phenobarbital, Primidoneb, or  Valproatea
  For Patients TAKING
  Carbamazepine, Phenytoin,
  Phenobarbital, or Primidoneband NOT TAKING Valproatea
  Weeks 1 and 2
  25 mg every other day
  25 mg every day
  50 mg/day
  Weeks 3 and 4
   
  25 mg every day
  50 mg/day
  100 mg/day
  (in 2 divided doses)
  Weeks 5 onwards
  to maintenance
  Increase by 25 to 50 mg/day every 1 to 2 weeks
  Increase by 50 mg/day every 1 to 2 weeks
  Increase by 100 mg/day every 1 to 2 weeks.
  Usual
  Maintenance Dose
   
  100 to 200 mg/day with
  valproate alone
  100 to 400 mg/day with valproate and other drugs that induce glucuronidation
  in 1 or 2 divided doses
  225 to 375 mg/day
  (in 2 divided doses)
  300 to 500 mg/day
  (in 2 divided doses)
  

  a Valproate has been shown to inhibit glucuronidation and decrease the apparent clearance of lamotrigine [see Drug Interactions (7), Clinical Pharmacology  (12.3)].

  Patients 2 to 12 Years of Age: Recommended dosing guidelines are summarized in Table 2.

  Smaller starting doses and slower dose escalations than those used in clinical trials are recommended because of the suggestion that the risk of rash may be decreased by smaller starting doses and slower dose escalations. Therefore, maintenance doses will take longer to reach in clinical practice than in clinical trials. It may take several weeks to months to achieve an individualized maintenance dose. Maintenance doses in patients weighing less than 30 kg, regardless of age or concomitant AED, may need to be increased as much as 50%, based on clinical response.

  Table 2. Escalation Regimen for Lamotrigine Tablets, USP in Patients 2 to 12 Years of Age With Epilepsy a Valproate has been shown to inhibit glucuronidation and decrease the apparent clearance of lamotrigine [see Drug Interactions (7), Clinical Pharmacology (12.3)].
  b These drugs induce lamotrigine glucuronidation and increase clearance [see Drug Interactions (7), Clinical Pharmacology (12.3)]. Other drugs that have similar effects include estrogen-containing oral contraceptives [see Drug Interactions (7), Clinical Pharmacology (12.3)]. Dosing recommendations for oral contraceptives can be found in General Dosing Considerations [see Dosage and Administration (2.1)]. Patients on rifampin or other drugs that induce lamotrigine glucuronidation and increase clearance, should follow the same dosing titration/maintenance regimen used with anticonvulsants that have this effect.
   
  For Patients TAKING Valproatea
  For Patients NOT TAKING Carbamazepine, Phenytoin, Phenobarbital, Primidoneb, or Valproatea
  For Patients Taking Carbamazepine, Phenytoin, Phenobarbital, or Primidoneb and NOT TAKING Valproatea
  Weeks 1 and 2
   
  0.15 mg/kg/day
  in 1 or 2 divided doses,
  rounded down to the nearest whole tablet (see Table 3 for weight based dosing guide)
  0.3 mg/kg/day
  in 1 or 2 divided doses, rounded down to the nearest whole tablet
  0.6 mg/kg/day
  in 2 divided doses, rounded down to the nearest whole tablet
  Weeks 3 and 4
   
  0.3 mg/kg/day
  in 1 or 2 divided doses,
  rounded down to the nearest whole tablet (see Table 3 for weight based dosing guide)
  0.6 mg/kg/day
  in 2 divided doses, rounded down to the nearest whole tablet
  1.2 mg/kg/day
  in 2 divided doses, rounded down to the nearest whole tablet
  Weeks 5 onwards to maintenance
   
  The dose should be increased every 1 to 2 weeks as follows: calculate 0.3 mg/kg/day, round this amount down to the nearest whole tablet, and add this amount to the previously administered daily dose
  The dose should be increased every 1 to 2 weeks as follows: calculate 0.6 mg/kg/day, round this
  amount down to the nearest whole tablet, and add this amount to the previously administered daily dose
  The dose should be increased every 1 to 2 weeks as follows: calculate 1.2 mg/kg/day, round this
  amount down to the nearest whole tablet, and add this amount to the previously administered daily dose
  Usual
  Maintenance Dose
   
  1 to 5 mg/kg/day
  (maximum 200 mg/day in 1 or 2 divided doses).
  1 to 3 mg/kg/day
  with valproate alone
  4.5 to 7.5 mg/kg/day
  (maximum 300 mg/day in 2 divided doses)
  5 to 15 mg/kg/day (maximum 400 mg/day in 2 divided doses)
  Maintenance
  dose in
  patients less
  than 30 kg
  May need to be increased
  by as much as 50%, based
  on clinical response
  May need to be increased by as much as 50%, based on clinical response
  May need to be increased by as much as 50%, based on clinical response
  Table 3. The Initial Weight-Based Dosing Guide for Patients 2 to 12 Years Taking Valproate (Weeks 1 to 4) With Epilepsy If the patient’s weight is
  Give this daily dose, using the most appropriate combination of lamotrigine 2-mg and 5-mg tablets
  Greater than
  And less than
  Weeks 1 and 2
  Weeks 3 and 4
  6.7 kg
  14 kg
  2 mg every other day
  2 mg every day
  14.1 kg
  27 kg
  2 mg every day
  4 mg every day
  27.1 kg
  34 kg
  4 mg every day
  8 mg every day
  34.1 kg
  40 kg
  5 mg every day
  10 mg every day
  

   

  Usual Adjunctive Maintenance Dose for Epilepsy: The usual maintenance doses identified in Tables 1 and 2 are derived from dosing regimens employed in the placebo-controlled adjunctive studies in which the efficacy of lamotrigine tablets, USP was established. In patients receiving multidrug regimens employing carbamazepine, phenytoin, phenobarbital, or primidone without valproate, maintenance doses of adjunctive lamotrigine tablets, USP as high as 700 mg/day have been used. In patients receiving valproate alone, maintenance doses of adjunctive lamotrigine tablets, USP as high as 200 mg/day have been used. The advantage of using doses above those recommended in Tables 1 through 4 has not been established in controlled trials.

  2.3 Epilepsy – Conversion From Adjunctive Therapy to Monotherapy

  The goal of the transition regimen is to effect the conversion to monotherapy with lamotrigine tablets, USP under conditions that ensure adequate seizure control while mitigating the risk of serious rash associated with the rapid titration of lamotrigine tablets, USP.

  The recommended maintenance dose of lamotrigine tablets, USP as monotherapy is 500 mg/day given in 2 divided doses.

  To avoid an increased risk of rash, the recommended initial dose and subsequent dose escalations of lamotrigine tablets, USP should not be exceeded [see Boxed Warning].

  Conversion From Adjunctive Therapy With Carbamazepine, Phenytoin, Phenobarbital, or Primidone to Monotherapy With Lamotrigine Tablets, USP: After achieving a dose of 500 mg/day of lamotrigine tablets, USP according to the guidelines in Table 1, the concomitant AED should be withdrawn by 20% decrements each week over a 4-week period. The regimen for the withdrawal of the concomitant AED is based on experience gained in the controlled monotherapy clinical trial.

  Conversion From Adjunctive Therapy With Valproate to Monotherapy With Lamotrigine Tablets, USP: The conversion regimen involves 4 steps outlined in Table 4.

  
  Table 4. Conversion From Adjunctive Therapy With Valproate to Monotherapy With Lamotrigine Tablets, USP in Patients ≥16 Years of Age With Epilepsy  
  Lamotrigine Tablets, USP
  Valproate
  Step 1
  Achieve a dose of 200 mg/day according to guidelines in Table 1 (if not already on
  200 mg/day).
  Maintain previous stable dose.
  Step 2
  Maintain at 200 mg/day.
  Decrease to 500 mg/day by decrements no greater than 500 mg/day/week and then maintain the dose of 500 mg/day for 1 week.
  Step 3
  Increase to 300 mg/day and maintain for 1 week.
  Simultaneously decrease to 250 mg/day and maintain for 1 week.
  Step 4
  Increase by 100 mg/day every week to achieve maintenance dose of 500 mg/day.
  Discontinue.
  

  Conversion from Adjunctive Therapy With Antiepileptic Drugs Other Than Carbamazepine, Phenytoin, Phenobarbital, Primidone, or Valproate to Monotherapy With Lamotrigine Tablets, USP: No specific dosing guidelines can be provided for conversion to monotherapy with lamotrigine tablets, USP with AEDs other than carbamazepine, phenobarbital, phenytoin, primidone, or valproate.

  2.4 Bipolar Disorder

  The goal of maintenance treatment with lamotrigine tablets, USP are to delay the time to occurrence of mood episodes (depression, mania, hypomania, mixed episodes) in patients treated for acute mood episodes with standard therapy. The target dose of lamotrigine tablets, USP are 200 mg/day (100 mg/day in patients taking valproate, which decreases the apparent clearance of lamotrigine, and 400 mg/day in patients not taking valproate and taking either carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin that increase the apparent clearance of lamotrigine). In the clinical trials, doses up to 400 mg/day as monotherapy were evaluated; however, no additional benefit was seen at 400 mg/day compared with 200 mg/day [see Clinical Studies (14.2)]. Accordingly, doses above 200 mg/day are not recommended. Treatment with lamotrigine tablets, USP are introduced, based on concurrent medications, according to the regimen outlined in Table 5. If other psychotropic medications are withdrawn following stabilization, the dose of lamotrigine tablets, USP should be adjusted. For patients discontinuing valproate, the dose of lamotrigine tablets, USP should be doubled over a 2-week period in equal weekly increments (see Table 6). For patients discontinuing carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin that induce lamotrigine glucuronidation, the dose of lamotrigine tablets, USP should remain constant for the first week and then should be decreased by half over a 2-week period in equal weekly decrements (see Table 6). The dose of lamotrigine tablets, USP may then be further adjusted to the target dose (200 mg) as clinically indicated.

  If other drugs are subsequently introduced, the dose of lamotrigine tablets, USP may need to be adjusted. In particular, the introduction of valproate requires reduction in the dose of lamotrigine tablets, USP [see Drug Interactions (7), Clinical Pharmacology (12.3)].

  To avoid an increased risk of rash, the recommended initial dose and subsequent dose escalations of lamotrigine tablets, USP should not be exceeded [see Boxed Warning].

  Table 5. Escalation Regimen for Lamotrigine Tablets, USP for Patients With Bipolar Disorder a Valproate has been shown to inhibit glucuronidation and decrease the apparent clearance of lamotrigine [see Drug Interactions (7), Clinical Pharmacology (12.3)].
  For Patients TAKING Valproatea
  For Patients NOT TAKING Carbamazepine, Phenytoin, Phenobarbital, Primidoneb, or Valproatea
  For Patients TAKING Carbamazepine, Phenytoin, Phenobarbital, or Primidoneb, and NOT TAKING Valproatea
  Weeks 1 and 2
  25 mg every other day
  25 mg daily
  50 mg daily
  Weeks 3 and 4
  25 mg daily
  50 mg daily
  100 mg daily, in divided doses
  Week 5
  50 mg daily
  100 mg daily
  200 mg daily, in divided doses
  Week 6
  100 mg daily
  200 mg daily
  300 mg daily, in divided doses
  Week 7
  100 mg daily
  200 mg daily
  up to 400 mg daily, in divided doses
  

   

  bThese drugs induce lamotrigine glucuronidation and increase clearance [see Drug Interactions (7), Clinical Pharmacology (12.3)]. Other drugs which have similar effects include estrogen containing oral contraceptives [see Drug Interactions (7), Clinical Pharmacology (12.3)]. Dosing recommendations for oral contraceptives can be found in General Dosing Considerations [see Dosage and Administration (2.1)]. Patients on rifampin, or other drugs that induce lamotrigine glucuronidation and increase clearance, should follow the same dosing titration/maintenance regimen as that used with anticonvulsants that have this effect.

  Table 6. Dosage Adjustments to Lamotrigine Tablets, USP for Patients With Bipolar Disorder Following Discontinuation of Psychotropic Medications Discontinuation of Psychotropic Drugs (excluding Carbamazepine, Phenytoin, Phenobarbital, Primidoneb, or Valproatea)
  After Discontinuation of Valproatea
  After Discontinuation of Carbamazepine, Phenytoin, Phenobarbital, or Primidoneb
  Current dose of lamotrigine tablets, USP (mg/day)
  100
  Current dose of lamotrigine tablets, USP (mg/day)
  400
  Week 1
   
  Maintain current dose of lamotrigine tablets, USP
  150
  400
  Week 2
   
  Maintain current dose of lamotrigine tablets, USP
  200
  300
  Week 3 onward
   
  Maintain current dose of lamotrigine tablets, USP
  200
  200
  

   

  a Valproate has been shown to inhibit glucuronidation and decrease the apparent clearance of lamotrigine [see Drug Interactions (7), Clinical Pharmacology (12.3)].

  bThese drugs induce lamotrigine glucuronidation and increase clearance [see Drug Interactions (7), Clinical Pharmacology (12.3)]. Other drugs that have similar effects include estrogen containing oral contraceptives [see Drug Interactions (7), Clinical Pharmacology (12.3)].Dosing recommendations for oral contraceptives can be found in General Dosing Considerations [see Dosage and Administration (2.1)]. Patients on rifampin, or other drugs that induce lamotrigine glucuronidation and increase clearance, should follow the same dosing titration/maintenance regimen as that used with anticonvulsants that have this effect.

  The benefit of continuing treatment in patients who had been stabilized in an 8- to 16-week open-label phase with lamotrigine tablets, USP was established in 2 randomized, placebo-controlled clinical maintenance trials [see Clinical Studies (14.2)]. However, the optimal duration of treatment with lamotrigine tablets, USP has not been established. Thus, patients should be periodically reassessed to determine the need for maintenance treatment.

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  2.1 General Dosing Considerations

  Rash:There are suggestions, yet to be proven, that the risk of severe, potentially life-threatening rash may be increased by (1) coadministration of lamotrigine tablets (chewable, dispersible) with valproate, (2) exceeding the recommended initial dose of lamotrigine tablets (chewable, dispersible), or (3) exceeding the recommended dose escalation for lamotrigine tablets (chewable, dispersible). However, cases have occurred in the absence of these factors [see Boxed Warning]. Therefore, it is important that the dosing recommendations be followed closely.

  The risk of nonserious rash may be increased when the recommended initial dose and/or the rate of dose escalation of lamotrigine tablets (chewable, dispersible) is exceeded and in patients with a history of allergy or rash to other AEDs.

  It is recommended that lamotrigine tablets (chewable, dispersible) not be restarted in patients who discontinued due to rash associated with prior treatment with lamotrigine, unless the potential benefits clearly outweigh the risks. If the decision is made to restart a patient who has discontinued lamotrigine, the need to restart with the initial dosing recommendations should be assessed. The greater the interval of time since the previous dose, the greater consideration should be given to restarting with the initial dosing recommendations. If a patient has discontinued lamotrigine for a period of more than 5 half-lives, it is recommended that initial dosing recommendations and guidelines be followed. The half-life of lamotrigine is affected by other concomitant medications [see Clinical Pharmacology (12.3)].

  Lamotrigine Tablets (Chewable, Dispersible) Added to Drugs Known to Induce or Inhibit Glucuronidation: Drugs other than those listed in the Clinical Pharmacology section [see Clinical Pharmacology (12.3)] have not been systematically evaluated in combination with lamotrigine. Because lamotrigine is metabolized predominantly by glucuronic acid conjugation, drugs that are known to induce or inhibit glucuronidation may affect the apparent clearance of lamotrigine and doses of lamotrigine tablets (chewable, dispersible) may require adjustment based on clinical response.

  Target Plasma Levels for Patients With Epilepsy or Bipolar Disorder: A therapeutic plasma concentration range has not been established for lamotrigine. Dosing of lamotrigine tablets (chewable, dispersible) should be based on therapeutic response [see Clinical Pharmacology (12.3)].

  Women Taking Estrogen-Containing Oral Contraceptives:Starting Lamotrigine Tablets (Chewable, Dispersible) in Women Taking Estrogen-Containing Oral Contraceptives: Although estrogen-containing oral contraceptives have been shown to increase the clearance of lamotrigine [see Clinical Pharmacology (12.3)], no adjustments to the recommended dose-escalation guidelines for lamotrigine tablets (chewable, dispersible) should be necessary solely based on the use of estrogen-containing oral contraceptives. Therefore, dose escalation should follow the recommended guidelines for initiating adjunctive therapy with lamotrigine tablets (chewable, dispersible) based on the concomitant AED or other concomitant medications (see Table 1 or Table 5). See below for adjustments to maintenance doses of lamotrigine tablets (chewable, dispersible) in women taking estrogen-containing oral contraceptives.

  Adjustments to the Maintenance Dose of Lamotrigine Tablets (Chewable, Dispersible) in Women Taking Estrogen-Containing Oral Contraceptives:

  (1) Taking Estrogen-Containing Oral Contraceptives:For women not taking carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin that induce lamotrigine glucuronidation [see Drug Interactions (7), Clinical Pharmacology (12.3)], the maintenance dose of lamotrigine tablets (chewable, dispersible) will in most cases need to be increased, by as much as 2-fold over the recommended target maintenance dose, in order to maintain a consistent lamotrigine plasma level [see Clinical Pharmacology (12.3)].

  (2) Starting Estrogen-Containing Oral Contraceptives:In women taking a stable dose of lamotrigine tablets (chewable, dispersible) and not taking carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin that induce lamotrigine glucuronidation [see Drug Interactions (7), Clinical Pharmacology (12.3)], the maintenance dose will in most cases need to be increased by as much as 2-fold in order to maintain a consistent lamotrigine plasma level. The dose increases should begin at the same time that the oral contraceptive is introduced and continue, based on clinical response, no more rapidly than 50 to 100 mg/day every week. Dose increases should not exceed the recommended rate (see Table 1 or Table 5) unless lamotrigine plasma levels or clinical response support larger increases. Gradual transient increases in lamotrigine plasma levels may occur during the week of inactive hormonal preparation (“pill-free” week), and these increases will be greater if dose increases are made in the days before or during the week of inactive hormonal preparation. Increased lamotrigine plasma levels could result in additional adverse reactions, such as dizziness, ataxia, and diplopia. If adverse reactions attributable to lamotrigine tablets (chewable, dispersible) consistently occur during the “pill-free” week, dose adjustments to the overall maintenance dose may be necessary. Dose adjustments limited to the “pill-free” week are not recommended. For women taking lamotrigine tablets (chewable, dispersible) in addition to carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin that induce lamotrigine glucuronidation [see Drug Interactions (7), Clinical Pharmacology (12.3)], no adjustment to the dose of lamotrigine tablets (chewable, dispersible) should be necessary.

  (3) Stopping Estrogen-Containing Oral Contraceptives:For women not taking carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin that induce lamotrigine glucuronidation [see Drug Interactions (7) , Clinical Pharmacology (12.3)], the maintenance dose of lamotrigine tablets (chewable, dispersible) will in most cases need to be decreased by as much as 50% in order to maintain a consistent lamotrigine plasma level. The decrease in dose of lamotrigine tablets (chewable, dispersible) should not exceed 25% of the total daily dose per week over a 2-week period, unless clinical response or lamotrigine plasma levels indicate otherwise [see Clinical Pharmacology (12.3)]. For women taking lamotrigine tablets (chewable, dispersible) in addition to carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin that induce lamotrigine glucuronidation [see Drug Interactions (7), Clinical Pharmacology (12.3)], no adjustment to the dose of lamotrigine tablets (chewable, dispersible) should be necessary.

  Women and Other Hormonal Contraceptive Preparations or Hormone Replacement Therapy: The effect of other hormonal contraceptive preparations or hormone replacement therapy on the pharmacokinetics of lamotrigine has not been systematically evaluated. It has been reported that ethinylestradiol, not progestogens, increased the clearance of lamotrigine up to 2-fold, and the progestin-only pills had no effect on lamotrigine plasma levels. Therefore, adjustments to the dosage of lamotrigine tablets (chewable, dispersible) in the presence of progestogens alone will likely not be needed.

  Patients With Hepatic Impairment: Experience in patients with hepatic impairment is limited. Based on a clinical pharmacology study in 24 patients with mild, moderate, and severe liver impairment [see Use in Specific Populations (8.6), Clinical Pharmacology (12.3)], the following general recommendations can be made. No dosage adjustment is needed in patients with mild liver impairment. Initial, escalation, and maintenance doses should generally be reduced by approximately 25% in patients with moderate and severe liver impairment without ascites and 50% in patients with severe liver impairment with ascites. Escalation and maintenance doses may be adjusted according to clinical response.

  Patients With Renal Impairment: Initial doses of lamotrigine tablets (chewable, dispersible) should be based on patients’ concomitant medications (see Tables 1-3 or Table 5); reduced maintenance doses may be effective for patients with significant renal impairment [see Use in Specific Populations (8.7), Clinical Pharmacology (12.3)]. Few patients with severe renal impairment have been evaluated during chronic treatment with lamotrigine tablets (chewable, dispersible). Because there is inadequate experience in this population, lamotrigine tablets (chewable, dispersible) should be used with caution in these patients.

  Discontinuation Strategy: Epilepsy: For patients receiving lamotrigine tablets (chewable, dispersible) in combination with other AEDs, a reevaluation of all AEDs in the regimen should be considered if a change in seizure control or an appearance or worsening of adverse reactions is observed.

  If a decision is made to discontinue therapy with lamotrigine tablets (chewable, dispersible), a step-wise reduction of dose over at least 2 weeks (approximately 50% per week) is recommended unless safety concerns require a more rapid withdrawal [see Warnings and Precautions (5.9)].

  Discontinuing carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin that induce lamotrigine glucuronidation should prolong the half-life of lamotrigine; discontinuing valproate should shorten the half-life of lamotrigine.

  Bipolar Disorder: In the controlled clinical trials, there was no increase in the incidence, type, or severity of adverse reactions following abrupt termination of lamotrigine tablets (chewable, dispersible). In clinical trials in patients with Bipolar Disorder, 2 patients experienced seizures shortly after abrupt withdrawal of lamotrigine tablets (chewable, dispersible). However, there were confounding factors that may have contributed to the occurrence of seizures in these bipolar patients. Discontinuation of lamotrigine tablets (chewable, dispersible) should involve a step-wise reduction of dose over at least 2 weeks (approximately 50% per week) unless safety concerns require a more rapid withdrawal [see Warnings and Precautions (5.9)].

  2.2 Epilepsy – Adjunctive Therapy

  This section provides specific dosing recommendations for patients greater than 12 years of age and patients 2 to 12 years of age. Within each of these age-groups, specific dosing recommendations are provided depending upon concomitant AED or other concomitant medications (Table 1 for patients greater than 12 years of age and Table 2 for patients 2 to 12 years of age). A weight-based dosing guide for patients 2 to 12 years of age on concomitant valproate is provided in Table 3.

  Patients Over 12 Years of Age: Recommended dosing guidelines are summarized in Table 1.

  Table 1. Escalation Regimen for Lamotrigine Tablets (Chewable, Dispersible) in Patients Over 12 Years of Age With Epilepsy    For Patients TAKING Valproatea  For Patients NOT TAKING Carbamazepine, Phenytoin, Phenobarbital, Primidone,b or Valproatea  For Patients TAKING Carbamazepine, Phenytoin, Phenobarbital, or Primidoneb and NOT TAKING Valproatea  Weeks 1 and 2  25 mg every other day  25 mg every day  50 mg/day  Weeks 3 and 4  25 mg every day  50 mg/day

  100 mg/day

  (in 2 divided doses)  Week 5 onwards to maintenance  Increase by 25 to 50 mg/day every 1 to 2 weeks  Increase by 50 mg/day every 1 to 2 weeks  Increase by 100 mg/day every 1 to 2 weeks.  Usual maintenance dose

  100 to 200 mg/day with valproate alone

  100 to 400 mg/day with valproate and other drugs that induce glucuronidation

  (in 1 or 2 divided doses)

  225 to 375 mg/day

  (in 2 divided doses)

  300 to 500 mg/day

  (in 2 divided doses)

  aValproate has been shown to inhibit glucuronidation and decrease the apparent clearance of lamotrigine [see Drug Interactions (7), Clinical Pharmacology (12.3)].
  bThese drugs induce lamotrigine glucuronidation and increase clearance [see Drug Interactions (7), Clinical Pharmacology (12.3)]. Other drugs that have similar effects include estrogen-containing oral contraceptives [see Drug Interactions (7), Clinical Pharmacology (12.3)]. Dosing recommendations for oral contraceptives can be found in General Dosing Considerations [see Dosage and Administration (2.1)]. Patients on rifampin, or other drugs that induce lamotrigine glucuronidation and increase clearance, should follow the same dosing titration/maintenance regimen as that used with anticonvulsants that have this effect.

  Patients 2 to 12 Years of Age: Recommended dosing guidelines are summarized in Table 2.

  Smaller starting doses and slower dose escalations than those used in clinical trials are recommended because of the suggestion that the risk of rash may be decreased by smaller starting doses and slower dose escalations. Therefore, maintenance doses will take longer to reach in clinical practice than in clinical trials. It may take several weeks to months to achieve an individualized maintenance dose. Maintenance doses in patients weighing less than 30 kg, regardless of age or concomitant AED, may need to be increased as much as 50%, based on clinical response.

  The smallest available strength of lamotrigine tablets (chewable, dispersible) is 2 mg, and only whole tablets should be administered. If the calculated dose cannot be achieved using whole tablets, the dose should be rounded down to the nearest whole tablet [see How Supplied/Storage and Handling (16) and Medication Guide].

  Table 2. Escalation Regimen for Lamotrigine Tablets (Chewable, Dispersible) in Patients 2 to 12 Years of Age With Epilepsy    For Patients TAKING Valproatea  For Patients NOT TAKING Carbamazepine, Phenytoin, Phenobarbital, Primidone,b or Valproatea  For Patients TAKING Carbamazepine, Phenytoin, Phenobarbital, or Primidoneb and NOT TAKING Valproate a  Weeks 1 and 2  

  0.15 mg/kg/day
  in 1 or 2 divided doses, rounded down to the nearest whole tablet (see Table 3 for weight-based dosing guide)

   

  0.3 mg/kg/day
  in 1 or 2 divided doses, rounded down to the nearest whole tablet

   

  0.6 mg/kg/day
  in 2 divided doses, rounded down to the nearest whole tablet

   Weeks 3 and 4  

  0.3 mg/kg/day

  in 1 or 2 divided doses, rounded down to the nearest whole tablet (see Table 3 for weight-based dosing guide)  

  0.6 mg/kg/day
  in 2 divided doses, rounded down to the nearest whole tablet

   

  1.2 mg/kg/day
  in 2 divided doses, rounded down to the nearest whole tablet

  Week 5 onwards to maintenance  The dose should be increased every 1 to 2 weeks as follows: calculate 0.3 mg/kg/day, round this amount down to the nearest whole tablet, and add this amount to the previously administered daily dose  The dose should be increased every 1 to 2 weeks as follows: calculate 0.6 mg/kg/day, round this amount down to the nearest whole tablet, and add this amount to the previously administered daily dose  The dose should be increased every 1 to 2 weeks as follows: calculate 1.2 mg/kg/day, round this amount down to the nearest whole tablet, and add this amount to the previously administered daily dose Usual maintenance dose

  1 to 5 mg/kg/day (maximum 200 mg/day in 1 or 2 divided doses)
  1 to 3 mg/kg/day with valproate alone 

  4.5 to 7.5 mg/kg/day
  (maximum 300 mg/day in 2 divided doses)

   5 to 15 mg/kg/day (maximum 400 mg/day in 2 divided doses) Maintenance dose in patients less than 30 kg

  May need to be increased by as much as 50%, based on clinical response

   May need to be increased by as much as 50%, based on clinical response  May need to be increased by as much as 50%, based on clinical response

  Note: Only whole tablets should be used for dosing.
  aValproate has been shown to inhibit glucuronidation and decrease the apparent clearance of lamotrigine [see Drug Interactions (7), Clinical Pharmacology (12.3)].
  bThese drugs induce lamotrigine glucuronidation and increase clearance [see Drug Interactions (7), Clinical Pharmacology (12.3)]. Other drugs that have similar effects include estrogen-containing oral contraceptives [see Drug Interactions (7), Clinical Pharmacology (12.3)]. Dosing recommendations for oral contraceptives can be found in General Dosing Considerations [see Dosage and Administration (2.1)]. Patients on rifampin, or other drugs that induce lamotrigine glucuronidation and increase clearance, should follow the same dosing titration/maintenance regimen as that used with anticonvulsants that have this effect.

  Table 3. The Initial Weight-Based Dosing Guide for Patients 2 to 12 Years of Age Taking Valproate (Weeks 1 to 4) With Epilepsy  If the patient’s weight is  Give this daily dose, using the most appropriate combination of lamotrigine tablets (chewable, dispersible) 2-mg and 5-mg  Greater than  And less than  Weeks 1 and 2  Weeks 3 and 4  6.7 kg  14 kg  2 mg every other day  2 mg every day  14.1 kg  27 kg  2 mg every day  4 mg every day  27.1 kg  34 kg  4 mg every day  8 mg every day  34.1 kg  40 kg  5 mg every day  10 mg every day

  Usual Adjunctive Maintenance Dose for Epilepsy: The usual maintenance doses identified in Tables 1 and 2 are derived from dosing regimens employed in the placebo-controlled adjunctive studies in which the efficacy of lamotrigine tablets (chewable, dispersible) was established. In patients receiving multidrug regimens employing carbamazepine, phenytoin, phenobarbital, or primidone without valproate, maintenance doses of adjunctive lamotrigine tablets (chewable, dispersible) as high as 700 mg/day have been used. In patients receiving valproate alone, maintenance doses of adjunctive lamotrigine tablets (chewable, dispersible) as high as 200 mg/day have been used. The advantage of using doses above those recommended in Tables 1 through 4 has not been established in controlled trials.

  2.3 Epilepsy – Conversion From Adjunctive Therapy to Monotherapy

  The goal of the transition regimen is to effect the conversion to monotherapy with lamotrigine tablets (chewable, dispersible) under conditions that ensure adequate seizure control while mitigating the risk of serious rash associated with the rapid titration of lamotrigine tablets (chewable, dispersible).

  The recommended maintenance dose of lamotrigine tablets (chewable, dispersible) as monotherapy is 500 mg/day given in 2 divided doses.

  To avoid an increased risk of rash, the recommended initial dose and subsequent dose escalations of lamotrigine tablets (chewable, dispersible) should not be exceeded [see Boxed Warning].

  Conversion From Adjunctive Therapy With Carbamazepine, Phenytoin, Phenobarbital, or Primidone to Monotherapy With Lamotrigine Tablets (Chewable, Dispersible): After achieving a dose of 500 mg/day of lamotrigine tablets (chewable, dispersible) according to the guidelines in Table 1, the concomitant AED should be withdrawn by 20% decrements each week over a 4-week period. The regimen for the withdrawal of the concomitant AED is based on experience gained in the controlled monotherapy clinical trial.

  Conversion From Adjunctive Therapy With Valproate to Monotherapy With Lamotrigine Tablets (Chewable, Dispersible): The conversion regimen involves 4 steps outlined in Table 4.

  Table 4. Conversion From Adjunctive Therapy With Valproate to Monotherapy With Lamotrigine Tablets (Chewable, Dispersible) in Patients ≥16 Years of Age With Epilepsy    Lamotrigine Tablets (Chewable, Dispersible)  Valproate  Step 1  Achieve a dose of 200 mg/day according to guidelines in Table 1 (if not already on 200 mg/day).  

  Maintain previous stable dose.

   Step 2  Maintain at 200 mg/day.  Decrease to 500 mg/day by decrements no greater than 500 mg/day/week and then maintain the dose of 500 mg/day for 1 week.  Step 3  Increase to 300 mg/day and maintain for 1 week.  Simultaneously decrease to 250 mg/day and maintain for 1 week.  Step 4  Increase by 100 mg/day every week to achieve maintenance dose of 500 mg/day.  Discontinue.

  Conversion From Adjunctive Therapy With Antiepileptic Drugs Other Than Carbamazepine, Phenytoin, Phenobarbital, Primidone, or Valproate to Monotherapy With Lamotrigine Tablets (Chewable, Dispersible): No specific dosing guidelines can be provided for conversion to monotherapy with lamotrigine tablets (chewable, dispersible) with AEDs other than carbamazepine, phenobarbital, phenytoin, primidone, or valproate.

  2.4 Bipolar Disorder

  The goal of maintenance treatment with lamotrigine tablets (chewable, dispersible) is to delay the time to occurrence of mood episodes (depression, mania, hypomania, mixed episodes) in patients treated for acute mood episodes with standard therapy. The target dose of lamotrigine tablets (chewable, dispersible) is 200 mg/day (100 mg/day in patients taking valproate, which decreases the apparent clearance of lamotrigine, and 400 mg/day in patients not taking valproate and taking either carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin that increase the apparent clearance of lamotrigine). In the clinical trials, doses up to 400 mg/day as monotherapy were evaluated; however, no additional benefit was seen at 400 mg/day compared with 200 mg/day [see Clinical Studies (14.2)]. Accordingly, doses above 200 mg/day are not recommended. Treatment with lamotrigine tablets (chewable, dispersible) is introduced, based on concurrent medications, according to the regimen outlined in Table 5. If other psychotropic medications are withdrawn following stabilization, the dose of lamotrigine tablets (chewable, dispersible) should be adjusted. For patients discontinuing valproate, the dose of lamotrigine tablets (chewable, dispersible) should be doubled over a 2-week period in equal weekly increments (see Table 6). For patients discontinuing carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin that induce lamotrigine glucuronidation, the dose of lamotrigine tablets (chewable, dispersible) should remain constant for the first week and then should be decreased by half over a 2-week period in equal weekly decrements (see Table 6). The dose of lamotrigine tablets (chewable, dispersible) may then be further adjusted to the target dose (200 mg) as clinically indicated.

  If other drugs are subsequently introduced, the dose of lamotrigine tablets (chewable, dispersible) may need to be adjusted. In particular, the introduction of valproate requires reduction in the dose of lamotrigine tablets (chewable, dispersible) [see Drug Interactions (7), Clinical Pharmacology (12.3)].

  To avoid an increased risk of rash, the recommended initial dose and subsequent dose escalations of lamotrigine tablets (chewable, dispersible) should not be exceeded [see Boxed Warning].

  Table 5. Escalation Regimen for Lamotrigine Tablets (Chewable, Dispersible) for Patients With Bipolar Disorder    For Patients TAKING Valproatea  For Patients NOT TAKING Carbamazepine, Phenytoin, Phenobarbital, Primidone,b or Valproatea  For Patients TAKING Carbamazepine, Phenytoin, Phenobarbital, or Primidoneb and NOT TAKING Valproatea  Weeks 1 and 2  25 mg every other day  25 mg daily  50 mg daily  Weeks 3 and 4  25 mg daily  50 mg daily  100 mg daily, in divided doses  Week 5  50 mg daily  100 mg daily  200 mg daily, in divided doses  Week 6  100 mg daily  200 mg daily  300 mg daily, in divided doses  Week 7  100 mg daily  200 mg daily  up to 400 mg daily, in divided doses

  aValproate has been shown to inhibit glucuronidation and decrease the apparent clearance of lamotrigine. [see Drug Interactions (7), Clinical Pharmacology (12.3)].
  bThese drugs induce lamotrigine glucuronidation and increase clearance [see Drug Interactions (7), Clinical Pharmacology (12.3)]. Other drugs that have similar effects include estrogen-containing oral contraceptives [see Drug Interactions (7), Clinical Pharmacology (12.3)]. Dosing recommendations for oral contraceptives can be found in General Dosing Considerations [see Dosage and Administration (2.1)]. Patients on rifampin, or other drugs that induce lamotrigine glucuronidation and increase clearance, should follow the same dosing titration/maintenance regimen as that used with anticonvulsants that have this effect.

  Table 6. Dosage Adjustments to Lamotrigine Tablets (Chewable, Dispersible) for Patients With Bipolar Disorder Following Discontinuation of Psychotropic Medications    Discontinuation of Psychotropic Drugs (excluding Carbamazepine, Phenytoin, Phenobarbital, Primidone,b or Valproatea)  After Discontinuation of Valproatea  After Discontinuation of Carbamazepine, Phenytoin, Phenobarbital, or Primidoneb  

  Current dose of lamotrigine tablets (chewable, dispersible) (mg/day)

  100  

  Current dose of lamotrigine tablets (chewable, dispersible) (mg/day)

  400  Week 1  Maintain current dose of lamotrigine tablets (chewable, dispersible)  150  400  Week 2  Maintain current dose of lamotrigine tablets (chewable, dispersible)  200  300  Week 3 onward  Maintain current dose of lamotrigine tablets (chewable, dispersible)  200  200

  aValproate has been shown to inhibit glucuronidation and decrease the apparent clearance of lamotrigine. [see Drug Interactions (7), Clinical Pharmacology (12.3)].
  bThese drugs induce lamotrigine glucuronidation and increase clearance [see Drug Interactions (7), Clinical Pharmacology (12.3)]. Other drugs that have similar effects include estrogen-containing oral contraceptives [see Drug Interactions (7), Clinical Pharmacology (12.3)]. Dosing recommendations for oral contraceptives can be found in General Dosing Considerations [see Dosage and Administration (2.1)]. Patients on rifampin, or other drugs that induce lamotrigine glucuronidation and increase clearance, should follow the same dosing titration/maintenance regimen as that used with anticonvulsants that have this effect.

  The benefit of continuing treatment in patients who had been stabilized in an 8- to 16-week open-label phase with lamotrigine tablets (chewable, dispersible) was established in 2 randomized, placebo-controlled clinical maintenance trials [see Clinical Studies (14.2)]. However, the optimal duration of treatment with lamotrigine tablets (chewable, dispersible) has not been established. Thus, patients should be periodically reassessed to determine the need for maintenance treatment.

  2.5 Administration of Lamotrigine Tablets (Chewable, Dispersible)

  Lamotrigine tablets (chewable, dispersible) may be swallowed whole, chewed, or dispersed in water or diluted fruit juice. If the tablets are chewed, consume a small amount of water or diluted fruit juice to aid in swallowing.

  To disperse lamotrigine tablets (chewable, dispersible), add the tablets to a small amount of liquid (1 teaspoon, or enough to cover the medication). Approximately 1 minute later, when the tablets are completely dispersed, swirl the solution and consume the entire quantity immediately. No attempt should be made to administer partial quantities of the dispersed tablets.

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  2.1 General Dosing Considerations

  Rash:There are suggestions, yet to be proven, that the risk of severe, potentially life-threatening rash may be increased by (1) coadministration of lamotrigine tablets (chewable, dispersible) with valproate, (2) exceeding the recommended initial dose of lamotrigine tablets (chewable, dispersible), or (3) exceeding the recommended dose escalation for lamotrigine tablets (chewable, dispersible). However, cases have occurred in the absence of these factors [see Boxed Warning]. Therefore, it is important that the dosing recommendations be followed closely.

  The risk of nonserious rash may be increased when the recommended initial dose and/or the rate of dose escalation of lamotrigine tablets (chewable, dispersible) is exceeded and in patients with a history of allergy or rash to other AEDs.

  It is recommended that lamotrigine tablets (chewable, dispersible) not be restarted in patients who discontinued due to rash associated with prior treatment with lamotrigine, unless the potential benefits clearly outweigh the risks. If the decision is made to restart a patient who has discontinued lamotrigine, the need to restart with the initial dosing recommendations should be assessed. The greater the interval of time since the previous dose, the greater consideration should be given to restarting with the initial dosing recommendations. If a patient has discontinued lamotrigine for a period of more than 5 half-lives, it is recommended that initial dosing recommendations and guidelines be followed. The half-life of lamotrigine is affected by other concomitant medications [see Clinical Pharmacology (12.3)].

  Lamotrigine Tablets (Chewable, Dispersible) Added to Drugs Known to Induce or Inhibit Glucuronidation: Drugs other than those listed in the Clinical Pharmacology section [see Clinical Pharmacology (12.3)] have not been systematically evaluated in combination with lamotrigine. Because lamotrigine is metabolized predominantly by glucuronic acid conjugation, drugs that are known to induce or inhibit glucuronidation may affect the apparent clearance of lamotrigine and doses of lamotrigine tablets (chewable, dispersible) may require adjustment based on clinical response.

  Target Plasma Levels for Patients With Epilepsy or Bipolar Disorder: A therapeutic plasma concentration range has not been established for lamotrigine. Dosing of lamotrigine tablets (chewable, dispersible) should be based on therapeutic response [see Clinical Pharmacology (12.3)].

  Women Taking Estrogen-Containing Oral Contraceptives:Starting Lamotrigine Tablets (Chewable, Dispersible) in Women Taking Estrogen-Containing Oral Contraceptives: Although estrogen-containing oral contraceptives have been shown to increase the clearance of lamotrigine [see Clinical Pharmacology (12.3)], no adjustments to the recommended dose-escalation guidelines for lamotrigine tablets (chewable, dispersible) should be necessary solely based on the use of estrogen-containing oral contraceptives. Therefore, dose escalation should follow the recommended guidelines for initiating adjunctive therapy with lamotrigine tablets (chewable, dispersible) based on the concomitant AED or other concomitant medications (see Table 1 or Table 5). See below for adjustments to maintenance doses of lamotrigine tablets (chewable, dispersible) in women taking estrogen-containing oral contraceptives.

  Adjustments to the Maintenance Dose of Lamotrigine Tablets (Chewable, Dispersible) in Women Taking Estrogen-Containing Oral Contraceptives:

  (1) Taking Estrogen-Containing Oral Contraceptives:For women not taking carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin that induce lamotrigine glucuronidation [see Drug Interactions (7), Clinical Pharmacology (12.3)], the maintenance dose of lamotrigine tablets (chewable, dispersible) will in most cases need to be increased, by as much as 2-fold over the recommended target maintenance dose, in order to maintain a consistent lamotrigine plasma level [see Clinical Pharmacology (12.3)].

  (2) Starting Estrogen-Containing Oral Contraceptives:In women taking a stable dose of lamotrigine tablets (chewable, dispersible) and not taking carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin that induce lamotrigine glucuronidation [see Drug Interactions (7), Clinical Pharmacology (12.3)], the maintenance dose will in most cases need to be increased by as much as 2-fold in order to maintain a consistent lamotrigine plasma level. The dose increases should begin at the same time that the oral contraceptive is introduced and continue, based on clinical response, no more rapidly than 50 to 100 mg/day every week. Dose increases should not exceed the recommended rate (see Table 1 or Table 5) unless lamotrigine plasma levels or clinical response support larger increases. Gradual transient increases in lamotrigine plasma levels may occur during the week of inactive hormonal preparation (“pill-free” week), and these increases will be greater if dose increases are made in the days before or during the week of inactive hormonal preparation. Increased lamotrigine plasma levels could result in additional adverse reactions, such as dizziness, ataxia, and diplopia. If adverse reactions attributable to lamotrigine tablets (chewable, dispersible) consistently occur during the “pill-free” week, dose adjustments to the overall maintenance dose may be necessary. Dose adjustments limited to the “pill-free” week are not recommended. For women taking lamotrigine tablets (chewable, dispersible) in addition to carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin that induce lamotrigine glucuronidation [see Drug Interactions (7), Clinical Pharmacology (12.3)], no adjustment to the dose of lamotrigine tablets (chewable, dispersible) should be necessary.

  (3) Stopping Estrogen-Containing Oral Contraceptives:For women not taking carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin that induce lamotrigine glucuronidation [see Drug Interactions (7) , Clinical Pharmacology (12.3)], the maintenance dose of lamotrigine tablets (chewable, dispersible) will in most cases need to be decreased by as much as 50% in order to maintain a consistent lamotrigine plasma level. The decrease in dose of lamotrigine tablets (chewable, dispersible) should not exceed 25% of the total daily dose per week over a 2-week period, unless clinical response or lamotrigine plasma levels indicate otherwise [see Clinical Pharmacology (12.3)]. For women taking lamotrigine tablets (chewable, dispersible) in addition to carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin that induce lamotrigine glucuronidation [see Drug Interactions (7), Clinical Pharmacology (12.3)], no adjustment to the dose of lamotrigine tablets (chewable, dispersible) should be necessary.

  Women and Other Hormonal Contraceptive Preparations or Hormone Replacement Therapy: The effect of other hormonal contraceptive preparations or hormone replacement therapy on the pharmacokinetics of lamotrigine has not been systematically evaluated. It has been reported that ethinylestradiol, not progestogens, increased the clearance of lamotrigine up to 2-fold, and the progestin-only pills had no effect on lamotrigine plasma levels. Therefore, adjustments to the dosage of lamotrigine tablets (chewable, dispersible) in the presence of progestogens alone will likely not be needed.

  Patients With Hepatic Impairment: Experience in patients with hepatic impairment is limited. Based on a clinical pharmacology study in 24 patients with mild, moderate, and severe liver impairment [see Use in Specific Populations (8.6), Clinical Pharmacology (12.3)], the following general recommendations can be made. No dosage adjustment is needed in patients with mild liver impairment. Initial, escalation, and maintenance doses should generally be reduced by approximately 25% in patients with moderate and severe liver impairment without ascites and 50% in patients with severe liver impairment with ascites. Escalation and maintenance doses may be adjusted according to clinical response.

  Patients With Renal Impairment: Initial doses of lamotrigine tablets (chewable, dispersible) should be based on patients’ concomitant medications (see Tables 1-3 or Table 5); reduced maintenance doses may be effective for patients with significant renal impairment [see Use in Specific Populations (8.7), Clinical Pharmacology (12.3)]. Few patients with severe renal impairment have been evaluated during chronic treatment with lamotrigine tablets (chewable, dispersible). Because there is inadequate experience in this population, lamotrigine tablets (chewable, dispersible) should be used with caution in these patients.

  Discontinuation Strategy: Epilepsy: For patients receiving lamotrigine tablets (chewable, dispersible) in combination with other AEDs, a reevaluation of all AEDs in the regimen should be considered if a change in seizure control or an appearance or worsening of adverse reactions is observed.

  If a decision is made to discontinue therapy with lamotrigine tablets (chewable, dispersible), a step-wise reduction of dose over at least 2 weeks (approximately 50% per week) is recommended unless safety concerns require a more rapid withdrawal [see Warnings and Precautions (5.9)].

  Discontinuing carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin that induce lamotrigine glucuronidation should prolong the half-life of lamotrigine; discontinuing valproate should shorten the half-life of lamotrigine.

  Bipolar Disorder: In the controlled clinical trials, there was no increase in the incidence, type, or severity of adverse reactions following abrupt termination of lamotrigine tablets (chewable, dispersible). In clinical trials in patients with Bipolar Disorder, 2 patients experienced seizures shortly after abrupt withdrawal of lamotrigine tablets (chewable, dispersible). However, there were confounding factors that may have contributed to the occurrence of seizures in these bipolar patients. Discontinuation of lamotrigine tablets (chewable, dispersible) should involve a step-wise reduction of dose over at least 2 weeks (approximately 50% per week) unless safety concerns require a more rapid withdrawal [see Warnings and Precautions (5.9)].

  2.2 Epilepsy – Adjunctive Therapy

  This section provides specific dosing recommendations for patients greater than 12 years of age and patients 2 to 12 years of age. Within each of these age-groups, specific dosing recommendations are provided depending upon concomitant AED or other concomitant medications (Table 1 for patients greater than 12 years of age and Table 2 for patients 2 to 12 years of age). A weight-based dosing guide for patients 2 to 12 years of age on concomitant valproate is provided in Table 3.

  Patients Over 12 Years of Age: Recommended dosing guidelines are summarized in Table 1.

  Table 1. Escalation Regimen for Lamotrigine Tablets (Chewable, Dispersible) in Patients Over 12 Years of Age With Epilepsy

   

   For Patients TAKING Valproatea

   For Patients NOT TAKING Carbamazepine, Phenytoin, Phenobarbital, Primidone,b or Valproatea

   For Patients TAKING Carbamazepine, Phenytoin, Phenobarbital, or Primidoneb and NOT TAKING Valproatea

   Weeks 1 and 2

   25 mg every other day

   25 mg every day

   50 mg/day

   Weeks 3 and 4

   25 mg every day

   50 mg/day

  100 mg/day

  (in 2 divided doses)

   Week 5 onwards to maintenance

   Increase by 25 to 50 mg/day every 1 to 2 weeks

   Increase by 50 mg/day every 1 to 2 weeks

   Increase by 100 mg/day every 1 to 2 weeks.

   Usual maintenance dose

  100 to 200 mg/day with valproate alone

  100 to 400 mg/day with valproate and other drugs that induce glucuronidation

  (in 1 or 2 divided doses)

  225 to 375 mg/day

  (in 2 divided doses)

  300 to 500 mg/day

  (in 2 divided doses)

  aValproate has been shown to inhibit glucuronidation and decrease the apparent clearance of lamotrigine [see Drug Interactions (7), Clinical Pharmacology (12.3)].
  bThese drugs induce lamotrigine glucuronidation and increase clearance [see Drug Interactions (7), Clinical Pharmacology (12.3)]. Other drugs that have similar effects include estrogen-containing oral contraceptives [see Drug Interactions (7), Clinical Pharmacology (12.3)]. Dosing recommendations for oral contraceptives can be found in General Dosing Considerations [see Dosage and Administration (2.1)]. Patients on rifampin, or other drugs that induce lamotrigine glucuronidation and increase clearance, should follow the same dosing titration/maintenance regimen as that used with anticonvulsants that have this effect.

  Patients 2 to 12 Years of Age: Recommended dosing guidelines are summarized in Table 2.

  Smaller starting doses and slower dose escalations than those used in clinical trials are recommended because of the suggestion that the risk of rash may be decreased by smaller starting doses and slower dose escalations. Therefore, maintenance doses will take longer to reach in clinical practice than in clinical trials. It may take several weeks to months to achieve an individualized maintenance dose. Maintenance doses in patients weighing less than 30 kg, regardless of age or concomitant AED, may need to be increased as much as 50%, based on clinical response.

  The smallest available strength of lamotrigine tablets (chewable, dispersible) is 2 mg, and only whole tablets should be administered. If the calculated dose cannot be achieved using whole tablets, the dose should be rounded down to the nearest whole tablet [see How Supplied/Storage and Handling (16) and Medication Guide].

  Table 2. Escalation Regimen for Lamotrigine Tablets (Chewable, Dispersible) in Patients 2 to 12 Years of Age With Epilepsy

   

   For Patients TAKING Valproatea

   For Patients NOT TAKING Carbamazepine, Phenytoin, Phenobarbital, Primidone,b or Valproatea

   For Patients TAKING Carbamazepine, Phenytoin, Phenobarbital, or Primidoneb and NOT TAKING Valproate a

   Weeks 1 and 2

   

  0.15 mg/kg/day
  in 1 or 2 divided doses, rounded down to the nearest whole tablet (see Table 3 for weight-based dosing guide)

   

  0.3 mg/kg/day
  in 1 or 2 divided doses, rounded down to the nearest whole tablet

   

  0.6 mg/kg/day
  in 2 divided doses, rounded down to the nearest whole tablet

   Weeks 3 and 4

   

  0.3 mg/kg/day

  in 1 or 2 divided doses, rounded down to the nearest whole tablet (see Table 3 for weight-based dosing guide)

   

  0.6 mg/kg/day
  in 2 divided doses, rounded down to the nearest whole tablet

   

  1.2 mg/kg/day
  in 2 divided doses, rounded down to the nearest whole tablet

  Week 5 onwards to maintenance

   The dose should be increased every 1 to 2 weeks as follows: calculate 0.3 mg/kg/day, round this amount down to the nearest whole tablet, and add this amount to the previously administered daily dose

   The dose should be increased every 1 to 2 weeks as follows: calculate 0.6 mg/kg/day, round this amount down to the nearest whole tablet, and add this amount to the previously administered daily dose

   The dose should be increased every 1 to 2 weeks as follows: calculate 1.2 mg/kg/day, round this amount down to the nearest whole tablet, and add this amount to the previously administered daily dose

  Usual maintenance dose

  1 to 5 mg/kg/day (maximum 200 mg/day in 1 or 2 divided doses)
  1 to 3 mg/kg/day with valproate alone 

  4.5 to 7.5 mg/kg/day
  (maximum 300 mg/day in 2 divided doses)

   5 to 15 mg/kg/day (maximum 400 mg/day in 2 divided doses)

  Maintenance dose in patients less than 30 kg

  May need to be increased by as much as 50%, based on clinical response

   May need to be increased by as much as 50%, based on clinical response

   May need to be increased by as much as 50%, based on clinical response

  Note: Only whole tablets should be used for dosing.
  aValproate has been shown to inhibit glucuronidation and decrease the apparent clearance of lamotrigine [see Drug Interactions (7), Clinical Pharmacology (12.3)].
  bThese drugs induce lamotrigine glucuronidation and increase clearance [see Drug Interactions (7), Clinical Pharmacology (12.3)]. Other drugs that have similar effects include estrogen-containing oral contraceptives [see Drug Interactions (7), Clinical Pharmacology (12.3)]. Dosing recommendations for oral contraceptives can be found in General Dosing Considerations [see Dosage and Administration (2.1)]. Patients on rifampin, or other drugs that induce lamotrigine glucuronidation and increase clearance, should follow the same dosing titration/maintenance regimen as that used with anticonvulsants that have this effect.

  Table 3. The Initial Weight-Based Dosing Guide for Patients 2 to 12 Years of Age Taking Valproate (Weeks 1 to 4) With Epilepsy

   If the patient’s weight is

   Give this daily dose, using the most appropriate combination of lamotrigine tablets (chewable, dispersible) 2-mg and 5-mg

   Greater than

   And less than

   Weeks 1 and 2

   Weeks 3 and 4

   6.7 kg

   14 kg

   2 mg every other day

   2 mg every day

   14.1 kg

   27 kg

   2 mg every day

   4 mg every day

   27.1 kg

   34 kg

   4 mg every day

   8 mg every day

   34.1 kg

   40 kg

   5 mg every day

   10 mg every day

  Usual Adjunctive Maintenance Dose for Epilepsy: The usual maintenance doses identified in Tables 1 and 2 are derived from dosing regimens employed in the placebo-controlled adjunctive studies in which the efficacy of lamotrigine tablets (chewable, dispersible) was established. In patients receiving multidrug regimens employing carbamazepine, phenytoin, phenobarbital, or primidone without valproate, maintenance doses of adjunctive lamotrigine tablets (chewable, dispersible) as high as 700 mg/day have been used. In patients receiving valproate alone, maintenance doses of adjunctive lamotrigine tablets (chewable, dispersible) as high as 200 mg/day have been used. The advantage of using doses above those recommended in Tables 1 through 4 has not been established in controlled trials.

  2.3 Epilepsy – Conversion From Adjunctive Therapy to Monotherapy

  The goal of the transition regimen is to effect the conversion to monotherapy with lamotrigine tablets (chewable, dispersible) under conditions that ensure adequate seizure control while mitigating the risk of serious rash associated with the rapid titration of lamotrigine tablets (chewable, dispersible).

  The recommended maintenance dose of lamotrigine tablets (chewable, dispersible) as monotherapy is 500 mg/day given in 2 divided doses.

  To avoid an increased risk of rash, the recommended initial dose and subsequent dose escalations of lamotrigine tablets (chewable, dispersible) should not be exceeded [see Boxed Warning].

  Conversion From Adjunctive Therapy With Carbamazepine, Phenytoin, Phenobarbital, or Primidone to Monotherapy With Lamotrigine Tablets (Chewable, Dispersible): After achieving a dose of 500 mg/day of lamotrigine tablets (chewable, dispersible) according to the guidelines in Table 1, the concomitant AED should be withdrawn by 20% decrements each week over a 4-week period. The regimen for the withdrawal of the concomitant AED is based on experience gained in the controlled monotherapy clinical trial.

  Conversion From Adjunctive Therapy With Valproate to Monotherapy With Lamotrigine Tablets (Chewable, Dispersible): The conversion regimen involves 4 steps outlined in Table 4.

  Table 4. Conversion From Adjunctive Therapy With Valproate to Monotherapy With Lamotrigine Tablets (Chewable, Dispersible) in Patients ≥16 Years of Age With Epilepsy

   

   Lamotrigine Tablets (Chewable, Dispersible)

   Valproate

   Step 1

   Achieve a dose of 200 mg/day according to guidelines in Table 1 (if not already on 200 mg/day).

   

  Maintain previous stable dose.

   Step 2

   Maintain at 200 mg/day.

   Decrease to 500 mg/day by decrements no greater than 500 mg/day/week and then maintain the dose of 500 mg/day for 1 week.

   Step 3

   Increase to 300 mg/day and maintain for 1 week.

   Simultaneously decrease to 250 mg/day and maintain for 1 week.

   Step 4

   Increase by 100 mg/day every week to achieve maintenance dose of 500 mg/day.

   Discontinue.

  Conversion From Adjunctive Therapy With Antiepileptic Drugs Other Than Carbamazepine, Phenytoin, Phenobarbital, Primidone, or Valproate to Monotherapy With Lamotrigine Tablets (Chewable, Dispersible): No specific dosing guidelines can be provided for conversion to monotherapy with lamotrigine tablets (chewable, dispersible) with AEDs other than carbamazepine, phenobarbital, phenytoin, primidone, or valproate.

  2.4 Bipolar Disorder

  The goal of maintenance treatment with lamotrigine tablets (chewable, dispersible) is to delay the time to occurrence of mood episodes (depression, mania, hypomania, mixed episodes) in patients treated for acute mood episodes with standard therapy. The target dose of lamotrigine tablets (chewable, dispersible) is 200 mg/day (100 mg/day in patients taking valproate, which decreases the apparent clearance of lamotrigine, and 400 mg/day in patients not taking valproate and taking either carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin that increase the apparent clearance of lamotrigine). In the clinical trials, doses up to 400 mg/day as monotherapy were evaluated; however, no additional benefit was seen at 400 mg/day compared with 200 mg/day [see Clinical Studies (14.2)]. Accordingly, doses above 200 mg/day are not recommended. Treatment with lamotrigine tablets (chewable, dispersible) is introduced, based on concurrent medications, according to the regimen outlined in Table 5. If other psychotropic medications are withdrawn following stabilization, the dose of lamotrigine tablets (chewable, dispersible) should be adjusted. For patients discontinuing valproate, the dose of lamotrigine tablets (chewable, dispersible) should be doubled over a 2-week period in equal weekly increments (see Table 6). For patients discontinuing carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin that induce lamotrigine glucuronidation, the dose of lamotrigine tablets (chewable, dispersible) should remain constant for the first week and then should be decreased by half over a 2-week period in equal weekly decrements (see Table 6). The dose of lamotrigine tablets (chewable, dispersible) may then be further adjusted to the target dose (200 mg) as clinically indicated.

  If other drugs are subsequently introduced, the dose of lamotrigine tablets (chewable, dispersible) may need to be adjusted. In particular, the introduction of valproate requires reduction in the dose of lamotrigine tablets (chewable, dispersible) [see Drug Interactions (7), Clinical Pharmacology (12.3)].

  To avoid an increased risk of rash, the recommended initial dose and subsequent dose escalations of lamotrigine tablets (chewable, dispersible) should not be exceeded [see Boxed Warning].

  Table 5. Escalation Regimen for Lamotrigine Tablets (Chewable, Dispersible) for Patients With Bipolar Disorder

   

   For Patients TAKING Valproatea

   For Patients NOT TAKING Carbamazepine, Phenytoin, Phenobarbital, Primidone,b or Valproatea

   For Patients TAKING Carbamazepine, Phenytoin, Phenobarbital, or Primidoneb and NOT TAKING Valproatea

   Weeks 1 and 2

   25 mg every other day

   25 mg daily

   50 mg daily

   Weeks 3 and 4

   25 mg daily

   50 mg daily

   100 mg daily, in divided doses

   Week 5

   50 mg daily

   100 mg daily

   200 mg daily, in divided doses

   Week 6

   100 mg daily

   200 mg daily

   300 mg daily, in divided doses

   Week 7

   100 mg daily

   200 mg daily

   up to 400 mg daily, in divided doses

  aValproate has been shown to inhibit glucuronidation and decrease the apparent clearance of lamotrigine. [see Drug Interactions (7), Clinical Pharmacology (12.3)].
  bThese drugs induce lamotrigine glucuronidation and increase clearance [see Drug Interactions (7), Clinical Pharmacology (12.3)]. Other drugs that have similar effects include estrogen-containing oral contraceptives [see Drug Interactions (7), Clinical Pharmacology (12.3)]. Dosing recommendations for oral contraceptives can be found in General Dosing Considerations [see Dosage and Administration (2.1)]. Patients on rifampin, or other drugs that induce lamotrigine glucuronidation and increase clearance, should follow the same dosing titration/maintenance regimen as that used with anticonvulsants that have this effect.

  Table 6. Dosage Adjustments to Lamotrigine Tablets (Chewable, Dispersible) for Patients With Bipolar Disorder Following Discontinuation of Psychotropic Medications

   

   Discontinuation of Psychotropic Drugs (excluding Carbamazepine, Phenytoin, Phenobarbital, Primidone,b or Valproatea)

   After Discontinuation of Valproatea

   After Discontinuation of Carbamazepine, Phenytoin, Phenobarbital, or Primidoneb

   

  Current dose of lamotrigine tablets (chewable, dispersible) (mg/day)

  100

   

  Current dose of lamotrigine tablets (chewable, dispersible) (mg/day)

  400

   Week 1

   Maintain current dose of lamotrigine tablets (chewable, dispersible)

   150

   400

   Week 2

   Maintain current dose of lamotrigine tablets (chewable, dispersible)

   200

   300

   Week 3 onward

   Maintain current dose of lamotrigine tablets (chewable, dispersible)

   200

   200

  aValproate has been shown to inhibit glucuronidation and decrease the apparent clearance of lamotrigine. [see Drug Interactions (7), Clinical Pharmacology (12.3)].
  bThese drugs induce lamotrigine glucuronidation and increase clearance [see Drug Interactions (7), Clinical Pharmacology (12.3)]. Other drugs that have similar effects include estrogen-containing oral contraceptives [see Drug Interactions (7), Clinical Pharmacology (12.3)]. Dosing recommendations for oral contraceptives can be found in General Dosing Considerations [see Dosage and Administration (2.1)]. Patients on rifampin, or other drugs that induce lamotrigine glucuronidation and increase clearance, should follow the same dosing titration/maintenance regimen as that used with anticonvulsants that have this effect.

  The benefit of continuing treatment in patients who had been stabilized in an 8- to 16-week open-label phase with lamotrigine tablets (chewable, dispersible) was established in 2 randomized, placebo-controlled clinical maintenance trials [see Clinical Studies (14.2)]. However, the optimal duration of treatment with lamotrigine tablets (chewable, dispersible) has not been established. Thus, patients should be periodically reassessed to determine the need for maintenance treatment.

  2.5 Administration of Lamotrigine Tablets (Chewable, Dispersible)

  Lamotrigine tablets (chewable, dispersible) may be swallowed whole, chewed, or dispersed in water or diluted fruit juice. If the tablets are chewed, consume a small amount of water or diluted fruit juice to aid in swallowing.

  To disperse lamotrigine tablets (chewable, dispersible), add the tablets to a small amount of liquid (1 teaspoon, or enough to cover the medication). Approximately 1 minute later, when the tablets are completely dispersed, swirl the solution and consume the entire quantity immediately. No attempt should be made to administer partial quantities of the dispersed tablets.

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  2.1 General Dosing Considerations 

  Rash: There are suggestions, yet to be proven, that the risk of severe, potentially life-threatening rash may be increased by (1) coadministration of lamotrigine tablets with valproate, (2) exceeding the recommended initial dose of lamotrigine tablets, or (3) exceeding the recommended dose escalation for lamotrigine tablets. However, cases have occurred in the absence of these factors [see Boxed Warning]. Therefore, it is important that the dosing recommendations be followed closely.

  The risk of nonserious rash may be increased when the recommended initial dose and/or the rate of dose escalation of lamotrigine tablets is exceeded and in patients with a history of allergy or rash to other AEDs.

  It is recommended that lamotrigine tablets not be restarted in patients who discontinued due to rash associated with prior treatment with lamotrigine, unless the potential benefits clearly outweigh the risks. If the decision is made to restart a patient who has discontinued lamotrigine, the need to restart with the initial dosing recommendations should be assessed. The greater the interval of time since the previous dose, the greater consideration should be given to restarting with the initial dosing recommendations. If a patient has discontinued lamotrigine for a period of more than 5 half-lives, it is recommended that initial dosing recommendations and guidelines be followed. The half-life of lamotrigine is affected by other concomitant medications [see Clinical Pharmacology (12.3)].

  Lamotrigine Added to Drugs Known to Induce or Inhibit Glucuronidation: Drugs other than those listed in the Clinical Pharmacology section [see Clinical Pharmacology (12.3)] have not been systematically evaluated in combination with lamotrigine. Because lamotrigine is metabolized predominantly by glucuronic acid conjugation, drugs that are known to induce or inhibit glucuronidation may affect the apparent clearance of lamotrigine and doses of lamotrigine tablets may require adjustment based on clinical response.

  Target Plasma Levels for Patients With Epilepsy or Bipolar Disorder: A therapeutic plasma concentration range has not been established for lamotrigine. Dosing of lamotrigine tablets should be based on therapeutic response [see Clinical Pharmacology (12.3)].

  Women Taking Estrogen-Containing Oral Contraceptives:  Starting Lamotrigine Tablets in Women Taking Estrogen-Containing Oral Contraceptives: Although estrogen-containing oral contraceptives have been shown to increase the clearance of lamotrigine [see Clinical Pharmacology (12.3)], no adjustments to the recommended dose-escalation guidelines for lamotrigine tablets should be necessary solely based on the use of estrogen-containing oral contraceptives. Therefore, dose escalation should follow the recommended guidelines for initiating adjunctive therapy with lamotrigine tablets based on the concomitant AED or other concomitant medications (see Table 1 or Table 5). See below for adjustments to maintenance doses of lamotrigine tablets in women taking estrogen-containing oral contraceptives.

  Adjustments to the Maintenance Dose of Lamotrigine Tablets in Women Taking Estrogen-Containing Oral Contraceptives:

  (1) Taking Estrogen-Containing Oral Contraceptives: For women not taking carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin that induce lamotrigine glucuronidation [see Drug Interactions (7), Clinical Pharmacology (12.3)], the maintenance dose of lamotrigine tablets will in most cases need to be increased, by as much as 2 fold over the recommended target maintenance dose, in order to maintain a consistent lamotrigine plasma level [see Clinical Pharmacology (12.3)].

  (2) Starting Estrogen-Containing Oral Contraceptives: In women taking a stable dose of lamotrigine tablets and not taking carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin that induce lamotrigine glucuronidation [see Drug Interactions (7), Clinical Pharmacology (12.3)], the maintenance dose will in most cases need to be increased by as much as 2 fold in order to maintain a consistent lamotrigine plasma level. The dose increases should begin at the same time that the oral contraceptive is introduced and continue, based on clinical response, no more rapidly than 50 to 100 mg/day every week. Dose increases should not exceed the recommended rate (seeTable 1 orTable 5) unless lamotrigine plasma levels or clinical response support larger increases. Gradual transient increases in lamotrigine plasma levels may occur during the week of inactive hormonal preparation (“pill-free” week), and these increases will be greater if dose increases are made in the days before or during the week of inactive hormonal preparation. Increased lamotrigine plasma levels could result in additional adverse reactions, such as dizziness, ataxia, and diplopia. If adverse reactions attributable to lamotrigine tablets consistently occur during the “pill-free” week, dose adjustments to the overall maintenance dose may be necessary. Dose adjustments limited to the “pill-free” week are not recommended. For women taking lamotrigine tablets in addition to carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin that induce lamotrigine glucuronidation [see Drug Interactions (7), Clinical Pharmacology (12.3)], no adjustment to the dose of lamotrigine tablets should be necessary.

  (3) Stopping Estrogen-Containing Oral Contraceptives: For women not taking carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin that induce lamotrigine glucuronidation [see Drug Interactions (7), Clinical Pharmacology (12.3)], the maintenance dose of lamotrigine tablets will in most cases need to be decreased by as much as 50% in order to maintain a consistent lamotrigine plasma level. The decrease in dose of lamotrigine tablets should not exceed 25% of the total daily dose per week over a 2 week period, unless clinical response or lamotrigine plasma levels indicate otherwise [see Clinical Pharmacology (12.3)]. For women taking lamotrigine tablets in addition to carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin that induce lamotrigine glucuronidation [see Drug Interactions (7), Clinical Pharmacology (12.3)], no adjustment to the dose of lamotrigine tablets should be necessary.

  Women and Other Hormonal Contraceptive Preparations or Hormone Replacement Therapy: The effect of other hormonal contraceptive preparations or hormone replacement therapy on the pharmacokinetics of lamotrigine has not been systematically evaluated. It has been reported that ethinylestradiol, not progestogens, increased the clearance of lamotrigine up to 2 fold, and the progestin-only pills had no effect on lamotrigine plasma levels. Therefore, adjustments to the dosage of lamotrigine tablets in the presence of progestogens alone will likely not be needed.

  Patients With Hepatic Impairment: Experience in patients with hepatic impairment is limited. Based on a clinical pharmacology study in 24 patients with mild, moderate, and severe liver impairment [see Use in Specific Populations (8.6), Clinical Pharmacology (12.3)], the following general recommendations can be made. No dosage adjustment is needed in patients with mild liver impairment. Initial, escalation, and maintenance doses should generally be reduced by approximately 25% in patients with moderate and severe liver impairment without ascites and 50% in patients with severe liver impairment with ascites. Escalation and maintenance doses may be adjusted according to clinical response.

  Patients With Renal Impairment: Initial doses of lamotrigine tablets should be based on patients' concomitant medications (see Tables 1to3 or Table 5); reduced maintenance doses may be effective for patients with significant renal impairment [see Use in Specific Populations (8.7), Clinical Pharmacology (12.3)]. Few patients with severe renal impairment have been evaluated during chronic treatment with lamotrigine tablets. Because there is inadequate experience in this population, lamotrigine tablets should be used with caution in these patients.

  Discontinuation Strategy:  Epilepsy: For patients receiving lamotrigine tablets in combination with other AEDs, a reevaluation of all AEDs in the regimen should be considered if a change in seizure control or an appearance or worsening of adverse reactions is observed.

  If a decision is made to discontinue therapy with lamotrigine tablets, a step-wise reduction of dose over at least 2 weeks (approximately 50% per week) is recommended unless safety concerns require a more rapid withdrawal [see Warnings and Precautions (5.9)].

  Discontinuing carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin that induce lamotrigine glucuronidation should prolong the half-life of lamotrigine; discontinuing valproate should shorten the half-life of lamotrigine.

  Bipolar Disorder: In the controlled clinical trials, there was no increase in the incidence, type, or severity of adverse reactions following abrupt termination of lamotrigine tablets. In clinical trials in patients with Bipolar Disorder, 2 patients experienced seizures shortly after abrupt withdrawal of lamotrigine tablets. However, there were confounding factors that may have contributed to the occurrence of seizures in these bipolar patients. Discontinuation of lamotrigine tablets should involve a step-wise reduction of dose over at least 2 weeks (approximately 50% per week) unless safety concerns require a more rapid withdrawal [see Warnings and Precautions (5.9)].

  2.2 Epilepsy – Adjunctive Therapy

  This section provides specific dosing recommendations for patients greater than 12 years of age and patients 2 to 12 years of age. Within each of these age-groups, specific dosing recommendations are provided depending upon concomitant AED or other concomitant medications (Table 1 for patients greater than 12 years of age and Table 2 for patients 2 to 12 years of age). A weight-based dosing guide for patients 2 to 12 years of age on concomitant valproate is provided in Table 3.

  Patients Over 12 Years of Age: Recommended dosing guidelines are summarized in Table 1.

  Table 1. Escalation Regimen for Lamotrigine in Patients Over 12 Years of Age With Epilepsy  * Valproate has been shown to inhibit glucuronidation and decrease the apparent clearance of lamotrigine [ see Drug Interactions (7), Clinical Pharmacology (12.3)] . † These drugs induce lamotrigine glucuronidation and increase clearance [ see Drug Interactions (7), Clinical Pharmacology (12.3)]. Other drugs that have similar effects include estrogen-containing oral contraceptives [ see Drug Interactions (7), Clinical Pharmacology (12.3)] . Dosing recommendations for oral contraceptives can be found in General Dosing Considerations [ see Dosage and Administration (2.1)] . Patients on rifampin, or other drugs that induce lamotrigine glucuronidation and increase clearance, should follow the same dosing titration/maintenance regimen as that used with anticonvulsants that have this effect. For Patients TAKING Valproate* For Patients NOT TAKING Carbamazepine, Phenytoin, Phenobarbital, Primidone,† or Valproate* For Patients TAKING Carbamazepine, Phenytoin, Phenobarbital, or Primidone† and NOT TAKING Valproate* Weeks 1 and 2 25 mg every other day 25 mg every day 50 mg/day Weeks 3 and 4 25 mg every day 50 mg/day 100 mg/day (in 2 divided doses) Week 5 onwards to maintenance Increase by 25 to 50 mg/day every 1 to 2 weeks Increase by 50 mg/day every 1 to 2 weeks Increase by 100 mg/day every 1 to 2 weeks Usual Maintenance Dose

  100 to 200 mg/day with valproate alone

  100 to 400 mg/day with valproate and other drugs that induce glucuronidation

  (in 1 or 2 divided doses)

  225 to 375 mg/day (in 2 divided doses)

  300 to 500 mg/day

   (in 2 divided doses)

  Patients 2 to 12 Years of Age: Recommended dosing guidelines are summarized in Table 2.

  Smaller starting doses and slower dose escalations than those used in clinical trials are recommended because of the suggestion that the risk of rash may be decreased by smaller starting doses and slower dose escalations. Therefore, maintenance doses will take longer to reach in clinical practice than in clinical trials. It may take several weeks to months to achieve an individualized maintenance dose. Maintenance doses in patients weighing less than 30 kg, regardless of age or concomitant AED, may need to be increased as much as 50%, based on clinical response.

  Table 2. Escalation Regimen for Lamotrigine in Patients 2 to 12 Years of Age With Epilepsy * Valproate has been shown to inhibit glucuronidation and decrease the apparent clearance of lamotrigine [ see Drug Interactions (7), Clinical Pharmacology (12.3)] . † These drugs induce lamotrigine glucuronidation and increase clearance [ see Drug Interactions (7), Clinical Pharmacology (12.3)]. Other drugs that have similar effects include estrogen-containing oral contraceptives [ see Drug Interactions (7), Clinical Pharmacology (12.3)] . Dosing recommendations for oral contraceptives can be found in General Dosing Considerations  [ see Dosage and Administration (2.1)] . Patients on rifampin, or other drugs that induce lamotrigine glucuronidation and increase clearance, should follow the same dosing titration/maintenance regimen as that used with anticonvulsants that have this effect. For Patients TAKING Valproate* For Patients NOT TAKING Carbamazepine, Phenytoin, Phenobarbital, Primidone,† or Valproate* For Patients TAKING Carbamazepine, Phenytoin, Phenobarbital, or Primidone† and NOT TAKING Valproate* Weeks 1 and 2 0.15 mg/kg/day in 1 or 2 divided doses, rounded down to the nearest whole tablet (see Table 3 for weight based dosing guide) 0.3 mg/kg/day in 1 or 2 divided doses, rounded down to the nearest whole tablet 0.6 mg/kg/day in 2 divided doses, rounded down to the nearest whole tablet Weeks 3 and 4 0.3 mg/kg/day in 1 or 2 divided doses, rounded down to the nearest whole tablet (see Table 3for weight based dosing guide) 0.6 mg/kg/day in 2 divided doses, rounded down to the nearest whole tablet 1.2 mg/kg/day in 2 divided doses, rounded down to the nearest whole tablet Week 5 onwards to maintenance The dose should be increased every 1 to 2 weeks as follows: calculate 0.3 mg/kg/day, round this amount down to the nearest whole tablet, and add this amount to the previously administered daily dose The dose should be increased every 1 to 2 weeks as follows: calculate 0.6 mg/kg/day, round this amount down to the nearest whole tablet, and add this amount to the previously administered daily dose The dose should be increased every 1 to 2 weeks as follows: calculate 1.2 mg/kg/day, round this amount down to the nearest whole tablet, and add this amount to the previously administered daily dose Usual Maintenance Dose 1 to 5 mg/kg/day (maximum 200 mg/day in 1 or 2 divided doses)
  1 to 3 mg/kg/day with valproate alone 4.5 to 7.5 mg/kg/day (maximum 300 mg/day in 2 divided doses) 5 to 15 mg/kg/day (maximum 400 mg/day in 2 divided doses) Maintenance dose in patients less than 30 kg May need to be increased by as much as 50%, based on clinical response May need to be increased by as much as 50%, based on clinical response May need to be increased by as much as 50%, based on clinical response

  Note: Only whole tablets should be used for dosing.

  Table 3. The Initial Weight-Based Dosing Guide for Patients 2 to 12 Years of Age Taking Valproate (Weeks 1 to 4) With Epilepsy If the patient’s weight is Give this daily dose, using the most appropriate combination of lamotrigine tablets, 2 mg and 5 mg Greater than And less than Weeks 1 and 2 Weeks 3 and 4 6.7 kg 14 kg 2 mg every other day 2 mg every day 14.1 kg 27 kg 2 mg every day 4 mg every day 27.1 kg 34 kg 4 mg every day 8 mg every day 34.1 kg 40 kg 5 mg every day 10 mg every day

  Usual Adjunctive Maintenance Dose for Epilepsy: The usual maintenance doses identified in Tables 1 and 2 are derived from dosing regimens employed in the placebo-controlled adjunctive studies in which the efficacy of lamotrigine tablets was established. In patients receiving multidrug regimens employing carbamazepine, phenytoin, phenobarbital, or primidone without valproate, maintenance doses of adjunctive lamotrigine tablets as high as 700 mg/day have been used. In patients receiving valproate alone, maintenance doses of adjunctive lamotrigine tablets as high as 200 mg/day have been used. The advantage of using doses above those recommended in Tables 1 through 4 has not been established in controlled trials.

  2.3 Epilepsy – Conversion From Adjunctive Therapy to Monotherapy

  The goal of the transition regimen is to effect the conversion to monotherapy with lamotrigine tablets under conditions that ensure adequate seizure control while mitigating the risk of serious rash associated with the rapid titration of lamotrigine tablets.

  The recommended maintenance dose of lamotrigine tablets as monotherapy is 500 mg/day given in 2 divided doses.

  To avoid an increased risk of rash, the recommended initial dose and subsequent dose escalations of lamotrigine tablets should not be exceeded [see Boxed Warning].

  Conversion From Adjunctive Therapy With Carbamazepine, Phenytoin, Phenobarbital, or Primidone to Monotherapy With Lamotrigine Tablets: After achieving a dose of 500 mg/day of lamotrigine tablets according to the guidelines in Table 1, the concomitant AED should be withdrawn by 20% decrements each week over a 4 week period. The regimen for the withdrawal of the concomitant AED is based on experience gained in the controlled monotherapy clinical trial.

  Conversion From Adjunctive Therapy With Valproate to Monotherapy With Lamotrigine Tablets: The conversion regimen involves 4 steps outlined in Table 4.

  Table 4. Conversion From Adjunctive Therapy With Valproate to Monotherapy With Lamotrigine in Patients ≥ 16 Years of Age With Epilepsy   Lamotrigine Valproate Step 1 Achieve a dose of 200 mg/day according to guidelines in Table 1 (if not already on 200 mg/day). Maintain previous stable dose. Step 2 Maintain at 200 mg/day. Decrease to 500 mg/day by decrements no greater than 500 mg/day/week and then maintain the dose of 500 mg/day for 1 week. Step 3 Increase to 300 mg/day and maintain for 1 week. Simultaneously decrease to 250 mg/day and maintain for 1 week. Step 4 Increase by 100 mg/day every week to achieve maintenance dose of 500 mg/day. Discontinue.

  Conversion From Adjunctive Therapy With Antiepileptic Drugs Other Than Carbamazepine, Phenytoin, Phenobarbital, Primidone, or Valproate to Monotherapy With Lamotrigine Tablets: No specific dosing guidelines can be provided for conversion to monotherapy with lamotrigine tablets with AEDs other than carbamazepine, phenobarbital, phenytoin, primidone, or valproate.

  2.4 Bipolar Disorder

  The goal of maintenance treatment with lamotrigine tablets is to delay the time to occurrence of mood episodes (depression, mania, hypomania, mixed episodes) in patients treated for acute mood episodes with standard therapy. The target dose of lamotrigine tablets is 200 mg/day (100 mg/day in patients taking valproate, which decreases the apparent clearance of lamotrigine, and 400 mg/day in patients not taking valproate and taking either carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin that increase the apparent clearance of lamotrigine). In the clinical trials, doses up to 400 mg/day as monotherapy were evaluated; however, no additional benefit was seen at 400 mg/day compared with 200 mg/day [see Clinical Studies (14.2)]. Accordingly, doses above 200 mg/day are not recommended. Treatment with lamotrigine tablets is introduced, based on concurrent medications, according to the regimen outlined in Table 5. If other psychotropic medications are withdrawn following stabilization, the dose of lamotrigine tablets should be adjusted. For patients discontinuing valproate, the dose of lamotrigine tablets should be doubled over a 2 week period in equal weekly increments (see Table 6). For patients discontinuing carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin that induce lamotrigine glucuronidation, the dose of lamotrigine tablets should remain constant for the first week and then should be decreased by half over a 2 week period in equal weekly decrements (see Table 6). The dose of lamotrigine tablets may then be further adjusted to the target dose (200 mg) as clinically indicated.

  If other drugs are subsequently introduced, the dose of lamotrigine tablets may need to be adjusted. In particular, the introduction of valproate requires reduction in the dose of lamotrigine tablets [see Drug Interactions (7), Clinical Pharmacology (12.3)].

  To avoid an increased risk of rash, the recommended initial dose and subsequent dose escalations of lamotrigine tablets should not be exceeded [see Boxed Warning].

   

  Table 5. Escalation Regimen for Lamotrigine for Patients With Bipolar Disorder * Valproate has been shown to inhibit glucuronidation and decrease the apparent clearance of lamotrigine [ see Drug Interactions (7), Clinical Pharmacology (12.3)]. † These drugs induce lamotrigine glucuronidation and increase clearance [ see Drug Interactions (7), Clinical Pharmacology (12.3)]. Other drugs that have similar effects include estrogen-containing oral contraceptives [ see Drug Interactions (7), Clinical Pharmacology (12.3)]. Dosing recommendations for oral contraceptives can be found in General Dosing Considerations [ see Dosage and Administration (2.1)]. Patients on rifampin, or other drugs that induce lamotrigine glucuronidation and increase clearance, should follow the same dosing titration/maintenance regimen as that used with anticonvulsants that have this effect. For Patients TAKING Valproate* For Patients NOT TAKING Carbamazepine, Phenytoin, Phenobarbital, Primidone,† or Valproate* For Patients TAKING Carbamazepine, Phenytoin, Phenobarbital, or Primidone† and NOT TAKING Valproate* Weeks 1 and 2 25 mg every other day 25 mg daily 50 mg daily Weeks 3 and 4 25 mg daily 50 mg daily 100 mg daily, in divided doses Week 5 50 mg daily 100 mg daily 200 mg daily, in divided doses Week 6 100 mg daily 200 mg daily 300 mg daily, in divided doses Week 7 100 mg daily 200 mg daily up to 400 mg daily, in divided doses Table 6. Dosage Adjustments to Lamotrigine for Patients With Bipolar Disorder Following Discontinuation of Psychotropic Medications * These drugs induce lamotrigine glucuronidation and increase clearance [ see Drug Interactions (7), Clinical Pharmacology (12.3)]. Other drugs that have similar effects include estrogen-containing oral contraceptives [ see Drug Interactions (7), Clinical Pharmacology (12.3)]. Dosing recommendations for oral contraceptives can be found in General Dosing Considerations [ see Dosage and Administration (2.1)]. Patients on rifampin, or other drugs that induce lamotrigine glucuronidation and increase clearance, should follow the same dosing titration/maintenance regimen as that used with anticonvulsants that have this effect. † Valproate has been shown to inhibit glucuronidation and decrease the apparent clearance of lamotrigine [ see Drug Interactions (7), Clinical Pharmacology (12.3)].   Discontinuation of Psychotropic Drugs (excluding Carbamazepine, Phenytoin, Phenobarbital, Primidone,* or Valproate†) After Discontinuation of Valproate† After Discontinuation of Carbamazepine, Phenytoin, Phenobarbital, or Primidone* Current dose of Lamotrigine (mg/day) 100

  Current dose of Lamotrigine (mg/day)

  400

  Week 1 Maintain current dose of lamotrigine 150 400 Week 2 Maintain current dose of lamotrigine 200 300 Week 3 onward Maintain current dose of lamotrigine 200 200

  The benefit of continuing treatment in patients who had been stabilized in an 8 to 16 week open-label phase with lamotrigine tablets was established in 2 randomized, placebo-controlled clinical maintenance trials [see Clinical Studies (14.2)]. However, the optimal duration of treatment with lamotrigine tablets has not been established. Thus, patients should be periodically reassessed to determine the need for maintenance treatment.

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  2.1 General Dosing Considerations

  Rash: There are suggestions, yet to be proven, that the risk of severe, potentially life-threatening rash may be increased by (1) coadministration of lamotrigine tablets with valproate, (2) exceeding the recommended initial dose of lamotrigine tablets, or (3) exceeding the recommended dose escalation for lamotrigine tablets. However, cases have occurred in the absence of these factors [see Boxed Warning ]. Therefore, it is important that the dosing recommendations be followed closely.

  The risk of nonserious rash may be increased when the recommended initial dose and/or the rate of dose escalation of lamotrigine tablet is exceeded and in patients with a history of allergy or rash to other AEDs.

  It is recommended that lamotrigine tablets not be restarted in patients who discontinued due to rash associated with prior treatment with lamotrigine, unless the potential benefits clearly outweigh the risks. If the decision is made to restart a patient who has discontinued lamotrigine, the need to restart with the initial dosing recommendations should be assessed. The greater the interval of time since the previous dose, the greater consideration should be given to restarting with the initial dosing recommendations. If a patient has discontinued lamotrigine for a period of more than 5 half-lives, it is recommended that initial dosing recommendations and guidelines be followed. The half-life of lamotrigine is affected by other concomitant medications [see Clinical Pharmacology (12.3) ].

  Lamotrigine Tablets Added to Drugs Known to Induce or Inhibit Glucuronidation: Drugs other than those listed in the Clinical Pharmacology section [see Clinical Pharmacology (12.3) ] have not been systematically evaluated in combination with lamotrigine. Because lamotrigine is metabolized predominantly by glucuronic acid conjugation, drugs that are known to induce or inhibit glucuronidation may affect the apparent clearance of lamotrigine and doses of lamotrigine tablets may require adjustment based on clinical response.

  Target Plasma Levels for Patients With Epilepsy or Bipolar Disorder: A therapeutic plasma concentration range has not been established for lamotrigine. Dosing of lamotrigine tablets should be based on therapeutic response [see Clinical Pharmacology (12.3) ].

  Women Taking Estrogen-Containing Oral Contraceptives: Starting Lamotrigine Tablets  in Women Taking Estrogen-Containing Oral Contraceptives: Although estrogen-containing oral contraceptives have been shown to increase the clearance of lamotrigine [see Clinical Pharmacology (12.3) ], no adjustments to the recommended dose-escalation guidelines for lamotrigine tablets should be necessary solely based on the use of estrogen-containing oral contraceptives. Therefore, dose escalation should follow the recommended guidelines for initiating adjunctive therapy with lamotrigine tablets based on the concomitant AED or other concomitant medications (see Table 1 or Table 5). See below for adjustments to maintenance doses of lamotrigine tablets in women taking estrogen-containing oral contraceptives.

  Adjustments to the Maintenance Dose of Lamotrigine Tablets In Women Taking Estrogen-Containing Oral Contraceptives:

  (1) Taking Estrogen-Containing Oral Contraceptives: For women not taking carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin that induce lamotrigine glucuronidation [see Drug Interactions (7), Clinical Pharmacology (12.3)], the maintenance dose of lamotrigine  tablets will in most cases need to be increased, by as much as 2-fold over the recommended target maintenance dose, in order to maintain a consistent lamotrigine plasma level [see Clinical Pharmacology (12.3) ].

  (2) Starting Estrogen-Containing Oral Contraceptives: In women taking a stable dose of lamotrigine tablets and not taking carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin that induce lamotrigine glucuronidation [see Drug Interactions (7), Clinical Pharmacology (12.3)], the maintenance dose will in most cases need to be increased by as much as 2-fold in order to maintain a consistent lamotrigine plasma level. The dose increases should begin at the same time that the oral contraceptive is introduced and continue, based on clinical response, no more rapidly than 50 to 100 mg/day every week. Dose increases should not exceed the recommended rate (see Table 1 or Table 5) unless lamotrigine plasma levels or clinical response support larger increases. Gradual transient increases in lamotrigine plasma levels may occur during the week of inactive hormonal preparation ("pill-free" week), and these increases will be greater if dose increases are made in the days before or during the week of inactive hormonal preparation. Increased lamotrigine plasma levels could result in additional adverse reactions, such as dizziness, ataxia, and diplopia. If adverse reactions attributable to lamotrigine tablets consistently occur during the "pill-free" week, dose adjustments to the overall maintenance dose may be necessary. Dose adjustments limited to the "pill-free" week are not recommended. For women taking lamotrigine tablets in addition to carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin that induce lamotrigine glucuronidation [see Drug Interactions (7), Clinical Pharmacology (12.3)], no adjustment to the dose of lamotrigine tablets should be necessary.

  (3) Stopping Estrogen-Containing Oral Contraceptives: For women not taking carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin that induce lamotrigine glucuronidation [see Drug Interactions (7), Clinical Pharmacology (12.3)], the maintenance dose of lamotrigine tablets will in most cases need to be decreased by as much as 50% in order to maintain a consistent lamotrigine plasma level. The decrease in dose of lamotrigine tablets should not exceed 25% of the total daily dose per week over a 2-week period, unless clinical response or lamotrigine plasma levels indicate otherwise [see Clinical Pharmacology (12.3) ]. For women taking lamotrigine tablets in addition to carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin that induce lamotrigine glucuronidation [see Drug Interactions (7), Clinical Pharmacology (12.3)], no adjustment to the dose of lamotrigine tablets should be necessary.

  Women and Other Hormonal Contraceptive Preparations or Hormone Replacement Therapy: The effect of other hormonal contraceptive preparations or hormone replacement therapy on the pharmacokinetics of lamotrigine has not been systematically evaluated. It has been reported that ethinylestradiol, not progestogens, increased the clearance of lamotrigine up to 2-fold, and the progestin-only pills had no effect on lamotrigine plasma levels. Therefore, adjustments to the dosage of lamotrigine tablets in the presence of progestogens alone will likely not be needed.

  Patients With Hepatic Impairment: Experience in patients with hepatic impairment is limited. Based on a clinical pharmacology study in 24 patients with mild, moderate, and severe liver impairment [see Use in Specific Populations (8.6) , Clinical Pharmacology (12.3) ], the following general recommendations can be made. No dosage adjustment is needed in patients with mild liver impairment. Initial, escalation, and maintenance doses should generally be reduced by approximately 25% in patients with moderate and severe liver impairment without ascites and 50% in patients with severe liver impairment with ascites. Escalation and maintenance doses may be adjusted according to clinical response.

  Patients With Renal Impairment: Initial doses of lamotrigine tablets should be based on patients' concomitant medications (see Tables 1-3 or Table 5); reduced maintenance doses may be effective for patients with significant renal impairment [see Use in Specific Populations (8.7) , Clinical Pharmacology (12.3) ]. Few patients with severe renal impairment have been evaluated during chronic treatment with lamotrigine tablets. Because there is inadequate experience in this population, lamotrigine tablets should be used with caution in these patients.

  Discontinuation Strategy:

  Epilepsy: For patients receiving lamotrigine tablets in combination with other AEDs, a reevaluation of all AEDs in the regimen should be considered if a change in seizure control or an appearance or worsening of adverse reactions is observed.

  If a decision is made to discontinue therapy with lamotrigine tablets, a step-wise reduction of dose over at least 2 weeks (approximately 50% per week) is recommended unless safety concerns require a more rapid withdrawal [see Warnings and Precautions (5.9) ].

  Discontinuing carbamazepine, phenytoin, phenobarbital, primidone or other drugs such as rifampin that induce lamotrigine glucuronidation should prolong the half-life of lamotrigine; discontinuing valproate should shorten the half-life of lamotrigine.

  Bipolar Disorder: In the controlled clinical trials, there was no increase in the incidence, type, or severity of adverse reactions following abrupt termination of lamotrigine tablets. In clinical trials in patients with Bipolar Disorder, 2 patients experienced seizures shortly after abrupt withdrawal of lamotrigine tablets. However, there were confounding factors that may have contributed to the occurrence of seizures in these bipolar patients. Discontinuation of lamotrigine tablets should involve a step-wise reduction of dose over at least 2 weeks (approximately 50% per week) unless safety concerns require a more rapid withdrawal [see Warnings and Precautions (5.9) ].

  2.2 Epilepsy – Adjunctive Therapy

  This section provides specific dosing recommendations for patients greater than 12 years of age and patients 2 to 12 years of age. Within each of these age-groups, specific dosing recommendations are provided depending upon concomitant AED or other concomitant medications (Table 1 for patients greater than 12 years of age and Table 2 for patients 2 to 12 years of age). A weight-based dosing guide for patients 2 to 12 years of age on concomitant valproate is provided in Table 3.

  Patients Over 12 Years of Age: Recommended dosing guidelines are summarized in Table 1.

  Table 1. Escalation Regimen for Lamotrigine Tablets in Patients Over 12 Years of Age With Epilepsy  

  a Valproate has been shown to inhibit glucuronidation and decrease the apparent clearance of lamotrigine [see Drug Interactions (7), Clinical Pharmacology (12.3)].

   

  b These drugs induce lamotrigine glucuronidation and increase clearance [see Drug Interactions (7), Clinical Pharmacology (12.3)]. Other drugs that have similar effects include estrogen-containing oral contraceptives [see Drug Interactions (7), Clinical Pharmacology (12.3)]. Dosing recommendations for oral contraceptives can be found in General Dosing Considerations [see Dosage and Administration (2.1)]. Patients on rifampin, or other drugs that induce lamotrigine glucuronidation and increase clearance, should follow the same dosing titration/maintenance regimen as that used with anticonvulsants that have this effect.

   
   For 
   For Patients NOT TAKING 
   For Patients 
   
   Patients
   Carbamazepine, 
   TAKING
   
   TAKING
   Phenytoin,
   Carbamazepine,
   
   Valproatea
   Phenobarbital,
   Phenytoin, 
   
   
   or Primidoneb,  
   Phenobarbital,
   
   
   or Valproatea
   or Primidoneb
   
   
   
   and NOT TAKING
   
   
   
   Valproatea
   Weeks 1 and 2
   25 mg every other day
   25 mg every day
   50 mg/day
   Weeks 3 and 4
   25 mg every day
   50 mg/day
   100 mg/day
  (in 2 divided doses)
   Weeks 5 onwards to 
  maintenance
   Increase by 25 to 
  50 mg/day every 1 to 2 weeks
   Increase by 50
  mg/day every 1
  to 2 weeks
   Increase by 
  100 mg/day every 
  1 to 2 weeks.
   Usual maintenance 
  dose
   100 to 200 mg/day
  with valproate alone
   225 to 375 mg/day
  (in 2 divided doses).
   300 to 500 mg/day
  (in 2 divided doses).
   
   100 to 400 mg/day
  with valproate
  and other drugs that induce glucuronidation
   
   
   
   (in 1 or 2 divided doses)
   
   
  

  Patients 2 to 12 Years Of Age: Recommended dosing guidelines are summarized in Table 2.

  Smaller starting doses and slower dose escalations than those used in clinical trials are recommended because of the suggestion that the risk of rash may be decreased by smaller starting doses and slower dose escalations. Therefore, maintenance doses will take longer to reach in clinical practice than in clinical trials. It may take several weeks to months to achieve an individualized maintenance dose. Maintenance doses in patients weighing less than 30 kg, regardless of age or concomitant AED, may need to be increased as much as 50%, based on clinical response.

  Table 2. Escalation Regimen for Lamotrigine Tablets in Patients 2 to 12 Years of Age With Epilepsy  

  Note: Only whole tablets should be used for dosing.

   

  a Valproate has been shown to inhibit glucuronidation and decrease the apparent clearance of lamotrigine [see Drug Interactions (7), Clinical Pharmacology (12.3)].

   

  b These drugs induce lamotrigine glucuronidation and increase clearance [see Drug Interactions (7), Clinical Pharmacology (12.3)]. Other drugs which have similar effects include estrogen-containing oral contraceptives [see Drug Interactions (7), Clinical Pharmacology (12.3)]. Dosing recommendations for oral contraceptives can be found in General Dosing Considerations [see Dosage and Administration (2.1)]. Patients on rifampin, or other drugs that induce lamotrigine glucuronidation and increase clearance, should follow the same dosing titration/maintenance regimen as that used with anticonvulsants that have this effect.

   
   For Patients TAKING 
  Valproatea
   For Patients NOT 
  TAKING Carbamazepine, Phenytoin, 
  Phenobarbital, Primidoneb, or 
  Valproatea
   For Patients TAKING 
  Carbamazepine, Phenytoin, Phenobarbital, or 
  Primidoneb and NOT 
  TAKING Valproatea
   Weeks 1 and 2
   0.15 mg/kg/day
  in 1 or 2 divided doses, rounded down to the 
  nearest whole tablet (see Table 3 for weight 
  based dosing guide).
   0.3 mg/kg/day
  in 1 or 2 divided doses, rounded down to the 
  nearest whole tablet.
   0.6 mg/kg/day
  in 2 divided doses, rounded down to the 
  nearest whole tablet.
   Weeks 3 and 4
   0.3 mg/kg/day
  in 1 or 2 divided doses,
  rounded down to the 
  nearest whole tablet 
  (see Table 3 for weight 
  based dosing guide).
   0.6 mg/kg/day
  in 2 divided doses,
  rounded down to the 
  nearest whole tablet.
   1.2 mg/kg/day
  in 2 divided doses, 
  rounded down to the 
  nearest whole tablet.
   Weeks 5 
  onwards to 
  maintenance
   The dose should be increased every 
  1 to 2 weeks as follows:
  calculate 0.3 mg/kg/day, round this amount 
  down to the nearest whole tablet, and 
  add this amount to the 
  previously administered daily dose.
   The dose should be increased every 
  1 to 2 weeks as follows:
  calculate 0.6 mg/kg/day, round this amount 
  down to the nearest whole tablet, and 
  add this amount to the 
  previously administered daily dose
   The dose should be increased every 
  1 to 2 weeks as follows:
  calculate 1.2 mg/kg/day, round this amount 
  down to the nearest whole tablet, and 
  add this amount to the 
  previously administered daily dose
   Usual 
  Maintenance 
  Dose
   1 to 5 mg/kg/day
  (maximum 200 mg/day 
  in 1 or 2 divided doses).
  1 to 3 mg/kg/day with valproate alone
   4.5 to 7.5 mg/kg/day
  (maximum 300 mg/day 
  in 2 divided doses)
   5 to 15 mg/kg/day
  (maximum 400 mg/day 
  in 2 divided doses)
   Maintenance dose in 
  patients 
  less than 30 kg
   May need to be increased 
  by as much as 50%, 
  based on clinical response
   May need to be increased 
  by as much as 50%, 
  based on clinical response
   May need to be increased 
  by as much as 50%, based 
  on clinical response
  Table 3. The Initial Weight-Based Dosing Guide for Patients 2 to 12 Years Taking Valproate (Weeks 1 to 4) With Epilepsy  If the patient’s weight is
   Give this daily dose, using the most appropriate combination of Lamotrigine 2-mg and 5-mg tablets
   Greater than
   And less than
   Weeks 1 and 2
   Weeks 3 and 4
   6.7 kg
   14 kg
   2 mg every other day
   2 mg every day
   14.1 kg
   27 kg
   2 mg every day
   4 mg every day
   27.1 kg
   34 kg
   4 mg every day
   8 mg every day
   34.1 kg
   40 kg
   5 mg every day
   10 mg every day
  

  Usual Adjunctive Maintenance Dose for Epilepsy: The usual maintenance doses identified in Tables 1 and 2 are derived from dosing regimens employed in the placebo-controlled adjunctive studies in which the efficacy of lamotrigine tablets was established. In patients receiving multidrug regimens employing carbamazepine, phenytoin, phenobarbital, or primidone without valproate, maintenance doses of adjunctive lamotrigine tablets as high as 700 mg/day have been used. In patients receiving valproate alone, maintenance doses of adjunctive lamotrigine tablets as high as 200 mg/day have been used. The advantage of using doses above those recommended in Tables 1 through 4 has not been established in controlled trials.

  2.3 Epilepsy – Conversion From Adjunctive Therapy to Monotherapy

  The goal of the transition regimen is to effect the conversion to monotherapy with lamotrigine tablets under conditions that ensure adequate seizure control while mitigating the risk of serious rash associated with the rapid titration of lamotrigine tablets.

  The recommended maintenance dose of lamotrigine tablets as monotherapy is 500 mg/day given in two divided doses.

  To avoid an increased risk of rash, the recommended initial dose and subsequent dose escalations of lamotrigine tablets should not be exceeded [see Boxed Warning].

  Conversion From Adjunctive Therapy With Carbamazepine, Phenytoin, Phenobarbital, or Primidone to Monotherapy With Lamotrigine Tablets: After achieving a dose of 500 mg/day of lamotrigine tablets according to the guidelines in Table 1, the concomitant AED should be withdrawn by 20% decrements each week over a 4-week period. The regimen for the withdrawal of the concomitant AED is based on experience gained in the controlled monotherapy clinical trial.

  Conversion from Adjunctive Therapy With Valproate to Monotherapy With Lamotrigine Tablets:

  The conversion regimen involves 4 steps outlined in Table 4.

  Table 4. Conversion From Adjunctive Therapy With Valproate to Monotherapy With Lamotrigine Tablets in Patients ≥16 Years of Age with Epilepsy  
   Lamotrigine Tablets
   Valproate
   Step 1
   Achieve a dose of 200 mg/day according to
  guidelines in Table 1
  (if not already on 200 mg/day).
   Maintain previous stable dose.
   Step 2
   Maintain at 200 mg/day.
   Decrease to 500 mg/day by decrements no greater than
  500 mg/day/week and then maintain the dose of
  500 mg/day for 1 week.
   Step 3
   Increase to 300 mg/day and maintain for 1 week.
   Simultaneously decrease to
  250 mg/day and maintain for 1 week.
   Step 4
   Increase by 100 mg/day every
  week to achieve maintenance dose of 500 mg/day.
   Discontinue.
  

  Conversion from Adjunctive Therapy With AEDs Other Than Carbamazepine, Phenytoin, Phenobarbital, Primidone, or Valproate to Monotherapy With Lamotrigine Tablets: No specific dosing guidelines can be provided for conversion to monotherapy with lamotrigine tablets with AEDs other than carbamazepine, phenobarbital, phenytoin, primidone, or valproate.

  2.4 Bipolar Disorder

  The goal of maintenance treatment with lamotrigine tablets is to delay the time to occurrence of mood episodes (depression, mania, hypomania, mixed episodes) in patients treated for acute mood episodes with standard therapy. The target dose of lamotrigine tablets is 200 mg/day (100 mg/day in patients taking valproate, which decreases the apparent clearance of lamotrigine, and 400 mg/day in patients not taking valproate and taking either carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin that increase the apparent clearance of lamotrigine). In the clinical trials, doses up to 400 mg/day as monotherapy were evaluated; however, no additional benefit was seen at 400 mg/day compared with 200 mg/day [see Clinical Studies (14.2) ]. Accordingly, doses above 200 mg/day are not recommended. Treatment with lamotrigine tablets is introduced, based on concurrent medications, according to the regimen outlined in Table 5. If other psychotropic medications are withdrawn following stabilization, the dose of lamotrigine tablets should be adjusted. For patients discontinuing valproate, the dose of lamotrigine tablets should be doubled over a 2-week period in equal weekly increments (see Table 6). For patients discontinuing carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin that induce lamotrigine glucuronidation, the dose of lamotrigine tablets should remain constant for the first week and then should be decreased by half over a 2-week period in equal weekly decrements (see Table 6). The dose of lamotrigine tablets may then be further adjusted to the target dose (200 mg) as clinically indicated.

  If other drugs are subsequently introduced, the dose of lamotrigine tablets may need to be adjusted. In particular, the introduction of valproate requires reduction in the dose of lamotrigine tablets [see Drug Interactions (7) , Clinical Pharmacology (12.3) ].

  To avoid an increased risk of rash, the recommended initial dose and subsequent dose escalations of lamotrigine tablets should not be exceeded [see Boxed Warning ].

  Table 5. Escalation Regimen for Lamotrigine Tablets for Patients With Bipolar Disorder  

  a Valproate has been shown to inhibit glucuronidation and decrease the apparent clearance of lamotrigine [see Drug Interactions (7), Clinical Pharmacology (12.3)].

   

  
  

   

  b These drugs induce lamotrigine glucuronidation and increase clearance [see Drug Interactions (7), Clinical Pharmacology (12.3)]. Other drugs which have similar effects include estrogen-containing oral contraceptives [see Drug Interactions (7), Clinical Pharmacology (12.3)]. Dosing recommendations for oral contraceptives can be found in General Dosing Considerations [see Dosage and Administration (2.1)]. Patients on rifampin, or other drugs that induce lamotrigine glucuronidation and increase clearance, should follow the same dosing titration/maintenance regimen as that used with anticonvulsants that have this effect.

   
   For Patients TAKING 
  Valproatea
   For Patients NOT TAKING 
  Carbamazepine, Phenytoin, Phenobarbital, 
  Primidoneb, or Valproatea
   For Patients TAKING 
  Carbamazepine, Phenytoin,
  Phenobarbital, or Primidoneband NOT TAKING 
  Valproatea
   Weeks 1 and 2
   25 mg every 
  other day
   25 mg daily
   50 mg daily
   Weeks 3 and 4
   25 mg daily
   50 mg daily
   100 mg daily, in divided doses
   Week 5
   50 mg daily
   100 mg daily
   200 mg daily, in divided doses
   Week 6
   100 mg daily
   200 mg daily
   300 mg daily, in divided doses
   Week 7
   100 mg daily
   200 mg daily
   up to 400 mg daily, in divided doses
  Table 6. Dosage Adjustments to Lamotrigine Tablets for Patients With Bipolar Disorder Following Discontinuation of Psychotropic Medications  
   Discontinuation of Psychotropic Drugs 
  (excluding Carbamazepine, Phenytoin, 
  Phenobarbital, Primidoneb, or 
  Valproatea)
   After Discontinuation of 
  Valproatea
   After Discontinuation of 
  Carbamazepine, Phenytoin, 
  Phenobarbital, or Primidoneb
   
   
   Current dose of lamotrigine tablets
  (mg/day)
  100
   Current dose of lamotrigine tablets
  (mg/day)
  400
   

  a Valproate has been shown to inhibit glucuronidation and decrease the apparent clearance of lamotrigine [see Drug Interactions (7), Clinical Pharmacology (12.3)].

   

  
  

   

  b These drugs induce lamotrigine glucuronidation and increase clearance [see Drug Interactions (7), Clinical Pharmacology (12.3)]. Other drugs which have similar effects include estrogen-containing oral contraceptives [see Drug Interactions (7), Clinical Pharmacology (12.3)]. Dosing recommendations for oral contraceptives can be found in General Dosing Considerations [see Dosage and Administration (2.1)]. Patients on rifampin, or other drugs that induce lamotrigine glucuronidation and increase clearance, should follow the same dosing titration/maintenance regimen as that used with anticonvulsants that have this effect.

   Week 1
   Maintain current dose of lamotrigine tablets
   150
   400
   Week 2
   Maintain current dose of lamotrigine tablets
   200
   300
   Week 3 onward
   Maintain current dose of lamotrigine tablets
   200
   200
  

  The benefit of continuing treatment in patients who had been stabilized in an 8- to 16-week open-label phase with lamotrigine tablets was established in two randomized, placebo-controlled clinical maintenance trials [see Clinical Studies (14.2) ]. However, the optimal duration of treatment with lamotrigine tablets has not been established. Thus, patients should be periodically reassessed to determine the need for maintenance treatment.

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  2.1 General Dosing Considerations 

  Rash: There are suggestions, yet to be proven, that the risk of severe, potentially life-threatening rash may be increased by (1) coadministration of Lamotrigine with valproate, (2) exceeding the recommended initial dose of Lamotrigine, or (3) exceeding the recommended dose escalation for Lamotrigine. However, cases have occurred in the absence of these factors [see Boxed Warning]. Therefore, it is important that the dosing recommendations be followed closely.

  The risk of nonserious rash may be increased when the recommended initial dose and/or the rate of dose escalation of Lamotrigine is exceeded and in patients with a history of allergy or rash to other AEDs.

  It is recommended that Lamotrigine not be restarted in patients who discontinued due to rash associated with prior treatment with Lamotrigine, unless the potential benefits clearly outweigh the risks. If the decision is made to restart a patient who has discontinued Lamotrigine, the need to restart with the initial dosing recommendations should be assessed. The greater the interval of time since the previous dose, the greater consideration should be given to restarting with the initial dosing recommendations. If a patient has discontinued Lamotrigine for a period of more than 5 half-lives, it is recommended that initial dosing recommendations and guidelines be followed. The half-life of Lamotrigine is affected by other concomitant medications [see Clinical Pharmacology (12.3)].

  Lamotrigine Added to Drugs Known to Induce or Inhibit Glucuronidation: Drugs other than those listed in the Clinical Pharmacology section [see Clinical Pharmacology (12.3)] have not been systematically evaluated in combination with Lamotrigine. Because Lamotrigine is metabolized predominantly by glucuronic acid conjugation, drugs that are known to induce or inhibit glucuronidation may affect the apparent clearance of Lamotrigine and doses of Lamotrigine may require adjustment based on clinical response.

  Target Plasma Levels for Patients With Epilepsy or Bipolar Disorder: A therapeutic plasma concentration range has not been established for Lamotrigine. Dosing of Lamotrigine should be based on therapeutic response [see Clinical Pharmacology (12.3)].

  Women Taking Estrogen-Containing Oral Contraceptives:  Starting Lamotrigine in Women Taking Estrogen-Containing Oral Contraceptives: Although estrogen-containing oral contraceptives have been shown to increase the clearance of Lamotrigine [see Clinical Pharmacology (12.3)], no adjustments to the recommended dose-escalation guidelines for Lamotrigine should be necessary solely based on the use of estrogen-containing oral contraceptives. Therefore, dose escalation should follow the recommended guidelines for initiating adjunctive therapy with Lamotrigine based on the concomitant AED or other concomitant medications (see Table 1 or Table 5). See below for adjustments to maintenance doses of Lamotrigine in women taking estrogen-containing oral contraceptives.

  Adjustments to the Maintenance Dose of Lamotrigine in Women Taking Estrogen-Containing Oral Contraceptives:

  (1) Taking Estrogen-Containing Oral Contraceptives: For women not taking carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin that induce Lamotrigine glucuronidation [see Drug Interactions (7), Clinical Pharmacology (12.3)], the maintenance dose of Lamotrigine will in most cases need to be increased, by as much as 2-fold over the recommended target maintenance dose, in order to maintain a consistent Lamotrigine plasma level [see Clinical Pharmacology (12.3)].

  (2) Starting Estrogen-Containing Oral Contraceptives: In women taking a stable dose of Lamotrigine and not taking carbamazepine, phenytoin, phenobarbital, primidone, or  other drugs such as rifampin that induce Lamotrigine glucuronidation [see Drug Interactions (7), Clinical Pharmacology (12.3)], the maintenance dose will in most cases need to be increased by as much as 2-fold in order to maintain a consistent Lamotrigine plasma level. The dose increases should begin at the same time that the oral contraceptive is introduced and continue, based on clinical response, no more rapidly than 50 to 100 mg/day every week. Dose increases should not exceed the recommended rate (see Table 1 or Table 5) unless Lamotrigine plasma levels or clinical response support larger increases. Gradual transient increases in Lamotrigine plasma levels may occur during the week of inactive hormonal preparation (“pill-free” week), and these increases will be greater if dose increases are made in the days before or during the week of inactive hormonal preparation. Increased Lamotrigine plasma levels could result in additional adverse reactions, such as dizziness, ataxia, and diplopia. If adverse reactions attributable to Lamotrigine consistently occur during the “pill-free” week, dose adjustments to the overall maintenance dose may be necessary. Dose adjustments limited to the “pill-free” week are not recommended. For women taking Lamotrigine in addition to carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin that induce Lamotrigine glucuronidation [see Drug Interactions (7), Clinical Pharmacology (12.3)], no adjustment to the dose of Lamotrigine should be necessary.

  (3) Stopping Estrogen-Containing Oral Contraceptives: For women not taking carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin that induce Lamotrigine glucuronidation [see Drug Interactions (7), Clinical Pharmacology (12.3)], the maintenance dose of Lamotrigine will in most cases need to be decreased by as much as 50% in order to maintain a consistent Lamotrigine plasma level. The decrease in dose of Lamotrigine should not exceed 25% of the total daily dose per week over a 2-week period, unless clinical response or Lamotrigine plasma levels indicate otherwise [see Clinical Pharmacology (12.3)]. For women taking Lamotrigine in addition to carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin that induce Lamotrigine glucuronidation [see Drug Interactions (7), Clinical Pharmacology (12.3)], no adjustment to the dose of Lamotrigine should be necessary.

  Women and Other Hormonal Contraceptive Preparations or Hormone Replacement Therapy: The effect of other hormonal contraceptive preparations or hormone replacement therapy on the pharmacokinetics of Lamotrigine has not been systematically evaluated. It has been reported that ethinylestradiol, not progestogens, increased the clearance of Lamotrigine up to 2-fold, and the progestin-only pills had no effect on Lamotrigine plasma levels. Therefore, adjustments to the dosage of Lamotrigine in the presence of progestogens alone will likely not be needed.

  Patients With Hepatic Impairment: Experience in patients with hepatic impairment is limited. Based on a clinical pharmacology study in 24 patients with mild, moderate, and severe liver impairment [see Use in Specific Populations (8.6), Clinical Pharmacology (12.3)], the following general recommendations can be made. No dosage adjustment is needed in patients with mild liver impairment. Initial, escalation, and maintenance doses should generally be reduced by approximately 25% in patients with moderate and severe liver impairment without ascites and 50% in patients with severe liver impairment with ascites. Escalation and maintenance doses may be adjusted according to clinical response.

  Patients With Renal Impairment: Initial doses of Lamotrigine should be based on patients' concomitant medications (see Tables 1-3 or Table 5); reduced maintenance doses may be effective for patients with significant renal impairment [see Use in Specific Populations (8.7), Clinical Pharmacology (12.3)]. Few patients with severe renal impairment have been evaluated during chronic treatment with Lamotrigine. Because there is inadequate experience in this population, Lamotrigine should be used with caution in these patients.

  Discontinuation Strategy:  Epilepsy: For patients receiving Lamotrigine in combination with other AEDs, a re-evaluation of all AEDs in the regimen should be considered if a change in seizure control or an appearance or worsening of adverse reactions is observed.

  If a decision is made to discontinue therapy with Lamotrigine, a step-wise reduction of dose over at least 2 weeks (approximately 50% per week) is recommended unless safety concerns require a more rapid withdrawal [see Warnings and Precautions (5.9)].

  Discontinuing carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin that induce Lamotrigine glucuronidation should prolong the half-life of Lamotrigine; discontinuing valproate should shorten the half-life of Lamotrigine.

  Bipolar Disorder: In the controlled clinical trials, there was no increase in the incidence, type, or severity of adverse reactions following abrupt termination of Lamotrigine. In clinical trials in patients with Bipolar Disorder, 2 patients experienced seizures shortly after abrupt withdrawal of Lamotrigine. However, there were confounding factors that may have contributed to the occurrence of seizures in these bipolar patients. Discontinuation of Lamotrigine should involve a step-wise reduction of dose over at least 2 weeks (approximately 50% per week) unless safety concerns require a more rapid withdrawal [see Warnings and Precautions (5.9)].

  2.2 Epilepsy – Adjunctive Therapy

  This section provides specific dosing recommendations for patients greater than 12 years of age and patients 2 to 12 years of age. Within each of these age-groups, specific dosing recommendations are provided depending upon concomitant AED or other concomitant medications (Table 1 for patients greater than 12 years of age and Table 2 for patients 2 to 12 years of age). A weight-based dosing guide for patients 2 to 12 years of age on concomitant valproate is provided in Table 3.

  Patients Over 12 Years of Age: Recommended dosing guidelines are summarized in Table 1.

  Table 1. Escalation Regimen for Lamotrigine in Patients Over 12 Years of Age With Epilepsy  * Valproate has been shown to inhibit glucuronidation and decrease the apparent clearance of Lamotrigine [see Drug Interactions ( 7 ), Clinical Pharmacology  ( 12.3 )]. † These drugs induce Lamotrigine glucuronidation and increase clearance [see Drug Interactions ( 7 ) Clinical Pharmacology ( 12.3 )]. Other drugs, that have similar effects include estrogen-containing oral contraceptives [see Drug Interactions ( 7 ), Clinical Pharmacology  ( 12.3 )]. Dosing recommendations for oral contraceptives can be found in General Dosing Considerations [see Dosage and Administration ( 2.1 )]. Patients on rifampin, or other drugs that induce Lamotrigine glucuronidation and increase clearance, should follow the same dosing titration/maintenance regimen as that used with anticonvulsants that have this effect.     For Patients TAKING Valproate*  For Patients NOT TAKING Carbamazepine, Phenytoin, Phenobarbital, Primidone†,or Valproate*  For Patients TAKING Carbamazepine, Phenytoin, Phenobarbital, or Primidone† and NOT TAKING Valproate*  Weeks 1 and 2  25 mg every other day  25 mg every day  50 mg/day  Weeks 3 and 4  25 mg every day  50 mg/day  100 mg/day (in 2 divided doses)  Weeks 5 onwards to maintenance  Increase by 25 to 50 mg/day every 1 to 2 weeks  Increase by 50 mg/day
  every 1 to 2 weeks  Increase by 100 mg/day every 1 to 2 weeks  Usual Maintenance Dose  100 to 200 mg/day with valproate alone
  
  100 to 400 mg/day with valproate and other drugs that induce glucuronidation
  (in 1 or 2 divided doses)  225 to 375 mg/day
  (in 2 divided doses)  300 to 500 mg/day  (in 2 divided doses)

  Patients 2 to 12 Years of Age: Recommended dosing guidelines are summarized in Table 2.

  Smaller starting doses and slower dose escalations than those used in clinical trials are recommended because of the suggestion that the risk of rash may be decreased by smaller starting doses and slower dose escalations. Therefore, maintenance doses will take longer to reach in clinical practice than in clinical trials. It may take several weeks to months to achieve an individualized maintenance dose. Maintenance doses in patients weighing less than 30 kg, regardless of age or concomitant AED, may need to be increased as much as 50%, based on clinical response. 

  Table 2. Escalation Regimen for Lamotrigine in Patients 2 to 12 Years of Age With Epilepsy * Valproate has been shown to inhibit glucuronidation and decrease the apparent clearance of Lamotrigine [see Drug Interactions (7 ), Clinical Pharmacology  (12.3)]. † These drugs induce Lamotrigine glucuronidation and increase clearance [see Drug Interactions (7 ) Clinical Pharmacology  (12.3)]. Other drugs, that have similar effects include estrogen-containing oral contraceptives [see Drug Interactions (7 ) Clinical Pharmacology  (12.3)].
  Dosing recommendations for oral contraceptives can be found in General Dosing Considerations [see Dosage and Administration ( 2.1 )]. Patients on rifampin, or other drugs that induce Lamotrigine glucuronidation and increase clearance, should follow the same dosing titration/maintenance regimen as that used with anticonvulsants that have this effect.     For Patients TAKING Valproate*  For Patients NOT TAKING Carbamazepine,
  Phenytoin,
  Phenobarbital,  
  Primidone†  or
   Valproate*  For Patients TAKING Carbamazepine, Phenytoin, Phenobarbital, or  Primidone† and NOT TAKING Valproate*  Weeks 1 and 2  0.15 mg/kg/day
   in 1 or 2 divided doses, rounded down to the nearest whole tablet (see Table 3 for weight based dosing guide)  0.3 mg/kg/day
  in 1 or 2 divided doses, rounded down to the nearest whole tablet  0.6 mg/kg/day
  in 2 divided doses, rounded down to the nearest whole tablet  Weeks 3 and 4  0.3 mg/kg/day
  in 1 or 2 divided doses, rounded down to the nearest whole tablet (see Table 3 for weight based dosing guide)  0.6 mg/kg/day
    in 2 divided doses, rounded down to the nearest whole tablet  1.2 mg/kg/day
    in 2 divided doses, rounded down to the nearest whole tablet  Weeks 5 onwards to maintenance  The dose should be increased every 1 to 2 weeks as follows: calculate 0.3 mg/kg/day, round this amount down to the nearest whole tablet, and add this amount to the previously administered daily dose  The dose should be increased every 1 to 2 weeks as follows: calculate 0.6 mg/kg/day, round this amount down to the nearest whole tablet, and add this amount to the previously administered daily dose  The dose should be increased every 1 to 2 weeks as follows: calculate 1.2 mg/kg/day, round this amount down to the nearest whole tablet, and add this amount to the previously administered daily dose  Usual Maintenance Dose  1 to 5 mg/kg/day (maximum 200 mg/day in 1 or 2 divided doses).
  1 to 3 mg/kg/day with valproate alone  4.5 to 7.5 mg/kg/day
   (maximum 300 mg/day in 2 divided doses)  5 to 15 mg/kg/day
   (maximum 400 mg/day in 2 divided doses)  Maintenance dose in patients less than 30 kg  May need to be increased by as much as 50%, based on clinical response  May need to be increased by as much as 50%, based on clinical response  May need to be increased by as much as 50%, based on clinical response  Note: Only whole tablets should be used for dosing. Table 3. The Initial Weight-Based Dosing Guide for Patients 2 to 12 Years Taking Valproate (Weeks 1 to 4) With Epilepsy  If the patient’s weight is  Give this daily dose, using the most appropriate combination of Lamotrigine 2-mg and 5-mg tablets  Greater than  And less than  Weeks 1 and 2  Weeks 3 and 4  6.7 kg  14 kg  2 mg every other day  2 mg every day  14.1 kg  27 kg  2 mg every day  4 mg every day  27.1 kg  34 kg  4 mg every day  8 mg every day  34.1 kg  40 kg  5 mg every day  10 mg every day

  Usual Adjunctive Maintenance Dose for Epilepsy: The usual maintenance doses identified in Tables 1 and 2 are derived from dosing regimens employed in the placebo-controlled adjunctive studies in which the efficacy of Lamotrigine was established. In patients receiving multidrug regimens employing carbamazepine, phenytoin, phenobarbital, or primidone without valproate, maintenance doses of adjunctive Lamotrigine as high as 700 mg/day have been used. In patients receiving valproate alone, maintenance doses of adjunctive Lamotrigine as high as 200 mg/day have been used. The advantage of using doses above those recommended in Tables 1 through 4 has not been established in controlled trials.

  2.3 Epilepsy – Conversion From Adjunctive Therapy to Monotherapy

  The goal of the transition regimen is to effect the conversion to monotherapy with Lamotrigine under conditions that ensure adequate seizure control while mitigating the risk of serious rash associated with the rapid titration of Lamotrigine.

  The recommended maintenance dose of Lamotrigine as monotherapy is 500 mg/day given in 2 divided doses.

  To avoid an increased risk of rash, the recommended initial dose and subsequent dose escalations of Lamotrigine should not be exceeded [see Boxed Warning].

  Conversion From Adjunctive Therapy With Carbamazepine, Phenytoin, Phenobarbital, or Primidone to Monotherapy With Lamotrigine: After achieving a dose of 500 mg/day of Lamotrigine according to the guidelines in Table 1, the concomitant AED should be withdrawn by 20% decrements each week over a 4-week period. The regimen for the withdrawal of the concomitant AED is based on experience gained in the controlled monotherapy clinical trial. 

  Conversion from Adjunctive Therapy With Valproate to Monotherapy With Lamotrigine: The conversion regimen involves 4 steps outlined in Table 4.

  Table 4. Conversion From Adjunctive Therapy With Valproate to Monotherapy With Lamotrigine in Patients ≥16 Years of Age with Epilepsy    

  Lamotrigine

   

  Valproate

   

  Step 1

   

  Achieve a dose of 200 mg/day according to guidelines in Table 1 (if not already on 200 mg/day).

   

  Maintain previous stable dose.

   

  Step 2

   

  Maintain at 200 mg/day.

   

  Decrease to 500 mg/day by decrements no greater than 500 mg/day/week and then maintain the dose of 500 mg/day for 1 week.

   

  Step 3

   

  Increase to 300 mg/day and maintain for 1 week.

   

  Simultaneously decrease to 250 mg/day and maintain for 1 week.

   

  Step 4

   

  Increase by 100 mg/day every week to achieve maintenance dose of 500 mg/day.

   

  Discontinue.

  
  Conversion from Adjunctive Therapy With Antiepileptic Drugs Other Than Carbamazepine, Phenytoin, Phenobarbital, Primidone, or Valproate to Monotherapy With Lamotrigine: No specific dosing guidelines can be provided for conversion to monotherapy with Lamotrigine with AEDs other than carbamazepine, phenobarbital, phenytoin, primidone, or valproate.

  2.4 Bipolar Disorder

  The goal of maintenance treatment with Lamotrigine is to delay the time to occurrence of mood episodes (depression, mania, hypomania, mixed episodes) in patients treated for acute mood episodes with standard therapy. The target dose of Lamotrigine is 200 mg/day (100 mg/day in patients taking valproate, which decreases the apparent clearance of Lamotrigine, and 400 mg/day in patients not taking valproate and taking either carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin, that  increase the apparent clearance of Lamotrigine). In the clinical trials, doses up to 400 mg/day as monotherapy were evaluated; however, no additional benefit was seen at 400 mg/day compared with 200 mg/day [see Clinical Studies (14.2)]. Accordingly, doses above 200 mg/day are not recommended. Treatment with Lamotrigine is introduced, based on concurrent medications, according to the regimen outlined in Table 5. If other psychotropic medications are withdrawn following stabilization, the dose of Lamotrigine should be adjusted. For patients discontinuing valproate, the dose of Lamotrigine should be doubled over a 2-week period in equal weekly increments (see Table 6). For patients discontinuing carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin that induce Lamotrigine glucuronidation, the dose of Lamotrigine should remain constant for the first week and then should be decreased by half over a 2-week period in equal weekly decrements (see Table 6). The dose of Lamotrigine may then be further adjusted to the target dose (200 mg) as clinically indicated.

  If other drugs are subsequently introduced, the dose of Lamotrigine may need to be adjusted. In particular, the introduction of valproate requires reduction in the dose of Lamotrigine [see Drug Interactions (7), Clinical Pharmacology (12.3)].

  To avoid an increased risk of rash, the recommended initial dose and subsequent dose escalations of Lamotrigine should not be exceeded [see Boxed Warning].

  Table 5. Escalation Regimen for Lamotrigine for Patients With Bipolar Disorder * Valproate has been shown to inhibit glucuronidation and decrease the apparent clearance of Lamotrigine [see Drug Interactions (7 ), Clinical Pharmacology (12.3)]. † These drugs induce Lamotrigine glucuronidation and increase clearance [see Drug Interactions (7 ), Clinical Pharmacology (12.3)]. Other drugs that have similar effects include estrogen- containing oral contraceptives [see Drug Interactions (7), Clinical Pharmacology (12.3)].
  Dosing recommendations for oral contraceptives can be found in General Dosing Considerations [see Dosage and Administration (2.1)]. Patients on rifampin, or other drugs that induce Lamotrigine glucuronidation and increase clearance, should follow the same dosing titration/ maintenance regimen as that used with anticonvulsants that have this effect.    For Patients TAKING Valproate*  For Patients NOT TAKING Carbamazepine, Phenytoin, Phenobarbital, Primidone†, or Valproate*  For Patients TAKING Carbamazepine, Phenytoin, Phenobarbital, or Primidone† and NOT TAKING Valproate*  Weeks 1 and 2  25 mg every other day  25 mg daily  50 mg daily  Weeks 3 and 4  25 mg daily  50 mg daily  100 mg daily, in divided doses  Week 5  50 mg daily  100 mg daily  200 mg daily, in divided doses  Week 6  100 mg daily  200 mg daily  300 mg daily, in divided doses  Week 7  100 mg daily  200 mg daily  up to 400 mg daily, in divided doses Table 6. Dosage Adjustments to Lamotrigine for Patients With Bipolar Disorder Following Discontinuation of Psychotropic Medications * These drugs induce Lamotrigine glucuronidation and increase clearance [see Drug Interactions (7 ), Clinical Pharmacology (12.3)]. Other drugs that have similar effects include estrogen-containing oral contraceptives [see Drug Interactions (7), Clinical Pharmacology (12.3)]. Dosing recommendations for oral contraceptives can be found in General Dosing Considerations [see Dosage and Administration (2.1)]. Patients on rifampin, or other drugs that induce Lamotrigine glucuronidation and increase clearance, should follow the same dosing titration/ maintenance regimen as that used with anticonvulsants that have this effect. † Valproate has been shown to inhibit glucuronidation and decrease the apparent clearance of Lamotrigine [see Drug Interactions (7), Clinical Pharmacology (12.3)].     

  Discontinuation of Psychotropic Drugs (excluding Carbamazepine, Phenytoin, Phenobarbital, Primidone*, or Valproate†)

   After Discontinuation of Valproate†  After Discontinuation of Carbamazepine, Phenytoin, Phenobarbital, or Primidone*  Current dose of Lamotrigine (mg/day) 100  

  Current dose of Lamotrigine (mg/day) 400

   Week 1  Maintain current dose of Lamotrigine  150  400  Week 2  Maintain current dose of Lamotrigine  200  300  Week 3 onward  Maintain current dose of Lamotrigine  200  200

  The benefit of continuing treatment in patients who had been stabilized in an 8- to 16-week open-label phase with Lamotrigine was established in 2 randomized, placebo-controlled clinical maintenance trials [see Clinical Studies (14.2)]. However, the optimal duration of treatment with Lamotrigine has not been established. Thus, patients should be periodically reassessed to determine the need for maintenance treatment.

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  2.1 General Dosing Considerations 

  Rash: There are suggestions, yet to be proven, that the risk of severe, potentially life-threatening rash may be increased by (1) coadministration of Lamotrigine with valproate, (2) exceeding the recommended initial dose of Lamotrigine, or (3) exceeding the recommended dose escalation for Lamotrigine. However, cases have occurred in the absence of these factors [see Boxed Warning]. Therefore, it is important that the dosing recommendations be followed closely.

  The risk of nonserious rash may be increased when the recommended initial dose and/or the rate of dose escalation of Lamotrigine is exceeded and in patients with a history of allergy or rash to other AEDs.

  It is recommended that Lamotrigine not be restarted in patients who discontinued due to rash associated with prior treatment with Lamotrigine, unless the potential benefits clearly outweigh the risks. If the decision is made to restart a patient who has discontinued Lamotrigine, the need to restart with the initial dosing recommendations should be assessed. The greater the interval of time since the previous dose, the greater consideration should be given to restarting with the initial dosing recommendations. If a patient has discontinued Lamotrigine for a period of more than 5 half-lives, it is recommended that initial dosing recommendations and guidelines be followed. The half-life of Lamotrigine is affected by other concomitant medications [see Clinical Pharmacology (12.3)].

  Lamotrigine Added to Drugs Known to Induce or Inhibit Glucuronidation: Drugs other than those listed in the Clinical Pharmacology section [see Clinical Pharmacology (12.3)] have not been systematically evaluated in combination with Lamotrigine. Because Lamotrigine is metabolized predominantly by glucuronic acid conjugation, drugs that are known to induce or inhibit glucuronidation may affect the apparent clearance of Lamotrigine and doses of Lamotrigine may require adjustment based on clinical response.

  Target Plasma Levels for Patients With Epilepsy or Bipolar Disorder: A therapeutic plasma concentration range has not been established for Lamotrigine. Dosing of Lamotrigine should be based on therapeutic response [see Clinical Pharmacology (12.3)].

  Women Taking Estrogen-Containing Oral Contraceptives:  Starting Lamotrigine in Women Taking Estrogen-Containing Oral Contraceptives: Although estrogen-containing oral contraceptives have been shown to increase the clearance of Lamotrigine [see Clinical Pharmacology (12.3)], no adjustments to the recommended dose-escalation guidelines for Lamotrigine should be necessary solely based on the use of estrogen-containing oral contraceptives. Therefore, dose escalation should follow the recommended guidelines for initiating adjunctive therapy with Lamotrigine based on the concomitant AED or other concomitant medications (see Table 1 or Table 5). See below for adjustments to maintenance doses of Lamotrigine in women taking estrogen-containing oral contraceptives.

  Adjustments to the Maintenance Dose of Lamotrigine in Women Taking Estrogen-Containing Oral Contraceptives:

  (1) Taking Estrogen-Containing Oral Contraceptives: For women not taking carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin that induce Lamotrigine glucuronidation [see Drug Interactions (7), Clinical Pharmacology (12.3)], the maintenance dose of Lamotrigine will in most cases need to be increased, by as much as 2-fold over the recommended target maintenance dose, in order to maintain a consistent Lamotrigine plasma level [see Clinical Pharmacology (12.3)].

  (2) Starting Estrogen-Containing Oral Contraceptives: In women taking a stable dose of Lamotrigine and not taking carbamazepine, phenytoin, phenobarbital, primidone, or  other drugs such as rifampin that induce Lamotrigine glucuronidation [see Drug Interactions (7), Clinical Pharmacology (12.3)], the maintenance dose will in most cases need to be increased by as much as 2-fold in order to maintain a consistent Lamotrigine plasma level. The dose increases should begin at the same time that the oral contraceptive is introduced and continue, based on clinical response, no more rapidly than 50 to 100 mg/day every week. Dose increases should not exceed the recommended rate (see Table 1 or Table 5) unless Lamotrigine plasma levels or clinical response support larger increases. Gradual transient increases in Lamotrigine plasma levels may occur during the week of inactive hormonal preparation (“pill-free” week), and these increases will be greater if dose increases are made in the days before or during the week of inactive hormonal preparation. Increased Lamotrigine plasma levels could result in additional adverse reactions, such as dizziness, ataxia, and diplopia. If adverse reactions attributable to Lamotrigine consistently occur during the “pill-free” week, dose adjustments to the overall maintenance dose may be necessary. Dose adjustments limited to the “pill-free” week are not recommended. For women taking Lamotrigine in addition to carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin that induce Lamotrigine glucuronidation [see Drug Interactions (7), Clinical Pharmacology (12.3)], no adjustment to the dose of Lamotrigine should be necessary.

  (3) Stopping Estrogen-Containing Oral Contraceptives: For women not taking carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin that induce Lamotrigine glucuronidation [see Drug Interactions (7), Clinical Pharmacology (12.3)], the maintenance dose of Lamotrigine will in most cases need to be decreased by as much as 50% in order to maintain a consistent Lamotrigine plasma level. The decrease in dose of Lamotrigine should not exceed 25% of the total daily dose per week over a 2-week period, unless clinical response or Lamotrigine plasma levels indicate otherwise [see Clinical Pharmacology (12.3)]. For women taking Lamotrigine in addition to carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin that induce Lamotrigine glucuronidation [see Drug Interactions (7), Clinical Pharmacology (12.3)], no adjustment to the dose of Lamotrigine should be necessary.

  Women and Other Hormonal Contraceptive Preparations or Hormone Replacement Therapy: The effect of other hormonal contraceptive preparations or hormone replacement therapy on the pharmacokinetics of Lamotrigine has not been systematically evaluated. It has been reported that ethinylestradiol, not progestogens, increased the clearance of Lamotrigine up to 2-fold, and the progestin-only pills had no effect on Lamotrigine plasma levels. Therefore, adjustments to the dosage of Lamotrigine in the presence of progestogens alone will likely not be needed.

  Patients With Hepatic Impairment: Experience in patients with hepatic impairment is limited. Based on a clinical pharmacology study in 24 patients with mild, moderate, and severe liver impairment [see Use in Specific Populations (8.6), Clinical Pharmacology (12.3)], the following general recommendations can be made. No dosage adjustment is needed in patients with mild liver impairment. Initial, escalation, and maintenance doses should generally be reduced by approximately 25% in patients with moderate and severe liver impairment without ascites and 50% in patients with severe liver impairment with ascites. Escalation and maintenance doses may be adjusted according to clinical response.

  Patients With Renal Impairment: Initial doses of Lamotrigine should be based on patients' concomitant medications (see Tables 1-3 or Table 5); reduced maintenance doses may be effective for patients with significant renal impairment [see Use in Specific Populations (8.7), Clinical Pharmacology (12.3)]. Few patients with severe renal impairment have been evaluated during chronic treatment with Lamotrigine. Because there is inadequate experience in this population, Lamotrigine should be used with caution in these patients.

  Discontinuation Strategy:  Epilepsy: For patients receiving Lamotrigine in combination with other AEDs, a re-evaluation of all AEDs in the regimen should be considered if a change in seizure control or an appearance or worsening of adverse reactions is observed.

  If a decision is made to discontinue therapy with Lamotrigine, a step-wise reduction of dose over at least 2 weeks (approximately 50% per week) is recommended unless safety concerns require a more rapid withdrawal [see Warnings and Precautions (5.9)].

  Discontinuing carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin that induce Lamotrigine glucuronidation should prolong the half-life of Lamotrigine; discontinuing valproate should shorten the half-life of Lamotrigine.

  Bipolar Disorder: In the controlled clinical trials, there was no increase in the incidence, type, or severity of adverse reactions following abrupt termination of Lamotrigine. In clinical trials in patients with Bipolar Disorder, 2 patients experienced seizures shortly after abrupt withdrawal of Lamotrigine. However, there were confounding factors that may have contributed to the occurrence of seizures in these bipolar patients. Discontinuation of Lamotrigine should involve a step-wise reduction of dose over at least 2 weeks (approximately 50% per week) unless safety concerns require a more rapid withdrawal [see Warnings and Precautions (5.9)].

  2.2 Epilepsy – Adjunctive Therapy

  This section provides specific dosing recommendations for patients greater than 12 years of age and patients 2 to 12 years of age. Within each of these age-groups, specific dosing recommendations are provided depending upon concomitant AED or other concomitant medications (Table 1 for patients greater than 12 years of age and Table 2 for patients 2 to 12 years of age). A weight-based dosing guide for patients 2 to 12 years of age on concomitant valproate is provided in Table 3.

  Patients Over 12 Years of Age: Recommended dosing guidelines are summarized in Table 1.

  Table 1. Escalation Regimen for Lamotrigine in Patients Over 12 Years of Age With Epilepsy  * Valproate has been shown to inhibit glucuronidation and decrease the apparent clearance of Lamotrigine [see Drug Interactions ( 7 ), Clinical Pharmacology  ( 12.3 )]. † These drugs induce Lamotrigine glucuronidation and increase clearance [see Drug Interactions ( 7 ) Clinical Pharmacology ( 12.3 )]. Other drugs, that have similar effects include estrogen-containing oral contraceptives [see Drug Interactions ( 7 ), Clinical Pharmacology  ( 12.3 )]. Dosing recommendations for oral contraceptives can be found in General Dosing Considerations [see Dosage and Administration ( 2.1 )]. Patients on rifampin, or other drugs that induce Lamotrigine glucuronidation and increase clearance, should follow the same dosing titration/maintenance regimen as that used with anticonvulsants that have this effect.

   

  For Patients TAKING Valproate*

  For Patients NOT TAKING Carbamazepine, Phenytoin, Phenobarbital, Primidone†,or Valproate*

  For Patients TAKING Carbamazepine, Phenytoin, Phenobarbital, or Primidone† and NOT TAKING Valproate*

  Weeks 1 and 2

  25 mg every other day

  25 mg every day

  50 mg/day

  Weeks 3 and 4

  25 mg every day

  50 mg/day

  100 mg/day (in 2 divided doses)

  Weeks 5 onwards to maintenance

  Increase by 25 to 50 mg/day every 1 to 2 weeks

  Increase by 50 mg/day
  every 1 to 2 weeks

  Increase by 100 mg/day every 1 to 2 weeks

  Usual Maintenance Dose

  100 to 200 mg/day with valproate alone
  
  100 to 400 mg/day with valproate and other drugs that induce glucuronidation
  (in 1 or 2 divided doses)

  225 to 375 mg/day
  (in 2 divided doses)

  300 to 500 mg/day  (in 2 divided doses)

  Patients 2 to 12 Years of Age: Recommended dosing guidelines are summarized in Table 2.

  Smaller starting doses and slower dose escalations than those used in clinical trials are recommended because of the suggestion that the risk of rash may be decreased by smaller starting doses and slower dose escalations. Therefore, maintenance doses will take longer to reach in clinical practice than in clinical trials. It may take several weeks to months to achieve an individualized maintenance dose. Maintenance doses in patients weighing less than 30 kg, regardless of age or concomitant AED, may need to be increased as much as 50%, based on clinical response. 

  Table 2. Escalation Regimen for Lamotrigine in Patients 2 to 12 Years of Age With Epilepsy * Valproate has been shown to inhibit glucuronidation and decrease the apparent clearance of Lamotrigine [see Drug Interactions (7 ), Clinical Pharmacology  (12.3)]. † These drugs induce Lamotrigine glucuronidation and increase clearance [see Drug Interactions (7 ) Clinical Pharmacology  (12.3)]. Other drugs, that have similar effects include estrogen-containing oral contraceptives [see Drug Interactions (7 ) Clinical Pharmacology  (12.3)].
  Dosing recommendations for oral contraceptives can be found in General Dosing Considerations [see Dosage and Administration ( 2.1 )]. Patients on rifampin, or other drugs that induce Lamotrigine glucuronidation and increase clearance, should follow the same dosing titration/maintenance regimen as that used with anticonvulsants that have this effect.

   

  For Patients TAKING Valproate*

  For Patients NOT TAKING Carbamazepine,
  Phenytoin,
  Phenobarbital,  
  Primidone†  or
   Valproate*

  For Patients TAKING Carbamazepine, Phenytoin, Phenobarbital, or  Primidone† and NOT TAKING Valproate*

  Weeks 1 and 2

  0.15 mg/kg/day
   in 1 or 2 divided doses, rounded down to the nearest whole tablet (see Table 3 for weight based dosing guide)

  0.3 mg/kg/day
  in 1 or 2 divided doses, rounded down to the nearest whole tablet

  0.6 mg/kg/day
  in 2 divided doses, rounded down to the nearest whole tablet

  Weeks 3 and 4

  0.3 mg/kg/day
  in 1 or 2 divided doses, rounded down to the nearest whole tablet (see Table 3 for weight based dosing guide)

  0.6 mg/kg/day
    in 2 divided doses, rounded down to the nearest whole tablet

  1.2 mg/kg/day
    in 2 divided doses, rounded down to the nearest whole tablet

  Weeks 5 onwards to maintenance

  The dose should be increased every 1 to 2 weeks as follows: calculate 0.3 mg/kg/day, round this amount down to the nearest whole tablet, and add this amount to the previously administered daily dose

  The dose should be increased every 1 to 2 weeks as follows: calculate 0.6 mg/kg/day, round this amount down to the nearest whole tablet, and add this amount to the previously administered daily dose

  The dose should be increased every 1 to 2 weeks as follows: calculate 1.2 mg/kg/day, round this amount down to the nearest whole tablet, and add this amount to the previously administered daily dose

  Usual Maintenance Dose

  1 to 5 mg/kg/day (maximum 200 mg/day in 1 or 2 divided doses).
  1 to 3 mg/kg/day with valproate alone

  4.5 to 7.5 mg/kg/day
   (maximum 300 mg/day in 2 divided doses)

  5 to 15 mg/kg/day
   (maximum 400 mg/day in 2 divided doses)

  Maintenance dose in patients less than 30 kg

  May need to be increased by as much as 50%, based on clinical response

  May need to be increased by as much as 50%, based on clinical response

  May need to be increased by as much as 50%, based on clinical response

  Note: Only whole tablets should be used for dosing.

  Table 3. The Initial Weight-Based Dosing Guide for Patients 2 to 12 Years Taking Valproate (Weeks 1 to 4) With Epilepsy

  If the patient’s weight is

  Give this daily dose, using the most appropriate combination of Lamotrigine 2-mg and 5-mg tablets

  Greater than

  And less than

  Weeks 1 and 2

  Weeks 3 and 4

  6.7 kg

  14 kg

  2 mg every other day

  2 mg every day

  14.1 kg

  27 kg

  2 mg every day

  4 mg every day

  27.1 kg

  34 kg

  4 mg every day

  8 mg every day

  34.1 kg

  40 kg

  5 mg every day

  10 mg every day

  Usual Adjunctive Maintenance Dose for Epilepsy: The usual maintenance doses identified in Tables 1 and 2 are derived from dosing regimens employed in the placebo-controlled adjunctive studies in which the efficacy of Lamotrigine was established. In patients receiving multidrug regimens employing carbamazepine, phenytoin, phenobarbital, or primidone without valproate, maintenance doses of adjunctive Lamotrigine as high as 700 mg/day have been used. In patients receiving valproate alone, maintenance doses of adjunctive Lamotrigine as high as 200 mg/day have been used. The advantage of using doses above those recommended in Tables 1 through 4 has not been established in controlled trials.

  2.3 Epilepsy – Conversion From Adjunctive Therapy to Monotherapy

  The goal of the transition regimen is to effect the conversion to monotherapy with Lamotrigine under conditions that ensure adequate seizure control while mitigating the risk of serious rash associated with the rapid titration of Lamotrigine.

  The recommended maintenance dose of Lamotrigine as monotherapy is 500 mg/day given in 2 divided doses.

  To avoid an increased risk of rash, the recommended initial dose and subsequent dose escalations of Lamotrigine should not be exceeded [see Boxed Warning].

  Conversion From Adjunctive Therapy With Carbamazepine, Phenytoin, Phenobarbital, or Primidone to Monotherapy With Lamotrigine: After achieving a dose of 500 mg/day of Lamotrigine according to the guidelines in Table 1, the concomitant AED should be withdrawn by 20% decrements each week over a 4-week period. The regimen for the withdrawal of the concomitant AED is based on experience gained in the controlled monotherapy clinical trial. 

  Conversion from Adjunctive Therapy With Valproate to Monotherapy With Lamotrigine: The conversion regimen involves 4 steps outlined in Table 4.

  Table 4. Conversion From Adjunctive Therapy With Valproate to Monotherapy With Lamotrigine in Patients ≥16 Years of Age with Epilepsy

  Lamotrigine

  Valproate

  Step 1

  Achieve a dose of 200 mg/day according to guidelines in Table 1 (if not already on 200 mg/day).

  Maintain previous stable dose.

  Step 2

  Maintain at 200 mg/day.

  Decrease to 500 mg/day by decrements no greater than 500 mg/day/week and then maintain the dose of 500 mg/day for 1 week.

  Step 3

  Increase to 300 mg/day and maintain for 1 week.

  Simultaneously decrease to 250 mg/day and maintain for 1 week.

  Step 4

  Increase by 100 mg/day every week to achieve maintenance dose of 500 mg/day.

  Discontinue.

  
  Conversion from Adjunctive Therapy With Antiepileptic Drugs Other Than Carbamazepine, Phenytoin, Phenobarbital, Primidone, or Valproate to Monotherapy With Lamotrigine: No specific dosing guidelines can be provided for conversion to monotherapy with Lamotrigine with AEDs other than carbamazepine, phenobarbital, phenytoin, primidone, or valproate.

  2.4 Bipolar Disorder

  The goal of maintenance treatment with Lamotrigine is to delay the time to occurrence of mood episodes (depression, mania, hypomania, mixed episodes) in patients treated for acute mood episodes with standard therapy. The target dose of Lamotrigine is 200 mg/day (100 mg/day in patients taking valproate, which decreases the apparent clearance of Lamotrigine, and 400 mg/day in patients not taking valproate and taking either carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin, that  increase the apparent clearance of Lamotrigine). In the clinical trials, doses up to 400 mg/day as monotherapy were evaluated; however, no additional benefit was seen at 400 mg/day compared with 200 mg/day [see Clinical Studies (14.2)]. Accordingly, doses above 200 mg/day are not recommended. Treatment with Lamotrigine is introduced, based on concurrent medications, according to the regimen outlined in Table 5. If other psychotropic medications are withdrawn following stabilization, the dose of Lamotrigine should be adjusted. For patients discontinuing valproate, the dose of Lamotrigine should be doubled over a 2-week period in equal weekly increments (see Table 6). For patients discontinuing carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin that induce Lamotrigine glucuronidation, the dose of Lamotrigine should remain constant for the first week and then should be decreased by half over a 2-week period in equal weekly decrements (see Table 6). The dose of Lamotrigine may then be further adjusted to the target dose (200 mg) as clinically indicated.

  If other drugs are subsequently introduced, the dose of Lamotrigine may need to be adjusted. In particular, the introduction of valproate requires reduction in the dose of Lamotrigine [see Drug Interactions (7), Clinical Pharmacology (12.3)].

  To avoid an increased risk of rash, the recommended initial dose and subsequent dose escalations of Lamotrigine should not be exceeded [see Boxed Warning].

   

  Table 5. Escalation Regimen for Lamotrigine for Patients With Bipolar Disorder * Valproate has been shown to inhibit glucuronidation and decrease the apparent clearance of Lamotrigine [see Drug Interactions (7 ), Clinical Pharmacology (12.3)]. † These drugs induce Lamotrigine glucuronidation and increase clearance [see Drug Interactions (7 ), Clinical Pharmacology (12.3)]. Other drugs that have similar effects include estrogen- containing oral contraceptives [see Drug Interactions (7), Clinical Pharmacology (12.3)].
  Dosing recommendations for oral contraceptives can be found in General Dosing Considerations [see Dosage and Administration (2.1)]. Patients on rifampin, or other drugs that induce Lamotrigine glucuronidation and increase clearance, should follow the same dosing titration/ maintenance regimen as that used with anticonvulsants that have this effect.

  For Patients TAKING Valproate*

  For Patients NOT TAKING Carbamazepine, Phenytoin, Phenobarbital, Primidone†, or Valproate*

  For Patients TAKING Carbamazepine, Phenytoin, Phenobarbital, or Primidone† and NOT TAKING Valproate*

  Weeks 1 and 2

  25 mg every other day

  25 mg daily

  50 mg daily

  Weeks 3 and 4

  25 mg daily

  50 mg daily

  100 mg daily, in divided doses

  Week 5

  50 mg daily

  100 mg daily

  200 mg daily, in divided doses

  Week 6

  100 mg daily

  200 mg daily

  300 mg daily, in divided doses

  Week 7

  100 mg daily

  200 mg daily

  up to 400 mg daily, in divided doses

  Table 6. Dosage Adjustments to Lamotrigine for Patients With Bipolar Disorder Following Discontinuation of Psychotropic Medications * These drugs induce Lamotrigine glucuronidation and increase clearance [see Drug Interactions (7 ), Clinical Pharmacology (12.3)]. Other drugs that have similar effects include estrogen-containing oral contraceptives [see Drug Interactions (7), Clinical Pharmacology (12.3)]. Dosing recommendations for oral contraceptives can be found in General Dosing Considerations [see Dosage and Administration (2.1)]. Patients on rifampin, or other drugs that induce Lamotrigine glucuronidation and increase clearance, should follow the same dosing titration/ maintenance regimen as that used with anticonvulsants that have this effect. † Valproate has been shown to inhibit glucuronidation and decrease the apparent clearance of Lamotrigine [see Drug Interactions (7), Clinical Pharmacology (12.3)].

   

  Discontinuation of Psychotropic Drugs (excluding Carbamazepine, Phenytoin, Phenobarbital, Primidone*, or Valproate†)

  After Discontinuation of Valproate†

  After Discontinuation of Carbamazepine, Phenytoin, Phenobarbital, or Primidone*

  Current dose of Lamotrigine (mg/day) 100

  Current dose of Lamotrigine (mg/day) 400

  Week 1

  Maintain current dose of Lamotrigine

  150

  400

  Week 2

  Maintain current dose of Lamotrigine

  200

  300

  Week 3 onward

  Maintain current dose of Lamotrigine

  200

  200

  The benefit of continuing treatment in patients who had been stabilized in an 8- to 16-week open-label phase with Lamotrigine was established in 2 randomized, placebo-controlled clinical maintenance trials [see Clinical Studies (14.2)]. However, the optimal duration of treatment with Lamotrigine has not been established. Thus, patients should be periodically reassessed to determine the need for maintenance treatment.

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  Lamotrigine | Pd-rx Pharmaceuticals, Inc.

  

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  General Principles:

  The goal of replacement therapy is to achieve and maintain a clinical and biochemical euthyroid state. The goal of suppressive therapy is to inhibit growth and/or function of abnormal thyroid tissue. The dose of Levothyroxine Sodium Tablets, USP that is adequate to achieve these goals depends on a variety of factors including the patient's age, body weight, cardiovascular status, concomitant medical conditions, including pregnancy, concomitant medications, and the specific nature of the condition being treated (see WARNINGS and PRECAUTIONS). Hence, the following recommendations serve only as dosing guidelines. Dosing must be individualized and adjustments made based on periodic assessment of the patient's clinical response and laboratory parameters (see PRECAUTIONS, Laboratory Tests).

  Levothyroxine Sodium Tablets, USP should be taken in the morning on an empty stomach, at least one-half hour to one hour before any food is eaten. Levothyroxine Sodium Tablets, USP should be taken at least 4 hours apart from drugs that are known to interfere with its absorption (see PRECAUTIONS, Drug Interactions).

  Due to the long half-life of levothyroxine, the peak therapeutic effect at a given dose of levothyroxine sodium may not be attained for 4-6 weeks.

  Caution should be exercised when administering Levothyroxine Sodium Tablets, USP to patients with underlying cardiovascular disease, to the elderly, and to those with concomitant adrenal insufficiency (see PRECAUTIONS).

  Specific Patient Populations:

  Hypothyroidism in Adults and in Children in Whom Growth and Puberty are Complete (see WARNINGS and PRECAUTIONS, Laboratory Tests).

  Therapy may begin at full replacement doses in otherwise healthy individuals less than 50 years old and in those older than 50 years who have been recently treated for hyperthyroidism or who have been hypothyroid for only a short time (such as a few months). The average full replacement dose of levothyroxine sodium is approximately 1.7 mcg/kg/day (e.g., 100-125 mcg/day for a 70 kg adult). Older patients may require less than 1 mcg/kg/day. Levothyroxine sodium doses greater than 200 mcg/day are seldom required. An inadequate response to daily doses ≥ 300 mcg/day is rare and may indicate poor compliance, malabsorption, and/or drug interactions.

  For most patients older than 50 years or for patients under 50 years of age with underlying cardiac disease, an initial starting dose of 25-50 mcg/day of levothyroxine sodium is recommended, with gradual increments in dose at 6-8 week intervals, as needed. The recommended starting dose of levothyroxine sodium in elderly patients with cardiac disease is 12.5-25 mcg/day, with gradual dose increments at 4-6 week intervals. The levothyroxine sodium dose is generally adjusted in 12.5-25 mcg increments until the patient with primary hypothyroidism is clinically euthyroid and the serum TSH has normalized.

  In patients with severe hypothyroidism, the recommended initial levothyroxine sodium dose is 12.5-25 mcg/day with increases of 25 mcg/day every 2-4 weeks, accompanied by clinical and laboratory assessment, until the TSH level is normalized.

  In patients with secondary (pituitary) or tertiary (hypothalamic) hypothyroidism, the levothyroxine sodium dose should be titrated until the patient is clinically euthyroid and the serum free-T4 level is restored to the upper half of the normal range.

  Pediatric Dosage - Congenital or Acquired Hypothyroidism (see PRECAUTIONS, Laboratory Tests)

  General Principles

  In general, levothyroxine therapy should be instituted at full replacement doses as soon as possible. Delays in diagnosis and institution of therapy may have deleterious effects on the child's intellectual and physical growth and development.

  Undertreatment and overtreatment should be avoided (see PRECAUTIONS, Pediatric Use).

  Levothyroxine Sodium Tablets, USP may be administered to infants and children who cannot swallow intact tablets by crushing the tablet and suspending the freshly crushed tablet in a small amount (5-10 mL or 1-2 teaspoons) of water. This suspension can be administered by spoon or dropper. DO NOT STORE THE SUSPENSION. Foods that decrease absorption of levothyroxine, such as soybean infant formula, should not be used for administering levothyroxine sodium tablets. (see PRECAUTIONS, Drug-Food Interactions).

  Newborns

  The recommended starting dose of levothyroxine sodium in newborn infants is 10-15 mcg/kg/day. A lower starting dose (e.g., 25 mcg/day) should be considered in infants at risk for cardiac failure, and the dose should be increased in 4-6 weeks as needed based on clinical and laboratory response to treatment. In infants with very low (< 5 mcg/dL) or undetectable serum T4 concentrations, the recommended initial starting dose is 50 mcg/day of levothyroxine sodium.

  Infants and Children

  Levothyroxine therapy is usually initiated at full replacement doses, with the recommended dose per body weight decreasing with age (see TABLE 3). However, in children with chronic or severe hypothyroidism, an initial dose of 25 mcg/day of levothyroxine sodium is recommended with increments of 25 mcg every 2-4 weeks until the desired effect is achieved.

  Hyperactivity in an older child can be minimized if the starting dose is one-fourth of the recommended full replacement dose, and the dose is then increased on a weekly basis by an amount equal to one-fourth the full-recommended replacement dose until the full recommended replacement dose is reached.

  Table 3: Levothyroxine Sodium Dosing Guidelines for Pediatric Hypothyroidism a. The dose should be adjusted based on clinical response and laboratory parameters (see PRECAUTlONS, Laboratory Tests and Pediatric Use). AGE Daily Dose Per Kg Body Weighta 0-3 months  10-15 mcg/kg/day 3-6 months  8-10 mcg/kg/day 6-12 months  6-8 mcg/kg/day 1-5 years  5-6 mcg/kg/day 6-12 years  4-5 mcg/kg/day >12 years but growth and puberty incomplete 2-3 mcg/kg/day  Growth and puberty complete  1.7 mcg/kg/day

  Pregnancy- Pregnancy may increase levothyroxine requirements (see PREGNANCY).

  Subclinical Hypothyroidism- If this condition is treated, a lower levothyroxine sodium dose (e.g., 1 mcg/kg/day) than that used for full replacement may be adequate to normalize the serum TSH level. Patients who are not treated should be monitored yearly for changes in clinical status and thyroid laboratory parameters.

  TSH Suppression in Well-differentiated Thyroid Cancer and Thyroid Nodules- The target level for TSH suppression in these conditions has not been established with controlled studies. In addition, the efficacy of TSH suppression for benign nodular disease is controversial. Therefore, the dose of Levothyroxine Sodium Tablets, USP used for TSH suppression should be individualized based on the specific disease and the patient being treated.

  In the treatment of well differentiated (papillary and follicular) thyroid cancer, levothyroxine is used as an adjunct to surgery and radioiodine therapy. Generally, TSH is suppressed to <0.1 mU/L, and this usually requires a levothyroxine sodium dose of greater than 2 mcg/kg/day. However, in patients with high-risk tumors, the target level for TSH suppression may be <0.01 mU/L.

  In the treatment of benign nodules and nontoxic multinodular goiter, TSH is generally suppressed to a higher target (e.g., 0.1-0.5 mU/L for nodules and 0.5-1.0 mU/L for multinodular goiter) than that used for the treatment of thyroid cancer. Levothyroxine sodium is contraindicated if the serum TSH is already suppressed due to the risk of precipitating overt thyrotoxicosis (see CONTRAINDICATIONS, WARNINGS and PRECAUTIONS).

  Myxedema Coma - Myxedema coma is a life-threatening emergency characterized by poor circulation and hypometabolism, and may result in unpredictable absorption of levothyroxine sodium from the gastrointestinal tract. Therefore, oral thyroid hormone drug products are not recommended to treat this condition. Thyroid hormone products formulated for intravenous administration should be administered.

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  2.1 General Dosing Considerations

  Rash: There are suggestions, yet to be proven, that the risk of severe, potentially life-threatening rash may be increased by (1) coadministration of lamotrigine with valproate, (2) exceeding the recommended initial dose of lamotrigine, or (3) exceeding the recommended dose escalation for lamotrigine. However, cases have occurred in the absence of these factors [see Boxed Warning]. Therefore, it is important that the dosing recommendations be followed closely.

  The risk of nonserious rash may be increased when the recommended initial dose and/or the rate of dose escalation of lamotrigine is exceeded and in patients with a history of allergy or rash to other AEDs.

  Lamotrigine Starter Kits provide lamotrigine at doses consistent with the recommended titration schedule for the first 5 weeks of treatment, based upon concomitant medications for patients with epilepsy (>12 years of age) and Bipolar I Disorder (≥18 years of age) and are intended to help reduce the potential for rash. The use of lamotrigine Starter Kits is recommended for appropriate patients who are starting or restarting lamotrigine [see How Supplied/Storage and Handling (16)].

  It is recommended that lamotrigine tablets, USP not be restarted in patients who discontinued due to rash associated with prior treatment with lamotrigine, unless the potential benefits clearly outweigh the risks. If the decision is made to restart a patient who has discontinued lamotrigine, the need to restart with the initial dosing recommendations should be assessed. The greater the interval of time since the previous dose, the greater consideration should be given to restarting with the initial dosing recommendations. If a patient has discontinued lamotrigine for a period of more than 5 half-lives, it is recommended that initial dosing recommendations and guidelines be followed. The half-life of lamotrigine is affected by other concomitant medications [see Clinical Pharmacology (12.3)].

  Lamotrigine Added to Drugs Known to Induce or Inhibit Glucuronidation: Drugs other than those listed in the Clinical Pharmacology section [see Clinical Pharmacology (12.3)] have not been systematically evaluated in combination with lamotrigine. Because lamotrigine is metabolized predominantly by glucuronic acid conjugation, drugs that are known to induce or inhibit glucuronidation may affect the apparent clearance of lamotrigine and doses of lamotrigine may require adjustment based on clinical response.

  Target Plasma Levels for Patients With Epilepsy or Bipolar Disorder: A therapeutic plasma concentration range has not been established for lamotrigine. Dosing of lamotrigine should be based on therapeutic response [see Clinical Pharmacology (12.3)].

  Women Taking Estrogen-Containing Oral Contraceptives: Starting Lamotrigine in Women Taking Estrogen-Containing Oral Contraceptives: Although estrogen-containing oral contraceptives have been shown to increase the clearance of lamotrigine [see Clinical Pharmacology (12.3)], no adjustments to the recommended dose-escalation guidelines for lamotrigine should be necessary solely based on the use of estrogen-containing oral contraceptives. Therefore, dose escalation should follow the recommended guidelines for initiating adjunctive therapy with lamotrigine based on the concomitant AED or other concomitant medications (see Table 1 or Table 5). See below for adjustments to maintenance doses of lamotrigine in women taking estrogen-containing oral contraceptives.

  Adjustments to the Maintenance Dose of Lamotrigine in Women Taking Estrogen-Containing Oral Contraceptives:

  (1) Taking Estrogen-Containing Oral Contraceptives: For women not taking carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin that induce lamotrigine glucuronidation [see Drug Interactions (7), Clinical Pharmacology (12.3)], the maintenance dose of lamotrigine will in most cases need to be increased, by as much as 2-fold over the recommended target maintenance dose, in order to maintain a consistent lamotrigine plasma level [see Clinical Pharmacology (12.3)].

  (2) Starting Estrogen-Containing Oral Contraceptives: In women taking a stable dose of lamotrigine and not taking carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin that induce lamotrigine glucuronidation [see Drug Interactions (7), Clinical Pharmacology (12.3)], the maintenance dose will in most cases need to be increased by as much as 2-fold in order to maintain a consistent lamotrigine plasma level. The dose increases should begin at the same time that the oral contraceptive is introduced and continue, based on clinical response, no more rapidly than 50 to 100 mg/day every week. Dose increases should not exceed the recommended rate (see Table 1 or Table 5) unless lamotrigine plasma levels or clinical response support larger increases. Gradual transient increases in lamotrigine plasma levels may occur during the week of inactive hormonal preparation ("pill-free" week), and these increases will be greater if dose increases are made in the days before or during the week of inactive hormonal preparation. Increased lamotrigine plasma levels could result in additional adverse reactions, such as dizziness, ataxia, and diplopia. If adverse reactions attributable to lamotrigine consistently occur during the "pill-free" week, dose adjustments to the overall maintenance dose may be necessary. Dose adjustments limited to the "pill-free" week are not recommended. For women taking lamotrigine in addition to carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin that induce lamotrigine glucuronidation [see Drug Interactions (7), Clinical Pharmacology (12.3)], no adjustment to the dose of lamotrigine should be necessary.  

  (3) Stopping Estrogen-Containing Oral Contraceptives: For women not taking carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin that induce lamotrigine glucuronidation [see Drug Interactions (7), Clinical Pharmacology (12.3)], the maintenance dose of lamotrigine will in most cases need to be decreased by as much as 50% in order to maintain a consistent lamotrigine plasma level. The decrease in dose of lamotrigine should not exceed 25% of the total daily dose per week over a 2-week period, unless clinical response or lamotrigine plasma levels indicate otherwise [see Clinical Pharmacology (12.3)]. For women taking lamotrigine in addition to carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin that induce lamotrigine glucuronidation [see Drug Interactions (7), Clinical Pharmacology (12.3)], no adjustment to the dose of lamotrigine should be necessary.

  Women and Other Hormonal Contraceptive Preparations or Hormone Replacement Therapy: The effect of other hormonal contraceptive preparations or hormone replacement therapy on the pharmacokinetics of lamotrigine has not been systematically evaluated. It has been reported that ethinylestradiol, not progestogens, increased the clearance of lamotrigine up to 2-fold, and the progestin-only pills had no effect on lamotrigine plasma levels. Therefore, adjustments to the dosage of lamotrigine in the presence of progestogens alone will likely not be needed.

  Patients With Hepatic Impairment: Experience in patients with hepatic impairment is limited. Based on a clinical pharmacology study in 24 patients with mild, moderate, and severe liver impairment [see Use in Specific Populations (8.6), Clinical Pharmacology (12.3)], the following general recommendations can be made. No dosage adjustment is needed in patients with mild liver impairment. Initial, escalation, and maintenance doses should generally be reduced by approximately 25% in patients with moderate and severe liver impairment without ascites and 50% in patients with severe liver impairment with ascites. Escalation and maintenance doses may be adjusted according to clinical response.

  Patients With Renal Impairment: Initial doses of lamotrigine should be based on patients' concomitant medications (see Tables 1-3 or Table 5); reduced maintenance doses may be effective for patients with significant renal impairment [see Use in Specific Populations (8.7), Clinical Pharmacology (12.3)]. Few patients with severe renal impairment have been evaluated during chronic treatment with lamotrigine. Because there is inadequate experience in this population, lamotrigine should be used with caution in these patients.

  Discontinuation Strategy: Epilepsy: For patients receiving lamotrigine in combination with other AEDs, a reevaluation of all AEDs in the regimen should be considered if a change in seizure control or an appearance or worsening of adverse reactions is observed.

  If a decision is made to discontinue therapy with lamotrigine, a step-wise reduction of dose over at least 2 weeks (approximately 50% per week) is recommended unless safety concerns require a more rapid withdrawal [see Warnings and Precautions (5.9)].

  Discontinuing carbamazepine, phenytoin, phenobarbital, primidone or other drugs such as rifampin that induce lamotrigine glucuronidation should prolong the half-life of lamotrigine; discontinuing valproate should shorten the half-life of lamotrigine.

  Bipolar Disorder: In the controlled clinical trials, there was no increase in the incidence, type, or severity of adverse reactions following abrupt termination of lamotrigine. In clinical trials in patients with Bipolar Disorder, 2 patients experienced seizures shortly after abrupt withdrawal of lamotrigine. However, there were confounding factors that may have contributed to the occurrence of seizures in these bipolar patients. Discontinuation of lamotrigine should involve a step-wise reduction of dose over at least 2 weeks (approximately 50% per week) unless safety concerns require a more rapid withdrawal [see Warnings and Precautions (5.9)].

  2.2 Epilepsy – Adjunctive Therapy

  This section provides specific dosing recommendations for patients greater than 12 years of age and patients 2 to 12 years of age. Within each of these age-groups, specific dosing recommendations are provided depending upon concomitant AED or other concomitant medications (Table 1 for patients greater than 12 years of age and Table 2 for patients 2 to 12 years of age). A weight-based dosing guide for patients 2 to 12 years of age on concomitant valproate is provided in Table 3.

  Patients Over 12 Years of Age: Recommended dosing guidelines are summarized in Table 1.

  Table 1. Escalation Regimen for Lamotrigine in Patients Over 12 Years of Age With Epilepsy

  a Valproate has been shown to inhibit glucuronidation and decrease the apparent clearance of lamotrigine [see Drug Interactions (7), Clinical Pharmacology (12.3)].

  b These drugs induce lamotrigine glucuronidation and increase clearance [see Drug Interactions (7), Clinical Pharmacology (12.3)]. Other drugs that have similar effects include estrogen-containing oral contraceptives [see Drug Interactions (7), Clinical Pharmacology (12.3)]. Dosing recommendations for oral contraceptives can be found in General Dosing Considerations [see Dosage and Administration (2.1)]. Patients on rifampin, or other drugs that induce lamotrigine glucuronidation and increase clearance, should follow the same dosing titration/maintenance regimen as that used with anticonvulsants that have this effect.

  
  For Patients TAKING
   Valproatea
  For Patients NOT 
  TAKING 
  Carbamazepine, 
  Phenytoin, 
  Phenobarbital,
   Primidoneb, or 
  Valproatea
  For Patients 
  TAKING 
  Carbamazepine, 
  Phenytoin, 
  Phenobarbital, or 
  Primidoneb and 
  NOT TAKING Valproatea
  Weeks 1 and 2
  25 mg every other day
  25 mg every day
  50 mg/day
  Weeks 3 and 4
  25 mg every day
  50 mg/day
  100 mg/day 
  (in 2 divided doses)
  Week 5
  onwards to
  maintenance
  Increase by 25 to 50
  mg/day every 1 to
  2 weeks
  Increase by 50
  mg/day every 1 to
  2 weeks
  Increase by 100
  mg/day every 1 to
  2 weeks.
  Usual
  Maintenance
  Dose
  100 to 200 mg/day
  with valproate 
  alone 
  100 to 400 mg/day 
  with valproate and 
  other drugs that 
  induce 
  glucuronidation 
  (in 1 or 2 divided 
  doses)
  225 to 375 mg/day 
  (in 2 divided doses)
  300 to 500 mg/day 
  (in 2 divided doses)
  

  Patients 2 to 12 Years of Age: Recommended dosing guidelines are summarized in Table 2.

  Smaller starting doses and slower dose escalations than those used in clinical trials are recommended because of the suggestion that the risk of rash may be decreased by smaller starting doses and slower dose escalations. Therefore, maintenance doses will take longer to reach in clinical practice than in clinical trials. It may take several weeks to months to achieve an individualized maintenance dose. Maintenance doses in patients weighing less than 30 kg, regardless of age or concomitant AED, may need to be increased as much as 50%, based on clinical response.

  The smallest available strength of lamotrigine tablets is 25 mg, and only whole tablets should be administered. If the calculated dose cannot be achieved using whole tablets, the dose should be rounded down to the nearest whole tablet [see How Supplied/Storage and Handling (16) and Medication Guide].

  Table 2. Escalation Regimen for Lamotrigine in Patients 2 to 12 Years of Age With Epilepsy

  Note: Only whole tablets should be used for dosing.
  

  aValproate has been shown to inhibit glucuronidation and decrease the apparent clearance of lamotrigine [see Drug Interactions (7),
  Clinical Pharmacology (12.3)].
  

  bThese drugs induce lamotrigine glucuronidation and increase clearance [see Drug Interactions (7), Clinical Pharmacology (12.3)].
  Other drugs that have similar effects include estrogen-containing oral contraceptives [see Drug Interactions (7), Clinical Pharmacology (12.3)]. Dosing recommendations for oral contraceptives can be found in General Dosing Considerations [see 
  Dosage and Administration (2.1)]. Patients on rifampin, or other drugs that induce lamotrigine glucuronidation and increase clearance, should follow the same dosing titration/maintenance regimen as that used with anticonvulsants that have this effect.
  

  
  For Patients 
  TAKING Valproatea
  For Patients NOT
   TAKING 
  Carbamazepine, 
  Phenytoin, 
  Phenobarbital, 
  Primidoneb, or 
  Valproatea
  For Patients TAKING
   Carbamazepine, 
  Phenytoin, 
  Phenobarbital, or 
  Primidoneb and NOT
  TAKING Valproatea
  Weeks 1 
  and 2 
  0.15 mg/kg/day 
  in 1 or 2 divided 
  doses, rounded 
  down to the nearest
  whole tablet (see 
  Table 3 for weight-based dosing guide)
  0.3 mg/kg/day 
  in 1 or 2 divided 
  doses, rounded down 
  to the nearest whole 
  tablet
  0.6 mg/kg/day 
  in 2 divided doses,
   rounded down to the
   nearest whole tablet
  Weeks 3 
  and 4 
  0.3 mg/kg/day 
  in 1 or 2 divided 
  doses, rounded 
  down to the nearest
  whole tablet (see
  Table 3 for weight-based dosing guide)
  0.6 mg/kg/day 
  in 2 divided doses, 
  rounded down to the 
  nearest whole tablet
  1.2 mg/kg/day 
  in 2 divided doses,
   rounded down to the
   nearest whole tablet
  Week 5 
  onwards to 
  maintenance
  The dose should be 
  increased every 1 to 
  2 weeks as follows:
  calculate 0.3 mg/kg/day, 
  round this amount
  down to the nearest
  whole tablet, and
  add this amount to
  the previously 
  administered daily
  dose
  The dose should be increased every 1 to 
  2 weeks as follows: calculate 
  0.6 mg/kg/day, round 
  this amount down to 
  the nearest whole 
  tablet, and add this 
  amount to the 
  previously 
  administered daily
   dose
  The dose should be increased every 1 to 
  2 weeks as follows: calculate 
  1.2 mg/kg/day, round
   this amount down to
   the nearest whole
   tablet, and add this
   amount to the
   previously
   administered daily
   dose
  Usual 
  Maintenance 
  Dose 
  1 to 5 mg/kg/day
   (maximum 
  200 mg/day in 1 or 2
   divided doses). 
  1 to 3 mg/kg/day 
  with valproate alone
  4.5 to 7.5 mg/kg/day
   (maximum 300 
  mg/day in 2 divided
  doses)
  5 to 15 mg/kg/day
   (maximum 400 
  mg/day in 2 divided
   doses)
  Maintenance 
  dose in 
  patients less 
  than 30 kg 
  May need to be 
  increased by as 
  much as 50%, based 
  on clinical response
  May need to be
   increased by as much
   as 50%, based on 
  clinical response
  May need to be 
  increased by as much
   as 50%, based on 
  clinical response
  Table 3. The Initial Weight-Based Dosing Guide for Patients 2 to 12 Years of Age Taking Valproate (Weeks 1 to 4) With Epilepsy If the patient’s weight is
  Give this daily dose, using the most appropriate combination of lamotrigine
  2-mg and 5-mg tablets 
  Greater than 
  And less than 
  Weeks 1 and 2
  Weeks 3 and 4
  6.7 kg 
  14 kg 
  2 mg every other day
  2 mg every day
  14.1 kg 
  27 kg 
  2 mg every day
  4 mg every day
  27.1 kg 
  34 kg 
  4 mg every day
  8 mg every day
  34.1 kg 
  40 kg 
  5 mg every day
  10 mg every day
  

  Usual Adjunctive Maintenance Dose for Epilepsy: The usual maintenance doses identified in Tables 1 and 2 are derived from dosing regimens employed in the placebo-controlled adjunctive studies in which the efficacy of lamotrigine was established. In patients receiving multidrug regimens employing carbamazepine, phenytoin, phenobarbital, or primidone without valproate, maintenance doses of adjunctive lamotrigine as high as 700 mg/day have been used. In patients receiving valproate alone, maintenance doses of adjunctive lamotrigine as high as 200 mg/day have been used. The advantage of using doses above those recommended in Tables 1 through 4 has not been established in controlled trials.

  2.3 Epilepsy – Conversion From Adjunctive Therapy to Monotherapy

  The goal of the transition regimen is to effect the conversion to monotherapy with lamotrigine under conditions that ensure adequate seizure control while mitigating the risk of serious rash associated with the rapid titration of lamotrigine.

  The recommended maintenance dose of lamotrigine as monotherapy is 500 mg/day given in 2 divided doses.

  To avoid an increased risk of rash, the recommended initial dose and subsequent dose escalations of lamotrigine should not be exceeded [see Boxed Warning].

  Conversion From Adjunctive Therapy With Carbamazepine, Phenytoin, Phenobarbital, or Primidone to Monotherapy With Lamotrigine: After achieving a dose of 500 mg/day of lamotrigine according to the guidelines in Table 1, the concomitant AED should be withdrawn by 20% decrements each week over a 4-week period. The regimen for the withdrawal of the concomitant AED is based on experience gained in the controlled monotherapy clinical trial.

  Conversion From Adjunctive Therapy With Valproate to Monotherapy With Lamotrigine: The conversion regimen involves 4 steps outlined in Table 4.

  Table 4. Conversion From Adjunctive Therapy With Valproate to Monotherapy With Lamotrigine in Patients ≥16 Years of Age With Epilepsy
  Lamotrigine
  Valproate
  Step 1 
  Achieve a dose of 200 mg/day according to 
  guidelines in Table 1 (if not already on 
  200 mg/day).
  Maintain previous stable dose.
  Step 2 
  Maintain at 200 mg/day.
  Decrease to 500 mg/day by 
  decrements no greater than 
  500 mg/day/week and then 
  maintain the dose of 
  500 mg/day for 1 week.
  Step 3 
  Increase to 300 mg/day and maintain for 1 
  week.
  Simultaneously decrease to 
  250 mg/day and maintain for 1 week.
  Step 4 
  Increase by 100 mg/day every week to achieve 
  maintenance dose of 500 mg/day.
  Discontinue.
  

  Conversion From Adjunctive Therapy With Antiepileptic Drugs Other Than Carbamazepine, Phenytoin, Phenobarbital, Primidone, or Valproate to Monotherapy With Lamotrigine: No specific dosing guidelines can be provided for conversion to monotherapy with lamotrigine with AEDs other than carbamazepine, phenobarbital, phenytoin, primidone, or valproate.

  2.4 Bipolar Disorder

  The goal of maintenance treatment with lamotrigine is to delay the time to occurrence of mood episodes (depression, mania, hypomania, mixed episodes) in patients treated for acute mood episodes with standard therapy. The target dose of lamotrigine is 200 mg/day (100 mg/day in patients taking valproate, which decreases the apparent clearance of lamotrigine, and 400 mg/day in patients not taking valproate and taking either carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin that increase the apparent clearance of lamotrigine). In the clinical trials, doses up to 400 mg/day as monotherapy were evaluated; however, no additional benefit was seen at 400 mg/day compared with 200 mg/day [see Clinical Studies (14.2)]. Accordingly, doses above 200 mg/day are not recommended. Treatment with lamotrigine is introduced, based on concurrent medications, according to the regimen outlined in Table 5. If other psychotropic medications are withdrawn following stabilization, the dose of lamotrigine should be adjusted. For patients discontinuing valproate, the dose of lamotrigine should be doubled over a 2-week period in equal weekly increments (see Table 6). For patients discontinuing carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin that induce lamotrigine glucuronidation, the dose of lamotrigine should remain constant for the first week and then should be decreased by half over a 2-week period in equal weekly decrements (see Table 6). The dose of lamotrigine may then be further adjusted to the target dose (200 mg) as clinically indicated.

  If other drugs are subsequently introduced, the dose of lamotrigine may need to be adjusted. In particular, the introduction of valproate requires reduction in the dose of lamotrigine [see Drug Interactions (7), Clinical Pharmacology (12.3)].

  To avoid an increased risk of rash, the recommended initial dose and subsequent dose escalations of lamotrigine should not be exceeded [see Boxed Warning].

  Table 5. Escalation Regimen for Lamotrigine for Patients With Bipolar Disorder

  a Valproate has been shown to inhibit glucuronidation and decrease the apparent clearance of lamotrigine [see Drug Interactions (7), Clinical Pharmacology (12.3)].

  b These drugs induce lamotrigine glucuronidation and increase clearance [see Drug Interactions (7), Clinical Pharmacology (12.3)]. Other drugs that have similar effects include estrogen-containing oral contraceptives [see Drug Interactions (7), Clinical Pharmacology (12.3)]. Dosing recommendations for oral contraceptives can be found in General Dosing Considerations [see Dosage and Administration (2.1)]. Patients on rifampin, or other drugs that induce lamotrigine glucuronidation and increase clearance, should follow the same dosing titration/maintenance regimen as that used with anticonvulsants that have this effect.

  
  For Patients TAKING Valproatea
  For Patients NOT TAKING
  Carbamazepine, Phenytoin, 
  Phenobarbital, Primidoneb, or
   Valproatea
  For Patients TAKING
   Carbamazepine, Phenytoin, Phenobarbital,
  or Primidoneb and 
  NOT TAKING Valproatea
  Weeks 1 and 2 
  25 mg every other day
  25 mg daily
  50 mg daily
  Weeks 3 and 4 
  25 mg daily
  50 mg daily
  100 mg daily, in divided doses
  Week 5 
  50 mg daily
  100 mg daily
  200 mg daily, in divided doses
  Week 6 
  100 mg daily
  200 mg daily
  300 mg daily, in divided doses
  Week 7 
  100 mg daily
  200 mg daily
  up to 400 mg daily, in
  divided doses
  Table 6. Dosage Adjustments to Lamotrigine for Patients With Bipolar Disorder Following Discontinuation of Psychotropic Medications

  a Valproate has been shown to inhibit glucuronidation and decrease the apparent clearance of lamotrigine [see Drug Interactions (7), Clinical Pharmacology (12.3)].

  b These drugs induce lamotrigine glucuronidation and increase clearance [see Drug Interactions (7), Clinical Pharmacology (12.3)]. Other drugs that have similar effects include estrogen-containing oral contraceptives [see Drug Interactions (7), Clinical Pharmacology (12.3)]. Dosing recommendations for oral contraceptives can be found in General Dosing Considerations [see Dosage and Administration (2.1)]. Patients on rifampin, or other drugs that induce lamotrigine glucuronidation and increase clearance, should follow the same dosing titration/maintenance regimen as that used with anticonvulsants that have this effect.

  
  Discontinuation of Psychotropic Drugs 
  (excluding Carbamazepine, Phenytoin, 
  After Discontinuation of Valproatea
  After Discontinuation of Carbamazepine, 
  Phenytoin, Phenobarbital,or
   Primidoneb
  
  Phenobarbital, Primidoneb, or Valproatea)
  Current dose of Lamotrigine (mg/day) 
  100
  Current dose of Lamotrigine (mg/day) 
  400
  Week 1 
  Maintain current dose of Lamotrigine
  150
  400
  Week 2 
  Maintain current dose of Lamotrigine
  200
  300
  Week 3 onward 
  Maintain current dose of Lamotrigine
  200
  200
  

  The benefit of continuing treatment in patients who had been stabilized in an 8- to 16-week open-label phase with lamotrigine was established in 2 randomized, placebo-controlled clinical maintenance trials [see Clinical Studies (14.2)]. However, the optimal duration of treatment with lamotrigine has not been established. Thus, patients should be periodically reassessed to determine the need for maintenance treatment.

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  2.1 General Dosing Considerations

  Rash: There are suggestions, yet to be proven, that the risk of severe, potentially life-threatening rash may be increased by (1) coadministration of lamotrigine with valproate, (2) exceeding the recommended initial dose of lamotrigine, or (3) exceeding the recommended dose escalation for lamotrigine. However, cases have occurred in the absence of these factors [see Boxed Warning]. Therefore, it is important that the dosing recommendations be followed closely.

  The risk of nonserious rash may be increased when the recommended initial dose and/or the rate of dose escalation for lamotrigine is exceeded and in patients with a history of allergy or rash to other AEDs.

  It is recommended that lamotrigine not be restarted in patients who discontinued due to rash associated with prior treatment with lamotrigine, unless the potential benefits clearly outweigh the risks. If the decision is made to restart a patient who has discontinued lamotrigine, the need to restart with the initial dosing recommendations should be assessed. The greater the interval of time since the previous dose, the greater consideration should be given to restarting with the initial dosing recommendations. If a patient has discontinued lamotrigine for a period of more than 5 half-lives, it is recommended that initial dosing recommendations and guidelines be followed. The half-life of lamotrigine is affected by other concomitant medications [see Clinical Pharmacology (12.3)].

  Lamotrigine Added to Drugs Known to Induce or Inhibit Glucuronidation:
  Because lamotrigine is metabolized predominantly by glucuronic acid conjugation, drugs that are known to induce or inhibit glucuronidation may affect the apparent clearance of lamotrigine. Drugs that induce glucuronidation include carbamazepine, phenytoin, phenobarbital, primidone, rifampin, estrogen-containing oral contraceptives, and the protease inhibitors lopinavir/ritonavir and atazanavir/ritonavir. Valproate inhibits glucuronidation. For dosing considerations for lamotrigine in patients on estrogen-containing contraceptives and atazanavir/ritonavir, see below and Table 13. For dosing considerations for lamotrigine in patients on other drugs known to induce or inhibit glucuronidation, see Tables 1, 2, 5-6, and 13.

  Target Plasma Levels for Patients With Epilepsy or Bipolar Disorder:
  A therapeutic plasma concentration range has not been established for lamotrigine. Dosing of lamotrigine should be based on therapeutic response [see Clinical Pharmacology (12.3)].

  Women Taking Estrogen-Containing Oral Contraceptives:Starting Lamotrigine in Women Taking Estrogen-Containing Oral Contraceptives:
  Although estrogen-containing oral contraceptives have been shown to increase the clearance of lamotrigine [see Clinical Pharmacology (12.3)], no adjustments to the recommended dose-escalation guidelines for lamotrigine should be necessary solely based on the use of estrogen-containing oral contraceptives. Therefore, dose escalation should follow the recommended guidelines for initiating adjunctive therapy with lamotrigine based on the concomitant AED or other concomitant medications (see Tables 1, 5, and 7). See below for adjustments to maintenance doses of lamotrigine in women taking estrogen-containing oral contraceptives.

  Adjustments to the Maintenance Dose of Lamotrigine In Women Taking Estrogen-Containing Oral Contraceptives:

  (1) Taking Estrogen-Containing Oral Contraceptives: In women not taking carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin and the protease inhibitors lopinavir/ritonavir and atazanavir/ritonavir that induce lamotrigine glucuronidation [see Drug Interactions (7), Clinical Pharmacology (12.3)], the maintenance dose of lamotrigine will in most cases need to be increased, by as much as 2-fold over the recommended target maintenance dose to maintain a consistent lamotrigine plasma level.

  (2) Starting Estrogen-Containing Oral Contraceptives: In women taking a stable dose of lamotrigine and not taking carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin and the protease inhibitors lopinavir/ritonavir and atazanavir/ritonavir that induce lamotrigine glucuronidation [see Drug Interactions (7), Clinical Pharmacology (12.3)], the maintenance dose will in most cases need to be increased by as much as 2-fold to maintain a consistent lamotrigine plasma level. The dose increases should begin at the same time that the oral contraceptive is introduced and continue, based on clinical response, no more rapidly than 50 to 100 mg/day every week. Dose increases should not exceed the recommended rate (see Tables 1 and 5) unless lamotrigine plasma levels or clinical response support larger increases. Gradual transient increases in lamotrigine plasma levels may occur during the week of inactive hormonal preparation (pill-free week), and these increases will be greater if dose increases are made in the days before or during the week of inactive hormonal preparation. Increased lamotrigine plasma levels could result in additional adverse reactions, such as dizziness, ataxia, and diplopia. If adverse reactions attributable to lamotrigine consistently occur during the pill-free week, dose adjustments to the overall maintenance dose may be necessary. Dose adjustments limited to the pill-free week are not recommended. For women taking lamotrigine in addition to carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin and the protease inhibitors lopinavir/ritonavir and atazanavir/ritonavir that induce lamotrigine glucuronidation [see Drug Interactions (7), Clinical Pharmacology (12.3)], no adjustment to the dose of lamotrigine should be necessary.

  (3) Stopping Estrogen-Containing Oral Contraceptives: In women not taking carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin and the protease inhibitors lopinavir/ritonavir and atazanavir/ritonavir that induce lamotrigine glucuronidation [see Drug Interactions (7), Clinical Pharmacology (12.3)], the maintenance dose of lamotrigine will in most cases need to be decreased by as much as 50% in order to maintain a consistent lamotrigine plasma level. The decrease in dose of lamotrigine should not exceed 25% of the total daily dose per week over a 2-week period, unless clinical response or lamotrigine plasma levels indicate otherwise [see Clinical Pharmacology (12.3)]. In women taking lamotrigine in addition to carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin and the protease inhibitors lopinavir/ritonavir and atazanavir/ritonavir that induce lamotrigine glucuronidation [see Drug Interactions (7), Clinical Pharmacology (12.3)], no adjustment to the dose of lamotrigine should be necessary.

  Women and Other Hormonal Contraceptive Preparations or Hormone Replacement Therapy: The effect of other hormonal contraceptive preparations or hormone replacement therapy on the pharmacokinetics of lamotrigine has not been systematically evaluated. It has been reported that ethinylestradiol, not progestogens, increased the clearance of lamotrigine up to 2-fold, and the progestin-only pills had no effect on lamotrigine plasma levels. Therefore, adjustments to the dosage of lamotrigine in the presence of progestogens alone will likely not be needed.

  Patients Taking Atazanavir/Ritonavir:

  While atazanavir/ritonavir does reduce the lamotrigine plasma concentration, no adjustments to the recommended dose-escalation guidelines for lamotrigine should be necessary solely based on the use of atazanavir/ritonavir. Dose escalation should follow the recommended guidelines for initiating adjunctive therapy with lamotrigine based on concomitant AED or other concomitant medications (see Tables 1, 2, and 5). In patients already taking maintenance doses of lamotrigine and not taking glucuronidation inducers, the dose of lamotrigine may need to be increased if atazanavir/ritonavir is added, or decreased if atazanavir/ritonavir is discontinued [see Clinical Pharmacology (12.3)].

  Patients With Hepatic Impairment:

  Experience in patients with hepatic impairment is limited. Based on a clinical pharmacology study in 24 subjects with mild, moderate, and severe liver impairment [see Use in Specific Populations (8.6), Clinical Pharmacology (12.3)], the following general recommendations can be made. No dosage adjustment is needed in patients with mild liver impairment. Initial, escalation, and maintenance doses should generally be reduced by approximately 25% in patients with moderate and severe liver impairment without ascites and 50% in patients with severe liver impairment with ascites. Escalation and maintenance doses may be adjusted according to clinical response.

  Patients With Renal Impairment:

  Initial doses of lamotrigine should be based on patients' concomitant medications (see Tables 1-3 and 5); reduced maintenance doses may be effective for patients with significant renal impairment [see Use in Specific Populations (8.7), Clinical Pharmacology (12.3)]. Few patients with severe renal impairment have been evaluated during chronic treatment with lamotrigine. Because there is inadequate experience in this population, lamotrigine should be used with caution in these patients.

  Discontinuation Strategy: Epilepsy:

  For patients receiving lamotrigine in combination with other AEDs, a re-evaluation of all AEDs in the regimen should be considered if a change in seizure control or an appearance or worsening of adverse reactions is observed.

  If a decision is made to discontinue therapy with lamotrigine, a step-wise reduction of dose over at least 2 weeks (approximately 50% per week) is recommended unless safety concerns require a more rapid withdrawal [see Warnings and Precautions (5.8)].

  Discontinuing carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin and the protease inhibitors lopinavir/ritonavir and atazanavir/ritonavir that induce lamotrigine glucuronidation should prolong the half-life of lamotrigine; discontinuing valproate should shorten the half-life of lamotrigine.

  Bipolar Disorder:

  In the controlled clinical trials, there was no increase in the incidence, type, or severity of adverse reactions following abrupt termination of lamotrigine. In the clinical development program in adults with bipolar disorder, 2 patients experienced seizures shortly after abrupt withdrawal of lamotrigine. Discontinuation of lamotrigine should involve a step-wise reduction of dose over at least 2 weeks (approximately 50% per week) unless safety concerns require a more rapid withdrawal [see Warnings and Precautions (5.8)].

  2.2 Epilepsy - Adjunctive Therapy

  This section provides specific dosing recommendations for patients older than 12 years and patients aged 2 to 12 years. Within each of these age-groups, specific dosing recommendations are provided depending upon concomitant AEDs or other concomitant medications (see Table 1 for patients older than 12 years and Table 2 for patients aged 2 to 12 years). A weight-based dosing guide for patients aged 2 to 12 years on concomitant valproate is provided in Table 3.

  Patients Older Than 12 Years:

  Recommended dosing guidelines are summarized in Table 1.

  Table 1. Escalation Regimen for Lamotrigine in Patients Older Than 12 Years With Epilepsy

  In Patients TAKING Valproatea

  In Patients NOT TAKING Carbamazepine, Phenytoin, Phenobarbital, Primidoneb, or Valproatea

  In Patients TAKING Carbamazepine, Phenytoin, Phenobarbital, or Primidoneb and NOT TAKING Valproatea

  Weeks 1 and 2

  25 mg every other day

  25 mg every day

  50 mg/day

  Weeks 3 and 4

  25 mg every day

  50 mg/day

  100 mg/day (in 2 divided doses)

  Week 5 onward to maintenance

  Increase by 25 to 50 mg/day every 1 to 2 weeks

  Increase by 50 mg/day every 1 to 2 weeks

  Increase by 100 mg/day every 1 to 2 weeks.

  Usual Maintenance Dose

  100 to 200 mg/day with valproate alone

  100 to 400 mg/day with valproate and other drugs that induce glucuronidation (in 1 or 2 divided doses)

  225 to 375 mg/day (in 2 divided doses)

  300 to 500 mg/day (in 2 divided doses)

  a Valproate has been shown to inhibit glucuronidation and decrease the apparent clearance of lamotrigine [see Drug Interactions (7), Clinical Pharmacology (12.3)].

  b Drugs that induce lamotrigine glucuronidation and clearance, other than the specified antiepileptic drugs, include estrogen-containing oral contraceptives, rifampin, and the protease inhibitors lopinavir/ritonavir and atazanavir/ritonavir. Dosing recommendations for oral contraceptives and the protease inhibitor atazanavir/ritonavir can be found in General Dosing Considerations [see Dosage and Administration (2.1)]. Patients on rifampin and the protease inhibitor lopinavir/ritonavir should follow the same dosing titration/maintenance regimen used with antiepileptic drugs that induce glucuronidation and increase clearance [see Dosage and Administration (2.1), Drug Interactions (7), Clinical Pharmacology (12.3)].

  Patients Aged 2 to 12 Years:

  Recommended dosing guidelines are summarized in Table 2.

  Lower starting doses and slower dose escalations than those used in clinical trials are recommended because of the suggestion that the risk of rash may be decreased by lower starting doses and slower dose escalations. Therefore, maintenance doses will take longer to reach in clinical practice than in clinical trials. It may take several weeks to months to achieve an individualized maintenance dose. Maintenance doses in patients weighing less than 30 kg, regardless of age or concomitant AED, may need to be increased as much as 50%, based on clinical response.

  The smallest available strength of lamotrigine tablets (chewable, dispersible) is 2 mg, and only whole tablets should be administered. If the calculated dose cannot be achieved using whole tablets, the dose should be rounded down to the nearest whole tablet[see How Supplied/Storage and Handling (16) and MEDICATION GUIDE].

  Table 2. Escalation Regimen for Lamotrigine in Patients Aged 2 to 12 Years With Epilepsy

  In Patients TAKING Valproatea

  In Patients NOT TAKING Carbamazepine, Phenytoin, Phenobarbital, Primidoneb, or Valproatea

  In Patients TAKING Carbamazepine, Phenytoin, Phenobarbital, or Primidoneb and NOT TAKING Valproatea

  Weeks 1 and 2

  0.15 mg/kg/day in 1 or 2 divided doses, rounded down to the nearest whole tablet (see Table 3 for weight based dosing guide)

  0.3 mg/kg/day in 1 or 2 divided doses, rounded down to the nearest whole tablet

  0.6 mg/kg/day in 2 divided doses, rounded down to the nearest whole tablet

  Weeks 3 and 4

  0.3 mg/kg/day in 1 or 2 divided doses, rounded down to the nearest whole tablet (see Table 3 for weight based dosing guide)

  0.6 mg/kg/day in 2 divided doses, rounded down to the nearest whole tablet

  1.2 mg/kg/day in 2 divided doses, rounded down to the nearest whole tablet

  Week 5 onward to maintenance

  The dose should be increased every 1 to 2 weeks as follows: calculate 0.3 mg/kg/day, round this amount down to the nearest whole tablet, and add this amount to the previously administered daily dose

  The dose should be increased every 1 to 2 weeks as follows: calculate 0.6 mg/kg/day, round this amount down to the nearest whole tablet, and add this amount to the previously administered daily dose

  The dose should be increased every 1 to 2 weeks as follows: calculate 1.2 mg/kg/day, round this amount down to the nearest whole tablet, and add this amount to the previously administered daily dose

  Usual Maintenance Dose

  1 to 5 mg/kg/day (maximum 200 mg/day in 1 or 2 divided doses) 1 to 3 mg/kg/day with valproate alone

  4.5 to 7.5 mg/kg/day (maximum 300 mg/day in 2 divided doses)

  5 to 15 mg/kg/day (maximum 400 mg/day in 2 divided doses)

  Maintenance dose in patients less than 30 kg

  May need to be increased by as much as 50%, based on clinical response

  May need to be increased by as much as 50%, based on clinical response

  May need to be increased by as much as 50%, based on clinical response

  Note: Only whole tablets should be used for dosing.

  a Valproate has been shown to inhibit glucuronidation and decrease the apparent clearance of lamotrigine [see Drug Interactions (7), Clinical Pharmacology (12.3)].

  b Drugs that induce lamotrigine glucuronidation and increase clearance, other than the specified antiepileptic drugs, include estrogen-containing oral contraceptives, rifampin, and the protease inhibitors lopinavir/ritonavir and atazanavir/ritonavir. Dosing recommendations for oral contraceptives and the protease inhibitor atazanavir/ritonavir can be found in General Dosing Considerations [see Dosage and Administration (2.1)]. Patients on rifampin and the protease inhibitor lopinavir/ritonavir should follow the same dosing titration/maintenance regimen used with antiepileptic drugs that induce glucuronidation and increase clearance [see Dosage and Administration (2.1), Drug Interactions (7), and Clinical Pharmacology (12.3)].

  Table 3. The Initial Weight-Based Dosing Guide for Patients Aged 2 to 12 Years Taking Valproate (Weeks 1 to 4) With Epilepsy

  If the patient’s weight is

  Give this daily dose, using the most appropriate combination of lamotrigine 2-mg and 5-mg tablets

  Greater than

  And less than

  Weeks 1 and 2

  Weeks 3 and 4

  6.7 kg

  14 kg

  2 mg every other day

  2 mg every day

  14.1 kg

  27 kg

  2 mg every day

  4 mg every day

  27.1 kg

  34 kg

  4 mg every day

  8 mg every day

  34.1 kg

  40 kg

  5 mg every day

  10 mg every day

  Usual Adjunctive Maintenance Dose for Epilepsy

  The usual maintenance doses identified in Tables 1 and 2 are derived from dosing regimens employed in the placebo-controlled adjunctive trials in which the efficacy of lamotrigine was established. In patients receiving multidrug regimens employing carbamazepine, phenytoin, phenobarbital, or primidone without valproate, maintenance doses of adjunctive lamotrigine as high as 700 mg/day have been used. In patients receiving valproate alone, maintenance doses of adjunctive lamotrigine as high as 200 mg/day have been used. The advantage of using doses above those recommended in Tables 1 - 4 has not been established in controlled trials.

  2.3 Epilepsy - Conversion From Adjunctive Therapy to Monotherapy

  The goal of the transition regimen is to attempt to maintain seizure control while mitigating the risk of serious rash associated with the rapid titration of lamotrigine.

  The recommended maintenance dose of lamotrigine as monotherapy is 500 mg/day given in 2 divided doses.

  To avoid an increased risk of rash, the recommended initial dose and subsequent dose escalations for lamotrigine should not be exceeded [see Boxed Warning].

  Conversion From Adjunctive Therapy With Carbamazepine, Phenytoin, Phenobarbital, or Primidone to Monotherapy With Lamotrigine

  After achieving a dose of 500 mg/day of lamotrigine using the guidelines in Table 1, the concomitant enzyme-inducing AED should be withdrawn by 20% decrements each week over a 4-week period. The regimen for the withdrawal of the concomitant AED is based on experience gained in the controlled monotherapy clinical trial.

  Conversion from Adjunctive Therapy With Valproate to Monotherapy With Lamotrigine

  The conversion regimen involves the 4 steps outlined in Table 4.

  Table 4. Conversion From Adjunctive Therapy With Valproate to Monotherapy With Lamotrigine in Patients Aged 16 Years and Older With Epilepsy

  Lamotrigine

  Valproate

  Step 1

  Achieve a dose of 200 mg/day according to guidelines in Table 1.

  Maintain established stable dose.

  Step 2

  Maintain at 200 mg/day.

  Decrease dose by decrements no greater than 500 mg/day/week to 500 mg/day and then maintain for 1 week.

  Step 3

  Increase to 300 mg/day and maintain for 1 week.

  Simultaneously decrease to 250 mg/day and maintain for 1 week.

  Step 4

  Increase by 100 mg/day every week to achieve maintenance dose of 500 mg/day.

  Discontinue.

  Conversion from Adjunctive Therapy With Antiepileptic Drugs Other Than Carbamazepine, Phenytoin, Phenobarbital, Primidone, or Valproate to Monotherapy With Lamotrigine

  No specific dosing guidelines can be provided for conversion to monotherapy with lamotrigine with AEDs other than carbamazepine, phenytoin, phenobarbital, primidone, or valproate.

  2.4 Bipolar Disorder

  The goal of maintenance treatment with lamotrigine is to delay the time to occurrence of mood episodes (depression, mania, hypomania, mixed episodes) in patients treated for acute mood episodes with standard therapy [see Indications and Usage (1)]. Patients taking lamotrigine for more than 16 weeks should be periodically reassessed to determine the need for maintenance treatment.

  Adults

  The target dose of lamotrigine is 200 mg/day (100 mg/day in patients taking valproate, which decreases the apparent clearance of lamotrigine, and 400 mg/day in patients not taking valproate and taking either carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin and the protease inhibitor lopinavir/ritonavir that increase the apparent clearance of lamotrigine). In the clinical trials, doses up to 400 mg/day as monotherapy were evaluated; however, no additional benefit was seen at 400 mg/day compared with 200 mg/day [see Clinical Studies (14.2)]. Accordingly, doses above 200 mg/day are not recommended.

  Treatment with lamotrigine is introduced, based on concurrent medications, according to the regimen outlined in Table 5. If other psychotropic medications are withdrawn following stabilization, the dose of lamotrigine should be adjusted. In patients discontinuing valproate, the dose of lamotrigine should be doubled over a 2-week period in equal weekly increments (see Table 6). In patients discontinuing carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin and the protease inhibitors lopinavir/ritonavir and atazanavir/ritonavir that induce lamotrigine glucuronidation, the dose of lamotrigine should remain constant for the first week and then should be decreased by half over a 2-week period in equal weekly decrements (see Table 6). The dose of lamotrigine may then be further adjusted to the target dose (200 mg) as clinically indicated.

  If other drugs are subsequently introduced, the dose of lamotrigine may need to be adjusted. In particular, the introduction of valproate requires reduction in the dose of lamotrigine [see Drug Interactions (7), Clinical Pharmacology (12.3)].

  To avoid an increased risk of rash, the recommended initial dose and subsequent dose escalations of lamotrigine should not be exceeded [see Boxed Warning].

  Table 5. Escalation Regimen for Lamotrigine in Adults With Bipolar Disorder

  In Patients TAKING Valproatea

  In Patients NOT TAKING Carbamazepine, Phenytoin, Phenobarbital, Primidoneb, or Valproatea

  In Patients TAKING Carbamazepine, Phenytoin, Phenobarbital, or Primidoneb and NOT TAKING Valproatea

  Weeks 1 and 2

  25 mg every other day

  25 mg daily

  50 mg daily

  Weeks 3 and 4

  25 mg daily

  50 mg daily

  100 mg daily, in divided doses

  Week 5

  50 mg daily

  100 mg daily

  200 mg daily, in divided doses

  Week 6

  100 mg daily

  200 mg daily

  300 mg daily, in divided doses

  Week 7

  100 mg daily

  200 mg daily

  up to 400 mg daily, in divided doses

  a Valproate has been shown to inhibit glucuronidation and decrease the apparent clearance of lamotrigine [see Drug Interactions (7), Clinical Pharmacology (12.3)].

  b Drugs that induce lamotrigine glucuronidation and increase clearance, other than the specified antiepileptic drugs, include estrogen-containing oral contraceptives, rifampin, and the protease inhibitors lopinavir/ritonavir and atazanavir/ritonavir. Dosing recommendations for oral contraceptives and the protease inhibitor atazanavir/ritonavir can be found in General Dosing Considerations [see Dosage and Administration (2.1)]. Patients on rifampin and the protease inhibitor lopinavir/ritonavir should follow the same dosing titration/maintenance regimen used with antiepileptic drugs that induce glucuronidation and increase clearance [see Dosage and Administration (2.1), Drug Interactions (7), and Clinical Pharmacology (12.3)].

  Table 6. Dosage Adjustments to Lamotrigine In Adults With Bipolar Disorder Following Discontinuation of Psychotropic Medications

  Discontinuation of Psychotropic Drugs (excluding Valproatea, Carbamazepine, Phenytoin, Phenobarbital or Primidoneb)

  After Discontinuation of Valproatea

  After Discontinuation of Carbamazepine, Phenytoin, Phenobarbital, or Primidoneb

  Current dose of lamotrigine (mg/day) 100

  Current dose of lamotrigine (mg/day) 400

  Week 1

  Maintain current dose of lamotrigine

  150

  400

  Week 2

  Maintain current dose of lamotrigine

  200

  300

  Week 3 onward

  Maintain current dose of lamotrigine

  200

  200

  a Valproate has been shown to inhibit glucuronidation and decrease the apparent clearance of lamotrigine [see Drug Interactions (7), Clinical Pharmacology (12.3)].

  b Drugs that induce lamotrigine glucuronidation and increase clearance, other than the specified antiepileptic drugs, include estrogen-containing oral contraceptives, rifampin, and the protease inhibitors lopinavir/ritonavir and atazanavir/ritonavir. Dosing recommendations for oral contraceptives and the protease inhibitor atazanavir/ritonavir can be found in General Dosing Considerations [see Dosage and Administration (2.1)]. Patients on rifampin and the protease inhibitor lopinavir/ritonavir should follow the same dosing titration/maintenance regimen used with antiepileptic drugs that induce glucuronidation and increase clearance [see Dosage and Administration (2.1), Drug Interactions (7), and Clinical Pharmacology (12.3)].

  2.5 Administration of Lamotrigine Tablets (chewable, dispersible)

  Lamotrigine tablets (chewable, dispersible) may be swallowed whole, chewed, or dispersed in water or diluted fruit juice. If the tablets are chewed, consume a small amount of water or diluted fruit juice to aid in swallowing.

  To disperse lamotrigine tablets (chewable, dispersible), add the tablets to a small amount of liquid (1 teaspoon, or enough to cover the medication). Approximately 1 minute later, when the tablets are completely dispersed, swirl the solution and consume the entire quantity immediately. No attempt should be made to administer partial quantities of the dispersed tablets.

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  2.1 General Dosing Considerations

  Rash: There are suggestions, yet to be proven, that the risk of severe, potentially life-threatening rash may be increased by (1) coadministration of lamotrigine with valproate, (2) exceeding the recommended initial dose of lamotrigine, or (3) exceeding the recommended dose escalation for lamotrigine. However, cases have occurred in the absence of these factors [see Boxed Warning]. Therefore, it is important that the dosing recommendations be followed closely.

  The risk of nonserious rash may be increased when the recommended initial dose and/or the rate of dose escalation for lamotrigine is exceeded and in patients with a history of allergy or rash to other AEDs.

  It is recommended that lamotrigine not be restarted in patients who discontinued due to rash associated with prior treatment with lamotrigine unless the potential benefits clearly outweigh the risks. If the decision is made to restart a patient who has discontinued lamotrigine, the need to restart with the initial dosing recommendations should be assessed. The greater the interval of time since the previous dose, the greater consideration should be given to restarting with the initial dosing recommendations. If a patient has discontinued lamotrigine for a period of more than 5 half-lives, it is recommended that initial dosing recommendations and guidelines be followed. The half-life of lamotrigine is affected by other concomitant medications [see Clinical Pharmacology (12.3)].

  Lamotrigine Added to Drugs Known to Induce or Inhibit Glucuronidation: Because lamotrigine is metabolized predominantly by glucuronic acid conjugation, drugs that are known to induce or inhibit glucuronidation may affect the apparent clearance of lamotrigine. Drugs that induce glucuronidation include carbamazepine, phenytoin, phenobarbital, primidone, rifampin, estrogen-containing oral contraceptives, and the protease inhibitors lopinavir/ritonavir and atazanavir/ritonavir. Valproate inhibits glucuronidation. For dosing considerations for lamotrigine in patients on estrogen-containing contraceptives and atazanavir/ritonavir, see below and Table 13. For dosing considerations for lamotrigine in patients on other drugs known to induce or inhibit glucuronidation, see Tables 1, 2, 5-6, and 13.

  Target Plasma Levels for Patients with Epilepsy or Bipolar Disorder: A therapeutic plasma concentration range has not been established for lamotrigine. Dosing of lamotrigine should be based on therapeutic response [see Clinical Pharmacology (12.3)].

  Women Taking Estrogen-Containing Oral Contraceptives: Starting Lamotrigine in Women Taking Estrogen-Containing Oral Contraceptives: Although estrogen-containing oral contraceptives have been shown to increase the clearance of lamotrigine [see Clinical Pharmacology (12.3)], no adjustments to the recommended dose-escalation guidelines for lamotrigine should be necessary solely based on the use of estrogen-containing oral contraceptives. Therefore, dose escalation should follow the recommended guidelines for initiating adjunctive therapy with lamotrigine based on the concomitant AED or other concomitant medications (see Tables 1, 5, and 7). See below for adjustments to maintenance doses of lamotrigine in women taking estrogen-containing oral contraceptives.

  Adjustments to the Maintenance Dose of Lamotrigine In Women Taking Estrogen-Containing Oral Contraceptives:

  (1) Taking Estrogen-Containing Oral Contraceptives: In women not taking carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin and the protease inhibitors lopinavir/ritonavir and atazanavir/ritonavir that induce lamotrigine glucuronidation [see Drug Interactions (7), Clinical Pharmacology (12.3)], the maintenance dose of lamotrigine will in most cases need to be increased by as much as 2-fold over the recommended target maintenance dose to maintain a consistent lamotrigine plasma level.

  (2) Starting Estrogen-Containing Oral Contraceptives: In women taking a stable dose of lamotrigine and not taking carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin and the protease inhibitors lopinavir/ritonavir and atazanavir/ritonavir that induce lamotrigine glucuronidation [see Drug Interactions (7), Clinical Pharmacology (12.3)], the maintenance dose will in most cases need to be increased by as much as 2-fold to maintain a consistent lamotrigine plasma level. The dose increases should begin at the same time that the oral contraceptive is introduced and continue, based on clinical response, no more rapidly than 50 to 100 mg/day every week. Dose increases should not exceed the recommended rate (see Tables 1 and 5) unless lamotrigine plasma levels or clinical response support larger increases. Gradual transient increases in lamotrigine plasma levels may occur during the week of inactive hormonal preparation (pill-free week), and these increases will be greater if dose increases are made in the days before or during the week of inactive hormonal preparation. Increased lamotrigine plasma levels could result in additional adverse reactions, such as dizziness, ataxia, and diplopia. If adverse reactions attributable to lamotrigine consistently occur during the pill-free week, dose adjustments to the overall maintenance dose may be necessary. Dose adjustments limited to the pill-free week are not recommended. For women taking lamotrigine in addition to carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin and the protease inhibitors lopinavir/ritonavir and atazanavir/ritonavir that induce lamotrigine glucuronidation [see Drug Interactions (7), Clinical Pharmacology (12.3)], no adjustment to the dose of lamotrigine should be necessary.

  (3) Stopping Estrogen-Containing Oral Contraceptives: In women not taking carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin and the protease inhibitors lopinavir/ritonavir and atazanavir/ritonavir that induce lamotrigine glucuronidation [see Drug Interactions (7), Clinical Pharmacology (12.3)], the maintenance dose of lamotrigine will in most cases need to be decreased by as much as 50% in order to maintain a consistent lamotrigine plasma level. The decrease in dose of lamotrigine should not exceed 25% of the total daily dose per week over a 2-week period, unless clinical response or lamotrigine plasma levels indicate otherwise [see Clinical Pharmacology (12.3)]. In women taking lamotrigine in addition to carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin and the protease inhibitors lopinavir/ritonavir and atazanavir/ritonavir that induce lamotrigine glucuronidation [see Drug Interactions (7), Clinical Pharmacology (12.3)], no adjustment to the dose of lamotrigine should be necessary.

  Women and Other Hormonal Contraceptive Preparations or Hormone Replacement Therapy: The effect of other hormonal contraceptive preparations or hormone replacement therapy on the pharmacokinetics of lamotrigine has not been systematically evaluated. It has been reported that ethinylestradiol, not progestogens, increased the clearance of lamotrigine up to 2-fold, and the progestin-only pills had no effect on lamotrigine plasma levels. Therefore, adjustments to the dosage of lamotrigine in the presence of progestogens alone will likely not be needed.

  Patients Taking Atazanavir/Ritonavir: While atazanavir/ritonavir does reduce the lamotrigine plasma concentration, no adjustments to the recommended dose-escalation guidelines for lamotrigine should be necessary solely based on the use of atazanavir/ritonavir. Dose escalation should follow the recommended guidelines for initiating adjunctive therapy with lamotrigine based on concomitant AED or other concomitant medications (see Tables 1, 2, and 5). In patients already taking maintenance doses of lamotrigine and not taking glucuronidation inducers, the dose of lamotrigine may need to be increased if atazanavir/ritonavir is added, or decreased if atazanavir/ritonavir is discontinued [see Clinical Pharmacology (12.3)].

  Patients with Hepatic Impairment: Experience in patients with hepatic impairment is limited. Based on a clinical pharmacology study in 24 subjects with mild, moderate, and severe liver impairment [see Use in Specific Populations (8.6), Clinical Pharmacology (12.3)], the following general recommendations can be made. No dosage adjustment is needed in patients with mild liver impairment. Initial, escalation, and maintenance doses should generally be reduced by approximately 25% in patients with moderate and severe liver impairment without ascites and 50% in patients with severe liver impairment with ascites. Escalation and maintenance doses may be adjusted according to clinical response.

  Patients with Renal Impairment: Initial doses of lamotrigine should be based on patients' concomitant medications (see Tables 1-3 and 5); reduced maintenance doses may be effective for patients with significant renal impairment [see Use in Specific Populations (8.7), Clinical Pharmacology (12.3)]. Few patients with severe renal impairment have been evaluated during chronic treatment with lamotrigine. Because there is inadequate experience in this population, lamotrigine should be used with caution in these patients.

  Discontinuation Strategy: Epilepsy: For patients receiving lamotrigine in combination with other AEDs, a re-evaluation of all AEDs in the regimen should be considered if a change in seizure control or an appearance or worsening of adverse reactions is observed.

  If a decision is made to discontinue therapy with lamotrigine, a step-wise reduction of dose over at least 2 weeks (approximately 50% per week) is recommended unless safety concerns require a more rapid withdrawal [see Warnings and Precautions (5.8)].

  Discontinuing carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin and the protease inhibitors lopinavir/ritonavir and atazanavir/ritonavir that induce lamotrigine glucuronidation should prolong the half-life of lamotrigine; discontinuing valproate should shorten the half-life of lamotrigine.

  Bipolar Disorder: In the controlled clinical trials, there was no increase in the incidence, type, or severity of adverse reactions following abrupt termination of lamotrigine. In the clinical development program in adults with bipolar disorder, 2 patients experienced seizures shortly after abrupt withdrawal of lamotrigine. Discontinuation of lamotrigine should involve a step-wise reduction of dose over at least 2 weeks (approximately 50% per week) unless safety concerns require a more rapid withdrawal [see Warnings and Precautions (5.8)].

  2.2 Epilepsy—Adjunctive Therapy

  This section provides specific dosing recommendations for patients older than 12 years and patients aged 2 to 12 years. Within each of these age-groups, specific dosing recommendations are provided depending upon concomitant AEDs or other concomitant medications (see Table 1 for patients older than 12 years and Table 2 for patients aged 2 to 12 years). A weight-based dosing guide for patients aged 2 to 12 years on concomitant valproate is provided in Table 3.

  Patients Older than 12 Years: Recommended dosing guidelines are summarized in Table 1.

  Table 1. Escalation Regimen for Lamotrigine in Patients Older than 12 Years with Epilepsy In Patients TAKING Valproate* In Patients NOT TAKING Carbamazepine, Phenytoin, Phenobarbital, Primidone,† or Valproate* In Patients TAKING Carbamazepine, Phenytoin, Phenobarbital, or Primidone† and NOT TAKING Valproate* * Valproate has been shown to inhibit glucuronidation and decrease the apparent clearance of lamotrigine [see Drug Interactions (7), Clinical Pharmacology (12.3)]. † Drugs that induce lamotrigine glucuronidation and increase clearance, other than the specified antiepileptic drugs, include estrogen-containing oral contraceptives, rifampin, and the protease inhibitors lopinavir/ritonavir and atazanavir/ritonavir. Dosing recommendations for oral contraceptives and the protease inhibitor atazanavir/ritonavir can be found in General Dosing Considerations [see Dosage and Administration (2.1)]. Patients on rifampin and the protease inhibitor lopinavir/ritonavir should follow the same dosing titration/maintenance regimen used with antiepileptic drugs that induce glucuronidation and increase clearance [see Dosage and Administration (2.1), Drug Interactions (7), and Clinical Pharmacology (12.3)]. Weeks 1 and 2 25 mg every other day 25 mg every day 50 mg/day Weeks 3 and 4 25 mg every day 50 mg/day 100 mg/day (in 2 divided doses) Week 5 onward to maintenance Increase by 25 to 50 mg/day every 1 to 2 weeks. Increase by 50 mg/day every 1 to 2 weeks. Increase by 100 mg/day every 1 to 2 weeks. Usual maintenance dose 100 to 200 mg/day with valproate alone
  100 to 400 mg/day with valproate and other drugs that induce glucuronidation
  (in 1 or 2 divided doses) 225 to 375 mg/day
  (in 2 divided doses) 300 to 500 mg/day
  (in 2 divided doses)

  Patients Aged 2 to 12 Years: Recommended dosing guidelines are summarized in Table 2.

  Lower starting doses and slower dose escalations than those used in clinical trials are recommended because of the suggestion that the risk of rash may be decreased by lower starting doses and slower dose escalations. Therefore, maintenance doses will take longer to reach in clinical practice than in clinical trials. It may take several weeks to months to achieve an individualized maintenance dose. Maintenance doses in patients weighing less than 30 kg, regardless of age or concomitant AED, may need to be increased as much as 50%, based on clinical response.

  Table 2. Escalation Regimen for Lamotrigine in Patients Aged 2 to 12 Years with Epilepsy In Patients TAKING Valproate* In Patients NOT TAKING Carbamazepine, Phenytoin, Phenobarbital, Primidone,† or Valproate* In Patients TAKING Carbamazepine, Phenytoin, Phenobarbital, or Primidone† and NOT TAKING Valproate* Note: Only whole tablets should be used for dosing. * Valproate has been shown to inhibit glucuronidation and decrease the apparent clearance of lamotrigine [see Drug Interactions (7), Clinical Pharmacology (12.3)]. † Drugs that induce lamotrigine glucuronidation and increase clearance, other than the specified antiepileptic drugs, include estrogen-containing oral contraceptives, rifampin, and the protease inhibitors lopinavir/ritonavir and atazanavir/ritonavir. Dosing recommendations for oral contraceptives and the protease inhibitor atazanavir/ritonavir can be found in General Dosing Considerations [see Dosage and Administration (2.1)]. Patients on rifampin and the protease inhibitor lopinavir/ritonavir should follow the same dosing titration/maintenance regimen used with antiepileptic drugs that induce glucuronidation and increase clearance [see Dosage and Administration (2.1), Drug Interactions (7), and Clinical Pharmacology (12.3)]. Weeks 1 and 2 0.15 mg/kg/day
  in 1 or 2 divided doses, rounded down to the nearest whole tablet (see Table 3 for weight-based dosing guide) 0.3 mg/kg/day
  in 1 or 2 divided doses, rounded down to the nearest whole tablet 0.6 mg/kg/day
  in 2 divided doses, rounded down to the nearest whole tablet Weeks 3 and 4 0.3 mg/kg/day
  in 1 or 2 divided doses, rounded down to the nearest whole tablet (see Table 3 for weight-based dosing guide) 0.6 mg/kg/day
  in 2 divided doses, rounded down to the nearest whole tablet 1.2 mg/kg/day
  in 2 divided doses, rounded down to the nearest whole tablet Week 5 onward to maintenance The dose should be increased every 1 to 2 weeks as follows: calculate 0.3 mg/kg/day, round this amount down to the nearest whole tablet, and add this amount to the previously administered daily dose. The dose should be increased every 1 to 2 weeks as follows: calculate 0.6 mg/kg/day, round this amount down to the nearest whole tablet, and add this amount to the previously administered daily dose. The dose should be increased every 1 to 2 weeks as follows: calculate 1.2 mg/kg/day, round this amount down to the nearest whole tablet, and add this amount to the previously administered daily dose. Usual maintenance dose 1 to 5 mg/kg/day
  (maximum 200 mg/day in 1 or 2 divided doses)
  1 to 3 mg/kg/day with valproate alone 4.5 to 7.5 mg/kg/day
  (maximum 300 mg/day in 2 divided doses) 5 to 15 mg/kg/day
  (maximum 400 mg/day in 2 divided doses) Maintenance dose in patients less than 30 kg May need to be increased by as much as 50%, based on clinical response. May need to be increased by as much as 50%, based on clinical response. May need to be increased by as much as 50%, based on clinical response. Table 3. The Initial Weight-Based Dosing Guide for Patients Aged 2 to 12 Years Taking Valproate (Weeks 1 to 4) with Epilepsy If the patient's weight is Give this daily dose, using the most appropriate combination of Lamotrigine 2- and 5-mg tablets Greater than And less than Weeks 1 and 2 Weeks 3 and 4 6.7 kg 14 kg 2 mg every other day 2 mg every day 14.1 kg 27 kg 2 mg every day 4 mg every day 27.1 kg 34 kg 4 mg every day 8 mg every day 34.1 kg 40 kg 5 mg every day 10 mg every day

  Usual Adjunctive Maintenance Dose for Epilepsy: The usual maintenance doses identified in Tables 1 and 2 are derived from dosing regimens employed in the placebo-controlled adjunctive trials in which the efficacy of lamotrigine was established. In patients receiving multidrug regimens employing carbamazepine, phenytoin, phenobarbital, or primidone without valproate, maintenance doses of adjunctive lamotrigine as high as 700 mg/day have been used. In patients receiving valproate alone, maintenance doses of adjunctive lamotrigine as high as 200 mg/day have been used. The advantage of using doses above those recommended in Tables 1-4 has not been established in controlled trials.

  2.3 Epilepsy—Conversion from Adjunctive Therapy to Monotherapy

  The goal of the transition regimen is to attempt to maintain seizure control while mitigating the risk of serious rash associated with the rapid titration of lamotrigine.

  The recommended maintenance dose of lamotrigine as monotherapy is 500 mg/day given in 2 divided doses.

  To avoid an increased risk of rash, the recommended initial dose and subsequent dose escalations for lamotrigine should not be exceeded [see Boxed Warning].

  Conversion from Adjunctive Therapy with Carbamazepine, Phenytoin, Phenobarbital, or Primidone to Monotherapy with Lamotrigine: After achieving a dose of 500 mg/day of lamotrigine using the guidelines in Table 1, the concomitant enzyme-inducing AED should be withdrawn by 20% decrements each week over a 4-week period. The regimen for the withdrawal of the concomitant AED is based on experience gained in the controlled monotherapy clinical trial.

  Conversion from Adjunctive Therapy with Valproate to Monotherapy with Lamotrigine: The conversion regimen involves the 4 steps outlined in Table 4.

  Table 4. Conversion from Adjunctive Therapy with Valproate to Monotherapy with Lamotrigine in Patients Aged 16 Years and Older With Epilepsy Lamotrigine Valproate Step 1 Achieve a dose of 200 mg/day according to guidelines in Table 1. Maintain established stable dose. Step 2 Maintain at 200 mg/day. Decrease dose by decrements no greater than 500 mg/day/week to 500 mg/day and then maintain for 1 week. Step 3 Increase to 300 mg/day and maintain for 1 week. Simultaneously decrease to 250 mg/day and maintain for 1 week. Step 4 Increase by 100 mg/day every week to achieve maintenance dose of 500 mg/day. Discontinue.

  Conversion from Adjunctive Therapy with Antiepileptic Drugs other than Carbamazepine, Phenytoin, Phenobarbital, Primidone, or Valproate to Monotherapy with Lamotrigine: No specific dosing guidelines can be provided for conversion to monotherapy with lamotrigine with AEDs other than carbamazepine, phenytoin, phenobarbital, primidone, or valproate.

  2.4 Bipolar Disorder

  The goal of maintenance treatment with lamotrigine is to delay the time to occurrence of mood episodes (depression, mania, hypomania, mixed episodes) in patients treated for acute mood episodes with standard therapy [see Indications and Usage (1)].

  Patients taking lamotrigine for more than 16 weeks should be periodically reassessed to determine the need for maintenance treatment.

  Adults

  The target dose of lamotrigine is 200 mg/day (100 mg/day in patients taking valproate, which decreases the apparent clearance of lamotrigine, and 400 mg/day in patients not taking valproate and taking either carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin and the protease inhibitor lopinavir/ritonavir that increase the apparent clearance of lamotrigine). In the clinical trials, doses up to 400 mg/day as monotherapy were evaluated; however, no additional benefit was seen at 400 mg/day compared with 200 mg/day [see Clinical Studies (14.2)]. Accordingly, doses above 200 mg/day are not recommended. Treatment with lamotrigine is introduced, based on concurrent medications, according to the regimen outlined in Table 5. If other psychotropic medications are withdrawn following stabilization, the dose of lamotrigine should be adjusted. In patients discontinuing valproate, the dose of lamotrigine should be doubled over a 2-week period in equal weekly increments (see Table 6). In patients discontinuing carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin and the protease inhibitors lopinavir/ritonavir and atazanavir/ritonavir that induce lamotrigine glucuronidation, the dose of lamotrigine should remain constant for the first week and then should be decreased by half over a 2-week period in equal weekly decrements (see Table 6). The dose of lamotrigine may then be further adjusted to the target dose (200 mg) as clinically indicated.

  If other drugs are subsequently introduced, the dose of lamotrigine may need to be adjusted. In particular, the introduction of valproate requires reduction in the dose of lamotrigine [see Drug Interactions (7), Clinical Pharmacology (12.3)].

  To avoid an increased risk of rash, the recommended initial dose and subsequent dose escalations of lamotrigine should not be exceeded [see Boxed Warning].

  Table 5. Escalation Regimen for Lamotrigine in Adults with Bipolar Disorder In Patients TAKING Valproate* In Patients NOT TAKING Carbamazepine, Phenytoin, Phenobarbital, Primidone,† or Valproate* In Patients TAKING Carbamazepine, Phenytoin, Phenobarbital, or Primidone† and NOT TAKING Valproate* * Valproate has been shown to inhibit glucuronidation and decrease the apparent clearance of lamotrigine [see Drug Interactions (7), Clinical Pharmacology (12.3)]. † Drugs that induce lamotrigine glucuronidation and increase clearance, other than the specified antiepileptic drugs, include estrogen-containing oral contraceptives, rifampin, and the protease inhibitors lopinavir/ritonavir and atazanavir/ritonavir. Dosing recommendations for oral contraceptives and the protease inhibitor atazanavir/ritonavir can be found in General Dosing Considerations [see Dosage and Administration (2.1)]. Patients on rifampin and the protease inhibitor lopinavir/ritonavir should follow the same dosing titration/maintenance regimen used with antiepileptic drugs that induce glucuronidation and increase clearance [see Dosage and Administration (2.1), Drug Interactions (7), and Clinical Pharmacology (12.3)]. Weeks 1 and 2 25 mg every other day 25 mg daily 50 mg daily Weeks 3 and 4 25 mg daily 50 mg daily 100 mg daily, in divided doses Week 5 50 mg daily 100 mg daily 200 mg daily, in divided doses Week 6 100 mg daily 200 mg daily 300 mg daily, in divided doses Week 7 100 mg daily 200 mg daily up to 400 mg daily, in divided doses Table 6. Dosage Adjustments to Lamotrigine in Adults with Bipolar Disorder Following Discontinuation of Psychotropic Medications Discontinuation of Psychotropic Drugs (excluding Valproate,* Carbamazepine, Phenytoin, Phenobarbital, or Primidone†) After Discontinuation of Valproate* After Discontinuation of Carbamazepine, Phenytoin, Phenobarbital, or Primidone† Current Dose of Lamotrigine (mg/day) 100 Current Dose of Lamotrigine (mg/day) 400 * Valproate has been shown to inhibit glucuronidation and decrease the apparent clearance of lamotrigine [see Drug Interactions (7), Clinical Pharmacology (12.3)]. † Drugs that induce lamotrigine glucuronidation and increase clearance, other than the specified antiepileptic drugs, include estrogen-containing oral contraceptives, rifampin, and the protease inhibitors lopinavir/ritonavir and atazanavir/ritonavir. Dosing recommendations for oral contraceptives and the protease inhibitor atazanavir/ritonavir can be found in General Dosing Considerations [see Dosage and Administration (2.1)]. Patients on rifampin and the protease inhibitor lopinavir/ritonavir should follow the same dosing titration/maintenance regimen used with antiepileptic drugs that induce glucuronidation and increase clearance [see Dosage and Administration (2.1), Drug Interactions (7), and Clinical Pharmacology (12.3)]. Week 1 Maintain current dose of Lamotrigine 150 400 Week 2 Maintain current dose of Lamotrigine 200 300 Week 3 onward Maintain current dose of Lamotrigine 200 200

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  Donepezil hydrochloride tablets should be taken in the evening, just prior to retiring.

  Donepezil hydrochloride tablets can be taken with or without food.

  2.1 Mild to Moderate Alzheimer’s Disease

  The dosages of donepezil hydrochloride tablets shown to be effective in controlled clinical trials are 5 mg and 10 mg administered once per day.

  The higher dose of 10 mg did not provide a statistically significantly greater clinical benefit than 5 mg. There is a suggestion, however, based upon order of group mean scores and dose trend analyses of data from these clinical trials, that a daily dose of 10 mg of donepezil hydrochloride tablets might provide additional benefit for some patients. Accordingly, whether or not to employ a dose of 10 mg is a matter of prescriber and patient preference.

  2.2 Severe Alzheimer’s Disease

  Donepezil hydrochloride tablets have been shown to be effective in controlled clinical trials at a dose of 10 mg administered once daily.

  2.3 Titration

  The recommended starting dose of donepezil hydrochloride tablets is 5 mg once daily. Evidence from the controlled trials in mild to moderate Alzheimer’s disease indicates that the 10 mg dose, with a one week titration, is likely to be associated with a higher incidence of cholinergic adverse events compared to the 5 mg dose. In open-label trials using a 6 week titration, the type and frequency of these same adverse events were similar between the 5 mg and 10 mg dose groups. Therefore, because donepezil hydrochloride tablets steady state is achieved about 15 days after it is started and because the incidence of untoward effects may be influenced by the rate of dose escalation, a dose of 10 mg should not be administered until patients have been on a daily dose of 5 mg for 4 to 6 weeks.

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  2.1 General Dosing Considerations 

  : There are suggestions, yet to be proven, that the risk of severe, potentially life-threatening rash may be increased by (1) coadministration of Lamotrigine with valproate, (2) exceeding the recommended initial dose of Lamotrigine, or (3) exceeding the recommended dose escalation for Lamotrigine. However, cases have occurred in the absence of these factors . Therefore, it is important that the dosing recommendations be followed closely. Rash[seeBoxed Warning]

  The risk of nonserious rash may be increased when the recommended initial dose and/or the rate of dose escalation of Lamotrigine is exceeded and in patients with a history of allergy or rash to other AEDs.

  It is recommended that Lamotrigine not be restarted in patients who discontinued due to rash associated with prior treatment with Lamotrigine, unless the potential benefits clearly outweigh the risks. If the decision is made to restart a patient who has discontinued Lamotrigine, the need to restart with the initial dosing recommendations should be assessed. The greater the interval of time since the previous dose, the greater consideration should be given to restarting with the initial dosing recommendations. If a patient has discontinued Lamotrigine for a period of more than 5 half-lives, it is recommended that initial dosing recommendations and guidelines be followed. The half-life of Lamotrigine is affected by other concomitant medications . [see Clinical Pharmacology (12.3)]

  : Drugs other than those listed in the Clinical Pharmacology section have not been systematically evaluated in combination with Lamotrigine. Because Lamotrigine is metabolized predominantly by glucuronic acid conjugation, drugs that are known to induce or inhibit glucuronidation may affect the apparent clearance of Lamotrigine and doses of Lamotrigine may require adjustment based on clinical response. Lamotrigine Added to Drugs Known to Induce or Inhibit Glucuronidation[see Clinical Pharmacology (12.3)]

  A therapeutic plasma concentration range has not been established for Lamotrigine. Dosing of Lamotrigine should be based on therapeutic response . Target Plasma Levels for Patients With Epilepsy or Bipolar Disorder:[see Clinical Pharmacology (12.3)]

  :   Although estrogen-containing oral contraceptives have been shown to increase the clearance of Lamotrigine , no adjustments to the recommended dose-escalation guidelines for Lamotrigine should be necessary solely based on the use of estrogen-containing oral contraceptives. Therefore, dose escalation should follow the recommended guidelines for initiating adjunctive therapy with Lamotrigine based on the concomitant AED or other concomitant medications (see or ). See below for adjustments to maintenance doses of Lamotrigine in women taking estrogen-containing oral contraceptives. Women Taking Estrogen-Containing Oral ContraceptivesStarting Lamotrigine in Women Taking Estrogen-Containing Oral Contraceptives:[see Clinical Pharmacology (12.3)]Table 1Table 5

  Adjustments to the Maintenance Dose of Lamotrigine in Women Taking Estrogen-Containing Oral Contraceptives:

  For women not taking carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin that induce Lamotrigine glucuronidation , the maintenance dose of Lamotrigine will in most cases need to be increased, by as much as 2-fold over the recommended target maintenance dose, in order to maintain a consistent Lamotrigine plasma level . (1) Taking Estrogen-Containing Oral Contraceptives:[see Drug Interactions ( ), 7Clinical Pharmacology ( )] 12.3[see Clinical Pharmacology (12.3)]

  In women taking a stable dose of Lamotrigine and not taking carbamazepine, phenytoin, phenobarbital, primidone, or  other drugs such as rifampin that induce Lamotrigine glucuronidation the maintenance dose will in most cases need to be increased by as much as 2-fold in order to maintain a consistent Lamotrigine plasma level. The dose increases should begin at the same time that the oral contraceptive is introduced and continue, based on clinical response, no more rapidly than 50 to 100 mg/day every week. Dose increases should not exceed the recommended rate (see or ) unless Lamotrigine plasma levels or clinical response support larger increases. Gradual transient increases in Lamotrigine plasma levels may occur during the week of inactive hormonal preparation (“pill-free” week), and these increases will be greater if dose increases are made in the days before or during the week of inactive hormonal preparation. Increased Lamotrigine plasma levels could result in additional adverse reactions, such as dizziness, ataxia, and diplopia. If adverse reactions attributable to Lamotrigine consistently occur during the “pill-free” week, dose adjustments to the overall maintenance dose may be necessary. Dose adjustments limited to the “pill-free” week are not recommended. For women taking Lamotrigine in addition to carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin that induce Lamotrigine glucuronidation , no adjustment to the dose of Lamotrigine should be necessary. (2) Starting Estrogen-Containing Oral Contraceptives:[see Drug Interactions ( ), Clinical Pharmacology ( )], 712.3Table 1Table 5[see Drug Interactions ( ), Clinical Pharmacology ( )] 712.3

  For women not taking carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin that induce Lamotrigine glucuronidation , the maintenance dose of Lamotrigine will in most cases need to be decreased by as much as 50% in order to maintain a consistent Lamotrigine plasma level. The decrease in dose of Lamotrigine should not exceed 25% of the total daily dose per week over a 2-week period, unless clinical response or Lamotrigine plasma levels indicate otherwise . For women taking Lamotrigine in addition to carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin that induce Lamotrigine glucuronidation , no adjustment to the dose of Lamotrigine should be necessary. (3) Stopping Estrogen-Containing Oral Contraceptives:[see Drug Interactions ( ), Clinical Pharmacology ( )] 712.3[see Clinical Pharmacology ( )] 12.3[see Drug Interactions ( ), Clinical Pharmacology ( )] 712.3

  : The effect of other hormonal contraceptive preparations or hormone replacement therapy on the pharmacokinetics of Lamotrigine has not been systematically evaluated. It has been reported that ethinylestradiol, not progestogens, increased the clearance of Lamotrigine up to 2-fold, and the progestin-only pills had no effect on Lamotrigine plasma levels. Therefore, adjustments to the dosage of Lamotrigine in the presence of progestogens alone will likely not be needed. Women and Other Hormonal Contraceptive Preparations or Hormone Replacement Therapy

  : Experience in patients with hepatic impairment is limited. Based on a clinical pharmacology study in 24 patients with mild, moderate, and severe liver impairment , the following general recommendations can be made. No dosage adjustment is needed in patients with mild liver impairment. Initial, escalation, and maintenance doses should generally be reduced by approximately 25% in patients with moderate and severe liver impairment without ascites and 50% in patients with severe liver impairment with ascites. Escalation and maintenance doses may be adjusted according to clinical response. Patients With Hepatic Impairment[see Use in Specific Populations (8.6), Clinical Pharmacology (12.3)]

  : Initial doses of Lamotrigine should be based on patients' concomitant medications (see or ); reduced maintenance doses may be effective for patients with significant renal impairment . Few patients with severe renal impairment have been evaluated during chronic treatment with Lamotrigine. Because there is inadequate experience in this population, Lamotrigine should be used with caution in these patients. Patients With Renal ImpairmentTables 1-3Table 5[see Use in Specific Populations (8.7), Clinical Pharmacology (12.3)]

  :   For patients receiving Lamotrigine in combination with other AEDs, a re-evaluation of all AEDs in the regimen should be considered if a change in seizure control or an appearance or worsening of adverse reactions is observed. Discontinuation StrategyEpilepsy:

  If a decision is made to discontinue therapy with Lamotrigine, a step-wise reduction of dose over at least 2 weeks (approximately 50% per week) is recommended unless safety concerns require a more rapid withdrawal [see Warnings and Precautions (5.9)].

  Discontinuing carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin that induce Lamotrigine glucuronidation should prolong the half-life of Lamotrigine; discontinuing valproate should shorten the half-life of Lamotrigine.

  In the controlled clinical trials, there was no increase in the incidence, type, or severity of adverse reactions following abrupt termination of Lamotrigine. In clinical trials in patients with Bipolar Disorder, 2 patients experienced seizures shortly after abrupt withdrawal of Lamotrigine. However, there were confounding factors that may have contributed to the occurrence of seizures in these bipolar patients. Discontinuation of Lamotrigine should involve a step-wise reduction of dose over at least 2 weeks (approximately 50% per week) unless safety concerns require a more rapid withdrawal . Bipolar Disorder:[see Warnings and Precautions (5.9)]

  2.2 Epilepsy – Adjunctive Therapy

  This section provides specific dosing recommendations for patients greater than 12 years of age and patients 2 to 12 years of age. Within each of these age-groups, specific dosing recommendations are provided depending upon concomitant AED or other concomitant medications ( for patients greater than 12 years of age and for patients 2 to 12 years of age). A weight-based dosing guide for patients 2 to 12 years of age on concomitant valproate is provided in . Table 1Table 2Table 3

  Recommended dosing guidelines are summarized in . Patients Over 12 Years of Age:Table 1

  Table 1. Escalation Regimen for Lamotrigine in Patients Over 12 Years of Age With Epilepsy  * Valproate has been shown to inhibit glucuronidation and decrease the apparent clearance of Lamotrigine [see Drug Interactions ( 7 ), Clinical Pharmacology  ( 12.3 )]. † These drugs induce Lamotrigine glucuronidation and increase clearance Other drugs, that have similar effects include estrogen-containing oral contraceptives Dosing recommendations for oral contraceptives can be found in General Dosing Considerations Patients on rifampin, or other drugs that induce Lamotrigine glucuronidation and increase clearance, should follow the same dosing titration/maintenance regimen as that used with anticonvulsants that have this effect. [see Drug Interactions ( 7 ) Clinical Pharmacology ( 12.3 )]. [see Drug Interactions ( 7 ), Clinical Pharmacology  ( 12.3 )]. [see Dosage and Administration ( 2.1 )].   For Patients TAKING Valproate * For Patients NOT TAKING Carbamazepine, Phenytoin, Phenobarbital, Primidone ,or Valproate †* For Patients TAKING Carbamazepine, Phenytoin, Phenobarbital, or Primidone and NOT TAKING Valproate †* Weeks 1 and 2 25 mg every day other 25 mg every day 50 mg/day Weeks 3 and 4 25 mg every day 50 mg/day (in 2 divided doses) 100 mg/day Weeks 5 onwards to maintenance Increase by 25 to 50 mg/day every 1 to 2 weeks Increase by 50 mg/day every 1 to 2 weeks
  Increase by 100 mg/day every 1 to 2 weeks Usual Maintenance Dose (in 1 or 2 divided doses) 100 to 200 mg/day with valproate alone
  
  100 to 400 mg/day with valproate and other drugs that induce glucuronidation
  (in 2 divided doses) 225 to 375 mg/day
   (in 2 divided doses) 300 to 500 mg/day

  Recommended dosing guidelines are summarized in . Patients 2 to 12 Years of Age:Table 2

  Smaller starting doses and slower dose escalations than those used in clinical trials are recommended because of the suggestion that the risk of rash may be decreased by smaller starting doses and slower dose escalations. Therefore, maintenance doses will take longer to reach in clinical practice than in clinical trials. It may take several weeks to months to achieve an individualized maintenance dose. Maintenance doses in patients weighing less than 30 kg, regardless of age or concomitant AED, may need to be increased as much as 50%, based on clinical response. 

  Table 2. Escalation Regimen for Lamotrigine in Patients 2 to 12 Years of Age With Epilepsy * Valproate has been shown to inhibit glucuronidation and decrease the apparent clearance of Lamotrigine [see Drug Interactions ( ), Clinical Pharmacology  ( )]. 712.3 † These drugs induce Lamotrigine glucuronidation and increase clearance . Other drugs, that have similar effects include estrogen-containing oral contraceptives . Dosing recommendations for oral contraceptives can be found in General Dosing Considerations Patients on rifampin, or other drugs that induce Lamotrigine glucuronidation and increase clearance, should follow the same dosing titration/maintenance regimen as that used with anticonvulsants that have this effect. [see Drug Interactions ( ) Clinical Pharmacology  ( )] 712.3 [see Drug Interactions ( ) Clinical Pharmacology  ( )] 712.3
  [see Dosage and Administration ( 2.1 )].   For Patients TAKING Valproate * For Patients NOT TAKING Carbamazepine, Phenytoin, Phenobarbital,   Primidone   or  Valproate
  
  
  †
  * For Patients TAKING Carbamazepine, Phenytoin, Phenobarbital, or  Primidone and NOT TAKING Valproate †* Weeks 1 and 2  in 1 or 2 divided doses, rounded down to the nearest whole tablet (see Table 3 for weight based dosing guide) 0.15 mg/kg/day
  in 1 or 2 divided doses, rounded down to the nearest whole tablet 0.3 mg/kg/day
  in 2 divided doses, rounded down to the nearest whole tablet 0.6 mg/kg/day
  Weeks 3 and 4 in 1 or 2 divided doses, rounded down to the nearest whole tablet (see Table 3 for weight based dosing guide) 0.3 mg/kg/day
  in 2 divided doses, rounded down to the nearest whole tablet 0.6 mg/kg/day  
  in 2 divided doses, rounded down to the nearest whole tablet 1.2 mg/kg/day  
  Weeks 5 onwards to maintenance The dose should be increased every 1 to 2 weeks as follows: calculate 0.3 mg/kg/day, round this amount down to the nearest whole tablet, and add this amount to the previously administered daily dose The dose should be increased every 1 to 2 weeks as follows: calculate 0.6 mg/kg/day, round this amount down to the nearest whole tablet, and add this amount to the previously administered daily dose The dose should be increased every 1 to 2 weeks as follows: calculate 1.2 mg/kg/day, round this amount down to the nearest whole tablet, and add this amount to the previously administered daily dose Usual Maintenance Dose (maximum 200 mg/day in 1 or 2 divided doses). with valproate alone 1 to 5 mg/kg/day1 to 3 mg/kg/day
   (maximum 300 mg/day in 2 divided doses) 4.5 to 7.5 mg/kg/day
   (maximum 400 mg/day in 2 divided doses) 5 to 15 mg/kg/day
  Maintenance dose in patients less than 30 kg May need to be increased by as much as 50%, based on clinical response May need to be increased by as much as 50%, based on clinical response May need to be increased by as much as 50%, based on clinical response Note: Only whole tablets should be used for dosing. Table 3. The Initial Weight-Based Dosing Guide for Patients 2 to 12 Years Taking Valproate (Weeks 1 to 4) With Epilepsy If the patient’s weight is Give this daily dose, using the most appropriate combination of Lamotrigine 2-mg and 5-mg tablets Greater than And less than Weeks 1 and 2 Weeks 3 and 4 6.7 kg 14 kg 2 mg every day other 2 mg every day 14.1 kg 27 kg 2 mg every day 4 mg every day 27.1 kg 34 kg 4 mg every day 8 mg every day 34.1 kg 40 kg 5 mg every day 10 mg every day

  The usual maintenance doses identified in Tables and are derived from dosing regimens employed in the placebo-controlled adjunctive studies in which the efficacy of Lamotrigine was established. In patients receiving multidrug regimens employing carbamazepine, phenytoin, phenobarbital, or primidone , maintenance doses of adjunctive Lamotrigine as high as 700 mg/day have been used. In patients receiving , maintenance doses of adjunctive Lamotrigine as high as 200 mg/day have been used. The advantage of using doses above those recommended in Tables has not been established in controlled trials. Usual Adjunctive Maintenance Dose for Epilepsy:12without valproatevalproate alone1 through 4

  2.3 Epilepsy – Conversion From Adjunctive Therapy to Monotherapy

  The goal of the transition regimen is to effect the conversion to monotherapy with Lamotrigine under conditions that ensure adequate seizure control while mitigating the risk of serious rash associated with the rapid titration of Lamotrigine.

  The recommended maintenance dose of Lamotrigine as monotherapy is 500 mg/day given in 2 divided doses.

  To avoid an increased risk of rash, the recommended initial dose and subsequent dose escalations of Lamotrigine should not be exceeded . [see ] Boxed Warning

  After achieving a dose of 500 mg/day of Lamotrigine according to the guidelines in , the concomitant AED should be withdrawn by 20% decrements each week over a 4-week period. The regimen for the withdrawal of the concomitant AED is based on experience gained in the controlled monotherapy clinical trial.  Conversion From Adjunctive Therapy With Carbamazepine, Phenytoin, Phenobarbital, or Primidone to Monotherapy With Lamotrigine:Table 1

  The conversion regimen involves 4 steps outlined in . Conversion from Adjunctive Therapy With Valproate to Monotherapy With Lamotrigine:Table 4

  Table 4. Conversion From Adjunctive Therapy With Valproate to Monotherapy With Lamotrigine in Patients ≥16 Years of Age with Epilepsy

  Lamotrigine

  Valproate

  Step 1

  Achieve a dose of 200 mg/day according to guidelines in (if not already on 200 mg/day). Table 1

  Maintain previous stable dose.

  Step 2

  Maintain at 200 mg/day.

  Decrease to 500 mg/day by decrements no greater than 500 mg/day/week and then maintain the dose of 500 mg/day for 1 week.

  Step 3

  Increase to 300 mg/day and maintain for 1 week.

  Simultaneously decrease to 250 mg/day and maintain for 1 week.

  Step 4

  Increase by 100 mg/day every week to achieve maintenance dose of 500 mg/day.

  Discontinue.

  No specific dosing guidelines can be provided for conversion to monotherapy with Lamotrigine with AEDs other than carbamazepine, phenobarbital, phenytoin, primidone, or valproate. Conversion from Adjunctive Therapy With Antiepileptic Drugs Other Than Carbamazepine, Phenytoin, Phenobarbital, Primidone, or Valproate to Monotherapy With Lamotrigine:
  

  2.4 Bipolar Disorder

  The goal of maintenance treatment with Lamotrigine is to delay the time to occurrence of mood episodes (depression, mania, hypomania, mixed episodes) in patients treated for acute mood episodes with standard therapy. The target dose of Lamotrigine is 200 mg/day (100 mg/day in patients taking valproate, which decreases the apparent clearance of Lamotrigine, and 400 mg/day in patients not taking valproate and taking either carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin, that  increase the apparent clearance of Lamotrigine). In the clinical trials, doses up to 400 mg/day as monotherapy were evaluated; however, no additional benefit was seen at 400 mg/day compared with 200 mg/day . Accordingly, doses above 200 mg/day are not recommended. Treatment with Lamotrigine is introduced, based on concurrent medications, according to the regimen outlined in . If other psychotropic medications are withdrawn following stabilization, the dose of Lamotrigine should be adjusted. For patients discontinuing valproate, the dose of Lamotrigine should be doubled over a 2-week period in equal weekly increments (see ). For patients discontinuing carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin that induce Lamotrigine glucuronidation, the dose of Lamotrigine should remain constant for the first week and then should be decreased by half over a 2-week period in equal weekly decrements (see ). The dose of Lamotrigine may then be further adjusted to the target dose (200 mg) as clinically indicated. [see Clinical Studies ( )] 14.2Table 5Table 6Table 6

  If other drugs are subsequently introduced, the dose of Lamotrigine may need to be adjusted. In particular, the introduction of valproate requires reduction in the dose of Lamotrigine  [see Drug Interactions ( ), Clinical Pharmacology ( )] 712.3.

  To avoid an increased risk of rash, the recommended initial dose and subsequent dose escalations of Lamotrigine should not be exceeded . [see ] Boxed Warning

   

  Table 5. Escalation Regimen for Lamotrigine for Patients With Bipolar Disorder * Valproate has been shown to inhibit glucuronidation and decrease the apparent clearance of Lamotrigine [see Drug Interactions ( ), Clinical Pharmacology ( )]. 712.3 † These drugs induce Lamotrigine glucuronidation and increase clearance Other drugs that have similar effects include estrogen- containing oral contraceptives . Dosing recommendations for oral contraceptives can be found in General Dosing Considerations . Patients on rifampin, or other drugs that induce Lamotrigine glucuronidation and increase clearance, should follow the same dosing titration/ maintenance regimen as that used with anticonvulsants that have this effect. [see Drug Interactions ( ), Clinical Pharmacology ( )]. 712.3 [see Drug Interactions ( ), Clinical Pharmacology ( )] 712.3
  [see Dosage and Administration ( )] 2.1 For Patients TAKING Valproate * For Patients NOT TAKING Carbamazepine, Phenytoin, Phenobarbital, Primidone , or Valproate †* For Patients TAKING Carbamazepine, Phenytoin, Phenobarbital, or Primidone and NOT TAKING Valproate †* Weeks 1 and 2 25 mg every day other 25 mg daily 50 mg daily Weeks 3 and 4 25 mg daily 50 mg daily 100 mg daily, in divided doses Week 5 50 mg daily 100 mg daily 200 mg daily, in divided doses Week 6 100 mg daily 200 mg daily 300 mg daily, in divided doses Week 7 100 mg daily 200 mg daily up to 400 mg daily, in divided doses Table 6. Dosage Adjustments to Lamotrigine for Patients With Bipolar Disorder Following Discontinuation of Psychotropic Medications * These drugs induce Lamotrigine glucuronidation and increase clearance Other drugs that have similar effects include estrogen-containing oral contraceptives . Dosing recommendations for oral contraceptives can be found in General Dosing Considerations . Patients on rifampin, or other drugs that induce Lamotrigine glucuronidation and increase clearance, should follow the same dosing titration/ maintenance regimen as that used with anticonvulsants that have this effect. [see Drug Interactions ( ), Clinical Pharmacology ( )]. 712.3 [see Drug Interactions ( ), Clinical Pharmacology ( )] 712.3 [see Dosage and Administration ( )] 2.1 † Valproate has been shown to inhibit glucuronidation and decrease the apparent clearance of Lamotrigine [see Drug Interactions ( ), Clinical Pharmacology ( )]. 712.3  

  Discontinuation of Psychotropic Drugs (excluding Carbamazepine, Phenytoin, Phenobarbital, Primidone , or Valproate ) *†

  After Discontinuation of Valproate † After Discontinuation of Carbamazepine, Phenytoin, Phenobarbital, or Primidone * Current dose of Lamotrigine (mg/day) 100

  Current dose of Lamotrigine (mg/day) 400

  Week 1 Maintain current dose of Lamotrigine 150 400 Week 2 Maintain current dose of Lamotrigine 200 300 Week 3 onward Maintain current dose of Lamotrigine 200 200

  The benefit of continuing treatment in patients who had been stabilized in an 8- to 16-week open-label phase with Lamotrigine was established in 2 randomized, placebo-controlled clinical maintenance trials . However, the optimal duration of treatment with Lamotrigine has not been established. Thus, patients should be periodically reassessed to determine the need for maintenance treatment. [see Clinical Studies ( )] 14.2

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  Dosing is based on concomitant medications, indication, and patient age. ( 2.2 , 2.4 ) To avoid an increased risk of rash, the recommended initial dose and subsequent dose escalations should not be exceeded. ( 2.1 ) Do not restart lamotrigine in patients who discontinued due to rash unless the potential benefits clearly outweigh the risks. ( 2.1 ) Adjustments to maintenance doses will in most cases be required in patients starting or stopping estrogen-containing oral contraceptives. ( 2.1 , 5.8 ) Lamotrigine tablets should be discontinued over a period of at least 2 weeks (approximately 50% reduction per week). ( 2.1 , 5.9 )

  Epilepsy

  Adjunctive therapy—See Table 1 for patients >12 years of age and Tables 2 and 3 for patients 2 to 12 years. ( 2.2 ) Conversion to monotherapy—See Table 4. ( 2.3 )

  Bipolar Disorder: See Tables 5 and 6 ( 2.4 )

   

  Rash: There are suggestions, yet to be proven, that the risk of severe, potentially life-threatening rash may be increased by (1) coadministration of lamotrigine tablets with valproate, (2) exceeding the recommended initial dose of lamotrigine tablets, or (3) exceeding the recommended dose escalation for lamotrigine tablets. However, cases have occurred in the absence of these factors [see Boxed Warning ]. Therefore, it is important that the dosing recommendations be followed closely.

  The risk of nonserious rash may be increased when the recommended initial dose and/or the rate of dose escalation of lamotrigine tablet is exceeded and in patients with a history of allergy or rash to other AEDs.

  It is recommended that lamotrigine tablets not be restarted in patients who discontinued due to rash associated with prior treatment with lamotrigine, unless the potential benefits clearly outweigh the risks. If the decision is made to restart a patient who has discontinued lamotrigine, the need to restart with the initial dosing recommendations should be assessed. The greater the interval of time since the previous dose, the greater consideration should be given to restarting with the initial dosing recommendations. If a patient has discontinued lamotrigine for a period of more than 5 half-lives, it is recommended that initial dosing recommendations and guidelines be followed. The half-life of lamotrigine is affected by other concomitant medications [see Clinical Pharmacology (12.3) ].

  Lamotrigine Tablets Added to Drugs Known to Induce or Inhibit Glucuronidation: Drugs other than those listed in the Clinical Pharmacology section [see Clinical Pharmacology (12.3) ] have not been systematically evaluated in combination with lamotrigine. Because lamotrigine is metabolized predominantly by glucuronic acid conjugation, drugs that are known to induce or inhibit glucuronidation may affect the apparent clearance of lamotrigine and doses of lamotrigine tablets may require adjustment based on clinical response.

  Target Plasma Levels for Patients With Epilepsy or Bipolar Disorder: A therapeutic plasma concentration range has not been established for lamotrigine. Dosing of lamotrigine tablets should be based on therapeutic response [see Clinical Pharmacology (12.3) ].

  Women Taking Estrogen-Containing Oral Contraceptives: Starting Lamotrigine Tablets  in Women Taking Estrogen-Containing Oral Contraceptives: Although estrogen-containing oral contraceptives have been shown to increase the clearance of lamotrigine [see Clinical Pharmacology (12.3) ], no adjustments to the recommended dose-escalation guidelines for lamotrigine tablets should be necessary solely based on the use of estrogen-containing oral contraceptives. Therefore, dose escalation should follow the recommended guidelines for initiating adjunctive therapy with lamotrigine tablets based on the concomitant AED or other concomitant medications (see Table 1 or Table 5). See below for adjustments to maintenance doses of lamotrigine tablets in women taking estrogen-containing oral contraceptives.

  Adjustments to the Maintenance Dose of Lamotrigine Tablets In Women Taking Estrogen-Containing Oral Contraceptives:

  (1) Taking Estrogen-Containing Oral Contraceptives: For women not taking carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin that induce lamotrigine glucuronidation [see Drug Interactions (7), Clinical Pharmacology (12.3)], the maintenance dose of lamotrigine  tablets will in most cases need to be increased, by as much as 2-fold over the recommended target maintenance dose, in order to maintain a consistent lamotrigine plasma level [see Clinical Pharmacology (12.3) ].

  (2) Starting Estrogen-Containing Oral Contraceptives: In women taking a stable dose of lamotrigine tablets and not taking carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin that induce lamotrigine glucuronidation [see Drug Interactions (7), Clinical Pharmacology (12.3)], the maintenance dose will in most cases need to be increased by as much as 2-fold in order to maintain a consistent lamotrigine plasma level. The dose increases should begin at the same time that the oral contraceptive is introduced and continue, based on clinical response, no more rapidly than 50 to 100 mg/day every week. Dose increases should not exceed the recommended rate (see Table 1 or Table 5) unless lamotrigine plasma levels or clinical response support larger increases. Gradual transient increases in lamotrigine plasma levels may occur during the week of inactive hormonal preparation ("pill-free" week), and these increases will be greater if dose increases are made in the days before or during the week of inactive hormonal preparation. Increased lamotrigine plasma levels could result in additional adverse reactions, such as dizziness, ataxia, and diplopia. If adverse reactions attributable to lamotrigine tablets consistently occur during the "pill-free" week, dose adjustments to the overall maintenance dose may be necessary. Dose adjustments limited to the "pill-free" week are not recommended. For women taking lamotrigine tablets in addition to carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin that induce lamotrigine glucuronidation [see Drug Interactions (7), Clinical Pharmacology (12.3)], no adjustment to the dose of lamotrigine tablets should be necessary.

  (3) Stopping Estrogen-Containing Oral Contraceptives: For women not taking carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin that induce lamotrigine glucuronidation [see Drug Interactions (7), Clinical Pharmacology (12.3)], the maintenance dose of lamotrigine tablets will in most cases need to be decreased by as much as 50% in order to maintain a consistent lamotrigine plasma level. The decrease in dose of lamotrigine tablets should not exceed 25% of the total daily dose per week over a 2-week period, unless clinical response or lamotrigine plasma levels indicate otherwise [see Clinical Pharmacology (12.3) ]. For women taking lamotrigine tablets in addition to carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin that induce lamotrigine glucuronidation [see Drug Interactions (7), Clinical Pharmacology (12.3)], no adjustment to the dose of lamotrigine tablets should be necessary.

  Women and Other Hormonal Contraceptive Preparations or Hormone Replacement Therapy: The effect of other hormonal contraceptive preparations or hormone replacement therapy on the pharmacokinetics of lamotrigine has not been systematically evaluated. It has been reported that ethinylestradiol, not progestogens, increased the clearance of lamotrigine up to 2-fold, and the progestin-only pills had no effect on lamotrigine plasma levels. Therefore, adjustments to the dosage of lamotrigine tablets in the presence of progestogens alone will likely not be needed.

  Patients With Hepatic Impairment: Experience in patients with hepatic impairment is limited. Based on a clinical pharmacology study in 24 patients with mild, moderate, and severe liver impairment [see Use in Specific Populations (8.6) , Clinical Pharmacology (12.3) ], the following general recommendations can be made. No dosage adjustment is needed in patients with mild liver impairment. Initial, escalation, and maintenance doses should generally be reduced by approximately 25% in patients with moderate and severe liver impairment without ascites and 50% in patients with severe liver impairment with ascites. Escalation and maintenance doses may be adjusted according to clinical response.

  Patients With Renal Impairment: Initial doses of lamotrigine tablets should be based on patients' concomitant medications (see Tables 1-3 or Table 5); reduced maintenance doses may be effective for patients with significant renal impairment [see Use in Specific Populations (8.7) , Clinical Pharmacology (12.3) ]. Few patients with severe renal impairment have been evaluated during chronic treatment with lamotrigine tablets. Because there is inadequate experience in this population, lamotrigine tablets should be used with caution in these patients.

  Discontinuation Strategy:

  Epilepsy: For patients receiving lamotrigine tablets in combination with other AEDs, a reevaluation of all AEDs in the regimen should be considered if a change in seizure control or an appearance or worsening of adverse reactions is observed.

  If a decision is made to discontinue therapy with lamotrigine tablets, a step-wise reduction of dose over at least 2 weeks (approximately 50% per week) is recommended unless safety concerns require a more rapid withdrawal [see Warnings and Precautions (5.9) ].

  Discontinuing carbamazepine, phenytoin, phenobarbital, primidone or other drugs such as rifampin that induce lamotrigine glucuronidation should prolong the half-life of lamotrigine; discontinuing valproate should shorten the half-life of lamotrigine.

  Bipolar Disorder: In the controlled clinical trials, there was no increase in the incidence, type, or severity of adverse reactions following abrupt termination of lamotrigine tablets. In clinical trials in patients with Bipolar Disorder, 2 patients experienced seizures shortly after abrupt withdrawal of lamotrigine tablets. However, there were confounding factors that may have contributed to the occurrence of seizures in these bipolar patients. Discontinuation of lamotrigine tablets should involve a step-wise reduction of dose over at least 2 weeks (approximately 50% per week) unless safety concerns require a more rapid withdrawal [see Warnings and Precautions (5.9) ].

   

  This section provides specific dosing recommendations for patients greater than 12 years of age and patients 2 to 12 years of age. Within each of these age-groups, specific dosing recommendations are provided depending upon concomitant AED or other concomitant medications (Table 1 for patients greater than 12 years of age and Table 2 for patients 2 to 12 years of age). A weight-based dosing guide for patients 2 to 12 years of age on concomitant valproate is provided in Table 3.

  Patients Over 12 Years of Age: Recommended dosing guidelines are summarized in Table 1.

  Table 1. Escalation Regimen for Lamotrigine Tablets in Patients Over 12 Years of Age With Epilepsy
  For 
  For Patients NOT TAKING 
  For Patients 
  
  Patients
  Carbamazepine, 
  TAKING
  
  TAKING
  Phenytoin,
  Carbamazepine,
  
  Valproatea
  Phenobarbital,
  Phenytoin, 
  
  
  or Primidoneb,  
  Phenobarbital,
  
  
  or Valproatea
  or Primidoneb
  
  
  
  and NOT TAKING
  
  
  
  Valproatea
  Weeks 1 and 2
  25 mg every other day
  25 mg every day
  50 mg/day
  Weeks 3 and 4
  25 mg every day
  50 mg/day
  100 mg/day
  (in 2 divided doses)
  Weeks 5 onwards to 
  maintenance
  Increase by 25 to 
  50 mg/day every 1 to 2 weeks
  Increase by 50
  mg/day every 1
  to 2 weeks
  Increase by 
  100 mg/day every 
  1 to 2 weeks.
  Usual maintenance 
  dose
  100 to 200 mg/day
  with valproate alone
  225 to 375 mg/day
  (in 2 divided doses).
  300 to 500 mg/day
  (in 2 divided doses).
  
  100 to 400 mg/day
  with valproate
  and other drugs that induce glucuronidation
  
  
  
  (in 1 or 2 divided doses)
  
  
  

  a Valproate has been shown to inhibit glucuronidation and decrease the apparent clearance of lamotrigine [see Drug Interactions (7), Clinical Pharmacology (12.3)].

  b These drugs induce lamotrigine glucuronidation and increase clearance [see Drug Interactions (7), Clinical Pharmacology (12.3)]. Other drugs that have similar effects include estrogen-containing oral contraceptives [see Drug Interactions (7), Clinical Pharmacology (12.3)]. Dosing recommendations for oral contraceptives can be found in General Dosing Considerations [see Dosage and Administration (2.1)]. Patients on rifampin, or other drugs that induce lamotrigine glucuronidation and increase clearance, should follow the same dosing titration/maintenance regimen as that used with anticonvulsants that have this effect.

  Patients 2 to 12 Years Of Age: Recommended dosing guidelines are summarized in Table 2.

  Smaller starting doses and slower dose escalations than those used in clinical trials are recommended because of the suggestion that the risk of rash may be decreased by smaller starting doses and slower dose escalations. Therefore, maintenance doses will take longer to reach in clinical practice than in clinical trials. It may take several weeks to months to achieve an individualized maintenance dose. Maintenance doses in patients weighing less than 30 kg, regardless of age or concomitant AED, may need to be increased as much as 50%, based on clinical response.

  Table 2. Escalation Regimen for Lamotrigine Tablets in Patients 2 to 12 Years of Age With Epilepsy
  For Patients TAKING 
  Valproatea
  For Patients NOT 
  TAKING Carbamazepine, Phenytoin, 
  Phenobarbital, Primidoneb, or 
  Valproatea
  For Patients TAKING 
  Carbamazepine, Phenytoin, Phenobarbital, or 
  Primidoneb and NOT 
  TAKING Valproatea
  Weeks 1 and 2
  0.15 mg/kg/day
  in 1 or 2 divided doses, rounded down to the 
  nearest whole tablet (see Table 3 for weight 
  based dosing guide).
  0.3 mg/kg/day
  in 1 or 2 divided doses, rounded down to the 
  nearest whole tablet.
  0.6 mg/kg/day
  in 2 divided doses, rounded down to the 
  nearest whole tablet.
  Weeks 3 and 4
  0.3 mg/kg/day
  in 1 or 2 divided doses,
  rounded down to the 
  nearest whole tablet 
  (see Table 3 for weight 
  based dosing guide).
  0.6 mg/kg/day
  in 2 divided doses,
  rounded down to the 
  nearest whole tablet.
  1.2 mg/kg/day
  in 2 divided doses, 
  rounded down to the 
  nearest whole tablet.
  Weeks 5 
  onwards to 
  maintenance
  The dose should be increased every 
  1 to 2 weeks as follows:
  calculate 0.3 mg/kg/day, round this amount 
  down to the nearest whole tablet, and 
  add this amount to the 
  previously administered daily dose.
  The dose should be increased every 
  1 to 2 weeks as follows:
  calculate 0.6 mg/kg/day, round this amount 
  down to the nearest whole tablet, and 
  add this amount to the 
  previously administered daily dose
  The dose should be increased every 
  1 to 2 weeks as follows:
  calculate 1.2 mg/kg/day, round this amount 
  down to the nearest whole tablet, and 
  add this amount to the 
  previously administered daily dose
  Usual 
  Maintenance 
  Dose
  1 to 5 mg/kg/day
  (maximum 200 mg/day 
  in 1 or 2 divided doses).
  1 to 3 mg/kg/day with valproate alone
  4.5 to 7.5 mg/kg/day
  (maximum 300 mg/day 
  in 2 divided doses)
  5 to 15 mg/kg/day
  (maximum 400 mg/day 
  in 2 divided doses)
  Maintenance dose in 
  patients 
  less than 30 kg
  May need to be increased 
  by as much as 50%, 
  based on clinical response
  May need to be increased 
  by as much as 50%, 
  based on clinical response
  May need to be increased 
  by as much as 50%, based 
  on clinical response
  

  Note: Only whole tablets should be used for dosing.

  a Valproate has been shown to inhibit glucuronidation and decrease the apparent clearance of lamotrigine [see Drug Interactions (7), Clinical Pharmacology (12.3)].

  b These drugs induce lamotrigine glucuronidation and increase clearance [see Drug Interactions (7), Clinical Pharmacology (12.3)]. Other drugs which have similar effects include estrogen-containing oral contraceptives [see Drug Interactions (7), Clinical Pharmacology (12.3)]. Dosing recommendations for oral contraceptives can be found in General Dosing Considerations [see Dosage and Administration (2.1)]. Patients on rifampin, or other drugs that induce lamotrigine glucuronidation and increase clearance, should follow the same dosing titration/maintenance regimen as that used with anticonvulsants that have this effect.

  Table 3. The Initial Weight-Based Dosing Guide for Patients 2 to 12 Years Taking Valproate (Weeks 1 to 4) With Epilepsy If the patient’s weight is
  Give this daily dose, using the most appropriate combination of Lamotrigine 2-mg and 5-mg tablets
  Greater than
  And less than
  Weeks 1 and 2
  Weeks 3 and 4
  6.7 kg
  14 kg
  2 mg every other day
  2 mg every day
  14.1 kg
  27 kg
  2 mg every day
  4 mg every day
  27.1 kg
  34 kg
  4 mg every day
  8 mg every day
  34.1 kg
  40 kg
  5 mg every day
  10 mg every day
  

  Usual Adjunctive Maintenance Dose for Epilepsy: The usual maintenance doses identified in Tables 1 and 2 are derived from dosing regimens employed in the placebo-controlled adjunctive studies in which the efficacy of lamotrigine tablets was established. In patients receiving multidrug regimens employing carbamazepine, phenytoin, phenobarbital, or primidone without valproate, maintenance doses of adjunctive lamotrigine tablets as high as 700 mg/day have been used. In patients receiving valproate alone, maintenance doses of adjunctive lamotrigine tablets as high as 200 mg/day have been used. The advantage of using doses above those recommended in Tables 1 through 4 has not been established in controlled trials.

   

  The goal of the transition regimen is to effect the conversion to monotherapy with lamotrigine tablets under conditions that ensure adequate seizure control while mitigating the risk of serious rash associated with the rapid titration of lamotrigine tablets.

  The recommended maintenance dose of lamotrigine tablets as monotherapy is 500 mg/day given in two divided doses.

  To avoid an increased risk of rash, the recommended initial dose and subsequent dose escalations of lamotrigine tablets should not be exceeded [see Boxed Warning].

  Conversion From Adjunctive Therapy With Carbamazepine, Phenytoin, Phenobarbital, or Primidone to Monotherapy With Lamotrigine Tablets: After achieving a dose of 500 mg/day of lamotrigine tablets according to the guidelines in Table 1, the concomitant AED should be withdrawn by 20% decrements each week over a 4-week period. The regimen for the withdrawal of the concomitant AED is based on experience gained in the controlled monotherapy clinical trial.

  Conversion from Adjunctive Therapy With Valproate to Monotherapy With Lamotrigine Tablets:

  The conversion regimen involves 4 steps outlined in Table 4.

  Table 4. Conversion From Adjunctive Therapy With Valproate to Monotherapy With Lamotrigine Tablets in Patients ≥16 Years of Age with Epilepsy
  Lamotrigine Tablets
  Valproate
  Step 1
  Achieve a dose of 200 mg/day according to
  guidelines in Table 1
  (if not already on 200 mg/day).
  Maintain previous stable dose.
  Step 2
  Maintain at 200 mg/day.
  Decrease to 500 mg/day by decrements no greater than
  500 mg/day/week and then maintain the dose of
  500 mg/day for 1 week.
  Step 3
  Increase to 300 mg/day and maintain for 1 week.
  Simultaneously decrease to
  250 mg/day and maintain for 1 week.
  Step 4
  Increase by 100 mg/day every
  week to achieve maintenance dose of 500 mg/day.
  Discontinue.
  

  Conversion from Adjunctive Therapy With AEDs Other Than Carbamazepine, Phenytoin, Phenobarbital, Primidone, or Valproate to Monotherapy With Lamotrigine Tablets: No specific dosing guidelines can be provided for conversion to monotherapy with lamotrigine tablets with AEDs other than carbamazepine, phenobarbital, phenytoin, primidone, or valproate.

   

  The goal of maintenance treatment with lamotrigine tablets is to delay the time to occurrence of mood episodes (depression, mania, hypomania, mixed episodes) in patients treated for acute mood episodes with standard therapy. The target dose of lamotrigine tablets is 200 mg/day (100 mg/day in patients taking valproate, which decreases the apparent clearance of lamotrigine, and 400 mg/day in patients not taking valproate and taking either carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin that increase the apparent clearance of lamotrigine). In the clinical trials, doses up to 400 mg/day as monotherapy were evaluated; however, no additional benefit was seen at 400 mg/day compared with 200 mg/day [see Clinical Studies (14.2) ]. Accordingly, doses above 200 mg/day are not recommended. Treatment with lamotrigine tablets is introduced, based on concurrent medications, according to the regimen outlined in Table 5. If other psychotropic medications are withdrawn following stabilization, the dose of lamotrigine tablets should be adjusted. For patients discontinuing valproate, the dose of lamotrigine tablets should be doubled over a 2-week period in equal weekly increments (see Table 6). For patients discontinuing carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin that induce lamotrigine glucuronidation, the dose of lamotrigine tablets should remain constant for the first week and then should be decreased by half over a 2-week period in equal weekly decrements (see Table 6). The dose of lamotrigine tablets may then be further adjusted to the target dose (200 mg) as clinically indicated.

  If other drugs are subsequently introduced, the dose of lamotrigine tablets may need to be adjusted. In particular, the introduction of valproate requires reduction in the dose of lamotrigine tablets [see Drug Interactions (7) , Clinical Pharmacology (12.3) ].

  To avoid an increased risk of rash, the recommended initial dose and subsequent dose escalations of lamotrigine tablets should not be exceeded [see Boxed Warning ].

  Table 5. Escalation Regimen for Lamotrigine Tablets for Patients With Bipolar Disorder
  For Patients TAKING 
  Valproatea
  For Patients NOT TAKING 
  Carbamazepine, Phenytoin, Phenobarbital, 
  Primidoneb, or Valproatea
  For Patients TAKING 
  Carbamazepine, Phenytoin,
  Phenobarbital, or Primidoneb and NOT TAKING 
  Valproatea
  Weeks 1 and 2
  25 mg every 
  other day
  25 mg daily
  50 mg daily
  Weeks 3 and 4
  25 mg daily
  50 mg daily
  100 mg daily, in divided doses
  Week 5
  50 mg daily
  100 mg daily
  200 mg daily, in divided doses
  Week 6
  100 mg daily
  200 mg daily
  300 mg daily, in divided doses
  Week 7
  100 mg daily
  200 mg daily
  up to 400 mg daily, in divided doses
  

  a Valproate has been shown to inhibit glucuronidation and decrease the apparent clearance of lamotrigine [see Drug Interactions (7), Clinical Pharmacology (12.3)].

  
  

  b These drugs induce lamotrigine glucuronidation and increase clearance [see Drug Interactions (7), Clinical Pharmacology (12.3)]. Other drugs which have similar effects include estrogen-containing oral contraceptives [see Drug Interactions (7), Clinical Pharmacology (12.3)]. Dosing recommendations for oral contraceptives can be found in General Dosing Considerations [see Dosage and Administration (2.1)]. Patients on rifampin, or other drugs that induce lamotrigine glucuronidation and increase clearance, should follow the same dosing titration/maintenance regimen as that used with anticonvulsants that have this effect.

  Table 6. Dosage Adjustments to Lamotrigine Tablets for Patients With Bipolar Disorder Following Discontinuation of Psychotropic Medications
  Discontinuation of Psychotropic Drugs 
  (excluding Carbamazepine, Phenytoin, 
  Phenobarbital, Primidoneb, or 
  Valproatea)
  After Discontinuation of 
  Valproatea
  After Discontinuation of 
  Carbamazepine, Phenytoin, 
  Phenobarbital, or Primidoneb
  
  
  Current dose of lamotrigine tablets
  (mg/day)
  100
  Current dose of lamotrigine tablets
  (mg/day)
  400
  Week 1
  Maintain current dose of lamotrigine tablets
  150
  400
  Week 2
  Maintain current dose of lamotrigine tablets
  200
  300
  Week 3 onward
  Maintain current dose of lamotrigine tablets
  200
  200
  

  The benefit of continuing treatment in patients who had been stabilized in an 8- to 16-week open-label phase with lamotrigine tablets was established in two randomized, placebo-controlled clinical maintenance trials [see Clinical Studies (14.2) ]. However, the optimal duration of treatment with lamotrigine tablets has not been established. Thus, patients should be periodically reassessed to determine the need for maintenance treatment.

   

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  2.1 General Dosing Considerations

  Rash

  There are suggestions, yet to be proven, that the risk of severe, potentially life-threatening rash may be increased by (1) coadministration of lamotrigine with valproate, (2) exceeding the recommended initial dose of lamotrigine, or (3) exceeding the recommended dose escalation for lamotrigine. However, cases have occurred in the absence of these factors [see BOXED WARNING]. Therefore, it is important that the dosing recommendations be followed closely.

  The risk of nonserious rash may be increased when the recommended initial dose and/or the rate of dose escalation of lamotrigine is exceeded and in patients with a history of allergy or rash to other AEDs.

  It is recommended that lamotrigine not be restarted in patients who discontinued due to rash associated with prior treatment with lamotrigine, unless the potential benefits clearly outweigh the risks. If the decision is made to restart a patient who has discontinued lamotrigine, the need to restart with the initial dosing recommendations should be assessed. The greater the interval of time since the previous dose, the greater consideration should be given to restarting with the initial dosing recommendations. If a patient has discontinued lamotrigine for a period of more than 5 half-lives, it is recommended that initial dosing recommendations and guidelines be followed. The half-life of lamotrigine is affected by other concomitant medications [see CLINICAL PHARMACOLOGY (12.3)].

  Lamotrigine Added to Drugs Known to Induce or Inhibit Glucuronidation

  Drugs other than those listed in the Clinical Pharmacology section [see CLINICAL PHARMACOLOGY (12.3)] have not been systematically evaluated in combination with lamotrigine. Because lamotrigine is metabolized predominantly by glucuronic acid conjugation, drugs that are known to induce or inhibit glucuronidation may affect the apparent clearance of lamotrigine and doses of lamotrigine may require adjustment based on clinical response.

  Target Plasma Levels for Patients with Epilepsy or Bipolar Disorder

  A therapeutic plasma concentration range has not been established for lamotrigine. Dosing of lamotrigine should be based on therapeutic response [see CLINICAL PHARMACOLOGY (12.3)].

  Women Taking Estrogen-Containing Oral Contraceptives

  Starting Lamotrigine in Women Taking Estrogen-Containing Oral Contraceptives

  Although estrogen-containing oral contraceptives have been shown to increase the clearance of lamotrigine [see CLINICAL PHARMACOLOGY (12.3)], no adjustments to the recommended dose-escalation guidelines for lamotrigine should be necessary solely based on the use of estrogen-containing oral contraceptives. Therefore, dose escalation should follow the recommended guidelines for initiating adjunctive therapy with lamotrigine based on the concomitant AED or other concomitant medications (see Table 1 or Table 5). See below for adjustments to maintenance doses of lamotrigine in women taking estrogen-containing oral contraceptives.

  Adjustments to the Maintenance Dose of Lamotrigine in Women Taking Estrogen-Containing Oral Contraceptives

  (1) Taking Estrogen-Containing Oral Contraceptives

  For women not taking carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin that induce lamotrigine glucuronidation [see DRUG INTERACTIONS (7), CLINICAL PHARMACOLOGY (12.3)], the maintenance dose of lamotrigine will in most cases need to be increased, by as much as 2-fold over the recommended target maintenance dose, in order to maintain a consistent lamotrigine plasma level [see CLINICAL PHARMACOLOGY (12.3)].

  (2) Starting Estrogen-Containing Oral Contraceptives

  In women taking a stable dose of lamotrigine and not taking carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin that induce lamotrigine glucuronidation [see DRUG INTERACTIONS (7), CLINICAL PHARMACOLOGY (12.3)], the maintenance dose will in most cases need to be increased by as much as 2-fold in order to maintain a consistent lamotrigine plasma level. The dose increases should begin at the same time that the oral contraceptive is introduced and continue, based on clinical response, no more rapidly than 50 to 100 mg/day every week. Dose increases should not exceed the recommended rate (see Table 1 or Table 5) unless lamotrigine plasma levels or clinical response support larger increases. Gradual transient increases in lamotrigine plasma levels may occur during the week of inactive hormonal preparation ("pill-free" week), and these increases will be greater if dose increases are made in the days before or during the week of inactive hormonal preparation. Increased lamotrigine plasma levels could result in additional adverse reactions, such as dizziness, ataxia, and diplopia. If adverse reactions attributable to lamotrigine consistently occur during the "pill-free" week, dose adjustments to the overall maintenance dose may be necessary. Dose adjustments limited to the "pill-free" week are not recommended. For women taking lamotrigine in addition to carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin that induce lamotrigine glucuronidation [see DRUG INTERACTIONS (7), CLINICAL PHARMACOLOGY (12.3)], no adjustment to the dose of lamotrigine should be necessary.

  (3) Stopping Estrogen-Containing Oral Contraceptives

  For women not taking carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin that induce lamotrigine glucuronidation [see DRUG INTERACTIONS (7), CLINICAL PHARMACOLOGY (12.3)], the maintenance dose of lamotrigine will in most cases need to be decreased by as much as 50% in order to maintain a consistent lamotrigine plasma level. The decrease in dose of lamotrigine should not exceed 25% of the total daily dose per week over a 2-week period, unless clinical response or lamotrigine plasma levels indicate otherwise [see CLINICAL PHARMACOLOGY (12.3)]. For women taking lamotrigine in addition to carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin that induce lamotrigine glucuronidation [see DRUG INTERACTIONS (7), CLINICAL PHARMACOLOGY (12.3)], no adjustment to the dose of lamotrigine should be necessary.

  Women and Other Hormonal Contraceptive Preparations or Hormone Replacement Therapy

  The effect of other hormonal contraceptive preparations or hormone replacement therapy on the pharmacokinetics of lamotrigine has not been systematically evaluated. It has been reported that ethinylestradiol, not progestogens, increased the clearance of lamotrigine up to 2-fold, and the progestin-only pills had no effect on lamotrigine plasma levels. Therefore, adjustments to the dosage of lamotrigine in the presence of progestogens alone will likely not be needed.

  Patients with Hepatic Impairment

  Experience in patients with hepatic impairment is limited. Based on a clinical pharmacology study in 24 patients with mild, moderate, and severe liver impairment [see USE IN SPECIFIC POPULATIONS (8.6), CLINICAL PHARMACOLOGY (12.3)], the following general recommendations can be made. No dosage adjustment is needed in patients with mild liver impairment. Initial, escalation, and maintenance doses should generally be reduced by approximately 25% in patients with moderate and severe liver impairment without ascites and 50% in patients with severe liver impairment with ascites. Escalation and maintenance doses may be adjusted according to clinical response.

  Patients with Renal Impairment

  Initial doses of lamotrigine should be based on patients' concomitant medications (see Tables 1 to 3 or Table 5); reduced maintenance doses may be effective for patients with significant renal impairment [see USE IN SPECIFIC POPULATIONS (8.6), CLINICAL PHARMACOLOGY (12.3)]. Few patients with severe renal impairment have been evaluated during chronic treatment with lamotrigine. Because there is inadequate experience in this population, lamotrigine should be used with caution in these patients.

  Discontinuation Strategy

  Epilepsy

  For patients receiving lamotrigine in combination with other AEDs, a re-evaluation of all AEDs in the regimen should be considered if a change in seizure control or an appearance or worsening of adverse reactions is observed.

  If a decision is made to discontinue therapy with lamotrigine, a step-wise reduction of dose over at least 2 weeks (approximately 50% per week) is recommended unless safety concerns require a more rapid withdrawal [see WARNINGS AND PRECAUTIONS (5.10)].

  Discontinuing carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin that induce lamotrigine glucuronidation should prolong the half-life of lamotrigine; discontinuing valproate should shorten the half-life of lamotrigine.

  Bipolar Disorder

  In the controlled clinical trials, there was no increase in the incidence, type, or severity of adverse reactions following abrupt termination of lamotrigine. In clinical trials in patients with Bipolar Disorder, 2 patients experienced seizures shortly after abrupt withdrawal of lamotrigine. However, there were confounding factors that may have contributed to the occurrence of seizures in these bipolar patients. Discontinuation of lamotrigine should involve a step-wise reduction of dose over at least 2 weeks (approximately 50% per week) unless safety concerns require a more rapid withdrawal [see WARNINGS AND PRECAUTIONS (5.10)].

  2.2 Epilepsy – Adjunctive Therapy

  This section provides specific dosing recommendations for patients greater than 12 years of age and patients 2 to 12 years of age. Within each of these age-groups, specific dosing recommendations are provided depending upon concomitant AED or other concomitant medications (Table 1 for patients greater than 12 years of age and Table 2 for patients 2 to 12 years of age). A weight-based dosing guide for patients 2 to 12 years of age on concomitant valproate is provided in Table 3.

  Patients Over 12 Years of Age

  Recommended dosing guidelines are summarized in Table 1.

  Table 1 Escalation Regimen for Lamotrigine in Patients Over 12 Years of Age With Epilepsy For Patients Taking Valproate*
  For Patients NOT TAKING Carbamazepine, Phenytoin, Phenobarbital, Primidone†, or Valproate*
  For Patients TAKING Carbamazepine, Phenytoin, Phenobarbital, or Primidone† and  NOT TAKING Valproate*
  * Valproate has been shown to inhibit glucuronidation and decrease the apparent clearance of lamotrigine [see DRUG INTERACTIONS ( 7), CLINICAL PHARMACOLOGY ( 12.3)]. † These drugs induce lamotrigine glucuronidation and increase clearance [see DRUG INTERACTIONS ( 7), CLINICAL PHARMACOLOGY ( 12.3)]. Other drugs which have similar effects include estrogen-containing oral contraceptives [see DRUG INTERACTIONS ( 7), CLINICAL PHARMACOLOGY ( 12.3)]. Dosing recommendations for oral contraceptives can be found in General Dosing Considerations [see DOSAGE AND ADMINISTRATION ( 2.1)]. Patients on rifampin, or other drugs that induce lamotrigine glucuronidation and increase clearance, should follow the same dosing titration/maintenance regimen as that used with anticonvulsants that have this effect.

  Weeks 1 and 2 
  

  25 mg every other day
  

  25 mg every day
  

  50 mg/day
  

  Weeks 3 and 4 
  

  25 mg every day
  

  50 mg/day
  

  100 mg/day
  (in 2 divided doses)
  

  Week 5 onwards to maintenance 
  

  Increase by 25 to 50 mg/day every 1 to 2 weeks
  

  Increase by 50 mg/day every 1 to 2 weeks
  

  Increase by 100 mg/day every 1 to 2 weeks.
  

  Usual Maintenance Dose 
  

  100 to 200 mg/day with valproate alone
  
  100 to 400 mg/day with valproate and other drugs that induce glucuronidation
  
  (in 1 or 2 divided doses)
  

  225 to 375 mg/day
  (in 2 divided doses)
  

  300 to 500 mg/day
  (in 2 divided doses)
  

  Patients 2 to 12 Years of Age

  Recommended dosing guidelines are summarized in Table 2.

  Smaller starting doses and slower dose escalations than those used in clinical trials are recommended because of the suggestion that the risk of rash may be decreased by smaller starting doses and slower dose escalations. Therefore, maintenance doses will take longer to reach in clinical practice than in clinical trials. It may take several weeks to months to achieve an individualized maintenance dose. Maintenance doses in patients weighing less than 30 kg, regardless of age or concomitant AED, may need to be increased as much as 50%, based on clinical response.

  Table 2 Escalation Regimen for Lamotrigine in Patients 2 to 12 Years of Age With Epilepsy For Patients TAKING Valproatea
  For Patients NOT TAKING Carbamazepine, Phenytoin, Phenobarbital, or Primidoneb, or Valproatea
  For Patients TAKING Carbamazepine, Phenytoin, Phenobarbital, or Primidoneb and  NOT TAKING Valproatea
  Note: Only whole tablets should be used for dosing. *Valproate has been shown to inhibit glucuronidation and decrease the apparent clearance of lamotrigine [see DRUG INTERACTIONS (7), Pharmacokinetics (12.3)]. bThese drugs induce lamotrigine glucuronidation and increase clearance [see DRUG INTERACTIONS (7), CLINICAL PHARMACOLOGY (12.3)]. Other drugs which have similar effects include estrogen-containing oral contraceptives [see DRUG INTERACTIONS (7), CLINICAL PHARMACOLOGY (12.3)]. Dosing recommendations for oral contraceptives can be found in General Dosing Considerations [see DOSAGE AND ADMINISTRATION (2.1)]. Patients on rifampin, or other drugs that induce lamotrigine glucuronidation and increase clearance, should follow the same dosing titration/maintenance regimen as that used with anticonvulsants that have this effect.

  Weeks 1 and 2 
  

  0.15 mg/kg/day
  in 1 or 2 divided doses, rounded down to the nearest
  whole tablet (see Table 3 for weight based dosing guide)
  

  0.3 mg/kg/day
  in 1 or 2 divided doses, rounded down to the nearest whole tablet
  

  0.6 mg/kg/day
  in 2 divided doses, rounded down to the nearest whole tablet
  

  Weeks 3 and 4 
  

  0.3 mg/kg/day
  in 1 or 2 divided doses, rounded down to the nearest
  whole tablet (see Table 3 for weight based dosing guide)
  

  0.6 mg/kg/day
  in 2 divided doses, rounded down to the nearest whole tablet
  

  1.2 mg/kg/day
  in 2 divided doses, rounded down to the nearest whole tablet
  

  Weeks 5 onwards to maintenance 
  

  The dose should be increased every 1 to 2 weeks as follows: calculate 0.3 mg/kg/day, round this amount down to the nearest whole tablet, and add this amount to the previously administered daily dose
  

  The dose should be increased every 1 to 2 weeks as follows: calculate 0.6 mg/kg/day, round this amount down to the nearest whole tablet, and add this amount to the previously administered daily dose
  

  The dose should be increased every 1 to 2 weeks as follows: calculate 1.2 mg/kg/day, round this amount down to the nearest whole tablet, and add this amount to the previously administered daily dose
  

  Usual Maintenance Dose 
  

  1 to 5 mg/kg/day (maximum 200 mg/day in 1 or 2 divided doses)
  1 to 3 mg/kg/day with valproate alone
  

  4.5 to 7.5 mg/kg/day
  (maximum 300 mg/day in 2 divided doses)
  

  5 to 15 mg/kg/day (maximum 400 mg/day in 2 divided doses)
  

  Maintenance dose in patients less than 30 kg 
  

  May need to be increased by as much as 50%,
  based on clinical response
  

  May need to be increased by as much as 50%,
  based on clinical response
  

  May need to be increased by as much as 50%,
  based on clinical response
  

  Table 3 The Initial Weight-Based Dosing Guide for Patients 2 to 12 Years Taking Valproate (Weeks 1 to 4) With Epilepsy

  If the patient’s weight is
  

  Give this daily dose, using the most appropriate combination of Lamotrigine 5 mg tablets
  

  Greater than 
  

  And less than 
  

  Weeks 1 and 2 
  

  Weeks 3 and 4 
  

  34.1 kg 
  

  40 kg 
  

  5 mg every day 
  

  10 mg every day 
  

  Usual Adjunctive Maintenance Dose for Epilepsy

  The usual maintenance doses identified in Tables 1 and 2 are derived from dosing regimens employed in the placebo-controlled adjunctive studies in which the efficacy of lamotrigine was established. In patients receiving multidrug regimens employing carbamazepine, phenytoin, phenobarbital, or primidone without valproate, maintenance doses of adjunctive lamotrigine as high as 700 mg/day have been used. In patients receiving valproate alone, maintenance doses of adjunctive lamotrigine as high as 200 mg/day have been used. The advantage of using doses above those recommended in Tables 1 through 4 has not been established in controlled trials.

  2.3 Epilepsy – Conversion from Adjunctive Therapy to Monotherapy

  The goal of the transition regimen is to effect the conversion to monotherapy with lamotrigine under conditions that ensure adequate seizure control while mitigating the risk of serious rash associated with the rapid titration of lamotrigine.

  The recommended maintenance dose of lamotrigine as monotherapy is 500 mg/day given in 2 divided doses.

  To avoid an increased risk of rash, the recommended initial dose and subsequent dose escalations of lamotrigine should not be exceeded [see BOXED WARNING].

  Conversion from Adjunctive Therapy with Carbamazepine, Phenytoin, Phenobarbital, or Primidone to Monotherapy with Lamotrigine

  After achieving a dose of 500 mg/day of lamotrigine according to the guidelines in Table 1, the concomitant AED should be withdrawn by 20% decrements each week over a 4-week period. The regimen for the withdrawal of the concomitant AED is based on experience gained in the controlled monotherapy clinical trial.

  Conversion from Adjunctive Therapy with Valproate to Monotherapy with Lamotrigine

  The conversion regimen involves 4 steps outlined in Table 4.

  Table 4 Conversion from Adjunctive Therapy With Valproate to Monotherapy With Lamotrigine in Patients ≥16 Years of Age With Epilepsy

  Lamotrigine
  

  Valproate 
  

  Step 1 
  

  Achieve a dose of 200 mg/day according to 
  guidelines in Table 1 (if not already on 200 mg/day). 
  

  Maintain previous stable dose. 
  

  Step 2 
  

  Maintain at 200 mg/day. 
  

  Decrease to 500 mg/day by decrements no greater than 500 mg/day/week and 
  then maintain the dose of 500 mg/day for 1 week. 
  

  Step 3 
  

  Increase to 300 mg/day and maintain for 1 week. 
  

  Simultaneously decrease to 250 mg/day and maintain for 1 week. 
  

  Step 4 
  

  Increase by 100 mg/day every week to achieve maintenance dose of 500 mg/day. 
  

  Discontinue. 
  

  Conversion from Adjunctive Therapy with AEDs Other Than Carbamazepine, Phenytoin, Phenobarbital, Primidone, or Valproate to Monotherapy with Lamotrigine

  No specific dosing guidelines can be provided for conversion to monotherapy with lamotrigine with AEDs other than carbamazepine, phenobarbital, phenytoin, primidone, or valproate.

  2.4 Bipolar Disorder

  The goal of maintenance treatment with lamotrigine is to delay the time to occurrence of mood episodes (depression, mania, hypomania, mixed episodes) in patients treated for acute mood episodes with standard therapy. The target dose of lamotrigine is 200 mg/day (100 mg/day in patients taking valproate, which decreases the apparent clearance of lamotrigine, and 400 mg/day in patients not taking valproate and taking either carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin  that increase the apparent clearance of lamotrigine). In the clinical trials, doses up to 400 mg/day as monotherapy were evaluated; however, no additional benefit was seen at 400 mg/day compared with 200 mg/day [see Clinical Studies (14.2)]. Accordingly, doses above 200 mg/day are not recommended. Treatment with lamotrigine is introduced, based on concurrent medications, according to the regimen outlined in Table 5. If other psychotropic medications are withdrawn following stabilization, the dose of lamotrigine should be adjusted. For patients discontinuing valproate, the dose of lamotrigine should be doubled over a 2-week period in equal weekly increments (see Table 6). For patients discontinuing carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin that induce lamotrigine glucuronidation, the dose of lamotrigine should remain constant for the first week and then should be decreased by half over a 2-week period in equal weekly decrements (see Table 6). The dose of lamotrigine may then be further adjusted to the target dose (200 mg) as clinically indicated.

  If other drugs are subsequently introduced, the dose of lamotrigine may need to be adjusted. In particular, the introduction of valproate requires reduction in the dose of lamotrigine [see DRUG INTERACTIONS (7), CLINICAL PHARMACOLOGY (12.3)].

  To avoid an increased risk of rash, the recommended initial dose and subsequent dose escalations of lamotrigine should not be exceeded [see BOXED WARNING].

  Table 5 Escalation Regimen for Lamotrigine for Patients With Bipolar Disorder *  Valproate has been shown to inhibit glucuronidation and decrease the apparent clearance of  lamotrigine [see DRUG INTERACTIONS ( 7), CLINICAL PHARMACOLOGY ( 12.3)]. †  These drugs induce lamotrigine glucuronidation and increase clearance [see DRUG INTERACTIONS  (7), CLINICAL PHARMACOLOGY ( 12.3)]. Other drugs which have similar effects include estrogen containing oral contraceptives [see DRUG INTERACTIONS (7), CLINICAL PHARMACOLOGY ( 12.3)]. Dosing recommendations for oral contraceptives can be found in General Dosing Considerations [see DOSAGE AND ADMINISTRATION ( 2.1)]. Patients on rifampin, or other drugs that induce lamotrigine glucuronidation and increase clearance, should follow the same dosing titration/maintenance regimen as that used with anticonvulsants that have this effect.

  For Patients TAKING Valproate*
  

  For Patients NOT TAKING Carbamazepine, Phenytoin, Phenobarbital, Primidone†, or Valproate*
  

  For Patients TAKING Carbamazepine, Phenytoin, Phenobarbital, or Primidone† and NOT TAKING Valproate*
  

  Weeks 1 and 2 
  

  25 mg every other day
  

  25 mg daily
  

  50 mg daily
  

  Weeks 3 and 4 
  

  25 mg daily
  

  50 mg daily
  

  100 mg daily, in divided doses
  

  Week 5 
  

  50 mg daily
  

  100 mg daily
  

  200 mg daily, in divided doses
  

  Week 6 
  

  100 mg daily
  

  200 mg daily
  

  300 mg daily, in divided doses
  

  Week 7 
  

  100 mg daily
  

  200 mg daily
  

  up to 400 mg daily, in divided doses
  

  Table 6 Dosage Adjustments to Lamotrigine for Patients With Bipolar Disorder Following Discontinuation of Psychotropic Medications * These drugs induce lamotrigine glucuronidation and increase clearance [see DRUG INTERACTIONS ( 7), CLINICAL PHARMACOLOGY ( 12.3)]. Other drugs which have similar effects include estrogen containing oral contraceptives [see DRUG INTERACTIONS ( 7), CLINICAL PHARMACOLOGY ( 12.3)]. Dosing recommendations for oral contraceptives can be found in General Dosing Considerations [see DOSAGE AND ADMINISTRATION ( 2.1)]. Patients on rifampin, or other drugs that induce lamotrigine glucuronidation and increase clearance, should follow the same dosing titration/maintenance regimen as that used with anticonvulsants that have this effect. † Valproate has been shown to inhibit glucuronidation and decrease the apparent clearance of lamotrigine [see DRUG INTERACTIONS ( 7), CLINICAL PHARMACOLOGY ( 12.3)].

  Discontinuation of Psychotropic Drugs (excluding Carbamazepine, Phenytoin, Phenobarbital, Primidone*, or Valproate†)
  

  After Discontinuation of Valproate†
  

  After Discontinuation of Carbamazepine, Phenytoin, Phenobarbital, or Primidone*
  

  Current dose of Lamotrigine (mg/day)
  100
  

  Current dose of Lamotrigine (mg/day)
  400
  

  Week 1 
  

  Maintain current dose of Lamotrigine
  

  150
  

  400
  

  Week 2 
  

  Maintain current dose of Lamotrigine
  

  200
  

  300
  

  Week 3 onward 
  

  Maintain current dose of Lamotrigine
  

  200
  

  200
  

  The benefit of continuing treatment in patients who had been stabilized in an 8- to 16-week open-label phase with lamotrigine was established in 2 randomized, placebo-controlled clinical maintenance trials [see Clinical Studies (14.2)]. However, the optimal duration of treatment with lamotrigine has not been established. Thus, patients should be periodically reassessed to determine the need for maintenance treatment.

  2.5 Administration of Lamotrigine Tablets (Chewable, Dispersible)

  Lamotrigine Tablets (Chewable, Dispersible) may be swallowed whole, chewed, or dispersed in water or diluted fruit juice. If the tablets are chewed, consume a small amount of water or diluted fruit juice to aid in swallowing.

  To disperse Lamotrigine Tablets (Chewable, Dispersible), add the tablets to a small amount of liquid (1 teaspoon, or enough to cover the medication). Approximately 1 minute later, when the tablets are completely dispersed, swirl the solution and consume the entire quantity immediately. No attempt should be made to administer partial quantities of the dispersed tablets.

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  2.1 General Dosing Considerations

  Rash: There are suggestions, yet to be proven, that the risk of severe, potentially life-threatening rash may be increased by (1) coadministration of lamotrigine  with valproate, (2) exceeding the recommended initial dose of lamotrigine, or (3) exceeding the recommended dose escalation for lamotrigine. However, cases have occurred in the absence of these factors [see Boxed Warning]. Therefore, it is important that the dosing recommendations be followed closely.

  The risk of nonserious rash may be increased when the recommended initial dose and/or the rate of dose escalation of lamotrigine  is exceeded and in patients with a history of allergy or rash to other AEDs.

  It is recommended that lamotrigine  not be restarted in patients who discontinued due to rash associated with prior treatment with lamotrigine, unless the potential benefits clearly outweigh the risks. If the decision is made to restart a patient who has discontinued lamotrigine, the need to restart with the initial dosing recommendations should be assessed. The greater the interval of time since the previous dose, the greater consideration should be given to restarting with the initial dosing recommendations. If a patient has discontinued lamotrigine for a period of more than 5 half-lives, it is recommended that initial dosing recommendations and guidelines be followed. The half-life of lamotrigine is affected by other concomitant medications [see Clinical Pharmacology (12.3)].

  Lamotrigine Added to Drugs Known to Induce or Inhibit Glucuronidation: Drugs other than those listed in the Clinical Pharmacology section [see Clinical Pharmacology (12.3)] have not been systematically evaluated in combination with lamotrigine. Because lamotrigine is metabolized predominantly by glucuronic acid conjugation, drugs that are known to induce or inhibit glucuronidation may affect the apparent clearance of lamotrigine and doses of lamotrigine  may require adjustment based on clinical response.

  Target Plasma Levels for Patients With Epilepsy or Bipolar Disorder: A therapeutic plasma concentration range has not been established for lamotrigine. Dosing of lamotrigine  should be based on therapeutic response [see Clinical Pharmacology (12.3)].

  Women Taking Estrogen-Containing Oral Contraceptives: Starting Lamotrigine in Women Taking Estrogen-Containing Oral Contraceptives: Although estrogen-containing oral contraceptives have been shown to increase the clearance of lamotrigine [see Clinical Pharmacology (12.3)], no adjustments to the recommended dose-escalation guidelines for lamotrigine  should be necessary solely based on the use of estrogen-containing oral contraceptives. Therefore, dose escalation should follow the recommended guidelines for initiating adjunctive therapy with lamotrigine  based on the concomitant AED or other concomitant medications (see Table 1 or Table 5). See below for adjustments to maintenance doses of lamotrigine  in women taking estrogen-containing oral contraceptives.

  Adjustments to the Maintenance Dose of Lamotrigine in Women Taking Estrogen-Containing Oral Contraceptives:

  (1) Taking Estrogen-Containing Oral Contraceptives: For women not taking carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin that induce lamotrigine glucuronidation [see Drug Interactions (7), Clinical Pharmacology (12.3)], the maintenance dose of lamotrigine  will in most cases need to be increased, by as much as 2-fold over the recommended target maintenance dose, in order to maintain a consistent lamotrigine plasma level [see Clinical Pharmacology (12.3)].

  (2) Starting Estrogen-Containing Oral Contraceptives: In women taking a stable dose of lamotrigine and not taking carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin that induce lamotrigine glucuronidation [see Drug Interactions (7), Clinical Pharmacology (12.3)], the maintenance dose will in most cases need to be increased by as much as 2-fold in order to maintain a consistent lamotrigine plasma level. The dose increases should begin at the same time that the oral contraceptive is introduced and continue, based on clinical response, no more rapidly than 50 to 100 mg/day every week. Dose increases should not exceed the recommended rate (see Table 1 or Table 5) unless lamotrigine plasma levels or clinical response support larger increases. Gradual transient increases in lamotrigine plasma levels may occur during the week of inactive hormonal preparation (“pill-free” week), and these increases will be greater if dose increases are made in the days before or during the week of inactive hormonal preparation. Increased lamotrigine plasma levels could result in additional adverse reactions, such as dizziness, ataxia, and diplopia. If adverse reactions attributable to lamotrigine consistently occur during the “pill-free” week, dose adjustments to the overall maintenance dose may be necessary. Dose adjustments limited to the “pill-free” week are not recommended. For women taking lamotrigine in addition to carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin that induce lamotrigine glucuronidation [see Drug Interactions (7), Clinical Pharmacology (12.3)], no adjustment to the dose of lamotrigine should be necessary.

  (3) Stopping Estrogen-Containing Oral Contraceptives: For women not taking carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin that induce lamotrigine glucuronidation [see Drug Interactions (7), Clinical Pharmacology (12.3)], the maintenance dose of lamotrigine will in most cases need to be decreased by as much as 50% in order to maintain a consistent lamotrigine plasma level. The decrease in dose of lamotrigine should not exceed 25% of the total daily dose per week over a 2-week period, unless clinical response or lamotrigine plasma levels indicate otherwise [see Clinical Pharmacology (12.3)]. For women taking lamotrigine in addition to carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin that induce lamotrigine glucuronidation [see Drug Interactions (7), Clinical Pharmacology (12.3)], no adjustment to the dose of lamotrigine should be necessary.

  Women and Other Hormonal Contraceptive Preparations or Hormone Replacement Therapy: The effect of other hormonal contraceptive preparations or hormone replacement therapy on the pharmacokinetics of lamotrigine has not been systematically evaluated. It has been reported that ethinylestradiol, not progestogens, increased the clearance of lamotrigine up to 2-fold, and the progestin-only pills had no effect on lamotrigine plasma levels. Therefore, adjustments to the dosage of lamotrigine  in the presence of progestogens alone will likely not be needed.

  Patients With Hepatic Impairment: Experience in patients with hepatic impairment is limited. Based on a clinical pharmacology study in 24 patients with mild, moderate, and severe liver impairment [see Use in Specific Populations (8.6), Clinical Pharmacology (12.3)], the following general recommendations can be made. No dosage adjustment is needed in patients with mild liver impairment. Initial, escalation, and maintenance doses should generally be reduced by approximately 25% in patients with moderate and severe liver impairment without ascites and 50% in patients with severe liver impairment with ascites. Escalation and maintenance doses may be adjusted according to clinical response.

  Patients With Renal Impairment: Initial doses of lamotrigine should be based on patients' concomitant medications (see Tables 1-3 or Table 5); reduced maintenance doses may be effective for patients with significant renal impairment [see Use in Specific Populations (8.7), Clinical Pharmacology (12.3)]. Few patients with severe renal impairment have been evaluated during chronic treatment with lamotrigine. Because there is inadequate experience in this population, lamotrigine should be used with caution in these patients.

  Discontinuation Strategy: Epilepsy:  For patients receiving lamotrigine  in combination with other AEDs, a reevaluation of all AEDs in the regimen should be considered if a change in seizure control or an appearance or worsening of adverse reactions is observed.

  If a decision is made to discontinue therapy with lamotrigine, a step-wise reduction of dose over at least 2 weeks (approximately 50% per week) is recommended unless safety concerns require a more rapid withdrawal [see Warnings and Precautions (5.9)].

  Discontinuing carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin that induce lamotrigine glucuronidation  should prolong the half-life of lamotrigine; discontinuing valproate should shorten the half-life of lamotrigine.

  Bipolar Disorder: In the controlled clinical trials, there was no increase in the incidence, type, or severity of adverse reactions following abrupt termination of lamotrigine. In clinical trials in patients with Bipolar Disorder, 2 patients experienced seizures shortly after abrupt withdrawal of lamotrigine. However, there were confounding factors that may have contributed to the occurrence of seizures in these bipolar patients. Discontinuation of lamotrigine should involve a step-wise reduction of dose over at least 2 weeks (approximately 50% per week) unless safety concerns require a more rapid withdrawal [see Warnings and Precautions (5.9)].

  2.2 Epilepsy - Adjunctive Therapy

  This section provides specific dosing recommendations for patients greater than 12 years of age and patients 2 to 12 years of age. Within each of these age-groups, specific dosing recommendations are provided depending upon concomitant AED or other concomitant medications (Table 1 for patients greater than 12 years of age and Table 2 for patients 2 to 12 years of age). A weight-based dosing guide for patients 2 to 12 years of age on concomitant valproate is provided in Table 3.

  Patients Over 12 Years of Age: Recommended dosing guidelines are summarized in Table 1.

  Table 1. Escalation Regimen for Lamotrigine in Patients Over 12 Years of Age With Epilepsy

   

  For Patients TAKING Valproate *

  For Patients NOT TAKING Carbamazepine, Phenytoin, Phenobarbital, Primidone† , or Valproate*

  For Patients TAKING Carbamazepine, Phenytoin, Phenobarbital, or Primidone† and NOT TAKING Valproate*

  Weeks 1 and 2

  25 mg every other day

  25 mg every day

  50 mg/day

  Weeks 3 and 4

  25 mg every day

  50 mg/day

  100 mg/day

  (in 2 divided doses)

  Week 5 onwards to maintenance

  Increase by 25 to 50 mg/day every 1 to 2 weeks

  Increase by 50 mg/day every 1 to 2 weeks

  Increase by 100 mg/day every 1 to 2 weeks.

  Usual maintenance dose

  100 to 200 mg/day with valproate alone

   

  100 to 400 mg/day with valproate and other drugs that induce glucuronidation

   

  (in 1 or 2 divided doses)

  225 to 375 mg/day

  (in 2 divided doses)

  300 to 500 mg/day

  (in 2 divided doses)

  *   Valproate has been shown to inhibit glucuronidation and decrease the apparent clearance of lamotrigine [see Drug Interactions (7), Clinical Pharmacology (12.3)].

  †    These drugs induce lamotrigine glucuronidation and increase clearance [see Drug Interactions (7), Clinical Pharmacology (12.3)]. Other drugs that have similar effects include estrogen-containing oral contraceptives [see Drug Interactions (7), Clinical Pharmacology (12.3)]. Dosing recommendations for oral contraceptives can be found in General Dosing Considerations [see Dosage and Administration (2.1)]. Patients on rifampin, or other drugs that induce lamotrigine glucuronidation and increase clearance, should follow the same dosing titration/maintenance regimen as that used with anticonvulsants that have this effect.

  Patients 2 to 12 Years of Age: Recommended dosing guidelines are summarized in Table 2.

  Smaller starting doses and slower dose escalations than those used in clinical trials are recommended because of the suggestion that the risk of rash may be decreased by smaller starting doses and slower dose escalations. Therefore, maintenance doses will take longer to reach in clinical practice than in clinical trials. It may take several weeks to months to achieve an individualized maintenance dose. Maintenance doses in patients weighing less than 30 kg, regardless of age or concomitant AED, may need to be increased as much as 50%, based on clinical response.

  The smallest available strength of lamotrigine tablets (chewable, dispersible) is 2 mg, and only whole tablets should be administered. If the calculated dose cannot be achieved using whole tablets, the dose should be rounded down to the nearest whole tablet [see How Supplied/Storage and Handling (16) and Medication Guide].

  Table 2. Escalation Regimen for Lamotrigine in Patients 2 to 12 Years of Age With Epilepsy

   

  For Patients TAKING Valproate *

  For Patients NOT TAKING Carbamazepine, Phenytoin, Phenobarbital, Primidone† ,  or Valproate*

  For Patients TAKING Carbamazepine, Phenytoin, Phenobarbital, or Primidone† and NOT TAKING Valproate*

  Weeks 1 and 2

   

  0.15 mg/kg/day

  in 1 or 2 divided doses, rounded down to the nearest whole tablet (see Table 3 for weight-based dosing guide)

  0.3 mg/kg/day

  in 1 or 2 divided doses, rounded down to the nearest whole tablet

  0.6 mg/kg/day

  in 2 divided doses, rounded down to the nearest whole tablet

  Weeks 3 and 4

   

  0.3 mg/kg/day

  in 1 or 2 divided doses, rounded down to the nearest whole tablet (see Table 3 for weight-based dosing guide)

  0.6 mg/kg/day

  in 2 divided doses, rounded down to the nearest whole tablet

  1.2 mg/kg/day

  in 2 divided doses, rounded down to the nearest whole tablet

  Week 5 onwards to maintenance

   

  The dose should be increased every 1 to 2 weeks as follows: calculate 0.3 mg/kg/day, round this amount down to the nearest whole tablet, and add this amount to the previously administered daily dose

  The dose should be increased every 1 to 2 weeks as follows: calculate 0.6 mg/kg/day, round this amount down to the nearest whole tablet, and add this amount to the previously administered daily dose

  The dose should be increased every 1 to 2 weeks as follows: calculate 1.2 mg/kg/day, round this amount down to the nearest whole tablet, and add this amount to the previously administered daily dose

  Usual maintenance dose

   

  1 to 5 mg/kg/day (maximum 200 mg/day in 1 or 2 divided doses)
  1 to 3 mg/kg/day with valproate alone

  4.5 to 7.5 mg/kg/day (maximum 300 mg/day in 2 divided doses)

  5 to 15 mg/kg/day (maximum 400 mg/day in 2 divided doses)

  Maintenance dose in patients less than 30 kg

   

  May need to be increased by as much as 50%, based on clinical response

  May need to be increased by as much as 50%, based on clinical response

  May need to be increased by as much as 50%, based on clinical response

  Note: Only whole tablets should be used for dosing.

  *    Valproate has been shown to inhibit glucuronidation and decrease the apparent clearance of lamotrigine [see Drug Interactions (7), Clinical Pharmacology (12.3)].
  †    These drugs induce lamotrigine glucuronidation and increase clearance [see Drug Interactions (7), Clinical Pharmacology (12.3)]. Other drugs that have similar effects include estrogen-containing oral contraceptives [see Drug Interactions (7), Clinical Pharmacology (12.3)]. Dosing recommendations for oral contraceptives can be found in General Dosing Considerations [see Dosage and Administration (2.1)]. Patients on rifampin, or other drugs that induce lamotrigine glucuronidation and increase clearance, should follow the same dosing titration/maintenance regimen as that used with anticonvulsants that have this effect.

  Table 3. The Initial Weight-Based Dosing Guide for Patients 2 to 12 Years of Age Taking Valproate (Weeks 1 to 4) With Epilepsy

  If the patient’s weight is

  Give this daily dose, using the most appropriate combination of lamotrigine 2-mg and 5-mg tablets

  Greater than

  And less than

  Weeks 1 and 2

  Weeks 3 and 4

  6.7 kg

  14 kg

  2 mg every other day

  2 mg every day

  14.1 kg

  27 kg

  2 mg every day

  4 mg every day

  27.1 kg

  34 kg

  4 mg every day

  8 mg every day

  34.1 kg

  40 kg

  5 mg every day

  10 mg every day

  Usual Adjunctive Maintenance Dose for Epilepsy: The usual maintenance doses identified in Tables 1 and 2 are derived from dosing regimens employed in the placebo-controlled adjunctive studies in which the efficacy of lamotrigine  was established. In patients receiving multidrug regimens employing carbamazepine, phenytoin, phenobarbital, or primidone without valproate, maintenance doses of adjunctive lamotrigine  as high as 700 mg/day have been used. In patients receiving valproate alone, maintenance doses of adjunctive lamotrigine  as high as 200 mg/day have been used. The advantage of using doses above those recommended in Tables 1 through 4 has not been established in controlled trials.

  2.3 Epilepsy – Conversion From Adjunctive Therapy to Monotherapy

  The goal of the transition regimen is to effect the conversion to monotherapy with lamotrigine  under conditions that ensure adequate seizure control while mitigating the risk of serious rash associated with the rapid titration of lamotrigine.

  The recommended maintenance dose of lamotrigine  as monotherapy is 500 mg/day given in 2 divided doses.

  To avoid an increased risk of rash, the recommended initial dose and subsequent dose escalations of lamotrigine  should not be exceeded [see Boxed Warning].

  Conversion From Adjunctive Therapy With Carbamazepine, Phenytoin, Phenobarbital, or Primidone to Monotherapy With Lamotrigine: After achieving a dose of 500 mg/day of lamotrigine  according to the guidelines in Table 1, the concomitant AED should be withdrawn by 20% decrements each week over a 4-week period. The regimen for the withdrawal of the concomitant AED is based on experience gained in the controlled monotherapy clinical trial.

  Conversion From Adjunctive Therapy With Valproate to Monotherapy With Lamotrigine: The conversion regimen involves 4 steps outlined in Table 4.

  Table 4. Conversion From Adjunctive Therapy With Valproate to Monotherapy With Lamotrigine in Patients ≥16 Years of Age With Epilepsy

   

  Lamotrigine

  Valproate

  Step 1

  Achieve a dose of 200 mg/day according to guidelines in Table 1 (if not already on 200 mg/day).

  Maintain previous stable dose.

  Step 2

  Maintain at 200 mg/day.

  Decrease to 500 mg/day by decrements no greater than 500 mg/day/week and then maintain the dose of 500 mg/day for 1 week.

  Step 3

  Increase to 300 mg/day and maintain for 1 week.

  Simultaneously decrease to 250 mg/day and maintain for 1 week.

  Step 4

  Increase by 100 mg/day every week to achieve maintenance dose of 500 mg/day.

  Discontinue.

  Conversion From Adjunctive Therapy With Antiepileptic Drugs Other Than Carbamazepine, Phenytoin, Phenobarbital, Primidone, or Valproate to Monotherapy With Lamotrigine: No specific dosing guidelines can be provided for conversion to monotherapy with lamotrigine with AEDs other than carbamazepine, phenobarbital, phenytoin, primidone, or valproate.

  2.4 Bipolar Disorder

  The goal of maintenance treatment with lamotrigine is to delay the time to occurrence of mood episodes (depression, mania, hypomania, mixed episodes) in patients treated for acute mood episodes with standard therapy. The target dose of lamotrigine is 200 mg/day (100 mg/day in patients taking valproate, which decreases the apparent clearance of lamotrigine, and 400 mg/day in patients not taking valproate and taking either carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin that increase the apparent clearance of lamotrigine). In the clinical trials, doses up to 400 mg/day as monotherapy were evaluated; however, no additional benefit was seen at 400 mg/day compared with 200 mg/day [see Clinical Studies (14.2)]. Accordingly, doses above 200 mg/day are not recommended. Treatment with lamotrigine is introduced, based on concurrent medications, according to the regimen outlined in Table 5. If other psychotropic medications are withdrawn following stabilization, the dose of lamotrigine should be adjusted. For patients discontinuing valproate, the dose of lamotrigine should be doubled over a 2-week period in equal weekly increments (see Table 6). For patients discontinuing carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin that induce lamotrigine glucuronidation, the dose of lamotrigine should remain constant for the first week and then should be decreased by half over a 2-week period in equal weekly decrements (see Table 6). The dose of lamotrigine may then be further adjusted to the target dose (200 mg) as clinically indicated.

  If other drugs are subsequently introduced, the dose of lamotrigine may need to be adjusted. In particular, the introduction of valproate requires reduction in the dose of lamotrigine [see Drug Interactions (7), Clinical Pharmacology (12.3)].

  To avoid an increased risk of rash, the recommended initial dose and subsequent dose escalations of lamotrigine should not be exceeded [see Boxed Warning].

  Table 5. Escalation Regimen for Lamotrigine for Patients With Bipolar Disorder

   

  For Patients TAKING Valproate‡

   

  For Patients NOT TAKING Carbamazepine, Phenytoin, Phenobarbital, Primidone† or Valproate‡

  For Patients TAKING Carbamazepine, Phenytoin, Phenobarbital or Primidone † and NOT TAKING Valproate‡

  Weeks 1 and 2

  25 mg every other day

  25 mg daily

  50 mg daily

  Weeks 3 and 4

  25 mg daily

  50 mg daily

  100 mg daily, in divided doses

  Week 5

  50 mg daily

  100 mg daily

  200 mg daily, in divided doses

  Week 6

  100 mg daily

  200 mg daily

  300 mg daily, in divided doses

  Week 7

  100 mg daily

  200 mg daily

  up to 400 mg daily, in divided doses

  
  

  ‡  Valproate has been shown to inhibit glucuronidation and decrease the apparent clearance of lamotrigine [see Drug Interactions (7), Clinical Pharmacology (12.3)].

  † These drugs induce lamotrigine glucuronidation and increase clearance [see Drug Interactions (7), Clinical Pharmacology (12.3)].  Other drugs that have similar effects include estrogen-containing oral contraceptives [see Drug Interactions (7), Clinical Pharmacology (12.3)]. Dosing recommendations for oral contraceptives can be found in General Dosing Considerations [see Dosage and Administration (2.1)]. Patients on rifampin, or other drugs that induce lamotrigine glucuronidation and increase clearance, should follow the same dosing titration/maintenance regimen as that used with anticonvulsants that have this effect.

  Table 6. Dosage Adjustments to Lamotrigine for Patients With Bipolar Disorder Following Discontinuation of Psychotropic Medications

   

   

  Discontinuation of Psychotropic Drugs (excluding Carbamazepine,
  Phenytoin, Phenobarbital, Primidone,  or Valproate‡)

  After Discontinuation of Valproate‡

  After Discontinuation of Carbamazepine, Phenytoin, Phenobarbital,or  Primidone†

  Current dose of Lamotrigine
  (mg/day)   100                 

  Current dose of Lamotrigine 
  (mg/day) 400                             

  Week 1

  Maintain current dose of Lamotrigine

  150

  400

  Week 2

  Maintain current dose of Lamotrigine

  200

  300

  Week 3 onward

  Maintain current dose of Lamotrigine

  200

  200

  ‡  Valproate has been shown to inhibit glucuronidation and decrease the apparent clearance of lamotrigine [see Drug Interactions (7), Clinical Pharmacology (12.3)].

  † These drugs induce lamotrigine glucuronidation and increase clearance [see Drug Interactions (7), Clinical Pharmacology (12.3)].  Other drugs that have similar effects include estrogen-containing oral contraceptives [see Drug Interactions (7), Clinical Pharmacology (12.3)]. Dosing recommendations for oral contraceptives can be found in General Dosing Considerations [see Dosage and Administration (2.1)]. Patients on rifampin, or other drugs that induce lamotrigine glucuronidation and increase clearance, should follow the same dosing titration/maintenance regimen as that used with anticonvulsants that have this effect.

  The benefit of continuing treatment in patients who had been stabilized in an 8- to 16-week open-label phase with lamotrigine was established in 2 randomized, placebo-controlled clinical maintenance trials [see Clinical Studies (14.2 )]. However, the optimal duration of treatment with lamotrigine has not been established. Thus, patients should be periodically reassessed to determine the need for maintenance treatment.

  2.5 Administration of Lamotrigine Tablets (Chewable, Dispersible)

  Lamotrigine tablets (chewable, dispersible) may be swallowed whole, chewed, or dispersed in water or diluted fruit juice. If the tablets are chewed, consume a small amount of water or diluted fruit juice to aid in swallowing.

  To disperse lamotrigine tablets (chewable, dispersible), add the tablets to a small amount of liquid (1 teaspoon, or enough to cover the medication). Approximately 1 minute later, when the tablets are completely dispersed, swirl the solution and consume the entire quantity immediately. No attempt should be made to administer partial quantities of the dispersed tablets.

  2.1 General Dosing Considerations

  Rash: There are suggestions, yet to be proven, that the risk of severe, potentially life-threatening rash may be increased by (1) coadministration of lamotrigine  with valproate, (2) exceeding the recommended initial dose of lamotrigine, or (3) exceeding the recommended dose escalation for lamotrigine. However, cases have occurred in the absence of these factors [see Boxed Warning]. Therefore, it is important that the dosing recommendations be followed closely.

  The risk of nonserious rash may be increased when the recommended initial dose and/or the rate of dose escalation of lamotrigine  is exceeded and in patients with a history of allergy or rash to other AEDs.

  It is recommended that lamotrigine  not be restarted in patients who discontinued due to rash associated with prior treatment with lamotrigine, unless the potential benefits clearly outweigh the risks. If the decision is made to restart a patient who has discontinued lamotrigine, the need to restart with the initial dosing recommendations should be assessed. The greater the interval of time since the previous dose, the greater consideration should be given to restarting with the initial dosing recommendations. If a patient has discontinued lamotrigine for a period of more than 5 half-lives, it is recommended that initial dosing recommendations and guidelines be followed. The half-life of lamotrigine is affected by other concomitant medications [see Clinical Pharmacology (12.3)].

  Lamotrigine Added to Drugs Known to Induce or Inhibit Glucuronidation: Drugs other than those listed in the Clinical Pharmacology section [see Clinical Pharmacology (12.3)] have not been systematically evaluated in combination with lamotrigine. Because lamotrigine is metabolized predominantly by glucuronic acid conjugation, drugs that are known to induce or inhibit glucuronidation may affect the apparent clearance of lamotrigine and doses of lamotrigine  may require adjustment based on clinical response.

  Target Plasma Levels for Patients With Epilepsy or Bipolar Disorder: A therapeutic plasma concentration range has not been established for lamotrigine. Dosing of lamotrigine  should be based on therapeutic response [see Clinical Pharmacology (12.3)].

  Women Taking Estrogen-Containing Oral Contraceptives: Starting Lamotrigine in Women Taking Estrogen-Containing Oral Contraceptives: Although estrogen-containing oral contraceptives have been shown to increase the clearance of lamotrigine [see Clinical Pharmacology (12.3)], no adjustments to the recommended dose-escalation guidelines for lamotrigine  should be necessary solely based on the use of estrogen-containing oral contraceptives. Therefore, dose escalation should follow the recommended guidelines for initiating adjunctive therapy with lamotrigine  based on the concomitant AED or other concomitant medications (see Table 1 or Table 5). See below for adjustments to maintenance doses of lamotrigine  in women taking estrogen-containing oral contraceptives.

  Adjustments to the Maintenance Dose of Lamotrigine in Women Taking Estrogen-Containing Oral Contraceptives:

  (1) Taking Estrogen-Containing Oral Contraceptives: For women not taking carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin that induce lamotrigine glucuronidation [see Drug Interactions (7), Clinical Pharmacology (12.3)], the maintenance dose of lamotrigine  will in most cases need to be increased, by as much as 2-fold over the recommended target maintenance dose, in order to maintain a consistent lamotrigine plasma level [see Clinical Pharmacology (12.3)].

  (2) Starting Estrogen-Containing Oral Contraceptives: In women taking a stable dose of lamotrigine and not taking carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin that induce lamotrigine glucuronidation [see Drug Interactions (7), Clinical Pharmacology (12.3)], the maintenance dose will in most cases need to be increased by as much as 2-fold in order to maintain a consistent lamotrigine plasma level. The dose increases should begin at the same time that the oral contraceptive is introduced and continue, based on clinical response, no more rapidly than 50 to 100 mg/day every week. Dose increases should not exceed the recommended rate (see Table 1 or Table 5) unless lamotrigine plasma levels or clinical response support larger increases. Gradual transient increases in lamotrigine plasma levels may occur during the week of inactive hormonal preparation (“pill-free” week), and these increases will be greater if dose increases are made in the days before or during the week of inactive hormonal preparation. Increased lamotrigine plasma levels could result in additional adverse reactions, such as dizziness, ataxia, and diplopia. If adverse reactions attributable to lamotrigine consistently occur during the “pill-free” week, dose adjustments to the overall maintenance dose may be necessary. Dose adjustments limited to the “pill-free” week are not recommended. For women taking lamotrigine in addition to carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin that induce lamotrigine glucuronidation [see Drug Interactions (7), Clinical Pharmacology (12.3)], no adjustment to the dose of lamotrigine should be necessary.

  (3) Stopping Estrogen-Containing Oral Contraceptives: For women not taking carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin that induce lamotrigine glucuronidation [see Drug Interactions (7), Clinical Pharmacology (12.3)], the maintenance dose of lamotrigine will in most cases need to be decreased by as much as 50% in order to maintain a consistent lamotrigine plasma level. The decrease in dose of lamotrigine should not exceed 25% of the total daily dose per week over a 2-week period, unless clinical response or lamotrigine plasma levels indicate otherwise [see Clinical Pharmacology (12.3)]. For women taking lamotrigine in addition to carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin that induce lamotrigine glucuronidation [see Drug Interactions (7), Clinical Pharmacology (12.3)], no adjustment to the dose of lamotrigine should be necessary.

  Women and Other Hormonal Contraceptive Preparations or Hormone Replacement Therapy: The effect of other hormonal contraceptive preparations or hormone replacement therapy on the pharmacokinetics of lamotrigine has not been systematically evaluated. It has been reported that ethinylestradiol, not progestogens, increased the clearance of lamotrigine up to 2-fold, and the progestin-only pills had no effect on lamotrigine plasma levels. Therefore, adjustments to the dosage of lamotrigine  in the presence of progestogens alone will likely not be needed.

  Patients With Hepatic Impairment: Experience in patients with hepatic impairment is limited. Based on a clinical pharmacology study in 24 patients with mild, moderate, and severe liver impairment [see Use in Specific Populations (8.6), Clinical Pharmacology (12.3)], the following general recommendations can be made. No dosage adjustment is needed in patients with mild liver impairment. Initial, escalation, and maintenance doses should generally be reduced by approximately 25% in patients with moderate and severe liver impairment without ascites and 50% in patients with severe liver impairment with ascites. Escalation and maintenance doses may be adjusted according to clinical response.

  Patients With Renal Impairment: Initial doses of lamotrigine should be based on patients' concomitant medications (see Tables 1-3 or Table 5); reduced maintenance doses may be effective for patients with significant renal impairment [see Use in Specific Populations (8.7), Clinical Pharmacology (12.3)]. Few patients with severe renal impairment have been evaluated during chronic treatment with lamotrigine. Because there is inadequate experience in this population, lamotrigine should be used with caution in these patients.

  Discontinuation Strategy: Epilepsy:  For patients receiving lamotrigine  in combination with other AEDs, a reevaluation of all AEDs in the regimen should be considered if a change in seizure control or an appearance or worsening of adverse reactions is observed.

  If a decision is made to discontinue therapy with lamotrigine, a step-wise reduction of dose over at least 2 weeks (approximately 50% per week) is recommended unless safety concerns require a more rapid withdrawal [see Warnings and Precautions (5.9)].

  Discontinuing carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin that induce lamotrigine glucuronidation  should prolong the half-life of lamotrigine; discontinuing valproate should shorten the half-life of lamotrigine.

  Bipolar Disorder: In the controlled clinical trials, there was no increase in the incidence, type, or severity of adverse reactions following abrupt termination of lamotrigine. In clinical trials in patients with Bipolar Disorder, 2 patients experienced seizures shortly after abrupt withdrawal of lamotrigine. However, there were confounding factors that may have contributed to the occurrence of seizures in these bipolar patients. Discontinuation of lamotrigine should involve a step-wise reduction of dose over at least 2 weeks (approximately 50% per week) unless safety concerns require a more rapid withdrawal [see Warnings and Precautions (5.9)].

  2.2 Epilepsy - Adjunctive Therapy

  This section provides specific dosing recommendations for patients greater than 12 years of age and patients 2 to 12 years of age. Within each of these age-groups, specific dosing recommendations are provided depending upon concomitant AED or other concomitant medications (Table 1 for patients greater than 12 years of age and Table 2 for patients 2 to 12 years of age). A weight-based dosing guide for patients 2 to 12 years of age on concomitant valproate is provided in Table 3.

  Patients Over 12 Years of Age: Recommended dosing guidelines are summarized in Table 1.

  Table 1. Escalation Regimen for Lamotrigine in Patients Over 12 Years of Age With Epilepsy

   

  For Patients TAKING Valproate *

  For Patients NOT TAKING Carbamazepine, Phenytoin, Phenobarbital, Primidone† , or Valproate*

  For Patients TAKING Carbamazepine, Phenytoin, Phenobarbital, or Primidone† and NOT TAKING Valproate*

  Weeks 1 and 2

  25 mg every other day

  25 mg every day

  50 mg/day

  Weeks 3 and 4

  25 mg every day

  50 mg/day

  100 mg/day

  (in 2 divided doses)

  Week 5 onwards to maintenance

  Increase by 25 to 50 mg/day every 1 to 2 weeks

  Increase by 50 mg/day every 1 to 2 weeks

  Increase by 100 mg/day every 1 to 2 weeks.

  Usual maintenance dose

  100 to 200 mg/day with valproate alone

   

  100 to 400 mg/day with valproate and other drugs that induce glucuronidation

   

  (in 1 or 2 divided doses)

  225 to 375 mg/day

  (in 2 divided doses)

  300 to 500 mg/day

  (in 2 divided doses)

  *   Valproate has been shown to inhibit glucuronidation and decrease the apparent clearance of lamotrigine [see Drug Interactions (7), Clinical Pharmacology (12.3)].

  †    These drugs induce lamotrigine glucuronidation and increase clearance [see Drug Interactions (7), Clinical Pharmacology (12.3)]. Other drugs that have similar effects include estrogen-containing oral contraceptives [see Drug Interactions (7), Clinical Pharmacology (12.3)]. Dosing recommendations for oral contraceptives can be found in General Dosing Considerations [see Dosage and Administration (2.1)]. Patients on rifampin, or other drugs that induce lamotrigine glucuronidation and increase clearance, should follow the same dosing titration/maintenance regimen as that used with anticonvulsants that have this effect.

  Patients 2 to 12 Years of Age: Recommended dosing guidelines are summarized in Table 2.

  Smaller starting doses and slower dose escalations than those used in clinical trials are recommended because of the suggestion that the risk of rash may be decreased by smaller starting doses and slower dose escalations. Therefore, maintenance doses will take longer to reach in clinical practice than in clinical trials. It may take several weeks to months to achieve an individualized maintenance dose. Maintenance doses in patients weighing less than 30 kg, regardless of age or concomitant AED, may need to be increased as much as 50%, based on clinical response.

  The smallest available strength of lamotrigine tablets (chewable, dispersible) is 2 mg, and only whole tablets should be administered. If the calculated dose cannot be achieved using whole tablets, the dose should be rounded down to the nearest whole tablet [see How Supplied/Storage and Handling (16) and Medication Guide].

  Table 2. Escalation Regimen for Lamotrigine in Patients 2 to 12 Years of Age With Epilepsy

   

  For Patients TAKING Valproate *

  For Patients NOT TAKING Carbamazepine, Phenytoin, Phenobarbital, Primidone† ,  or Valproate*

  For Patients TAKING Carbamazepine, Phenytoin, Phenobarbital, or Primidone† and NOT TAKING Valproate*

  Weeks 1 and 2

   

  0.15 mg/kg/day

  in 1 or 2 divided doses, rounded down to the nearest whole tablet (see Table 3 for weight-based dosing guide)

  0.3 mg/kg/day

  in 1 or 2 divided doses, rounded down to the nearest whole tablet

  0.6 mg/kg/day

  in 2 divided doses, rounded down to the nearest whole tablet

  Weeks 3 and 4

   

  0.3 mg/kg/day

  in 1 or 2 divided doses, rounded down to the nearest whole tablet (see Table 3 for weight-based dosing guide)

  0.6 mg/kg/day

  in 2 divided doses, rounded down to the nearest whole tablet

  1.2 mg/kg/day

  in 2 divided doses, rounded down to the nearest whole tablet

  Week 5 onwards to maintenance

   

  The dose should be increased every 1 to 2 weeks as follows: calculate 0.3 mg/kg/day, round this amount down to the nearest whole tablet, and add this amount to the previously administered daily dose

  The dose should be increased every 1 to 2 weeks as follows: calculate 0.6 mg/kg/day, round this amount down to the nearest whole tablet, and add this amount to the previously administered daily dose

  The dose should be increased every 1 to 2 weeks as follows: calculate 1.2 mg/kg/day, round this amount down to the nearest whole tablet, and add this amount to the previously administered daily dose

  Usual maintenance dose

   

  1 to 5 mg/kg/day (maximum 200 mg/day in 1 or 2 divided doses)
  1 to 3 mg/kg/day with valproate alone

  4.5 to 7.5 mg/kg/day (maximum 300 mg/day in 2 divided doses)

  5 to 15 mg/kg/day (maximum 400 mg/day in 2 divided doses)

  Maintenance dose in patients less than 30 kg

   

  May need to be increased by as much as 50%, based on clinical response

  May need to be increased by as much as 50%, based on clinical response

  May need to be increased by as much as 50%, based on clinical response

  Note: Only whole tablets should be used for dosing.

  *    Valproate has been shown to inhibit glucuronidation and decrease the apparent clearance of lamotrigine [see Drug Interactions (7), Clinical Pharmacology (12.3)].
  †    These drugs induce lamotrigine glucuronidation and increase clearance [see Drug Interactions (7), Clinical Pharmacology (12.3)]. Other drugs that have similar effects include estrogen-containing oral contraceptives [see Drug Interactions (7), Clinical Pharmacology (12.3)]. Dosing recommendations for oral contraceptives can be found in General Dosing Considerations [see Dosage and Administration (2.1)]. Patients on rifampin, or other drugs that induce lamotrigine glucuronidation and increase clearance, should follow the same dosing titration/maintenance regimen as that used with anticonvulsants that have this effect.

  Table 3. The Initial Weight-Based Dosing Guide for Patients 2 to 12 Years of Age Taking Valproate (Weeks 1 to 4) With Epilepsy

  If the patient’s weight is

  Give this daily dose, using the most appropriate combination of lamotrigine 2-mg and 5-mg tablets

  Greater than

  And less than

  Weeks 1 and 2

  Weeks 3 and 4

  6.7 kg

  14 kg

  2 mg every other day

  2 mg every day

  14.1 kg

  27 kg

  2 mg every day

  4 mg every day

  27.1 kg

  34 kg

  4 mg every day

  8 mg every day

  34.1 kg

  40 kg

  5 mg every day

  10 mg every day

  Usual Adjunctive Maintenance Dose for Epilepsy: The usual maintenance doses identified in Tables 1 and 2 are derived from dosing regimens employed in the placebo-controlled adjunctive studies in which the efficacy of lamotrigine  was established. In patients receiving multidrug regimens employing carbamazepine, phenytoin, phenobarbital, or primidone without valproate, maintenance doses of adjunctive lamotrigine  as high as 700 mg/day have been used. In patients receiving valproate alone, maintenance doses of adjunctive lamotrigine  as high as 200 mg/day have been used. The advantage of using doses above those recommended in Tables 1 through 4 has not been established in controlled trials.

  2.3 Epilepsy – Conversion From Adjunctive Therapy to Monotherapy

  The goal of the transition regimen is to effect the conversion to monotherapy with lamotrigine  under conditions that ensure adequate seizure control while mitigating the risk of serious rash associated with the rapid titration of lamotrigine.

  The recommended maintenance dose of lamotrigine  as monotherapy is 500 mg/day given in 2 divided doses.

  To avoid an increased risk of rash, the recommended initial dose and subsequent dose escalations of lamotrigine  should not be exceeded [see Boxed Warning].

  Conversion From Adjunctive Therapy With Carbamazepine, Phenytoin, Phenobarbital, or Primidone to Monotherapy With Lamotrigine: After achieving a dose of 500 mg/day of lamotrigine  according to the guidelines in Table 1, the concomitant AED should be withdrawn by 20% decrements each week over a 4-week period. The regimen for the withdrawal of the concomitant AED is based on experience gained in the controlled monotherapy clinical trial.

  Conversion From Adjunctive Therapy With Valproate to Monotherapy With Lamotrigine: The conversion regimen involves 4 steps outlined in Table 4.

  Table 4. Conversion From Adjunctive Therapy With Valproate to Monotherapy With Lamotrigine in Patients ≥16 Years of Age With Epilepsy

   

  Lamotrigine

  Valproate

  Step 1

  Achieve a dose of 200 mg/day according to guidelines in Table 1 (if not already on 200 mg/day).

  Maintain previous stable dose.

  Step 2

  Maintain at 200 mg/day.

  Decrease to 500 mg/day by decrements no greater than 500 mg/day/week and then maintain the dose of 500 mg/day for 1 week.

  Step 3

  Increase to 300 mg/day and maintain for 1 week.

  Simultaneously decrease to 250 mg/day and maintain for 1 week.

  Step 4

  Increase by 100 mg/day every week to achieve maintenance dose of 500 mg/day.

  Discontinue.

  Conversion From Adjunctive Therapy With Antiepileptic Drugs Other Than Carbamazepine, Phenytoin, Phenobarbital, Primidone, or Valproate to Monotherapy With Lamotrigine: No specific dosing guidelines can be provided for conversion to monotherapy with lamotrigine with AEDs other than carbamazepine, phenobarbital, phenytoin, primidone, or valproate.

  2.4 Bipolar Disorder

  The goal of maintenance treatment with lamotrigine is to delay the time to occurrence of mood episodes (depression, mania, hypomania, mixed episodes) in patients treated for acute mood episodes with standard therapy. The target dose of lamotrigine is 200 mg/day (100 mg/day in patients taking valproate, which decreases the apparent clearance of lamotrigine, and 400 mg/day in patients not taking valproate and taking either carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin that increase the apparent clearance of lamotrigine). In the clinical trials, doses up to 400 mg/day as monotherapy were evaluated; however, no additional benefit was seen at 400 mg/day compared with 200 mg/day [see Clinical Studies (14.2)]. Accordingly, doses above 200 mg/day are not recommended. Treatment with lamotrigine is introduced, based on concurrent medications, according to the regimen outlined in Table 5. If other psychotropic medications are withdrawn following stabilization, the dose of lamotrigine should be adjusted. For patients discontinuing valproate, the dose of lamotrigine should be doubled over a 2-week period in equal weekly increments (see Table 6). For patients discontinuing carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin that induce lamotrigine glucuronidation, the dose of lamotrigine should remain constant for the first week and then should be decreased by half over a 2-week period in equal weekly decrements (see Table 6). The dose of lamotrigine may then be further adjusted to the target dose (200 mg) as clinically indicated.

  If other drugs are subsequently introduced, the dose of lamotrigine may need to be adjusted. In particular, the introduction of valproate requires reduction in the dose of lamotrigine [see Drug Interactions (7), Clinical Pharmacology (12.3)].

  To avoid an increased risk of rash, the recommended initial dose and subsequent dose escalations of lamotrigine should not be exceeded [see Boxed Warning].

  Table 5. Escalation Regimen for Lamotrigine for Patients With Bipolar Disorder

   

  For Patients TAKING Valproate‡

   

  For Patients NOT TAKING Carbamazepine, Phenytoin, Phenobarbital, Primidone† or Valproate‡

  For Patients TAKING Carbamazepine, Phenytoin, Phenobarbital or Primidone † and NOT TAKING Valproate‡

  Weeks 1 and 2

  25 mg every other day

  25 mg daily

  50 mg daily

  Weeks 3 and 4

  25 mg daily

  50 mg daily

  100 mg daily, in divided doses

  Week 5

  50 mg daily

  100 mg daily

  200 mg daily, in divided doses

  Week 6

  100 mg daily

  200 mg daily

  300 mg daily, in divided doses

  Week 7

  100 mg daily

  200 mg daily

  up to 400 mg daily, in divided doses

  
  

  ‡  Valproate has been shown to inhibit glucuronidation and decrease the apparent clearance of lamotrigine [see Drug Interactions (7), Clinical Pharmacology (12.3)].

  † These drugs induce lamotrigine glucuronidation and increase clearance [see Drug Interactions (7), Clinical Pharmacology (12.3)].  Other drugs that have similar effects include estrogen-containing oral contraceptives [see Drug Interactions (7), Clinical Pharmacology (12.3)]. Dosing recommendations for oral contraceptives can be found in General Dosing Considerations [see Dosage and Administration (2.1)]. Patients on rifampin, or other drugs that induce lamotrigine glucuronidation and increase clearance, should follow the same dosing titration/maintenance regimen as that used with anticonvulsants that have this effect.

  Table 6. Dosage Adjustments to Lamotrigine for Patients With Bipolar Disorder Following Discontinuation of Psychotropic Medications

   

   

  Discontinuation of Psychotropic Drugs (excluding Carbamazepine,
  Phenytoin, Phenobarbital, Primidone,  or Valproate‡)

  After Discontinuation of Valproate‡

  After Discontinuation of Carbamazepine, Phenytoin, Phenobarbital,or  Primidone†

  Current dose of Lamotrigine
  (mg/day)   100                 

  Current dose of Lamotrigine 
  (mg/day) 400                             

  Week 1

  Maintain current dose of Lamotrigine

  150

  400

  Week 2

  Maintain current dose of Lamotrigine

  200

  300

  Week 3 onward

  Maintain current dose of Lamotrigine

  200

  200

  ‡  Valproate has been shown to inhibit glucuronidation and decrease the apparent clearance of lamotrigine [see Drug Interactions (7), Clinical Pharmacology (12.3)].

  † These drugs induce lamotrigine glucuronidation and increase clearance [see Drug Interactions (7), Clinical Pharmacology (12.3)].  Other drugs that have similar effects include estrogen-containing oral contraceptives [see Drug Interactions (7), Clinical Pharmacology (12.3)]. Dosing recommendations for oral contraceptives can be found in General Dosing Considerations [see Dosage and Administration (2.1)]. Patients on rifampin, or other drugs that induce lamotrigine glucuronidation and increase clearance, should follow the same dosing titration/maintenance regimen as that used with anticonvulsants that have this effect.

  The benefit of continuing treatment in patients who had been stabilized in an 8- to 16-week open-label phase with lamotrigine was established in 2 randomized, placebo-controlled clinical maintenance trials [see Clinical Studies (14.2 )]. However, the optimal duration of treatment with lamotrigine has not been established. Thus, patients should be periodically reassessed to determine the need for maintenance treatment.

  2.5 Administration of Lamotrigine Tablets (Chewable, Dispersible)

  Lamotrigine tablets (chewable, dispersible) may be swallowed whole, chewed, or dispersed in water or diluted fruit juice. If the tablets are chewed, consume a small amount of water or diluted fruit juice to aid in swallowing.

  To disperse lamotrigine tablets (chewable, dispersible), add the tablets to a small amount of liquid (1 teaspoon, or enough to cover the medication). Approximately 1 minute later, when the tablets are completely dispersed, swirl the solution and consume the entire quantity immediately. No attempt should be made to administer partial quantities of the dispersed tablets.

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  2.1 General Dosing Considerations 

  Rash: There are suggestions, yet to be proven, that the risk of severe, potentially life-threatening rash may be increased by (1) coadministration of Lamotrigine with valproate, (2) exceeding the recommended initial dose of Lamotrigine, or (3) exceeding the recommended dose escalation for Lamotrigine. However, cases have occurred in the absence of these factors [see Boxed Warning]. Therefore, it is important that the dosing recommendations be followed closely.

  The risk of nonserious rash may be increased when the recommended initial dose and/or the rate of dose escalation of Lamotrigine is exceeded and in patients with a history of allergy or rash to other AEDs.

  It is recommended that Lamotrigine not be restarted in patients who discontinued due to rash associated with prior treatment with Lamotrigine, unless the potential benefits clearly outweigh the risks. If the decision is made to restart a patient who has discontinued Lamotrigine, the need to restart with the initial dosing recommendations should be assessed. The greater the interval of time since the previous dose, the greater consideration should be given to restarting with the initial dosing recommendations. If a patient has discontinued Lamotrigine for a period of more than 5 half-lives, it is recommended that initial dosing recommendations and guidelines be followed. The half-life of Lamotrigine is affected by other concomitant medications [see Clinical Pharmacology (12.3)].

  Lamotrigine Added to Drugs Known to Induce or Inhibit Glucuronidation: Drugs other than those listed in the Clinical Pharmacology section [see Clinical Pharmacology (12.3)] have not been systematically evaluated in combination with Lamotrigine. Because Lamotrigine is metabolized predominantly by glucuronic acid conjugation, drugs that are known to induce or inhibit glucuronidation may affect the apparent clearance of Lamotrigine and doses of Lamotrigine may require adjustment based on clinical response.

  Target Plasma Levels for Patients With Epilepsy or Bipolar Disorder: A therapeutic plasma concentration range has not been established for Lamotrigine. Dosing of Lamotrigine should be based on therapeutic response [see Clinical Pharmacology (12.3)].

  Women Taking Estrogen-Containing Oral Contraceptives:  Starting Lamotrigine in Women Taking Estrogen-Containing Oral Contraceptives: Although estrogen-containing oral contraceptives have been shown to increase the clearance of Lamotrigine [see Clinical Pharmacology (12.3)], no adjustments to the recommended dose-escalation guidelines for Lamotrigine should be necessary solely based on the use of estrogen-containing oral contraceptives. Therefore, dose escalation should follow the recommended guidelines for initiating adjunctive therapy with Lamotrigine based on the concomitant AED or other concomitant medications (see Table 1 or Table 5). See below for adjustments to maintenance doses of Lamotrigine in women taking estrogen-containing oral contraceptives.

  Adjustments to the Maintenance Dose of Lamotrigine in Women Taking Estrogen-Containing Oral Contraceptives:

  (1) Taking Estrogen-Containing Oral Contraceptives: For women not taking carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin that induce Lamotrigine glucuronidation [see Drug Interactions (7), Clinical Pharmacology (12.3)], the maintenance dose of Lamotrigine will in most cases need to be increased, by as much as 2-fold over the recommended target maintenance dose, in order to maintain a consistent Lamotrigine plasma level [see Clinical Pharmacology (12.3)].

  (2) Starting Estrogen-Containing Oral Contraceptives: In women taking a stable dose of Lamotrigine and not taking carbamazepine, phenytoin, phenobarbital, primidone, or  other drugs such as rifampin that induce Lamotrigine glucuronidation [see Drug Interactions (7), Clinical Pharmacology (12.3)], the maintenance dose will in most cases need to be increased by as much as 2-fold in order to maintain a consistent Lamotrigine plasma level. The dose increases should begin at the same time that the oral contraceptive is introduced and continue, based on clinical response, no more rapidly than 50 to 100 mg/day every week. Dose increases should not exceed the recommended rate (see Table 1 or Table 5) unless Lamotrigine plasma levels or clinical response support larger increases. Gradual transient increases in Lamotrigine plasma levels may occur during the week of inactive hormonal preparation (“pill-free” week), and these increases will be greater if dose increases are made in the days before or during the week of inactive hormonal preparation. Increased Lamotrigine plasma levels could result in additional adverse reactions, such as dizziness, ataxia, and diplopia. If adverse reactions attributable to Lamotrigine consistently occur during the “pill-free” week, dose adjustments to the overall maintenance dose may be necessary. Dose adjustments limited to the “pill-free” week are not recommended. For women taking Lamotrigine in addition to carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin that induce Lamotrigine glucuronidation [see Drug Interactions (7), Clinical Pharmacology (12.3)], no adjustment to the dose of Lamotrigine should be necessary.

  (3) Stopping Estrogen-Containing Oral Contraceptives: For women not taking carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin that induce Lamotrigine glucuronidation [see Drug Interactions (7), Clinical Pharmacology (12.3)], the maintenance dose of Lamotrigine will in most cases need to be decreased by as much as 50% in order to maintain a consistent Lamotrigine plasma level. The decrease in dose of Lamotrigine should not exceed 25% of the total daily dose per week over a 2-week period, unless clinical response or Lamotrigine plasma levels indicate otherwise [see Clinical Pharmacology (12.3)]. For women taking Lamotrigine in addition to carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin that induce Lamotrigine glucuronidation [see Drug Interactions (7), Clinical Pharmacology (12.3)], no adjustment to the dose of Lamotrigine should be necessary.

  Women and Other Hormonal Contraceptive Preparations or Hormone Replacement Therapy: The effect of other hormonal contraceptive preparations or hormone replacement therapy on the pharmacokinetics of Lamotrigine has not been systematically evaluated. It has been reported that ethinylestradiol, not progestogens, increased the clearance of Lamotrigine up to 2-fold, and the progestin-only pills had no effect on Lamotrigine plasma levels. Therefore, adjustments to the dosage of Lamotrigine in the presence of progestogens alone will likely not be needed.

  Patients With Hepatic Impairment: Experience in patients with hepatic impairment is limited. Based on a clinical pharmacology study in 24 patients with mild, moderate, and severe liver impairment [see Use in Specific Populations (8.6), Clinical Pharmacology (12.3)], the following general recommendations can be made. No dosage adjustment is needed in patients with mild liver impairment. Initial, escalation, and maintenance doses should generally be reduced by approximately 25% in patients with moderate and severe liver impairment without ascites and 50% in patients with severe liver impairment with ascites. Escalation and maintenance doses may be adjusted according to clinical response.

  Patients With Renal Impairment: Initial doses of Lamotrigine should be based on patients' concomitant medications (see Tables 1-3 or Table 5); reduced maintenance doses may be effective for patients with significant renal impairment [see Use in Specific Populations (8.7), Clinical Pharmacology (12.3)]. Few patients with severe renal impairment have been evaluated during chronic treatment with Lamotrigine. Because there is inadequate experience in this population, Lamotrigine should be used with caution in these patients.

  Discontinuation Strategy:  Epilepsy: For patients receiving Lamotrigine in combination with other AEDs, a re-evaluation of all AEDs in the regimen should be considered if a change in seizure control or an appearance or worsening of adverse experiences is observed.

  If a decision is made to discontinue therapy with Lamotrigine, a step-wise reduction of dose over at least 2 weeks (approximately 50% per week) is recommended unless safety concerns require a more rapid withdrawal [see Warnings and Precautions (5.9)].

  Discontinuing carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin that induce Lamotrigine glucuronidation should prolong the half-life of Lamotrigine; discontinuing valproate should shorten the half-life of Lamotrigine.

  Bipolar Disorder: In the controlled clinical trials, there was no increase in the incidence, type, or severity of adverse reactions following abrupt termination of Lamotrigine. In clinical trials in patients with Bipolar Disorder, 2 patients experienced seizures shortly after abrupt withdrawal of Lamotrigine. However, there were confounding factors that may have contributed to the occurrence of seizures in these bipolar patients. Discontinuation of Lamotrigine should involve a step-wise reduction of dose over at least 2 weeks (approximately 50% per week) unless safety concerns require a more rapid withdrawal [see Warnings and Precautions (5.9)].

  2.2 Epilepsy – Adjunctive Therapy

  This section provides specific dosing recommendations for patients greater than 12 years of age and patients 2 to 12 years of age. Within each of these age-groups, specific dosing recommendations are provided depending upon concomitant AED or other concomitant medications (Table 1 for patients greater than 12 years of age and Table 2 for patients 2 to 12 years of age). A weight-based dosing guide for patients 2 to 12 years of age on concomitant valproate is provided in Table 3.

  Patients Over 12 Years of Age: Recommended dosing guidelines are summarized in Table 1.

  Table 1. Escalation Regimen for Lamotrigine in Patients Over 12 Years of Age With Epilepsy  * Valproate has been shown to inhibit glucuronidation and decrease the apparent clearance of Lamotrigine [see Drug Interactions ( 7 ), Clinical Pharmacology  ( 12.3 )]. † These drugs induce Lamotrigine glucuronidation and increase clearance [see Drug Interactions ( 7 ) Clinical Pharmacology ( 12.3 )]. Other drugs, which have similar effects include estrogen-containing oral contraceptives [see Drug Interactions ( 7 ), Clinical Pharmacology  ( 12.3 )]. Dosing recommendations for oral contraceptives can be found in General Dosing Considerations [see Dosage and Administration ( 2.1 )]. Patients on rifampin, or other drugs that induce Lamotrigine glucuronidation and increase clearance, should follow the same dosing titration/maintenance regimen as that used with anticonvulsants that have this effect.   For Patients TAKING Valproate* For Patients NOT TAKING Carbamazepine, Phenytoin, Phenobarbital, Primidone†,or Valproate* For Patients TAKING Carbamazepine, Phenytoin, Phenobarbital, or Primidone† and NOT TAKING Valproate* Weeks 1 and 2 25 mg every other day 25 mg every day 50 mg/day Weeks 3 and 4 25 mg every day 50 mg/day 100 mg/day (in 2 divided doses) Weeks 5 onwards to maintenance Increase by 25 to 50 mg/day every 1 to 2 weeks Increase by 50 mg/day
  every 1 to 2 weeks Increase by 100 mg/day every 1 to 2 weeks Usual Maintenance Dose 100 to 200 mg/day with valproate alone
  
  100 to 400 mg/day with valproate and other drugs that induce glucuronication
  (in 1 or 2 divided doses) 225 to 375 mg/day
  (in 2 divided doses) 300 to 500 mg/day  (in 2 divided doses)

  Patients 2 to 12 Years of Age: Recommended dosing guidelines are summarized in Table 2.

  Smaller starting doses and slower dose escalations than those used in clinical trials are recommended because of the suggestion that the risk of rash may be decreased by smaller starting doses and slower dose escalations. Therefore, maintenance doses will take longer to reach in clinical practice than in clinical trials. It may take several weeks to months to achieve an individualized maintenance dose. Maintenance doses in patients weighing less than 30 kg, regardless of age or concomitant AED, may need to be increased as much as 50%, based on clinical response. 

  Table 2. Escalation Regimen for Lamotrigine in Patients 2 to 12 Years of Age With Epilepsy * Valproate has been shown to inhibit glucuronidation and decrease the apparent clearance of Lamotrigine [see Drug Interactions (7 ), Clinical Pharmacology  (12.3)]. † These drugs induce Lamotrigine glucuronidation and increase clearance [see Drug Interactions (7 ) Clinical Pharmacology  (12.3)]. Other drugs, which have similar effects include estrogen-containing oral contraceptives [see Drug Interactions (7 ) Clinical Pharmacology  (12.3)].
  Dosing recommendations for oral contraceptives can be found in General Dosing Considerations [see Dosage and Administration (2.1)]. Patients on rifampin, or other drugs that induce Lamotrigine glucuronidation and increase clearance, should follow the same dosing titration/maintenance regimen as that used with anticonvulsants that have this effect.   For Patients TAKING Valproate* For Patients NOT TAKING Carbamazepine,
  Phenytoin,
  Phenobarbital,  
  Primidone†  or
   Valproate* For Patients TAKING Carbamazepine, Phenytoin, Phenobarbital, or  Primidone† and NOT TAKING Valproate* Weeks 1 and 2 0.15 mg/kg/day
   in 1 or 2 divided doses, rounded down to the nearest whole tablet (see Table 3 for weight based dosing guide) 0.3 mg/kg/day
  in 1 or 2 divided doses, rounded down to the nearest whole tablet 0.6 mg/kg/day
  in 2 divided doses, rounded down to the nearest whole tablet Weeks 3 and 4 0.3 mg/kg/day
  in 1 or 2 divided doses, rounded down to the nearest whole tablet (see Table 3 for weight based dosing guide) 0.6 mg/kg/day
    in 2 divided doses, rounded down to the nearest whole tablet 1.2 mg/kg/day
    in 2 divided doses, rounded down to the nearest whole tablet Weeks 5 onwards to maintenance The dose should be increased every 1 to 2 weeks as follows: calculate 0.3 mg/kg/day, round this amount down to the nearest whole tablet, and add this amount to the previously administered daily dose The dose should be increased every 1 to 2 weeks as follows: calculate 0.6 mg/kg/day, round this amount down to the nearest whole tablet, and add this amount to the previously administered daily dose The dose should be increased every 1 to 2 weeks as follows: calculate 1.2 mg/kg/day, round this amount down to the nearest whole tablet, and add this amount to the previously administered daily dose Usual Maintenance Dose 1 to 5 mg/kg/day (maximum 200 mg/day in 1 or 2 divided doses).
  1 to 3 mg/kg/day with valproate alone 4.5 to 7.5 mg/kg/day
   (maximum 300 mg/day in 2 divided doses) 5 to 15 mg/kg/day
   (maximum 400 mg/day in 2 divided doses) Maintenance dose in patients less than 30 kg May need to be increased by as much as 50%, based on clinical response May need to be increased by as much as 50%, based on clinical response May need to be increased by as much as 50%, based on clinical response Note: Only whole tablets should be used for dosing. Table 3. The Initial Weight-Based Dosing Guide for Patients 2 to 12 Years Taking Valproate (Weeks 1 to 4) With Epilepsy If the patient’s weight is Give this daily dose, using the most appropriate combination of Lamotrigine 2-mg and 5-mg tablets Greater than And less than Weeks 1 and 2 Weeks 3 and 4 6.7 kg 14 kg 2 mg every other day 2 mg every day 14.1 kg 27 kg 2 mg every day 4 mg every day 27.1 kg 34 kg 4 mg every day 8 mg every day 34.1 kg 40 kg 5 mg every day 10 mg every day

  Usual Adjunctive Maintenance Dose for Epilepsy: The usual maintenance doses identified in Tables 1 and 2 are derived from dosing regimens employed in the placebo-controlled adjunctive studies in which the efficacy of Lamotrigine was established. In patients receiving multidrug regimens employing carbamazepine, phenytoin, phenobarbital, or primidone without valproate, maintenance doses of adjunctive Lamotrigine as high as 700 mg/day have been used. In patients receiving valproate alone, maintenance doses of adjunctive Lamotrigine as high as 200 mg/day have been used. The advantage of using doses above those recommended in Tables 1 through 4 has not been established in controlled trials.

  2.3 Epilepsy – Conversion From Adjunctive Therapy to Monotherapy

  The goal of the transition regimen is to effect the conversion to monotherapy with Lamotrigine under conditions that ensure adequate seizure control while mitigating the risk of serious rash associated with the rapid titration of Lamotrigine.

  The recommended maintenance dose of Lamotrigine as monotherapy is 500 mg/day given in 2 divided doses.

  To avoid an increased risk of rash, the recommended initial dose and subsequent dose escalations of Lamotrigine should not be exceeded [see Boxed Warning].

  Conversion From Adjunctive Therapy With Carbamazepine, Phenytoin, Phenobarbital, or Primidone to Monotherapy With Lamotrigine: After achieving a dose of 500 mg/day of Lamotrigine according to the guidelines in Table 1, the concomitant AED should be withdrawn by 20% decrements each week over a 4-week period. The regimen for the withdrawal of the concomitant AED is based on experience gained in the controlled monotherapy clinical trial. 

  Conversion from Adjunctive Therapy With Valproate to Monotherapy With Lamotrigine: The conversion regimen involves 4 steps outlined in Table 4.

  Table 4. Conversion From Adjunctive Therapy With Valproate to Monotherapy With Lamotrigine in Patients ≥16 Years of Age with Epilepsy

  Lamotrigine

  Valproate

  Step 1

  Achieve a dose of 200 mg/day according to guidelines in Table 1 (if not already on 200 mg/day).

  Maintain previous stable dose.

  Step 2

  Maintain at 200 mg/day.

  Decrease to 500 mg/day by decrements no greater than 500 mg/day/week and then maintain the dose of 500 mg/day for 1 week.

  Step 3

  Increase to 300 mg/day and maintain for 1 week.

  Simultaneously decrease to 250 mg/day and maintain for 1 week.

  Step 4

  Increase by 100 mg/day every week to achieve maintenance dose of 500 mg/day.

  Discontinue.

  
  Conversion from Adjunctive Therapy With AEDs Other Than Carbamazepine, Phenytoin, Phenobarbital, Primidone, or Valproate to Monotherapy With Lamotrigine: No specific dosing guidelines can be provided for conversion to monotherapy with Lamotrigine with AEDs other than carbamazepine, phenobarbital, phenytoin, primidone, or valproate.

  2.4 Bipolar Disorder

  The goal of maintenance treatment with Lamotrigine is to delay the time to occurrence of mood episodes (depression, mania, hypomania, mixed episodes) in patients treated for acute mood episodes with standard therapy. The target dose of Lamotrigine is 200 mg/day (100 mg/day in patients taking valproate, which decreases the apparent clearance of Lamotrigine, and 400 mg/day in patients not taking valproate and taking either carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin, that  increase the apparent clearance of Lamotrigine). In the clinical trials, doses up to 400 mg/day as monotherapy were evaluated; however, no additional benefit was seen at 400 mg/day compared with 200 mg/day [see Clinical Studies (14.2)]. Accordingly, doses above 200 mg/day are not recommended. Treatment with Lamotrigine is introduced, based on concurrent medications, according to the regimen outlined in Table 5. If other psychotropic medications are withdrawn following stabilization, the dose of Lamotrigine should be adjusted. For patients discontinuing valproate, the dose of Lamotrigine should be doubled over a 2-week period in equal weekly increments (see Table 6). For patients discontinuing carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin that induce Lamotrigine glucuronidation, the dose of Lamotrigine should remain constant for the first week and then should be decreased by half over a 2-week period in equal weekly decrements (see Table 6). The dose of Lamotrigine may then be further adjusted to the target dose (200 mg) as clinically indicated.

  If other drugs are subsequently introduced, the dose of Lamotrigine may need to be adjusted. In particular, the introduction of valproate requires reduction in the dose of Lamotrigine [see Drug Interactions (7), Clinical Pharmacology (12.3)].

  To avoid an increased risk of rash, the recommended initial dose and subsequent dose escalations of Lamotrigine should not be exceeded [see Boxed Warning].

   

  Table 5. Escalation Regimen for Lamotrigine for Patients With Bipolar Disorder * Valproate has been shown to inhibit glucuronidation and decrease the apparent clearance of Lamotrigine [see Drug Interactions (7 ), Clinical Pharmacology (12.3)]. † These drugs induce Lamotrigine glucuronidation and increase clearance [see Drug Interactions (7 ), Clinical Pharmacology (12.3)]. Other drugs which have similar effects include estrogen- containing oral contraceptives [see Drug Interactions (7), Clinical Pharmacology (12.3)].
  Dosing recommendations for oral contraceptives can be found in General Dosing Considerations [see Dosage and Administration (2.1)]. Patients on rifampin, or other drugs that induce Lamotrigine glucuronidation and increase clearance, should follow the same dosing titration/ maintenance regimen as that used with anticonvulsants that have this effect. For Patients TAKING Valproate* For Patients NOT TAKING Carbamazepine, Phenytoin, Phenobarbital, Primidone†, or Valproate* For Patients TAKING Carbamazepine, Phenytoin, Phenobarbital, or Primidone† and NOT TAKING Valproate* Weeks 1 and 2 25 mg every other day 25 mg daily 50 mg daily Weeks 3 and 4 25 mg daily 50 mg daily 100 mg daily, in divided doses Week 5 50 mg daily 100 mg daily 200 mg daily, in divided doses Week 6 100 mg daily 200 mg daily 300 mg daily, in divided doses Week 7 100 mg daily 200 mg daily up to 400 mg daily, in divided doses Table 6. Dosage Adjustments to Lamotrigine for Patients With Bipolar Disorder Following Discontinuation of Psychotropic Medications * These drugs induce Lamotrigine glucuronidation and increase clearance [see Drug Interactions (7 ), Clinical Pharmacology (12.3)]. Other drugs which have similar effects include estrogen-containing oral contraceptives [see Drug Interactions (7), Clinical Pharmacology (12.3)]. Dosing recommendations for oral contraceptives can be found in General Dosing Considerations [see Dosage and Administration (2.1)]. Patients on rifampin, or other drugs that induce Lamotrigine glucuronidation and increase clearance, should follow the same dosing titration/ maintenance regimen as that used with anticonvulsants that have this effect. † Valproate has been shown to inhibit glucuronidation and decrease the apparent clearance of Lamotrigine [see Drug Interactions (7), Clinical Pharmacology (12.3)].  

  Discontinuation of Psychotropic Drugs (excluding Carbamazepine, Phenytoin, Phenobarbital, Primidone*, or Valproate†)

  After Discontinuation of Valproate† After Discontinuation of Carbamazepine, Phenytoin, Phenobarbital, or Primidone* Current dose of Lamotrigine (mg/day) 100

  Current dose of Lamotrigine (mg/day) 400

  Week 1 Maintain current dose of Lamotrigine 150 400 Week 2 Maintain current dose of Lamotrigine 200 300 Week 3 onward Maintain current dose of Lamotrigine 200 200

  The benefit of continuing treatment in patients who had been stabilized in an 8- to 16-week open-label phase with Lamotrigine was established in 2 randomized, placebo-controlled clinical maintenance trials [see Clinical Studies (14.2)]. However, the optimal duration of treatment with Lamotrigine has not been established. Thus, patients should be periodically reassessed to determine the need for maintenance treatment.

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  2.1 General Dosing Considerations Rash

  There are suggestions, yet to be proven, that the risk of severe, potentially life threatening rash may be increased by (1) coadministration of lamotrigine tablets with valproate, (2) exceeding the recommended initial dose of lamotrigine tablets, or (3) exceeding the recommended dose escalation for lamotrigine tablets. However, cases have occurred in the absence of these factors [see Boxed Warning]. Therefore, it is important that the dosing recommendations be followed closely.

  The risk of nonserious rash may be increased when the recommended initial dose and/or the rate of dose escalation of lamotrigine tablets are exceeded and in patients with a history of allergy or rash to other AEDs.

  It is recommended that lamotrigine tablets not be restarted in patients who discontinued due to rash associated with prior treatment with lamotrigine, unless the potential benefits clearly outweigh the risks. If the decision is made to restart a patient who has discontinued lamotrigine, the need to restart with the initial dosing recommendations should be assessed. The greater the interval of time since the previous dose, the greater consideration should be given to restarting with the initial dosing recommendations. If a patient has discontinued lamotrigine for a period of more than 5 half-lives, it is recommended that initial dosing recommendations and guidelines be followed. The half-life of lamotrigine is affected by other concomitant medications [see Clinical Pharmacology (12.3)].

  Lamotrigine Tablets Added to Drugs Known to Induce or Inhibit Glucuronidation

  Drugs other than those listed in the Clinical Pharmacology section [see Clinical Pharmacology (12.3)] have not been systematically evaluated in combination with lamotrigine. Because lamotrigine is metabolized predominantly by glucuronic acid conjugation, drugs that are known to induce or inhibit glucuronidation may affect the apparent clearance of lamotrigine and doses of lamotrigine tablets may require adjustment based on clinical response.

  Target Plasma Levels for Patients with Epilepsy or Bipolar Disorder

  A therapeutic plasma concentration range has not been established for lamotrigine. Dosing of lamotrigine tablets should be based on therapeutic response [see Clinical Pharmacology (12.3)].

  Women taking Estrogen-Containing Oral Contraceptives Starting Lamotrigine Tablets in Women taking Estrogen-Containing Oral Contraceptives

  Although estrogen-containing oral contraceptives have been shown to increase the clearance of lamotrigine [see Clinical Pharmacology (12.3)], no adjustments to the recommended dose-escalation guidelines for lamotrigine tablets should be necessary solely based on the use of estrogen-containing oral contraceptives. Therefore, dose escalation should follow the recommended guidelines for initiating adjunctive therapy with lamotrigine tablets based on the concomitant AED or other concomitant medications (see Table 1 or Table 5). See below for adjustments to maintenance doses of lamotrigine tablets in women taking estrogen-containing oral contraceptives.

  Adjustments to the Maintenance Dose of Lamotrigine Tablets in Women taking Estrogen-Containing Oral Contraceptives

  (1) Taking Estrogen-Containing Oral Contraceptives: For women not taking carbamazepine, phenytoin, phenobarbital, primidone or other drugs such as rifampin that induce lamotrigine glucuronidation [see Drug Interactions (7), Clinical Pharmacology (12.3)], the maintenance dose of lamotrigine tablets will in most cases need to be increased, by as much as 2-fold over the recommended target maintenance dose, in order to maintain a consistent lamotrigine plasma level [see Clinical Pharmacology (12.3)].

  (2) Starting Estrogen-Containing Oral Contraceptives: In women taking a stable dose of lamotrigine tablets and not taking carbamazepine, phenytoin, phenobarbital, primidone or other drugs such as rifampin that induce lamotrigine glucuronidation [see Drug Interactions (7), Clinical Pharmacology (12.3)], the maintenance dose will in most cases need to be increased by as much as 2-fold in order to maintain a consistent lamotrigine plasma level. The dose increases should begin at the same time that the oral contraceptive is introduced and continue, based on clinical response, no more rapidly than 50 to 100 mg/day every week. Dose increases should not exceed the recommended rate (see Table 1 or Table 5) unless lamotrigine plasma levels or clinical response support larger increases. Gradual transient increases in lamotrigine plasma levels may occur during the week of inactive hormonal preparation (“pill-free” week), and these increases will be greater if dose increases are made in the days before or during the week of inactive hormonal preparation. Increased lamotrigine plasma levels could result in additional adverse reactions, such as dizziness, ataxia and diplopia. If adverse reactions attributable to lamotrigine tablets consistently occur during the “pill-free” week, dose adjustments to the overall maintenance dose may be necessary. Dose adjustments limited to the “pill-free” week are not recommended. For women taking lamotrigine tablets in addition to carbamazepine, phenytoin, phenobarbital, primidone or other drugs such as rifampin that induce lamotrigine glucuronidation [see Drug Interactions (7), Clinical Pharmacology (12.3)], no adjustment to the dose of lamotrigine tablets should be necessary.

  (3) Stopping Estrogen-Containing Oral Contraceptives: For women not taking carbamazepine, phenytoin, phenobarbital, primidone or other drugs such as rifampin that induce lamotrigine glucuronidation [see Drug Interactions (7), Clinical Pharmacology (12.3)], the maintenance dose of lamotrigine tablets will in most cases need to be decreased by as much as 50% in order to maintain a consistent lamotrigine plasma level. The decrease in dose of lamotrigine tablets should not exceed 25% of the total daily dose per week over a 2-week period, unless clinical response or lamotrigine plasma levels indicate otherwise [see Clinical Pharmacology (12.3)]. For women taking lamotrigine tablets in addition to carbamazepine, phenytoin, phenobarbital, primidone or other drugs such as rifampin that induce lamotrigine glucuronidation [see Drug Interactions (7), Clinical Pharmacology (12.3)], no adjustment to the dose of lamotrigine tablets should be necessary.

  Women and Other Hormonal Contraceptive Preparations or Hormone Replacement Therapy

  The effect of other hormonal contraceptive preparations or hormone replacement therapy on the pharmacokinetics of lamotrigine has not been systematically evaluated. It has been reported that ethinylestradiol, not progestogens, increased the clearance of lamotrigine up to 2-fold, and the progestin-only pills had no effect on lamotrigine plasma levels. Therefore, adjustments to the dosage of lamotrigine tablets in the presence of progestogens alone will likely not be needed.

  Patients with Hepatic Impairment

  Experience in patients with hepatic impairment is limited. Based on a clinical pharmacology study in 24 patients with mild, moderate and severe liver impairment [see Use in Specific Populations (8.6), Clinical Pharmacology (12.3)], the following general recommendations can be made. No dosage adjustment is needed in patients with mild liver impairment. Initial, escalation, and maintenance doses should generally be reduced by approximately 25% in patients with moderate and severe liver impairment without ascites and 50% in patients with severe liver impairment with ascites. Escalation and maintenance doses may be adjusted according to clinical response.

  Patients with Renal Impairment

  Initial doses of lamotrigine tablets should be based on patients' concomitant medications (see Tables 1 to 3 or Table 5); reduced maintenance doses may be effective for patients with significant renal impairment [see Use in Specific Populations (8.7), Clinical Pharmacology (12.3)]. Few patients with severe renal impairment have been evaluated during chronic treatment with lamotrigine tablets. Because there is inadequate experience in this population, lamotrigine tablets should be used with caution in these patients.

  Discontinuation Strategy Epilepsy

  For patients receiving lamotrigine tablets in combination with other AEDs, a reevaluation of all AEDs in the regimen should be considered if a change in seizure control or an appearance or worsening of adverse reactions is observed.

  If a decision is made to discontinue therapy with lamotrigine tablets, a step-wise reduction of dose over at least 2 weeks (approximately 50% per week) is recommended unless safety concerns require a more rapid withdrawal [see Warnings and Precautions (5.10)].

  Discontinuing carbamazepine, phenytoin, phenobarbital, primidone or other drugs such as rifampin that induce lamotrigine glucuronidation should prolong the half-life of lamotrigine; discontinuing valproate should shorten the half-life of lamotrigine.

  Bipolar Disorder

  In the controlled clinical trials, there was no increase in the incidence, type, or severity of adverse reactions following abrupt termination of lamotrigine tablets. In clinical trials in patients with bipolar disorder, two patients experienced seizures shortly after abrupt withdrawal of lamotrigine tablets. However, there were confounding factors that may have contributed to the occurrence of seizures in these bipolar patients. Discontinuation of lamotrigine tablets should involve a step-wise reduction of dose over at least 2 weeks (approximately 50% per week) unless safety concerns require a more rapid withdrawal [see Warnings and Precautions (5.10)].

  2.2 Epilepsy – Adjunctive Therapy

  This section provides specific dosing recommendations for patients greater than 12 years of age and patients 2 to 12 years of age. Within each of these age groups, specific dosing recommendations are provided depending upon concomitant AED or other concomitant medications (Table 1 for patients greater than 12 years of age and Table 2 for patients 2 to 12 years of age). A weight-based dosing guide for patients 2 to 12 years of age on concomitant valproate is provided in Table 3.

  Patients Over 12 Years of Age

  Recommended dosing guidelines are summarized in Table 1.

  Table 1. Escalation Regimen for Lamotrigine Tablets in Patients Over 12 Years of Age with Epilepsy * Valproate has been shown to inhibit glucuronidation and decrease the apparent clearance of lamotrigine [see Drug Interactions (7), Clinical Pharmacology (12.3)]. † These drugs induce lamotrigine glucuronidation and increase clearance [see Drug Interactions (7), Clinical Pharmacology (12.3)]. Other drugs that have similar effects include estrogen-containing oral contraceptives [see Drug Interactions (7), Clinical Pharmacology (12.3)]. Dosing recommendations for oral contraceptives can be found in General Dosing Considerations [see Dosage and Administration (2.1)]. Patients on rifampin, or other drugs that induce lamotrigine glucuronidation and increase clearance, should follow the same dosing titration/maintenance regimen as that used with anticonvulsants that have this effect.

  For Patients TAKING
  Valproate*

  For Patients NOT
  TAKING
  Carbamazepine,
  Phenytoin,
  Phenobarbital,
  Primidone† or
  Valproate*

  For Patients
  TAKING
  Carbamazepine,
  Phenytoin,
  Phenobarbital or
  Primidone† and
  NOT
  TAKING
  Valproate*

  Weeks 1 and 2

  25 mg every other day

  25 mg every day

  50 mg/day

  Weeks 3 and 4

  25 mg every day

  50 mg/day

  100 mg/day
  (in 2 divided doses)

  Week 5 onwards
  to maintenance

  Increase by 25 to 50 mg/day every 1 to 2 weeks

  Increase by 50 mg/day every 1 to 2 weeks

  Increase by 100 mg/day every 1 to 2 weeks

  Usual Maintenance
  Dose

  100 to 200 mg/day with valproate alone
  
  100 to 400 mg/day with valproate and other drugs that induce glucuronidation
  
  (in 1 or 2 divided doses)

  225 to 375 mg/day
  (in 2 divided doses)

  300 to 500 mg/day
  (in 2 divided doses)

  Patients 2 to 12 Years of Age

  Recommended dosing guidelines are summarized in Table 2.

  Smaller starting doses and slower dose escalations than those used in clinical trials are recommended because of the suggestion that the risk of rash may be decreased by smaller starting doses and slower dose escalations. Therefore, maintenance doses will take longer to reach in clinical practice than in clinical trials. It may take several weeks to months to achieve an individualized maintenance dose. Maintenance doses in patients weighing less than 30 kg, regardless of age or concomitant AED, may need to be increased as much as 50%, based on clinical response.

  Table 2. Escalation Regimen for Lamotrigine Tablets in Patients 2 to 12 Years of Age with Epilepsy * Valproate has been shown to inhibit glucuronidation and decrease the apparent clearance of lamotrigine [see Drug Interactions (7), Clinical Pharmacology (12.3)]. † These drugs induce lamotrigine glucuronidation and increase clearance [see Drug Interactions (7), Clinical Pharmacology (12.3)]. Other drugs that have similar effects include estrogen-containing oral contraceptives [see Drug Interactions (7), Clinical Pharmacology (12.3)]. Dosing recommendations for oral contraceptives can be found in General Dosing Considerations [see Dosage and Administration (2.1)]. Patients on rifampin, or other drugs that induce lamotrigine glucuronidation and increase clearance, should follow the same dosing titration/maintenance regimen as that used with anticonvulsants that have this effect.

  For Patients TAKING

  Valproate*

  For Patients NOT
  TAKING
  Carbamazepine,
  Phenytoin, Phenobarbital, Primidone† or Valproate*

  For Patients TAKING
  Carbamazepine,
  Phenytoin,
  Phenobarbital or
  Primidone† and NOT
  TAKING Valproate*

  Weeks
  1 and 2

  0.15 mg/kg/day
  in 1 or 2 divided doses,
  rounded down to the
  nearest whole tablet (see
  Table 3 for weight based
  dosing guide).

  0.3 mg/kg/day
  in 1 or 2 divided doses,
  rounded down to the
  nearest whole tablet.

  0.6 mg/kg/day
  in 2 divided doses,
  rounded down to the
  nearest whole tablet.

  Weeks
  3 and 4

  0.3 mg/kg/day

  in 1 or 2 divided doses,
  rounded down to the
  nearest whole tablet
  (see Table 3 for weight
  based dosing guide).

  0.6 mg/kg/day
  in 2 divided doses,
  rounded down to the
  nearest whole tablet.

  1.2 mg/kg/day
  in 2 divided doses,
  rounded down to the
  nearest whole tablet.

  Week 5
  onwards to
  

  maintenance

  The dose should be
  increased every 1 to
  2 weeks as follows:
  calculate 0.3 mg/kg/day, round this amount down to the nearest whole tablet
  and add this
  amount to the previously
  administered daily dose.

  The dose should be increased every 1 to 2 weeks as follows: calculate 0.6 mg/kg/day,

  round this amount down to the nearest whole tablet and add this amount to the previously administered daily dose.

  The dose should be
  increased every 1 to 2 weeks as follows:
  calculate
  1.2 mg/kg/day, round this amount
  down to the nearest
  whole tablet and
  add this amount to
  the previously
  administered daily
  dose.

  Usual

  Maintenance

  Dose

  1 to 5 mg/kg/day
  (maximum 200 mg/day in
  1 or 2 divided doses).
  1 to 3 mg/kg/day with
  valproate alone.

  4.5 to 7.5 mg/kg/day
  (maximum 300 mg/day in 2 divided doses).

  5 to 15 mg/kg/day
  (maximum 400 mg/day in 2 divided doses).

  Maintenance

  dose in

  patients less

  than 30 kg

  May need to be increased
  by as much as 50%, based
  on clinical response.

  May need to be increased by as much as 50%, based on clinical response.

  May need to be
  increased by as
  much as 50%, based
  on clinical response.

  Note: Only whole tablets should be used for dosing.

  Table 3. The Initial Weight-Based Dosing Guide for Patients 2 to 12 Years of Age taking Valproate (Weeks 1 to 4) with Epilepsy

  If the patient's weight is

  Give this daily dose, using the most appropriate combination of lamotrigine 2 mg and 5 mg tablets

  Greater than

  And less than

  Weeks 1 and 2

  Weeks 3 and 4

  6.7 kg

  14 kg

  2 mg every other day

  2 mg every day

  14.1 kg

  27 kg

  2 mg every day

  4 mg every day

  27.1 kg

  34 kg

  4 mg every day

  8 mg every day

  34.1 kg

  40 kg

  5 mg every day

  10 mg every day

  Usual Adjunctive Maintenance Dose for Epilepsy

  The usual maintenance doses identified in Tables 1 and 2 are derived from dosing regimens employed in the placebo-controlled adjunctive studies in which the efficacy of lamotrigine was established. In patients receiving multidrug regimens employing carbamazepine, phenytoin, phenobarbital or primidone without valproate, maintenance doses of adjunctive lamotrigine tablets as high as 700 mg/day have been used. In patients receiving valproate alone, maintenance doses of adjunctive lamotrigine tablets as high as 200 mg/day have been used. The advantage of using doses above those recommended in Tables 1 through 4 has not been established in controlled trials.

  2.3 Epilepsy – Conversion from Adjunctive Therapy to Monotherapy

  The goal of the transition regimen is to effect the conversion to monotherapy with lamotrigine tablets under conditions that ensure adequate seizure control while mitigating the risk of serious rash associated with the rapid titration of lamotrigine.

  The recommended maintenance dose of lamotrigine tablets as monotherapy is 500 mg/day given in two divided doses.

  To avoid an increased risk of rash, the recommended initial dose and subsequent dose escalations of lamotrigine tablets should not be exceeded [see Boxed Warning].

  Conversion from Adjunctive Therapy with Carbamazepine, Phenytoin, Phenobarbital or Primidone to Monotherapy with Lamotrigine Tablets

  After achieving a dose of 500 mg/day of lamotrigine tablets according to the guidelines in Table 1, the concomitant AED should be withdrawn by 20% decrements each week over a 4-week period. The regimen for the withdrawal of the concomitant AED is based on experience gained in the controlled monotherapy clinical trial.

  Conversion from Adjunctive Therapy with Valproate to Monotherapy with Lamotrigine Tablets

  The conversion regimen involves four steps outlined in Table 4.

  Table 4. Conversion from Adjunctive Therapy with Valproate to Monotherapy with Lamotrigine Tablets in Patients ≥ 16 Years of Age with Epilepsy

  Lamotrigine Tablets

  Valproate

  Step 1

  Achieve a dose of 200 mg/day according to
  guidelines in Table 1 (if not already on

  200 mg/day).

  Maintain previous stable dose.

  Step 2

  Maintain at 200 mg/day.

  Decrease to 500 mg/day by
  decrements no greater than
  500 mg/day/week and then
  maintain the dose of
  500 mg/day for one week.

  Step 3

  Increase to 300 mg/day and maintain
  for one week.

  Simultaneously decrease to
  250 mg/day and maintain for
  one week.

  Step 4

  Increase by 100 mg/day every week to achieve
  maintenance dose of 500 mg/day.

  Discontinue.

  Conversion from Adjunctive Therapy with Antiepileptic Drugs Other than Carbamazepine, Phenytoin, Phenobarbital, Primidone or Valproate to Monotherapy with Lamotrigine Tablets

  No specific dosing guidelines can be provided for conversion to monotherapy with lamotrigine tablets with AEDs other than carbamazepine, phenobarbital, phenytoin, primidone or valproate.

  2.4 Bipolar Disorder

  The goal of maintenance treatment with lamotrigine tablets is to delay the time to occurrence of mood episodes (depression, mania, hypomania, mixed episodes) in patients treated for acute mood episodes with standard therapy. The target dose of lamotrigine tablets is 200 mg/day (100 mg/day in patients taking valproate, which decreases the apparent clearance of lamotrigine and 400 mg/day in patients not taking valproate and taking either carbamazepine, phenytoin, phenobarbital, primidone or other drugs such as rifampin that increase the apparent clearance of lamotrigine). In the clinical trials, doses up to 400 mg/day as monotherapy were evaluated; however, no additional benefit was seen at 400 mg/day compared with 200 mg/day [see Clinical Studies (14.2)]. Accordingly, doses above 200 mg/day are not recommended. Treatment with lamotrigine tablets is introduced, based on concurrent medications, according to the regimen outlined in Table 5. If other psychotropic medications are withdrawn following stabilization, the dose of lamotrigine tablets should be adjusted. For patients discontinuing valproate, the dose of lamotrigine tablets should be doubled over a 2-week period in equal weekly increments (see Table 6). For patients discontinuing carbamazepine, phenytoin, phenobarbital, primidone or other drugs such as rifampin that induce lamotrigine glucuronidation, the dose of lamotrigine tablets should remain constant for the first week and then should be decreased by half over a 2-week period in equal weekly decrements (see Table 6). The dose of lamotrigine tablets may then be further adjusted to the target dose (200 mg) as clinically indicated.

  If other drugs are subsequently introduced, the dose of lamotrigine tablets may need to be adjusted. In particular, the introduction of valproate requires reduction in the dose of lamotrigine tablets [see Drug Interactions (7), Clinical Pharmacology (12.3)].

  To avoid an increased risk of rash, the recommended initial dose and subsequent dose escalations of lamotrigine tablets should not be exceeded [see Boxed Warning].

  Table 5. Escalation Regimen for Lamotrigine Tablets for Patients with Bipolar Disorder * Valproate has been shown to inhibit glucuronidation and decrease the apparent clearance of lamotrigine [see Drug Interactions (7), Clinical Pharmacology (12.3)]. † These drugs induce lamotrigine glucuronidation and increase clearance [see Drug Interactions (7), Clinical Pharmacology (12.3)]. Other drugs that have similar effects include estrogen-containing oral contraceptives [see Drug Interactions (7), Clinical Pharmacology (12.3)]. Dosing recommendations for oral contraceptives can be found in General Dosing Considerations [see Dosage and Administration (2.1)]. Patients on rifampin, or other drugs that induce lamotrigine glucuronidation and increase clearance, should follow the same dosing titration/maintenance regimen as that used with anticonvulsants that have this effect.

  For Patients
  TAKING
  Valproate*

  For Patients NOT
  TAKING
  Carbamazepine,
  Phenytoin,
  Phenobarbital,
  Primidone† or
  Valproate*

  For Patients
  TAKING
  Carbamazepine,
  Phenytoin, Phenobarbital or
  Primidone† and
  NOT TAKING
  Valproate*

  Weeks 1 and 2

  25 mg every other day

  25 mg daily

  50 mg daily

  Weeks 3 and 4

  25 mg daily

  50 mg daily

  100 mg daily, in divided doses

  Week 5

  50 mg daily

  100 mg daily

  200 mg daily, in divided doses

  Week 6

  100 mg daily

  200 mg daily

  300 mg daily, in divided doses

  Week 7

  100 mg daily

  200 mg daily

  up to 400 mg daily, in divided doses

  Table 6. Dosage Adjustments to Lamotrigine Tablets for Patients with Bipolar Disorder Following Discontinuation of Psychotropic Medications * These drugs induce lamotrigine glucuronidation and increase clearance [see Drug Interactions (7), Clinical Pharmacology (12.3)]. Other drugs that have similar effects include estrogen-containing oral contraceptives [see Drug Interactions (7), Clinical Pharmacology (12.3)]. Dosing recommendations for oral contraceptives can be found in General Dosing Considerations [see Dosage and Administration (2.1)]. Patients on rifampin, or other drugs that induce lamotrigine glucuronidation and increase clearance, should follow the same dosing titration/maintenance regimen as that used with anticonvulsants that have this effect. † Valproate has been shown to inhibit glucuronidation and decrease the apparent clearance of lamotrigine [see Drug Interactions (7), Clinical Pharmacology (12.3)].

  Discontinuation of
  Psychotropic Drugs
  (excluding Carbamazepine,
  Phenytoin, Phenobarbital,
  Primidone*
  or Valproate†)

  After
  Discontinuation
  of Valproate†

  After Discontinuation
  of Carbamazepine,
  Phenytoin,
  Phenobarbital or
  Primidone*

  Current dose of lamotrigine tablets (mg/day)
  100

  Current dose of lamotrigine tablets (mg/day)
  400

  Week 1

  Maintain current dose of lamotrigine tablets

  150

  400

  Week 2

  Maintain current dose of lamotrigine tablets

  200

  300

  Week 3 onward

  Maintain current dose of lamotrigine tablets

  200

  200

  The benefit of continuing treatment in patients who had been stabilized in an 8- to 16-week open-label phase with lamotrigine tablets was established in two randomized, placebo-controlled clinical maintenance trials [see Clinical Studies (14.2)]. However, the optimal duration of treatment with lamotrigine tablets has not been established. Thus, patients should be periodically reassessed to determine the need for maintenance treatment.

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  Dosing is based on concomitant medications, indication, and patient age. ( 2.2 , 2.4 ) To avoid an increased risk of rash, the recommended initial dose and subsequent dose escalations should not be exceeded. ( 2.1 ) Do not restart lamotrigine in patients who discontinued due to rash unless the potential benefits clearly outweigh the risks. ( 2.1 ) Adjustments to maintenance doses will in most cases be required in patients starting or stopping estrogen-containing oral contraceptives. ( 2.1 , 5.8 ) Lamotrigine tablets should be discontinued over a period of at least 2 weeks (approximately 50% reduction per week). ( 2.1 , 5.9 )

  Epilepsy

  Adjunctive therapy—See Table 1 for patients >12 years of age and Tables 2 and 3 for patients 2 to 12 years. ( 2.2 ) Conversion to monotherapy—See Table 4. ( 2.3 )

  Bipolar Disorder: See Tables 5 and 6 ( 2.4 )

   

  Rash: There are suggestions, yet to be proven, that the risk of severe, potentially life-threatening rash may be increased by (1) coadministration of lamotrigine tablets with valproate, (2) exceeding the recommended initial dose of lamotrigine tablets, or (3) exceeding the recommended dose escalation for lamotrigine tablets. However, cases have occurred in the absence of these factors [see Boxed Warning ]. Therefore, it is important that the dosing recommendations be followed closely.

  The risk of nonserious rash may be increased when the recommended initial dose and/or the rate of dose escalation of lamotrigine tablet is exceeded and in patients with a history of allergy or rash to other AEDs.

  It is recommended that lamotrigine tablets not be restarted in patients who discontinued due to rash associated with prior treatment with lamotrigine, unless the potential benefits clearly outweigh the risks. If the decision is made to restart a patient who has discontinued lamotrigine, the need to restart with the initial dosing recommendations should be assessed. The greater the interval of time since the previous dose, the greater consideration should be given to restarting with the initial dosing recommendations. If a patient has discontinued lamotrigine for a period of more than 5 half-lives, it is recommended that initial dosing recommendations and guidelines be followed. The half-life of lamotrigine is affected by other concomitant medications [see Clinical Pharmacology (12.3) ].

  Lamotrigine Tablets Added to Drugs Known to Induce or Inhibit Glucuronidation: Drugs other than those listed in the Clinical Pharmacology section [see Clinical Pharmacology (12.3) ] have not been systematically evaluated in combination with lamotrigine. Because lamotrigine is metabolized predominantly by glucuronic acid conjugation, drugs that are known to induce or inhibit glucuronidation may affect the apparent clearance of lamotrigine and doses of lamotrigine tablets may require adjustment based on clinical response.

  Target Plasma Levels for Patients With Epilepsy or Bipolar Disorder: A therapeutic plasma concentration range has not been established for lamotrigine. Dosing of lamotrigine tablets should be based on therapeutic response [see Clinical Pharmacology (12.3) ].

  Women Taking Estrogen-Containing Oral Contraceptives: Starting Lamotrigine Tablets  in Women Taking Estrogen-Containing Oral Contraceptives: Although estrogen-containing oral contraceptives have been shown to increase the clearance of lamotrigine [see Clinical Pharmacology (12.3) ], no adjustments to the recommended dose-escalation guidelines for lamotrigine tablets should be necessary solely based on the use of estrogen-containing oral contraceptives. Therefore, dose escalation should follow the recommended guidelines for initiating adjunctive therapy with lamotrigine tablets based on the concomitant AED or other concomitant medications (see Table 1 or Table 5). See below for adjustments to maintenance doses of lamotrigine tablets in women taking estrogen-containing oral contraceptives.

  Adjustments to the Maintenance Dose of Lamotrigine Tablets In Women Taking Estrogen-Containing Oral Contraceptives:

  (1) Taking Estrogen-Containing Oral Contraceptives: For women not taking carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin that induce lamotrigine glucuronidation [see Drug Interactions (7), Clinical Pharmacology (12.3)], the maintenance dose of lamotrigine  tablets will in most cases need to be increased, by as much as 2-fold over the recommended target maintenance dose, in order to maintain a consistent lamotrigine plasma level [see Clinical Pharmacology (12.3) ].

  (2) Starting Estrogen-Containing Oral Contraceptives: In women taking a stable dose of lamotrigine tablets and not taking carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin that induce lamotrigine glucuronidation [see Drug Interactions (7), Clinical Pharmacology (12.3)], the maintenance dose will in most cases need to be increased by as much as 2-fold in order to maintain a consistent lamotrigine plasma level. The dose increases should begin at the same time that the oral contraceptive is introduced and continue, based on clinical response, no more rapidly than 50 to 100 mg/day every week. Dose increases should not exceed the recommended rate (see Table 1 or Table 5) unless lamotrigine plasma levels or clinical response support larger increases. Gradual transient increases in lamotrigine plasma levels may occur during the week of inactive hormonal preparation ("pill-free" week), and these increases will be greater if dose increases are made in the days before or during the week of inactive hormonal preparation. Increased lamotrigine plasma levels could result in additional adverse reactions, such as dizziness, ataxia, and diplopia. If adverse reactions attributable to lamotrigine tablets consistently occur during the "pill-free" week, dose adjustments to the overall maintenance dose may be necessary. Dose adjustments limited to the "pill-free" week are not recommended. For women taking lamotrigine tablets in addition to carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin that induce lamotrigine glucuronidation [see Drug Interactions (7), Clinical Pharmacology (12.3)], no adjustment to the dose of lamotrigine tablets should be necessary.

  (3) Stopping Estrogen-Containing Oral Contraceptives: For women not taking carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin that induce lamotrigine glucuronidation [see Drug Interactions (7), Clinical Pharmacology (12.3)], the maintenance dose of lamotrigine tablets will in most cases need to be decreased by as much as 50% in order to maintain a consistent lamotrigine plasma level. The decrease in dose of lamotrigine tablets should not exceed 25% of the total daily dose per week over a 2-week period, unless clinical response or lamotrigine plasma levels indicate otherwise [see Clinical Pharmacology (12.3) ]. For women taking lamotrigine tablets in addition to carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin that induce lamotrigine glucuronidation [see Drug Interactions (7), Clinical Pharmacology (12.3)], no adjustment to the dose of lamotrigine tablets should be necessary.

  Women and Other Hormonal Contraceptive Preparations or Hormone Replacement Therapy: The effect of other hormonal contraceptive preparations or hormone replacement therapy on the pharmacokinetics of lamotrigine has not been systematically evaluated. It has been reported that ethinylestradiol, not progestogens, increased the clearance of lamotrigine up to 2-fold, and the progestin-only pills had no effect on lamotrigine plasma levels. Therefore, adjustments to the dosage of lamotrigine tablets in the presence of progestogens alone will likely not be needed.

  Patients With Hepatic Impairment: Experience in patients with hepatic impairment is limited. Based on a clinical pharmacology study in 24 patients with mild, moderate, and severe liver impairment [see Use in Specific Populations (8.6) , Clinical Pharmacology (12.3) ], the following general recommendations can be made. No dosage adjustment is needed in patients with mild liver impairment. Initial, escalation, and maintenance doses should generally be reduced by approximately 25% in patients with moderate and severe liver impairment without ascites and 50% in patients with severe liver impairment with ascites. Escalation and maintenance doses may be adjusted according to clinical response.

  Patients With Renal Impairment: Initial doses of lamotrigine tablets should be based on patients' concomitant medications (see Tables 1-3 or Table 5); reduced maintenance doses may be effective for patients with significant renal impairment [see Use in Specific Populations (8.7) , Clinical Pharmacology (12.3) ]. Few patients with severe renal impairment have been evaluated during chronic treatment with lamotrigine tablets. Because there is inadequate experience in this population, lamotrigine tablets should be used with caution in these patients.

  Discontinuation Strategy:

  Epilepsy: For patients receiving lamotrigine tablets in combination with other AEDs, a reevaluation of all AEDs in the regimen should be considered if a change in seizure control or an appearance or worsening of adverse reactions is observed.

  If a decision is made to discontinue therapy with lamotrigine tablets, a step-wise reduction of dose over at least 2 weeks (approximately 50% per week) is recommended unless safety concerns require a more rapid withdrawal [see Warnings and Precautions (5.9) ].

  Discontinuing carbamazepine, phenytoin, phenobarbital, primidone or other drugs such as rifampin that induce lamotrigine glucuronidation should prolong the half-life of lamotrigine; discontinuing valproate should shorten the half-life of lamotrigine.

  Bipolar Disorder: In the controlled clinical trials, there was no increase in the incidence, type, or severity of adverse reactions following abrupt termination of lamotrigine tablets. In clinical trials in patients with Bipolar Disorder, 2 patients experienced seizures shortly after abrupt withdrawal of lamotrigine tablets. However, there were confounding factors that may have contributed to the occurrence of seizures in these bipolar patients. Discontinuation of lamotrigine tablets should involve a step-wise reduction of dose over at least 2 weeks (approximately 50% per week) unless safety concerns require a more rapid withdrawal [see Warnings and Precautions (5.9) ].

   

  This section provides specific dosing recommendations for patients greater than 12 years of age and patients 2 to 12 years of age. Within each of these age-groups, specific dosing recommendations are provided depending upon concomitant AED or other concomitant medications (Table 1 for patients greater than 12 years of age and Table 2 for patients 2 to 12 years of age). A weight-based dosing guide for patients 2 to 12 years of age on concomitant valproate is provided in Table 3.

  Patients Over 12 Years of Age: Recommended dosing guidelines are summarized in Table 1.

  Table 1. Escalation Regimen for Lamotrigine Tablets in Patients Over 12 Years of Age With Epilepsy
  For 
  For Patients NOT TAKING 
  For Patients 
  
  Patients
  Carbamazepine, 
  TAKING
  
  TAKING
  Phenytoin,
  Carbamazepine,
  
  Valproatea
  Phenobarbital,
  Phenytoin, 
  
  
  or Primidoneb,  
  Phenobarbital,
  
  
  or Valproatea
  or Primidoneb
  
  
  
  and NOT TAKING
  
  
  
  Valproatea
  Weeks 1 and 2
  25 mg every other day
  25 mg every day
  50 mg/day
  Weeks 3 and 4
  25 mg every day
  50 mg/day
  100 mg/day
  (in 2 divided doses)
  Weeks 5 onwards to 
  maintenance
  Increase by 25 to 
  50 mg/day every 1 to 2 weeks
  Increase by 50
  mg/day every 1
  to 2 weeks
  Increase by 
  100 mg/day every 
  1 to 2 weeks.
  Usual maintenance 
  dose
  100 to 200 mg/day
  with valproate alone
  225 to 375 mg/day
  (in 2 divided doses).
  300 to 500 mg/day
  (in 2 divided doses).
  
  100 to 400 mg/day
  with valproate
  and other drugs that induce glucuronidation
  
  
  
  (in 1 or 2 divided doses)
  
  
  

  a Valproate has been shown to inhibit glucuronidation and decrease the apparent clearance of lamotrigine [see Drug Interactions (7), Clinical Pharmacology (12.3)].

  b These drugs induce lamotrigine glucuronidation and increase clearance [see Drug Interactions (7), Clinical Pharmacology (12.3)]. Other drugs that have similar effects include estrogen-containing oral contraceptives [see Drug Interactions (7), Clinical Pharmacology (12.3)]. Dosing recommendations for oral contraceptives can be found in General Dosing Considerations [see Dosage and Administration (2.1)]. Patients on rifampin, or other drugs that induce lamotrigine glucuronidation and increase clearance, should follow the same dosing titration/maintenance regimen as that used with anticonvulsants that have this effect.

  Patients 2 to 12 Years Of Age: Recommended dosing guidelines are summarized in Table 2.

  Smaller starting doses and slower dose escalations than those used in clinical trials are recommended because of the suggestion that the risk of rash may be decreased by smaller starting doses and slower dose escalations. Therefore, maintenance doses will take longer to reach in clinical practice than in clinical trials. It may take several weeks to months to achieve an individualized maintenance dose. Maintenance doses in patients weighing less than 30 kg, regardless of age or concomitant AED, may need to be increased as much as 50%, based on clinical response.

  Table 2. Escalation Regimen for Lamotrigine Tablets in Patients 2 to 12 Years of Age With Epilepsy
  For Patients TAKING 
  Valproatea
  For Patients NOT 
  TAKING Carbamazepine, Phenytoin, 
  Phenobarbital, Primidoneb, or 
  Valproatea
  For Patients TAKING 
  Carbamazepine, Phenytoin, Phenobarbital, or 
  Primidoneb and NOT 
  TAKING Valproatea
  Weeks 1 and 2
  0.15 mg/kg/day
  in 1 or 2 divided doses, rounded down to the 
  nearest whole tablet (see Table 3 for weight 
  based dosing guide).
  0.3 mg/kg/day
  in 1 or 2 divided doses, rounded down to the 
  nearest whole tablet.
  0.6 mg/kg/day
  in 2 divided doses, rounded down to the 
  nearest whole tablet.
  Weeks 3 and 4
  0.3 mg/kg/day
  in 1 or 2 divided doses,
  rounded down to the 
  nearest whole tablet 
  (see Table 3 for weight 
  based dosing guide).
  0.6 mg/kg/day
  in 2 divided doses,
  rounded down to the 
  nearest whole tablet.
  1.2 mg/kg/day
  in 2 divided doses, 
  rounded down to the 
  nearest whole tablet.
  Weeks 5 
  onwards to 
  maintenance
  The dose should be increased every 
  1 to 2 weeks as follows:
  calculate 0.3 mg/kg/day, round this amount 
  down to the nearest whole tablet, and 
  add this amount to the 
  previously administered daily dose.
  The dose should be increased every 
  1 to 2 weeks as follows:
  calculate 0.6 mg/kg/day, round this amount 
  down to the nearest whole tablet, and 
  add this amount to the 
  previously administered daily dose
  The dose should be increased every 
  1 to 2 weeks as follows:
  calculate 1.2 mg/kg/day, round this amount 
  down to the nearest whole tablet, and 
  add this amount to the 
  previously administered daily dose
  Usual 
  Maintenance 
  Dose
  1 to 5 mg/kg/day
  (maximum 200 mg/day 
  in 1 or 2 divided doses).
  1 to 3 mg/kg/day with valproate alone
  4.5 to 7.5 mg/kg/day
  (maximum 300 mg/day 
  in 2 divided doses)
  5 to 15 mg/kg/day
  (maximum 400 mg/day 
  in 2 divided doses)
  Maintenance dose in 
  patients 
  less than 30 kg
  May need to be increased 
  by as much as 50%, 
  based on clinical response
  May need to be increased 
  by as much as 50%, 
  based on clinical response
  May need to be increased 
  by as much as 50%, based 
  on clinical response
  

  Note: Only whole tablets should be used for dosing.

  a Valproate has been shown to inhibit glucuronidation and decrease the apparent clearance of lamotrigine [see Drug Interactions (7), Clinical Pharmacology (12.3)].

  b These drugs induce lamotrigine glucuronidation and increase clearance [see Drug Interactions (7), Clinical Pharmacology (12.3)]. Other drugs which have similar effects include estrogen-containing oral contraceptives [see Drug Interactions (7), Clinical Pharmacology (12.3)]. Dosing recommendations for oral contraceptives can be found in General Dosing Considerations [see Dosage and Administration (2.1)]. Patients on rifampin, or other drugs that induce lamotrigine glucuronidation and increase clearance, should follow the same dosing titration/maintenance regimen as that used with anticonvulsants that have this effect.

  Table 3. The Initial Weight-Based Dosing Guide for Patients 2 to 12 Years Taking Valproate (Weeks 1 to 4) With Epilepsy If the patient’s weight is
  Give this daily dose, using the most appropriate combination of Lamotrigine 2-mg and 5-mg tablets
  Greater than
  And less than
  Weeks 1 and 2
  Weeks 3 and 4
  6.7 kg
  14 kg
  2 mg every other day
  2 mg every day
  14.1 kg
  27 kg
  2 mg every day
  4 mg every day
  27.1 kg
  34 kg
  4 mg every day
  8 mg every day
  34.1 kg
  40 kg
  5 mg every day
  10 mg every day
  

  Usual Adjunctive Maintenance Dose for Epilepsy: The usual maintenance doses identified in Tables 1 and 2 are derived from dosing regimens employed in the placebo-controlled adjunctive studies in which the efficacy of lamotrigine tablets was established. In patients receiving multidrug regimens employing carbamazepine, phenytoin, phenobarbital, or primidone without valproate, maintenance doses of adjunctive lamotrigine tablets as high as 700 mg/day have been used. In patients receiving valproate alone, maintenance doses of adjunctive lamotrigine tablets as high as 200 mg/day have been used. The advantage of using doses above those recommended in Tables 1 through 4 has not been established in controlled trials.

   

  The goal of the transition regimen is to effect the conversion to monotherapy with lamotrigine tablets under conditions that ensure adequate seizure control while mitigating the risk of serious rash associated with the rapid titration of lamotrigine tablets.

  The recommended maintenance dose of lamotrigine tablets as monotherapy is 500 mg/day given in two divided doses.

  To avoid an increased risk of rash, the recommended initial dose and subsequent dose escalations of lamotrigine tablets should not be exceeded [see Boxed Warning].

  Conversion From Adjunctive Therapy With Carbamazepine, Phenytoin, Phenobarbital, or Primidone to Monotherapy With Lamotrigine Tablets: After achieving a dose of 500 mg/day of lamotrigine tablets according to the guidelines in Table 1, the concomitant AED should be withdrawn by 20% decrements each week over a 4-week period. The regimen for the withdrawal of the concomitant AED is based on experience gained in the controlled monotherapy clinical trial.

  Conversion from Adjunctive Therapy With Valproate to Monotherapy With Lamotrigine Tablets:

  The conversion regimen involves 4 steps outlined in Table 4.

  Table 4. Conversion From Adjunctive Therapy With Valproate to Monotherapy With Lamotrigine Tablets in Patients ≥16 Years of Age with Epilepsy
  Lamotrigine Tablets
  Valproate
  Step 1
  Achieve a dose of 200 mg/day according to
  guidelines in Table 1
  (if not already on 200 mg/day).
  Maintain previous stable dose.
  Step 2
  Maintain at 200 mg/day.
  Decrease to 500 mg/day by decrements no greater than
  500 mg/day/week and then maintain the dose of
  500 mg/day for 1 week.
  Step 3
  Increase to 300 mg/day and maintain for 1 week.
  Simultaneously decrease to
  250 mg/day and maintain for 1 week.
  Step 4
  Increase by 100 mg/day every
  week to achieve maintenance dose of 500 mg/day.
  Discontinue.
  

  Conversion from Adjunctive Therapy With AEDs Other Than Carbamazepine, Phenytoin, Phenobarbital, Primidone, or Valproate to Monotherapy With Lamotrigine Tablets: No specific dosing guidelines can be provided for conversion to monotherapy with lamotrigine tablets with AEDs other than carbamazepine, phenobarbital, phenytoin, primidone, or valproate.

   

  The goal of maintenance treatment with lamotrigine tablets is to delay the time to occurrence of mood episodes (depression, mania, hypomania, mixed episodes) in patients treated for acute mood episodes with standard therapy. The target dose of lamotrigine tablets is 200 mg/day (100 mg/day in patients taking valproate, which decreases the apparent clearance of lamotrigine, and 400 mg/day in patients not taking valproate and taking either carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin that increase the apparent clearance of lamotrigine). In the clinical trials, doses up to 400 mg/day as monotherapy were evaluated; however, no additional benefit was seen at 400 mg/day compared with 200 mg/day [see Clinical Studies (14.2) ]. Accordingly, doses above 200 mg/day are not recommended. Treatment with lamotrigine tablets is introduced, based on concurrent medications, according to the regimen outlined in Table 5. If other psychotropic medications are withdrawn following stabilization, the dose of lamotrigine tablets should be adjusted. For patients discontinuing valproate, the dose of lamotrigine tablets should be doubled over a 2-week period in equal weekly increments (see Table 6). For patients discontinuing carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin that induce lamotrigine glucuronidation, the dose of lamotrigine tablets should remain constant for the first week and then should be decreased by half over a 2-week period in equal weekly decrements (see Table 6). The dose of lamotrigine tablets may then be further adjusted to the target dose (200 mg) as clinically indicated.

  If other drugs are subsequently introduced, the dose of lamotrigine tablets may need to be adjusted. In particular, the introduction of valproate requires reduction in the dose of lamotrigine tablets [see Drug Interactions (7) , Clinical Pharmacology (12.3) ].

  To avoid an increased risk of rash, the recommended initial dose and subsequent dose escalations of lamotrigine tablets should not be exceeded [see Boxed Warning ].

  Table 5. Escalation Regimen for Lamotrigine Tablets for Patients With Bipolar Disorder
  For Patients TAKING 
  Valproatea
  For Patients NOT TAKING 
  Carbamazepine, Phenytoin, Phenobarbital, 
  Primidoneb, or Valproatea
  For Patients TAKING 
  Carbamazepine, Phenytoin,
  Phenobarbital, or Primidoneb and NOT TAKING 
  Valproatea
  Weeks 1 and 2
  25 mg every 
  other day
  25 mg daily
  50 mg daily
  Weeks 3 and 4
  25 mg daily
  50 mg daily
  100 mg daily, in divided doses
  Week 5
  50 mg daily
  100 mg daily
  200 mg daily, in divided doses
  Week 6
  100 mg daily
  200 mg daily
  300 mg daily, in divided doses
  Week 7
  100 mg daily
  200 mg daily
  up to 400 mg daily, in divided doses
  

  a Valproate has been shown to inhibit glucuronidation and decrease the apparent clearance of lamotrigine [see Drug Interactions (7), Clinical Pharmacology (12.3)].

  
  

  b These drugs induce lamotrigine glucuronidation and increase clearance [see Drug Interactions (7), Clinical Pharmacology (12.3)]. Other drugs which have similar effects include estrogen-containing oral contraceptives [see Drug Interactions (7), Clinical Pharmacology (12.3)]. Dosing recommendations for oral contraceptives can be found in General Dosing Considerations [see Dosage and Administration (2.1)]. Patients on rifampin, or other drugs that induce lamotrigine glucuronidation and increase clearance, should follow the same dosing titration/maintenance regimen as that used with anticonvulsants that have this effect.

  Table 6. Dosage Adjustments to Lamotrigine Tablets for Patients With Bipolar Disorder Following Discontinuation of Psychotropic Medications
  Discontinuation of Psychotropic Drugs 
  (excluding Carbamazepine, Phenytoin, 
  Phenobarbital, Primidoneb, or 
  Valproatea)
  After Discontinuation of 
  Valproatea
  After Discontinuation of 
  Carbamazepine, Phenytoin, 
  Phenobarbital, or Primidoneb
  
  
  Current dose of lamotrigine tablets
  (mg/day)
  100
  Current dose of lamotrigine tablets
  (mg/day)
  400
  Week 1
  Maintain current dose of lamotrigine tablets
  150
  400
  Week 2
  Maintain current dose of lamotrigine tablets
  200
  300
  Week 3 onward
  Maintain current dose of lamotrigine tablets
  200
  200
  

  The benefit of continuing treatment in patients who had been stabilized in an 8- to 16-week open-label phase with lamotrigine tablets was established in two randomized, placebo-controlled clinical maintenance trials [see Clinical Studies (14.2) ]. However, the optimal duration of treatment with lamotrigine tablets has not been established. Thus, patients should be periodically reassessed to determine the need for maintenance treatment.

   

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  Lamotrigine | X-gen Pharmaceuticals, Inc.

  

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  Dosage

  
  2.1 Dosage

  PANCRELIPASE is not interchangeable with other pancrelipase products other than ZENPEP ®.

  PANCRELIPASE is orally administered. Therapy should be initiated at the lowest recommended dose and gradually increased. The dosage of PANCRELIPASE should be individualized based on clinical symptoms, the degree of steatorrhea present, and the fat content of the diet (see Limitations on Dosing below).

  Dosage recommendations for pancreatic enzyme replacement therapy were published following the Cystic Fibrosis Foundation Consensus Conferences. 1, 2, 3 PANCRELIPASE should be administered in a manner consistent with the recommendations of the Conferences provided in the following paragraphs. Patients may be dosed on a fat ingestion based or actual body weight based dosing scheme.

  Infants (up to 12 months)                                                                                                                                                                                 Infants may be given 3,000 lipase units (one capsule) per 120 mL of formula or per breast-feeding. Do not mix PANCRELIPASE capsule contents directly into formula or breast milk prior to administration [see Dosage and Administration (2.2)].

  Children Older than 12 Months and Younger than 4 Years                                                                                                                              Enzyme dosing should begin with 1,000 lipase units/kg of body weight per meal for children less than age 4 years to a maximum of 2,500 lipase units/kg of body weight per meal (or less than or equal to 10,000 lipase units/kg of body weight per day), or less than 4,000 lipase units/g fat ingested per day.

  Children 4 Years and Older and Adults                                                                                                                                                       Enzyme dosing should begin with 500 lipase units/kg of body weight per meal for those older than age 4 years to a maximum of 2,500 lipase units/kg of body weight per meal (or less than or equal to 10,000 lipase units/kg of body weight per day), or less than 4,000 lipase units/g fat ingested per day.

  Usually, half of the prescribed PANCRELIPASE dose for an individualized full meal should be given with each snack. The total daily dose should reflect approximately three meals plus two or three snacks per day.

  Enzyme doses expressed as lipase units/kg of body weight per meal should be decreased in older patients because they weigh more but tend to ingest less fat per kilogram of body weight.

  Limitations on Dosing                                                                                                                                                                                    Dosing should not exceed the recommended maximum dosage set forth by the Cystic Fibrosis Foundation Consensus Conferences Guidelines. 1, 2, 3

  If symptoms and signs of steatorrhea persist, the dosage may be increased by a healthcare professional. Patients should be instructed not to increase the dosage on their own. There is great inter individual variation in response to enzymes; thus, a range of doses is recommended. Changes in dosage may require an adjustment period of several days. If doses are to exceed 2,500 lipase units/kg of body weight per meal, further investigation is warranted.

  Doses greater than 2,500 lipase units/kg of body weight per meal (or greater than 10,000 lipase units/kg of body weight per day) should be used with caution and only if they are documented to be effective by 3-day fecal fat measures that indicate a significantly improved coefficient of fat absorption. Doses greater than 6,000 lipase units/kg of body weight per meal have been associated with colonic strictures, indicative of fibrosing colonopathy, in children with cystic fibrosis less than 12 years of age [see Warnings and Precautions (5.1)]. Patients currently receiving higher doses than 6,000 lipase units/kg of body weight per meal should be examined and the dosage either immediately decreased or titrated downward to a lower range.

  2.2 Administration

  PANCRELIPASE should always be taken as prescribed by a healthcare professional.

  Infants (up to 12 Months)                                                                                                                                                              PANCRELIPASE should be administered to infants immediately prior to each feeding, using a dosage of 2,000 to 4,000 lipase units per 120 mL of formula or per breast-feeding. Contents of the capsule may be administered with a small amount of applesauce, or other acidic food with a pH of 4.5 or less (e.g., commercially available preparations of bananas, or pears). Contents of the capsule may also be administered directly to the mouth. Administration should be followed by breast milk or formula. Contents of the capsule should not be mixed directly into formula or breast milk as this may diminish efficacy. Care should be taken to ensure that PANCRELIPASE is not crushed or chewed or retained in the mouth, to avoid irritation of the oral mucosa.

  Children and Adults                                                                                                                                                                       PANCRELIPASE should be taken during meals or snacks, with sufficient fluid. PANCRELIPASE capsules and capsule contents should not be crushed or chewed. Capsules should be swallowed whole.

  For patients who are unable to swallow intact capsules, the capsules may be carefully opened and the contents sprinkled on small amounts of acidic soft food of pH 4.5 or less (e.g., commercially available preparations of bananas, pears and applesauce).

  The PANCRELIPASE-soft food mixture should be swallowed immediately without crushing or chewing, and followed with water or juice to ensure complete ingestion. Care should be taken to ensure that no drug is retained in the mouth.

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  Lamotrigine | Aurobindo Pharma Limited

  

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  2.1 General Dosing Considerations

  Rash
  
  There are suggestions, yet to be proven, that the risk of severe, potentially life-threatening rash may be increased by (1) coadministration of lamotrigine tablets with valproate, (2) exceeding the recommended initial dose of lamotrigine tablets, or (3) exceeding the recommended dose escalation for lamotrigine tablets. However, cases have occurred in the absence of these factors [see Boxed Warning]. Therefore, it is important that the dosing recommendations be followed closely.

  
  

  The risk of nonserious rash may be increased when the recommended initial dose and/or the rate of dose escalation for lamotrigine tablets is exceeded and in patients with a history of allergy or rash to other AEDs.

  
  

  It is recommended that lamotrigine tablets not be restarted in patients who discontinued due to rash associated with prior treatment with lamotrigine unless the potential benefits clearly outweigh the risks. If the decision is made to restart a patient who has discontinued lamotrigine tablets, the need to restart with the initial dosing recommendations should be assessed. The greater the interval of time since the previous dose, the greater consideration should be given to restarting with the initial dosing recommendations. If a patient has discontinued lamotrigine for a period of more than 5 half-lives, it is recommended that initial dosing recommendations and guidelines be followed. The half-life of lamotrigine is affected by other concomitant medications [see Clinical Pharmacology (12.3)].

  Lamotrigine Tablets Added to Drugs Known to Induce or Inhibit Glucuronidation
  
  Because lamotrigine is metabolized predominantly by glucuronic acid conjugation, drugs that are known to induce or inhibit glucuronidation may affect the apparent clearance of lamotrigine. Drugs that induce glucuronidation include carbamazepine, phenytoin, phenobarbital, primidone, rifampin, estrogen-containing oral contraceptives, and the protease inhibitors lopinavir/ritonavir and atazanavir/ritonavir. Valproate inhibits glucuronidation. For dosing considerations for lamotrigine tablets in patients on estrogen-containing contraceptives and atazanavir/ritonavir, see below and Table 13. For dosing considerations for lamotrigine tablets in patients on other drugs known to induce or inhibit glucuronidation, see Table 1, Table 2, Table 5, Table 6, and Table 13.

  
  

  Target Plasma Levels for Patients With Epilepsy or Bipolar Disorder
  
  A therapeutic plasma concentration range has not been established for lamotrigine. Dosing of lamotrigine tablets should be based on therapeutic response [see Clinical Pharmacology (12.3)].

  
  

  Women Taking Estrogen-Containing Oral Contraceptives
  
  Starting Lamotrigine Tablets in Women Taking Estrogen-Containing Oral Contraceptives: Although estrogen-containing oral contraceptives have been shown to increase the clearance of lamotrigine [see Clinical Pharmacology (12.3)], no adjustments to the recommended dose-escalation guidelines for lamotrigine tablets should be necessary solely based on the use of estrogen-containing oral contraceptives. Therefore, dose escalation should follow the recommended guidelines for initiating adjunctive therapy with lamotrigine tablets based on the concomitant AED or other concomitant medications (see Table 1 or Table 5). See below for adjustments to maintenance doses of lamotrigine tablets in women taking estrogen-containing oral contraceptives.

  
  

  Adjustments to the Maintenance Dose of Lamotrigine Tablets in Women Taking Estrogen-Containing Oral Contraceptives

  (1) Taking Estrogen-Containing Oral Contraceptives: In women not taking carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin  and the protease inhibitors lopinavir/ritonavir and atazanavir/ritonavir that induce lamotrigine glucuronidation [see Drug Interactions (7), Clinical Pharmacology (12.3)], the maintenance dose of lamotrigine tablets will in most cases need to be increased by as much as 2-fold over the recommended target maintenance dose to maintain a consistent lamotrigine plasma level.

  
  

  (2) Starting Estrogen-Containing Oral Contraceptives:In women taking a stable dose of lamotrigine tablets and not taking carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin and the protease inhibitors lopinavir/ritonavir and atazanavir/ritonavir that induce lamotrigine glucuronidation [see Drug Interactions (7), Clinical Pharmacology (12.3)], the maintenance dose will in most cases need to be increased by as much as 2-fold to maintain a consistent lamotrigine plasma level. The dose increases should begin at the same time that the oral contraceptive is introduced and continue, based on clinical response, no more rapidly than 50 to 100 mg/day every week. Dose increases should not exceed the recommended rate (see Table 1 or Table 5) unless lamotrigine plasma levels or clinical response support larger increases. Gradual transient increases in lamotrigine plasma levels may occur during the week of inactive hormonal preparation (pill-free week), and these increases will be greater if dose increases are made in the days before or during the week of inactive hormonal preparation. Increased lamotrigine plasma levels could result in additional adverse reactions, such as dizziness, ataxia, and diplopia. If adverse reactions attributable to lamotrigine tablets consistently occur during the pill-free week, dose adjustments to the overall maintenance dose may be necessary. Dose adjustments limited to the pill-free week are not recommended. For women taking lamotrigine tablets in addition to carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin and the protease inhibitors lopinavir/ritonavir and atazanavir/ritonavir that induce lamotrigine glucuronidation [see Drug Interactions (7), Clinical Pharmacology (12.3)], no adjustment to the dose of lamotrigine tablets should be necessary.

  (3) Stopping Estrogen-Containing Oral Contraceptives: In women not taking carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin and the protease inhibitors lopinavir/ritonavir and atazanavir/ritonavir that induce lamotrigine glucuronidation [see Drug Interactions (7), Clinical Pharmacology (12.3)], the maintenance dose of lamotrigine tablets will in most cases need to be decreased by as much as 50% in order to maintain a consistent lamotrigine plasma level. The decrease in dose of lamotrigine tablets should not exceed 25% of the total daily dose per week over a 2-week period, unless clinical response or lamotrigine plasma levels indicate otherwise [see Clinical Pharmacology (12.3)]. In women taking lamotrigine tablets in addition to carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin and the protease inhibitors lopinavir/ritonavir and atazanavir/ritonavir that induce lamotrigine glucuronidation [see Drug Interactions (7), Clinical Pharmacology (12.3)], no adjustment to the dose of lamotrigine tablets should be necessary.

  
  

  Women and Other Hormonal Contraceptive Preparations or Hormone Replacement Therapy
  
  The effect of other hormonal contraceptive preparations or hormone replacement therapy on the pharmacokinetics of lamotrigine has not been systematically evaluated. It has been reported that ethinylestradiol, not progestogens, increased the clearance of lamotrigine up to 2-fold, and the progestin-only pills had no effect on lamotrigine plasma levels. Therefore, adjustments to the dosage of lamotrigine tablets in the presence of progestogens alone will likely not be needed.

  
  

  Patients Taking Atazanavir/Ritonavir
  
  While atazanavir/ritonavir does reduce the lamotrigine plasma concentration, no adjustments to the recommended dose-escalation guidelines for lamotrigine tablets should be necessary solely based on the use of atazanavir/ritonavir. Dose escalation should follow the recommended guidelines for initiating adjunctive therapy with lamotrigine tablets based on concomitant AED or other concomitant medications (see Tables 1, 2, and 5). In patients already taking maintenance doses of lamotrigine tablets and not taking glucuronidation inducers, the dose of lamotrigine tablets may need to be increased if atazanavir/ritonavir is added, or decreased if atazanavir/ritonavir is discontinued [see Clinical Pharmacology (12.3)].

  
  

  Patients With Hepatic Impairment
  
  Experience in patients with hepatic impairment is limited. Based on a clinical pharmacology study in 24 subjects with mild, moderate, and severe liver impairment [see Use in Specific Populations (8.6), Clinical Pharmacology (12.3)], the following general recommendations can be made. No dosage adjustment is needed in patients with mild liver impairment. Initial, escalation, and maintenance doses should generally be reduced by approximately 25% in patients with moderate and severe liver impairment without ascites and 50% in patients with severe liver impairment with ascites. Escalation and maintenance doses may be adjusted according to clinical response.

  
  

  Patients With Renal Impairment
  
  Initial doses of lamotrigine tablets should be based on patients' concomitant medications (see Tables 1 to 3 or Table 5); reduced maintenance doses may be effective for patients with significant renal impairment [see Use in Specific Populations (8.7), Clinical Pharmacology (12.3)]. Few patients with severe renal impairment have been evaluated during chronic treatment with lamotrigine tablets. Because there is inadequate experience in this population, lamotrigine tablets should be used with caution in these patients.

  
  

  Discontinuation Strategy
  
  Epilepsy: For patients receiving lamotrigine tablets in combination with other AEDs, a re-evaluation of all AEDs in the regimen should be considered if a change in seizure control or an appearance or worsening of adverse reactions is observed.

  
  

  If a decision is made to discontinue therapy with lamotrigine tablets, a step-wise reduction of dose over at least 2 weeks (approximately 50% per week) is recommended unless safety concerns require a more rapid withdrawal [see Warnings and Precautions (5.9)].

  Discontinuing carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin and the protease inhibitors lopinavir/ritonavir and atazanavir/ritonavir that induce lamotrigine glucuronidation should prolong the half-life of lamotrigine; discontinuing valproate should shorten the half-life of lamotrigine.

  
  

  Bipolar Disorder: In the controlled clinical trials, there was no increase in the incidence, type, or severity of adverse reactions following abrupt termination of lamotrigine tablets. In clinical trials in patients with bipolar disorder, 2 patients experienced seizures shortly after abrupt withdrawal of lamotrigine tablets. However, there were confounding factors that may have contributed to the occurrence of seizures in these patients with bipolar disorder. Discontinuation of lamotrigine tablets should involve a step-wise reduction of dose over at least 2 weeks (approximately 50% per week) unless safety concerns require a more rapid withdrawal [see Warnings and Precautions (5.9)].

  2.2 Epilepsy - Adjunctive Therapy

  This section provides specific dosing recommendations for patients older than 12 years and patients aged 2 to 12 years. Within each of these age-groups, specific dosing recommendations are provided depending upon concomitant AEDs or other concomitant medications (see Table 1 for patients older than 12 years and Table 2 for patients aged 2 to 12 years). A weight-based dosing guide for patients aged 2 to 12 years on concomitant valproate is provided in Table 3.

  
  

  Patients Older Than 12 Years

  
  

  Recommended dosing guidelines are summarized in    Table 1.

  
  Table 1. Escalation Regimen for Lamotrigine Tablets in Patients Older Than 12 Years With Epilepsy a  Valproate has been shown to inhibit glucuronidation and decrease the apparent clearance of lamotrigine [see Drug Interactions (7), Clinical Pharmacology (12.3)].
  b  Drugs that induce lamotrigine glucuronidation and increase clearance, other than the specified antiepileptic drugs, include estrogen-containing oral contraceptives, rifampin, and the protease inhibitors lopinavir/ritonavir and atazanavir/ritonavir. Dosing recommendations for oral contraceptives and the protease inhibitor atazanavir/ritonavir can be found in General Dosing Considerations [see Dosage and Administration (2.1)]. Patients on rifampin and the protease inhibitor lopinavir/ritonavir should follow the same dosing titration/maintenance regimen used with antiepileptic drugs that induce glucuronidation and increase clearance [see Dosage and Administration (2.1), Drug Interactions (7), and Clinical Pharmacology (12.3)].
   
  In Patients TAKING Valproatea
  In Patients NOT TAKING
  Carbamazepine,
  Phenytoin, Phenobarbital, Primidone,b or Valproatea
  In Patients TAKING Carbamazepine, Phenytoin, Phenobarbital, or Primidoneb and NOT TAKING Valproatea
  Weeks 1 and 2
  25 mg every other day
  25 mg every day
  50 mg/day
  Weeks 3 and 4
  25 mg every day
  50 mg/day
  100 mg/day
  (in 2 divided doses)
  Week 5 onward
  to maintenance
  Increase by 25 to
  50 mg/day every 1 to
  2 weeks.
  Increase by 50 mg/day
  every 1 to 2 weeks.
  Increase by
  100 mg/day every
  1 to 2 weeks.
  Usual maintenance
  dose
  100 to 200 mg/day with valproate alone
  100 to 400 mg/day with valproate and other drugs that induce glucuronidation
  (in 1 or 2 divided doses)
  225 to 375 mg/day
  (in 2 divided doses)
  300 to 500 mg/day
  (in 2 divided doses)
  

  Patients Aged 2 to 12 Years

  
  

  Recommended dosing guidelines are summarized in Table 2.

  
  

  Smaller starting doses and slower dose escalations than those used in clinical trials are recommended because of the suggestion that the risk of rash may be decreased by smaller starting doses and slower dose escalations. Therefore, maintenance doses will take longer to reach in clinical practice than in clinical trials. It may take several weeks to months to achieve an individualized maintenance dose. Maintenance doses in patients weighing less than 30 kg, regardless of age or concomitant AED, may need to be increased as much as 50%, based on clinical response.

   

  Table 2. Escalation Regimen for Lamotrigine Tablets in Patients Aged 2 to 12 Years With Epilepsy Note: Only whole tablets should be used for dosing. 
  a Valproate has been shown to inhibit glucuronidation and decrease the apparent clearance of lamotrigine [see Drug Interactions (7), Clinical Pharmacology (12.3)].
  b Drugs that induce lamotrigine glucuronidation and increase clearance, other than the specified antiepileptic drugs, include estrogen-containing oral contraceptives, rifampin, and the protease inhibitors lopinavir/ritonavir and atazanavir/ritonavir. Dosing recommendations for oral contraceptives and the protease inhibitor atazanavir/ritonavir can be found in General Dosing Considerations [see Dosage and Administration (2.1)]. Patients on rifampin and the protease inhibitor lopinavir/ritonavir should follow the same dosing titration/maintenance regimen used with antiepileptic drugs that induce glucuronidation and increase clearance [see Dosage and Administration (2.1), Drug Interactions (7), and Clinical Pharmacology (12.3)].
   
  In Patients TAKING Valproatea
  In Patients NOT TAKING
  Carbamazepine,
  Phenytoin, Phenobarbital, Primidone,b or Valproatea
  In Patients TAKING Carbamazepine, Phenytoin, Phenobarbital, or Primidoneb and NOT TAKING Valproatea
  Weeks 1 and 2
  0.15 mg/kg/day
  in 1 or 2 divided doses, rounded down to the nearest whole tablet (see Table 3 for weight-based dosing guide)
  0.3 mg/kg/day
  in 1 or 2 divided doses, rounded down to the nearest whole tablet
  0.6 mg/kg/day
  in 2 divided doses, rounded down to the nearest whole tablet
  Weeks 3 and 4
  0.3 mg/kg/day
  in 1 or 2 divided doses, rounded down to the nearest whole tablet (see Table 3 for weight-based dosing guide)
  0.6 mg/kg/day
  in 2 divided doses, rounded down to the nearest whole tablet
  1.2 mg/kg/day
  in 2 divided doses, rounded down to the nearest whole tablet
  Week 5 onward to maintenance
  The dose should be increased every 1 to 2 weeks as follows: calculate 0.3 mg/kg/day, round this amount down to the nearest whole tablet, and add this amount to the previously administered daily dose.
  The dose should be increased every 1 to 2 weeks as follows:  calculate 0.6 mg/kg/day, round this amount down to the nearest whole tablet, and add this amount to the previously administered daily dose.
  The dose should be increased every 1 to 2 weeks as follows: calculate
  1.2 mg/kg/day, round this amount down to the nearest whole tablet, and add this amount to the previously administered daily dose.
  Usual
  maintenance
  dose
  1 to 5 mg/kg/day
  (maximum 200 mg/day in
  1 or 2 divided doses)
  1 to 3 mg/kg/day with
  valproate alone
  4.5 to 7.5 mg/kg/day (maximum 300 mg/day in
  2 divided doses)
  5 to 15 mg/kg/day
  (maximum
  400 mg/day in 2
  divided doses)
  Maintenance
  dose in
  patients less
  than 30 kg
  May need to be increased
  by as much as 50%, based
  on clinical response
  May need to be increased
  by as much as 50%, based
  on clinical response
  May need to be
  increased by as
  much as 50%, based
  on clinical response
  Table 3.     The Initial Weight-Based Dosing Guide for Patients Aged 2 to 12 Years Taking Valproate (Weeks 1 to 4) With Epilepsy If the patient’s weight is
  Give this daily dose, using the most appropriate combination of lamotrigine 2 mg and 5 mg tablets
  Greater than
  And less than
  Weeks 1 and 2
  Weeks 3 and 4
  6.7 kg
  14 kg
  2 mg every other day
  2 mg every day
  14.1 kg
  27 kg
  2 mg every day
  4 mg every day
  27.1 kg
  34 kg
  4 mg every day
  8 mg every day
  34.1 kg
  40 kg
  5 mg every day
  10 mg every day
  

  Usual Adjunctive Maintenance Dose for Epilepsy:

  
  

  The usual maintenance doses identified in Tables 1 and 2 are derived from dosing regimens employed in the placebo-controlled adjunctive trials in which the efficacy of lamotrigine tablets was established. In patients receiving multidrug regimens employing carbamazepine,  phenytoin, phenobarbital, or primidone  without valproate, maintenance doses of adjunctive lamotrigine tablets as high as 700 mg/day have been used. In patients receiving valproate alone, maintenance doses of adjunctive lamotrigine tablets as high as 200 mg/day have been used. The advantage of using doses above those recommended in Tables 1 to 4 has not been established in controlled trials.

  2.3 Epilepsy - Conversion From Adjunctive Therapy to Monotherapy

  The goal of the transition regimen is to attempt to maintain seizure control while mitigating the risk of serious rash associated with the rapid titration of lamotrigine tablets.

  
  

  The recommended maintenance dose of lamotrigine tablets as monotherapy is 500 mg/day given in 2 divided doses.

  
  

  To avoid an increased risk of rash, the recommended initial dose and subsequent dose escalations for lamotrigine tablets should not be exceeded [see Boxed Warning].

  
  

  Conversion From Adjunctive Therapy With Carbamazepine, Phenytoin, Phenobarbital, or Primidone to Monotherapy With Lamotrigine Tablets
  
  After achieving a dose of 500 mg/day of lamotrigine tablets using the guidelines in Table 1, the concomitant enzyme-inducing AED should be withdrawn by 20% decrements each week over a 4-week period. The regimen for the withdrawal of the concomitant AED is based on experience gained in the controlled monotherapy clinical trial.

  
  

  Conversion From Adjunctive Therapy With Valproate to Monotherapy With Lamotrigine Tablets
  
  The conversion regimen involves the 4 steps outlined in Table 4.

  
  Table 4. Conversion From Adjunctive Therapy With Valproate to Monotherapy With Lamotrigine Tablets in Patients Aged 16 Years and Older With Epilepsy  
  Lamotrigine Tablets
  Valproate
  Step 1
  Achieve a dose of 200 mg/day according to guidelines in Table 1.
  Maintain established stable dose.
  Step 2
  Maintain at 200 mg/day.
  Decrease dose by decrements no greater than 500 mg/day/week to 500 mg/day and then maintain for 1 week.
  Step 3
  Increase to 300 mg/day and maintain for
  1 week.
  Simultaneously decrease to
  250 mg/day and maintain for
  1 week.
  Step 4
  Increase by 100 mg/day every week to achieve maintenance dose of 500 mg/day.
  Discontinue.
  

  Conversion From Adjunctive Therapy With Antiepileptic Drugs Other Than Carbamazepine, Phenytoin, Phenobarbital, Primidone, or Valproate to Monotherapy With Lamotrigine Tablets
  
  No specific dosing guidelines can be provided for conversion to monotherapy with lamotrigine tablets with AEDs other than carbamazepine, phenytoin, phenobarbital, primidone, or valproate.

  2.4 Bipolar Disorder

  The goal of maintenance treatment with lamotrigine tablets is to delay the time to occurrence of mood episodes (depression, mania, hypomania, mixed episodes) in patients treated for acute mood episodes with standard therapy. The target dose of lamotrigine tablets is 200 mg/day (100 mg/day in patients taking valproate, which decreases the apparent clearance of lamotrigine, and 400 mg/day in patients not taking valproate and taking either carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin and the protease inhibitor lopinavir/ritonavir that increase the apparent clearance of lamotrigine). In the clinical trials, doses up to 400 mg/day as monotherapy were evaluated; however, no additional benefit was seen at 400 mg/day compared with 200 mg/day [see Clinical Studies (14.2)]. Accordingly, doses above 200 mg/day are not recommended. Treatment with lamotrigine tablets is introduced, based on concurrent medications, according to the regimen outlined in Table 5. If other psychotropic medications are withdrawn following stabilization, the dose of lamotrigine tablets should be adjusted. For patients discontinuing valproate, the dose of lamotrigine tablets should be doubled over a 2-week period in equal weekly increments (see Table 6). For patients discontinuing carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin and the protease inhibitors lopinavir/ritonavir and atazanavir/ritonavir that induce lamotrigine glucuronidation, the dose of lamotrigine tablets should remain constant for the first week and then should be decreased by half over a 2-week period in equal weekly decrements (see Table 6). The dose of lamotrigine tablets may then be further adjusted to the target dose (200 mg) as clinically indicated.

  
  

  If other drugs are subsequently introduced, the dose of lamotrigine tablets may need to be adjusted. In particular, the introduction of valproate requires reduction in the dose of lamotrigine tablets [see Drug Interactions (7), Clinical Pharmacology (12.3)].

  To avoid an increased risk of rash, the recommended initial dose and subsequent dose escalations of lamotrigine tablets should not be exceeded [see Boxed Warning]. 

  
  Table 5. Escalation Regimen for Lamotrigine Tablets in Patients With Bipolar Disorder a Valproate has been shown to inhibit glucuronidation and decrease the apparent clearance of lamotrigine [see Drug Interactions (7), Clinical Pharmacology (12.3)].
  b  Drugs that induce lamotrigine glucuronidation and increase clearance, other than the  specified antiepileptic drugs, include estrogen-containing oral contraceptives, rifampin, and  the protease inhibitors lopinavir/ritonavir and atazanavir/ritonavir. Dosing recommendations for oral contraceptives and the protease inhibitor atazanavir/ritonavir can be found in General Dosing Considerations [see Dosage and Administration (2.1)]. Patients on rifampin and the protease inhibitor lopinavir/ritonavir should follow the same dosing titration/maintenance regimen used with antiepileptic drugs that induce glucuronidation and increase clearance [see Dosage and Administration (2.1), Drug Interactions (7), and Clinical Pharmacology (12.3)].
   
  In Patients TAKING Valproatea
  In Patients NOT
  TAKING
  Carbamazepine,
  Phenytoin,
  Phenobarbital,
  Primidone,b or
  Valproatea
  In Patients TAKING Carbamazepine, Phenytoin, Phenobarbital, or Primidoneb and NOT TAKING Valproatea
  Weeks 1 and 2
  25 mg every other day
  25 mg daily
  50 mg daily
  Weeks 3 and 4
  25 mg daily
  50 mg daily
  100 mg daily, in divided doses
  Week 5
  50 mg daily
  100 mg daily
  200 mg daily, in divided doses
  Week 6
  100 mg daily
  200 mg daily
  300 mg daily, in divided doses
  Week 7
  100 mg daily
  200 mg daily
  up to 400 mg daily, in divided doses
  
  
  Table 6. Dosage Adjustments to Lamotrigine Tablets in Patients With Bipolar Disorder Following Discontinuation of Psychotropic Medications a Valproate has been shown to inhibit glucuronidation and decrease the apparent clearance of lamotrigine [see Drug Interactions (7), Clinical Pharmacology (12.3)].
  b  Drugs that induce lamotrigine glucuronidation and increase clearance, other than the specified antiepileptic drugs, include estrogen-containing oral contraceptives, rifampin, and the protease inhibitors lopinavir/ritonavir and atazanavir/ritonavir. Dosing recommendations for oral contraceptives and the protease inhibitor atazanavir/ritonavir can be found in General Dosing Considerations [see Dosage and Administration (2.1)]. Patients on rifampin and the protease inhibitor lopinavir/ritonavir should follow the same dosing titration/maintenance regimen used with antiepileptic drugs that induce glucuronidation and increase clearance [see Dosage and Administration (2.1), Drug Interactions (7), and Clinical Pharmacology (12.3)].
   
  Discontinuation of
  Psychotropic Drugs
  (excluding Valproate,a
  Carbamazepine,
  Phenytoin,
  Phenobarbital, or
  Primidoneb)
  After Discontinuation of Valproatea
  After Discontinuation of
  Carbamazepine,
  Phenytoin, Phenobarbital, or Primidoneb
  Current dose of lamotrigine tablets (mg/day)
  100
  Current dose of lamotrigine tablets  (mg/day)
  400
  Week 1
  Maintain current dose of lamotrigine tablets
  150
  400
  Week 2
  Maintain current dose of lamotrigine tablets
  200
  300
  Week 3 onward
  Maintain current dose of lamotrigine tablets
  200
  200
  
  
  

  The benefit of continuing treatment in patients who had been stabilized in an 8- to 16-week open-label phase with lamotrigine tablets was established in 2 randomized, placebo-controlled clinical maintenance trials [see Clinical Studies (14.2 )]. However, the optimal duration of treatment with lamotrigine tablets has not been established. Thus, patients should be periodically reassessed to determine the need for maintenance treatment.

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   Lamotrigine extended-release tablets are taken once daily, with or without food.  Tablets must be swallowed whole and must not be chewed, crushed, or divided.

  2.1 General Dosing Considerations

  Rash: There are suggestions, yet to be proven, that the risk of severe, potentially life-threatening rash may be increased by (1) coadministration of lamotrigine extended-release tablets with valproate, (2) exceeding the recommended initial dose of lamotrigine extended-release tablets, or (3) exceeding the recommended dose escalation for lamotrigine extended-release tablets. However, cases have occurred in the absence of these factors [see BoxedWarning]. Therefore, it is important that the dosing recommendations be followed closely.  

  The risk of nonserious rash may be increased when the recommended initial dose and/or the rate of dose escalation for lamotrigine extended-release tablets are exceeded and in patients with a history of allergy or rash to other AEDs.  

  It is recommended that lamotrigine extended-release tablets not be restarted in patients who discontinued due to rash associated with prior treatment with lamotrigine, unless the potential benefits clearly outweigh the risks. If the decision is made to restart a patient who has discontinued lamotrigine extended-release tablets, the need to restart with the initial dosing recommendations should be assessed. The greater the interval of time since the previous dose, the greater consideration should be given to restarting with the initial dosing recommendations. If a patient has discontinued lamotrigine for a period of more than 5 half-lives, it is recommended that initial dosing recommendations and guidelines be followed. The half-life of lamotrigine is affected by other concomitant medications [see Clinical Pharmacology (12.3)].  

  Lamotrigine Extended-Release Tablets Added to Drugs Known to Induce or Inhibit Glucuronidation: Because lamotrigine is metabolized predominantly by glucuronic acid conjugation, drugs that are known to induce or inhibit glucuronidation may affect the apparent clearance of lamotrigine. Drugs that induce glucuronidation include carbamazepine, phenytoin, phenobarbital, primidone, rifampin, estrogen-containing oral contraceptives, and the protease inhibitors lopinavir/ritonavir and atazanavir/ritonavir. Valproate inhibits glucuronidation. For dosing considerations for lamotrigine extended-release tablets in patients on estrogen-containing contraceptives and atazanavir/ritonavir, see below and Table 5. For dosing considerations for lamotrigine extended-release tablets in patients on other drugs known to induce or inhibit glucuronidation, see Table 1 and Table 5.

  Target Plasma Levels: A therapeutic plasma concentration range has not been established for lamotrigine. Dosing of lamotrigine extended-release tablets should be based on therapeutic response [see Clinical Pharmacology (12.3)].  

  Women Taking Estrogen-Containing Oral Contraceptives: Starting Lamotrigine Extended-Release Tablets in Women Taking Estrogen-Containing Oral Contraceptives: Although estrogen-containing oral contraceptives have been shown to increase the clearance of lamotrigine [see Clinical Pharmacology (12.3)], no adjustments to the recommended dose-escalation guidelines for lamotrigine extended-release tablets should be necessary solely based on the use of estrogen-containing oral contraceptives. Therefore, dose escalation should follow the recommended guidelines for initiating adjunctive therapy with lamotrigine extended-release tablets based on the concomitant AED or other concomitant medications (see Table 1). See below for adjustments to maintenance doses of lamotrigine extended-release tablets in women taking estrogen-containing oral contraceptives.  

  Adjustments to the Maintenance Dose of Lamotrigine Extended-Release Tablets in Women Taking Estrogen-Containing Oral Contraceptives: 

  (1) Taking Estrogen-Containing Oral Contraceptives: In women not taking carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin and the protease inhibitors lopinavir/ritonavir and atazanavir/ritonavir  that induce lamotrigine glucuronidation [see Drug Interactions (7), Clinical Pharmacology (12.3)] the maintenance dose of lamotrigine extended-release tablets will in most cases need to be increased by as much as 2-fold over the recommended target maintenance dose to maintain a consistent lamotrigine plasma level.

  (2) Starting Estrogen-Containing Oral Contraceptives: In women taking a stable dose of lamotrigine extended-release tablets and not taking carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin and the protease inhibitors lopinavir/ritonavir and atazanavir/ritonavir that induce lamotrigine glucuronidation [see Drug Interactions (7), Clinical Pharmacology (12.3)], the maintenance dose will in most cases need to be increased by as much as 2-fold to maintain a consistent lamotrigine plasma level. The dose increases should begin at the same time that the oral contraceptive is introduced and continue, based on clinical response, no more rapidly than 50 to 100 mg/day every week. Dose increases should not exceed the recommended rate (see Table 1) unless lamotrigine plasma levels or clinical response support larger increases. Gradual transient increases in lamotrigine plasma levels may occur during the week of inactive hormonal preparation (pill-free week), and these increases will be greater if dose increases are made in the days before or during the week of inactive hormonal preparation. Increased lamotrigine plasma levels could result in additional adverse reactions, such as dizziness, ataxia, and diplopia. If adverse reactions attributable to lamotrigine extended-release tablets consistently occur during the pill-free week, dose adjustments to the overall maintenance dose may be necessary. Dose adjustments limited to the pill-free week are not recommended. For women taking lamotrigine extended-release tablets in addition to carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin and the protease inhibitors lopinavir/ritonavir and atazanavir/ritonavir that induce lamotrigine glucuronidation [see Drug Interactions (7), Clinical Pharmacology (12.3)], no adjustment to the dose of lamotrigine extended-release tablets should be necessary.

  (3) Stopping Estrogen-Containing Oral Contraceptives: In women not taking carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin and the protease inhibitors lopinavir/ritonavir and atazanavir/ritonavir that induce lamotrigine glucuronidation [see Drug Interactions (7), Clinical Pharmacology (12.3)], the maintenance dose of lamotrigine extended-release tablets will in most cases need to be decreased by as much as 50% in order to maintain a consistent lamotrigine plasma level. The decrease in dose of lamotrigine extended-release tablets should not exceed 25% of the total daily dose per week over a 2-week period, unless clinical response or lamotrigine plasma levels indicate otherwise [see ClinicalPharmacology (12.3)].In women taking lamotrigine extended-release tablets in addition to carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin and the protease inhibitors lopinavir/ritonavir and atazanavir/ritonavir that induce lamotrigine glucuronidation [see Drug Interactions (7), Clinical Pharmacology (12.3)], no adjustment to the dose of lamotrigine extended-release tablets should be necessary.  

  Women and Other Hormonal Contraceptive Preparations or Hormone Replacement Therapy: The effect of other hormonal contraceptive preparations or hormone replacement therapy on the pharmacokinetics of lamotrigine has not been systematically evaluated. It has been reported that ethinylestradiol, not progestogens, increased the clearance of lamotrigine up to 2-fold, and the progestin-only pills had no effect on lamotrigine plasma levels. Therefore, adjustments to the dosage of lamotrigine extended-release tablets in the presence of progestogens alone will likely not be needed.  

  Patients Taking Atazanavir/Ritonavir: While atazanavir/ritonavir does reduce the lamotrigine plasma concentration, no adjustments to the recommended dose-escalation guidelines for lamotrigine extended-release tablets should be necessary solely based on the use of atazanavir/ritonavir. Dose escalation should follow the recommended guidelines for initiating adjunctive therapy with lamotrigine extended-release tablets based on concomitant AED or other concomitant medications (see Tables 1 and 5). In patients already taking maintenance doses of lamotrigine extended-release tablets and not taking glucuronidation inducers, the dose of lamotrigine extended-release tablets may need to be increased if atazanavir/ritonavir is added, or decreased if atazanavir/ritonavir is discontinued [see Clinical Pharmacology (12.3)].

  Patients With Hepatic Impairment: Experience in patients with hepatic impairment is limited. Based on a clinical pharmacology study in 24 subjects with mild, moderate, and severe liver impairment [see Use in Specific Populations (8.6), Clinical Pharmacology (12.3)], the following general recommendations can be made. No dosage adjustment is needed in patients with mild liver impairment. Initial, escalation, and maintenance doses should generally be reduced by approximately 25% in patients with moderate and severe liver impairment without ascites and 50% in patients with severe liver impairment with ascites. Escalation and maintenance doses may be adjusted according to clinical response.  

  Patients With Renal Impairment: Initial doses of lamotrigine extended-release tablets should be based on patients’ concomitant medications (see Table 1); reduced maintenance doses may be effective for patients with significant renal impairment [see Use in Specific Populations (8.7), ClinicalPharmacology (12.3)]. Few patients with severe renal impairment have been evaluated during chronic treatment with immediate-release lamotrigine. Because there is inadequate experience in this population, lamotrigine extended-release tablets should be used with caution in these patients.  

  Discontinuation Strategy: For patients receiving lamotrigine extended-release tablets in combination with other AEDs, a re-evaluation of all AEDs in the regimen should be considered if a change in seizure control or an appearance or worsening of adverse reactions is observed.  

  If a decision is made to discontinue therapy with lamotrigine extended-release tablets, a step-wise reduction of dose over at least 2 weeks (approximately 50% per week) is recommended unless safety concerns require a more rapid withdrawal [see Warnings and Precautions (5.8)].  

  Discontinuing carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin and the protease inhibitors lopinavir/ritonavir and atazanavir/ritonavir that induce lamotrigine glucuronidation should prolong the half-life of lamotrigine; discontinuing valproate should shorten the half-life of lamotrigine.

  2.2 Adjunctive Therapy for Primary Generalized Tonic-Clonic and Partial-Onset Seizures

   This section provides specific dosing recommendations for patients aged 13 years and older. Specific dosing recommendations are provided depending upon concomitant AEDs or other concomitant medications.

  Table 1. Escalation Regimen for Lamotrigine Extended-Release Tablets in Patients Aged 13 Years and Older 

    For Patients TAKING Valproatea  For PatientsNOT TAKING Carbamazepine, Phenytoin,Phenobarbital, Primidone,b or Valproatea For Patients TAKING Carbamazepine, Phenytoin,Phenobarbital, or Primidoneb and NOT TAKING Valproatea  Weeks 1 and 2 25 mg every other day 25 mg every day 50 mg every day Weeks 3 and 4 25 mg every day 50 mg every day 100 mg every day Week 5 50 mg every day 100 mg every day 200 mg every day Week 6 100 mg every day 150 mg every day 300 mg every day Week 7 150 mg every day 200 mg every day 400 mg every day Maintenance range (week 8 and onward) 200 to 250 mg everydayc 300 to 400 mg every dayc 400 to 600 mg every dayc

  a Valproate has been shown to inhibit glucuronidation and decrease the apparent clearance of lamotrigine [see Drug Interactions (7), Clinical Pharmacology (12.3)]. 

  b Drugs that induce lamotrigine glucuronidation and increase clearance, other than the specified antiepileptic drugs, include estrogen-containing oral contraceptives, rifampin, and the protease inhibitors lopinavir/ritonavir and atazanavir/ritonavir. Dosing recommendations for oral contraceptives and the protease inhibitor atazanavir/ritonavir can be found in General Dosing Considerations [see Dosage and Administration (2.1)]. Patients on rifampin and the protease inhibitor lopinavir/ritonavir should follow the same dosing titration/maintenance regimen used with antiepileptic drugs that induce glucuronidation and increase clearance [see Dosage and Administration (2.1), Drug Interactions (7), and Clinical Pharmacology (12.3)].

  c Dose increases at week 8 or later should not exceed 100 mg daily at weekly intervals. 

  2.3 Conversion From Adjunctive Therapy to Monotherapy

  The goal of the transition regimen is to attempt to maintain seizure control while mitigating the risk of serious rash associated with the rapid titration of lamotrigine extended-release tablets.

  To avoid an increased risk of rash, the recommended maintenance dosage range of lamotrigine extended-release tablets as monotherapy is 250 to 300 mg given once daily.

  The recommended initial dose and subsequent dose escalations for lamotrigine extended-release tablets should not be exceeded [see Boxed Warning].

  Conversion From Adjunctive Therapy With Carbamazepine, Phenytoin, Phenobarbital, or Primidone to Monotherapy With Lamotrigine Extended-Release Tablets:

  After achieving a dose of 500 mg/day of lamotrigine extended-release tablets using the guidelines in Table 1, the concomitant enzyme-inducing AED should be withdrawn by 20% decrements each week over a 4-week period. Two weeks after completion of withdrawal of the enzyme-inducing AED, the dosage of lamotrigine extended-release tablets may be decreased no faster than 100 mg/day each week to achieve the monotherapy maintenance dosage range of 250 to 300 mg/day.

  The regimen for the withdrawal of the concomitant AED is based on experience gained in the controlled monotherapy clinical trial using immediate-release lamotrigine.

  Conversion From Adjunctive Therapy With Valproate to Monotherapy With Lamotrigine Extended-Release Tablets:

  The conversion regimen involves the 4 steps outlined in Table 2.

  Table 2. Conversion From Adjunctive Therapy With Valproate to Monotherapy With Lamotrigine Extended-Release Tablets in Patients Aged 13 Years and Older  With Epilepsy

    Lamotrigine Extended-Release Tablets Valproate Step 1 Achieve a dose of 150 mg/day according to guidelines in Table 1. Maintain established stable dose. Step 2 Maintain at 150 mg/day. Decrease dose by decrements no greater than 500 mg/day/week to 500 mg/day and then maintain for 1 week. Step 3 Increase to 200 mg/day. Simultaneously decrease to 250 mg/day and maintain for 1 week. Step 4 Increase to 250 or 300 mg/day. Discontinue. 

  Conversion From Adjunctive Therapy With Antiepileptic Drugs Other Than Carbamazepine, Phenytoin, Phenobarbital, Primidone, or Valproate to Monotherapy With Lamotrigine Extended-Release Tablets:

  After achieving a dosage of 250 to 300 mg/day of lamotrigine extended-release tablets using the guidelines in Table 1, the concomitant AED should be withdrawn by 20% decrements each week over a 4-week period. No adjustment to the monotherapy dose of lamotrigine extended-release tablets is needed.

  2.4 Conversion From Immediate-Release Lamotrigine Tablets to Lamotrigine Extended-Release Tablets

   Patients may be converted directly from immediate-release lamotrigine to lamotrigine extended-release tablets. The initial dose of lamotrigine extended-release tablets should match the total daily dose of immediate-release lamotrigine. However, some subjects on concomitant enzyme inducing agents may have lower plasma levels of lamotrigine on conversion and should be monitored [see Clinical Pharmacology (12.3)]. 

  Following conversion to lamotrigine extended-release tablets, all patients (but especially those on drugs that induce lamotrigine glucuronidation) should be closely monitored for seizure control [see Drug Interactions (7)]. Depending on the therapeutic response after conversion, the total daily dose may need to be adjusted within the recommended dosing instructions (Table 1).

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  2.1 General Dosing Considerations

  Rash
  
  There are suggestions, yet to be proven, that the risk of severe, potentially life-threatening rash may be increased by (1) coadministration of lamotrigine tablets (chewable, dispersible) with valproate, (2) exceeding the recommended initial dose of lamotrigine tablets (chewable, dispersible), or (3) exceeding the recommended dose escalation for lamotrigine tablets (chewable, dispersible). However, cases have occurred in the absence of these factors [see Boxed Warning]. Therefore, it is important that the dosing recommendations be followed closely.

  
  

  The risk of nonserious rash may be increased when the recommended initial dose and/or the rate of dose escalation for lamotrigine tablets (chewable, dispersible) is exceeded and in patients with a history of allergy or rash to other AEDs.

  
  

  It is recommended that lamotrigine tablets (chewable, dispersible) not be restarted in patients who discontinued due to rash associated with prior treatment with lamotrigine unless the potential benefits clearly outweigh the risks. If the decision is made to restart a patient who has discontinued lamotrigine tablets (chewable, dispersible), the need to restart with the initial dosing recommendations should be assessed. The greater the interval of time since the previous dose, the greater consideration should be given to restarting with the initial dosing recommendations. If a patient has discontinued lamotrigine for a period of more than 5 half-lives, it is recommended that initial dosing recommendations and guidelines be followed. The half-life of lamotrigine is affected by other concomitant medications [see Clinical Pharmacology (12.3)].

  Lamotrigine Tablets (Chewable, Dispersible) Added to Drugs Known to Induce or Inhibit Glucuronidation
  
  Because lamotrigine is metabolized predominantly by glucuronic acid conjugation, drugs that are known to induce or inhibit glucuronidation may affect the apparent clearance of lamotrigine. Drugs that induce glucuronidation include carbamazepine, phenytoin, phenobarbital, primidone, rifampin, estrogen-containing oral contraceptives, and the protease inhibitors lopinavir/ritonavir and atazanavir/ritonavir. Valproate inhibits glucuronidation. For dosing considerations for lamotrigine tablets (chewable, dispersible) in patients on estrogen-containing contraceptives and atazanavir/ritonavir, see below and Table 13. For dosing considerations for lamotrigine tablets (chewable, dispersible) in patients on other drugs known to induce or inhibit glucuronidation, see Tables 1, 2, 5 to 6, and 13.

  
  

  Target Plasma Levels for Patients with Epilepsy or Bipolar Disorder
  
  A therapeutic plasma concentration range has not been established for lamotrigine. Dosing of lamotrigine tablets (chewable, dispersible) should be based on therapeutic response [see Clinical Pharmacology (12.3)].

  
  

  Women Taking Estrogen-Containing Oral Contraceptives
  
  Starting Lamotrigine Tablets (Chewable, Dispersible) in Women Taking Estrogen-Containing Oral Contraceptives: Although estrogen-containing oral contraceptives have been shown to increase the clearance of lamotrigine [see Clinical Pharmacology (12.3)], no adjustments to the recommended dose-escalation guidelines for lamotrigine tablets (chewable, dispersible) should be necessary solely based on the use of estrogen-containing oral contraceptives. Therefore, dose escalation should follow the recommended guidelines for initiating adjunctive therapy with lamotrigine tablets (chewable, dispersible) based on the concomitant AED or other concomitant medications (see Tables 1, 5, and 7). See below for adjustments to maintenance doses of lamotrigine tablets (chewable, dispersible) in women taking estrogen-containing oral contraceptives.

  
  

  Adjustments to the Maintenance Dose of Lamotrigine Tablets (Chewable, Dispersible) in Women Taking Estrogen-Containing Oral Contraceptives:

  (1) Taking Estrogen-Containing Oral Contraceptives: In women not taking carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin and the protease inhibitors lopinavir/ritonavir and atazanavir/ritonavir that induce lamotrigine glucuronidation [see Drug Interactions (7), Clinical Pharmacology (12.3)], the maintenance dose of lamotrigine tablets (chewable, dispersible) will in most cases need to be increased by as much as 2-fold over the recommended target maintenance dose to maintain a consistent lamotrigine plasma level.

  
  

  (2) Starting Estrogen-Containing Oral Contraceptives:  In women taking a stable dose of lamotrigine tablets (chewable, dispersible) and not taking carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin and the protease inhibitors lopinavir/ritonavir and atazanavir/ritonavir that induce lamotrigine glucuronidation [see Drug Interactions (7), Clinical Pharmacology (12.3)], the maintenance dose will in most cases need to be increased by as much as 2-fold to maintain a consistent lamotrigine plasma level. The dose increases should begin at the same time that the oral contraceptive is introduced and continue, based on clinical response, no more rapidly than 50 to 100 mg/day every week. Dose increases should not exceed the recommended rate (see Tables 1 and 5) unless lamotrigine plasma levels or clinical response support larger increases. Gradual transient increases in lamotrigine plasma levels may occur during the week of inactive hormonal preparation (pill-free week), and these increases will be greater if dose increases are made in the days before or during the week of inactive hormonal preparation. Increased lamotrigine plasma levels could result in additional adverse reactions, such as dizziness, ataxia, and diplopia. If adverse reactions attributable to lamotrigine tablets (chewable, dispersible) consistently occur during the pill-free week, dose adjustments to the overall maintenance dose may be necessary. Dose adjustments limited to the pill-free week are not recommended. For women taking lamotrigine tablets (chewable, dispersible) in addition to carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin and the protease inhibitors lopinavir/ritonavir and atazanavir/ritonavir that induce lamotrigine glucuronidation [see Drug Interactions (7), Clinical Pharmacology (12.3)], no adjustment to the dose of lamotrigine tablets (chewable, dispersible) should be necessary.

  
  

  (3) Stopping Estrogen-Containing Oral Contraceptives: In women not taking carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin and the protease inhibitors lopinavir/ritonavir and atazanavir/ritonavir that induce lamotrigine glucuronidation [see Drug Interactions (7), Clinical Pharmacology (12.3)], the maintenance dose of lamotrigine tablets (chewable, dispersible) will in most cases need to be decreased by as much as 50% in order to maintain a consistent lamotrigine plasma level. The decrease in dose of lamotrigine tablets (chewable, dispersible) should not exceed 25% of the total daily dose per week over a 2-week period, unless clinical response or lamotrigine plasma levels indicate otherwise [see Clinical Pharmacology (12.3)]. In women taking lamotrigine tablets (chewable, dispersible) in addition to carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin and the protease inhibitors lopinavir/ritonavir and atazanavir/ritonavir that induce lamotrigine glucuronidation [see Drug Interactions (7), Clinical Pharmacology (12.3)], no adjustment to the dose of lamotrigine tablets (chewable, dispersible) should be necessary.

  
  

  Women and Other Hormonal Contraceptive Preparations or Hormone Replacement Therapy
  
  The effect of other hormonal contraceptive preparations or hormone replacement therapy on the pharmacokinetics of lamotrigine has not been systematically evaluated. It has been reported that ethinylestradiol, not progestogens, increased the clearance of lamotrigine up to 2-fold, and the progestin-only pills had no effect on lamotrigine plasma levels. Therefore, adjustments to the dosage of lamotrigine tablets (chewable, dispersible) in the presence of progestogens alone will likely not be needed.

  
  

  Patients Taking Atazanavir/Ritonavir
  
  While atazanavir/ritonavir does reduce the lamotrigine plasma concentration, no adjustments to the recommended dose-escalation guidelines for lamotrigine tablets (chewable, dispersible) should be necessary solely based on the use of atazanavir/ritonavir. Dose escalation should follow the recommended guidelines for initiating adjunctive therapy with lamotrigine tablets (chewable, dispersible) based on concomitant AED or other concomitant medications (see Tables 1, 2, and 5). In patients already taking maintenance doses of lamotrigine tablets (chewable, dispersible) and  not taking glucuronidation inducers, the dose of lamotrigine tablets (chewable, dispersible) may need to be increased if atazanavir/ritonavir is added, or decreased if atazanavir/ritonavir is discontinued [see Clinical Pharmacology (12.3)].

  
  

  Patients with Hepatic Impairment
  
  Experience in patients with hepatic impairment is limited. Based on a clinical pharmacology study in 24 subjects with mild, moderate, and severe liver impairment [see Use in Specific Populations (8.6), Clinical Pharmacology (12.3)], the following general recommendations can be made. No dosage adjustment is needed in patients with mild liver impairment. Initial, escalation, and maintenance doses should generally be reduced by approximately 25% in patients with moderate and severe liver impairment without ascites and 50% in patients with severe liver impairment with ascites. Escalation and maintenance doses may be adjusted according to clinical response.

  
  

  Patients with Renal Impairment
  
  Initial doses of lamotrigine tablets (chewable, dispersible) should be based on patients’ concomitant medications (see Tables 1 to 3, and 5); reduced maintenance doses may be effective for patients with significant renal impairment [see Use in Specific Populations (8.7), Clinical Pharmacology (12.3)]. Few patients with severe renal impairment have been evaluated during chronic treatment with lamotrigine tablets (chewable, dispersible). Because there is inadequate experience in this population, lamotrigine tablets (chewable, dispersible) should be used with caution in these patients.

  
  

  Discontinuation Strategy
  
  Epilepsy: For patients receiving lamotrigine tablets (chewable, dispersible) in combination with other AEDs, a re-evaluation of all AEDs in the regimen should be considered if a change in seizure control or an appearance or worsening of adverse reactions is observed.

  
  

  If a decision is made to discontinue therapy with lamotrigine tablets (chewable, dispersible), a step-wise reduction of dose over at least 2 weeks (approximately 50% per week) is recommended unless safety concerns require a more rapid withdrawal [see Warnings and Precautions (5.8)].

  
  

  Discontinuing carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin and the protease inhibitors lopinavir/ritonavir and atazanavir/ritonavir that induce lamotrigine glucuronidation should prolong the half-life of lamotrigine; discontinuing valproate should shorten the half-life of lamotrigine.

  
  

  Bipolar Disorder: In the controlled clinical trials, there was no increase in the incidence, type, or severity of adverse reactions following abrupt termination of lamotrigine tablets (chewable, dispersible). In the clinical development program in adults with bipolar disorder, 2 patients experienced seizures shortly after abrupt withdrawal of lamotrigine tablets (chewable, dispersible). Discontinuation of lamotrigine tablets (chewable, dispersible) should involve a step-wise reduction of dose over at least 2 weeks (approximately 50% per week) unless safety concerns require a more rapid withdrawal [see Warnings and Precautions (5.8)].

  2.2 Epilepsy - Adjunctive Therapy

  This section provides specific dosing recommendations for patients older than 12 years and patients aged 2 to 12 years. Within each of these age-groups, specific dosing recommendations are provided depending upon concomitant AEDs or other concomitant medications (see Table 1 for patients older than 12 years and Table 2 for patients aged 2 to 12 years). A weight-based dosing guide for patients aged 2 to 12 years on concomitant valproate is provided in Table 3.
  
  Patients Older than 12 Years
  
  Recommended dosing guidelines are summarized in Table 1.

  Table 1. Escalation Regimen for Lamotrigine Tablets (Chewable, Dispersible) in Patients Older than 12 Years with Epilepsy a Valproate has been shown to inhibit glucuronidation and decrease the apparent clearance of lamotrigine [see Drug Interactions (7), Clinical Pharmacology (12.3)].
  b Drugs that induce lamotrigine glucuronidation and increase clearance, other than the specified antiepileptic drugs, include estrogen-containing oral contraceptives, rifampin, and the protease inhibitors lopinavir/ritonavir and atazanavir/ritonavir. Dosing recommendations for oral contraceptives and the protease inhibitor atazanavir/ritonavir can be found in General Dosing Considerations [see Dosage and Administration (2.1)]. Patients on rifampin and the protease inhibitor lopinavir/ritonavir should follow the same dosing titration/maintenance regimen used with antiepileptic drugs that induce glucuronidation and increase clearance [see Dosage and Administration (2.1), Drug Interactions (7), and Clinical Pharmacology (12.3)].
  In Patients TAKING
  Valproatea
  In Patients NOT TAKING
  Carbamazepine, Phenytoin,
  Phenobarbital, Primidone,b
  or Valproatea
  In Patients TAKING
  Carbamazepine,
  Phenytoin,
  Phenobarbital, or
  Primidoneb and NOT
  TAKING Valproatea
   Weeks 1 and 2
  25 mg every other day
  25 mg every day
  50 mg/day
   Weeks 3 and 4
  25 mg every day
  50 mg/day
  100 mg/day
  (in 2 divided doses)
   Week 5 onward
   to maintenance
  Increase by 25 to
  50 mg/day every 1 to
  2 weeks.
  Increase by 50 mg/day
  every 1 to 2 weeks.
  Increase by
  100 mg/day every
  1 to 2 weeks.
   Usual maintenance
   dose
  100 to 200 mg/day with
  valproate alone
  100 to 400 mg/day with
  valproate and other
  drugs that induce
  glucuronidation
  (in 1 or 2 divided doses)
  225 to 375 mg/day
  (in 2 divided doses)
  300 to 500 mg/day
  (in 2 divided doses)
  

  Patients Aged 2 to 12 Years
  
  Recommended dosing guidelines are summarized in Table 2.
  
  Lower starting doses and slower dose escalations than those used in clinical trials are recommended because of the suggestion that the risk of rash may be decreased by lower starting doses and slower dose escalations. Therefore, maintenance doses will take longer to reach in clinical practice than in clinical trials. It may take several weeks to months to achieve an individualized maintenance dose. Maintenance doses in patients weighing less than 30 kg, regardless of age or concomitant AED, may need to be increased as much as 50%, based on clinical response.
  
  The smallest available strength of lamotrigine tablets (chewable, dispersible) is 2 mg, and only whole tablets should be administered. If the calculated dose cannot be achieved using whole tablets, the dose should be rounded down to the nearest whole tablet [see How Supplied/Storage and Handling (16) and Medication Guide].

  Table 2. Escalation Regimen for Lamotrigine Tablets (Chewable, Dispersible) in Patients Aged 2 to 12 Years with Epilepsy Note: Only whole tablets should be used for dosing.
  a Valproate has been shown to inhibit glucuronidation and decrease the apparent clearance of lamotrigine [see Drug Interactions (7), Clinical Pharmacology (12.3)].
  b Drugs that induce lamotrigine glucuronidation and increase clearance, other than the specified antiepileptic drugs, include estrogen-containing oral contraceptives, rifampin, and the protease inhibitors lopinavir/ritonavir and atazanavir/ritonavir. Dosing recommendations for oral contraceptives and the protease inhibitor atazanavir/ritonavir can be found in General Dosing Considerations [see Dosage and Administration (2.1)]. Patients on rifampin and the protease inhibitor lopinavir/ritonavir should follow the same dosing titration/maintenance regimen used with antiepileptic drugs that induce glucuronidation and increase clearance [see Dosage and Administration (2.1), Drug Interactions (7), and Clinical Pharmacology (12.3)].
   
  In Patients TAKING
  Valproatea
  In Patients NOT TAKING
  Carbamazepine,
  Phenytoin, Phenobarbital,
  Primidone,b or Valproatea
  In Patients TAKING
  Carbamazepine,
  Phenytoin,
  Phenobarbital, or
  Primidoneb and NOT
  TAKING Valproatea
   Weeks 1 and 2
  0.15 mg/kg/day
  in 1 or 2 divided doses,
  rounded down to the nearest
  whole tablet (see Table 3 for
  weight-based dosing guide)
  0.3 mg/kg/day
  in 1 or 2 divided doses,
  rounded down to the nearest
  whole tablet
  0.6 mg/kg/day
  in 2 divided doses,
  rounded down to the
  nearest whole tablet
   Weeks 3 and 4
  0.3 mg/kg/day
  in 1 or 2 divided doses,
  rounded down to the nearest
  whole tablet (see Table 3 for
  weight-based dosing guide)
  0.6 mg/kg/day
  in 2 divided doses, rounded down to the nearest whole tablet
  1.2 mg/kg/day
  in 2 divided doses, rounded down to the nearest whole tablet
   Week 5 onward to  maintenance
  The dose should be increased
  every 1 to 2 weeks as follows:
  calculate 0.3 mg/kg/day,
  round this amount down to
  the nearest whole tablet, and
  add this amount to the
  previously administered daily
  dose.
  The dose should be
  increased every 1 to 2 weeks
  as follows:  calculate 0.6
  mg/kg/day, round this
  amount down to the nearest
  whole tablet, and add this
  amount to the previously
  administered daily dose.
  The dose should be
  increased every 1 to 2
  weeks as follows: calculate
  1.2 mg/kg/day, round this
  amount down to the
  nearest whole tablet, and
  add this amount to the
  previously administered
  daily dose.
   Usual
   maintenance
   dose
  1 to 5 mg/kg/day
  (maximum 200 mg/day in
  1 or 2 divided doses)
  1 to 3 mg/kg/day with
  valproate alone
  4.5 to 7.5 mg/kg/day
  (maximum 300 mg/day in
  2 divided doses)
  5 to 15 mg/kg/day
  (maximum
  400 mg/day in 2
  divided doses)
   Maintenance
   dose in
   patients less
   than 30 kg
  May need to be increased
  by as much as 50%, based
  on clinical response.
  May need to be increased
  by as much as 50%, based
  on clinical response.
  May need to be
  increased by as
  much as 50%, based
  on clinical response.
  
  Table 3. The Initial Weight-Based Dosing Guide for Patients Aged 2 to 12 Years Taking Valproate (Weeks 1 to 4) with Epilepsy If the patient’s weight is
  Give this daily dose, using the most appropriate
  combination of lamotrigine tablets (chewable, dispersible)
  2 mg and 5 mg
  Greater than
  And less than
  Weeks 1 and 2
  Weeks 3 and 4
  6.7 kg
  14 kg
  2 mg every other day
  2 mg every day
  14.1 kg
  27 kg
  2 mg every day
  4 mg every day
  27.1 kg
  34 kg
  4 mg every day
  8 mg every day
  34.1 kg
  40 kg
  5 mg every day
  10 mg every day
  

  Usual Adjunctive Maintenance Dose for Epilepsy
  
  The usual maintenance doses identified in Tables 1 and 2 are derived from dosing regimens employed in the placebo-controlled adjunctive trials in which the efficacy of lamotrigine tablets (chewable, dispersible) was established. In patients receiving multidrug regimens employing carbamazepine, phenytoin, phenobarbital, or primidone without valproate, maintenance doses of adjunctive lamotrigine tablets (chewable, dispersible) as high as 700 mg/day have been used. In patients receiving valproate alone, maintenance doses of adjunctive lamotrigine tablets (chewable, dispersible) as high as 200 mg/day have been used. The advantage of using doses above those recommended in Tables 1 to 4 has not been established in controlled trials.

  2.3 Epilepsy - Conversion from Adjunctive Therapy to Monotherapy

  The goal of the transition regimen is to attempt to maintain seizure control while mitigating the risk of serious rash associated with the rapid titration of lamotrigine tablets (chewable, dispersible).

  
  

  The recommended maintenance dose of lamotrigine tablets (chewable, dispersible) as monotherapy is 500 mg/day given in 2 divided doses.

  
  

  To avoid an increased risk of rash, the recommended initial dose and subsequent dose escalations for lamotrigine tablets (chewable, dispersible) should not be exceeded [see Boxed Warning].
  
  Conversion from Adjunctive Therapy with Carbamazepine, Phenytoin, Phenobarbital, or Primidone to Monotherapy with Lamotrigine Tablets (Chewable, Dispersible)
  
  After achieving a dose of 500 mg/day of lamotrigine tablets (chewable, dispersible) using the guidelines in Table 1, the concomitant enzyme-inducing AED should be withdrawn by 20% decrements each week over a 4-week period. The regimen for the withdrawal of the concomitant AED is based on experience gained in the controlled monotherapy clinical trial.
  
  Conversion from Adjunctive Therapy with Valproate to Monotherapy with Lamotrigine Tablets (Chewable, Dispersible)
  
  The conversion regimen involves the 4 steps outlined in Table 4. 

  Table 4. Conversion from Adjunctive Therapy with Valproate to Monotherapy with Lamotrigine Tablets (Chewable, Dispersible) in Patients Aged 16 Years and Older with Epilepsy  
  Lamotrigine Tablets
  (Chewable, Dispersible)
  Valproate
  Step 1
  Achieve a dose of 200 mg/day according to guidelines in Table 1.
  Maintain established stable dose.
  Step 2
  Maintain at 200 mg/day.
  Decrease dose by decrements no greater than 500 mg/day/week to 500 mg/day and then maintain for 1 week.
  Step 3
  Increase to 300 mg/day and maintain for
  1 week.
  Simultaneously decrease to 250 mg/day and maintain for 1 week.
  Step 4
  Increase by 100 mg/day every week to achieve maintenance dose of 500 mg/day.
  Discontinue.
  

  Conversion from Adjunctive Therapy with Antiepileptic Drugs other than Carbamazepine, Phenytoin, Phenobarbital, Primidone, or Valproate to Monotherapy with Lamotrigine Tablets (Chewable, Dispersible)
  
  No specific dosing guidelines can be provided for conversion to monotherapy with lamotrigine tablets (chewable, dispersible) with AEDs other than carbamazepine, phenytoin, phenobarbital, primidone, or valproate.

  2.4 Bipolar Disorder

  The goal of maintenance treatment with lamotrigine tablets (chewable, dispersible) is to delay the time to occurrence of mood episodes (depression, mania, hypomania, mixed episodes) in patients treated for acute mood episodes with standard therapy [see Indications and Usage (1)].
  
  Patients taking lamotrigine tablets (chewable, dispersible) for more than 16 weeks should be periodically reassessed to determine the need for maintenance treatment.
  
  Adults
  
  The target dose of lamotrigine tablets (chewable, dispersible) is 200 mg/day (100 mg/day in patients taking valproate, which decreases the apparent clearance of lamotrigine, and 400 mg/day in patients not taking valproate and taking either carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin and the protease inhibitor lopinavir/ritonavir that increase the apparent clearance of lamotrigine). In the clinical trials, doses up to 400 mg/day as monotherapy were evaluated; however, no additional benefit was seen at 400 mg/day compared with 200 mg/day [see Clinical Studies (14.2)]. Accordingly, doses above 200 mg/day are not recommended.
  
  Treatment with lamotrigine tablets (chewable, dispersible) is introduced, based on concurrent medications, according to the regimen outlined in Table 5. If other psychotropic medications are withdrawn following stabilization, the dose of lamotrigine tablets (chewable, dispersible) should be adjusted. In patients discontinuing valproate, the dose of lamotrigine tablets (chewable, dispersible) should be doubled over a 2-week period in equal weekly increments (see Table 6). In patients discontinuing carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin and the protease inhibitors lopinavir/ritonavir and atazanavir/ritonavir that induce lamotrigine glucuronidation, the dose of lamotrigine tablets (chewable, dispersible) should remain constant for the first week and then should be decreased by half over a 2-week period in equal weekly decrements (see Table 6). The dose of lamotrigine tablets (chewable, dispersible) may then be further adjusted to the target dose (200 mg) as clinically indicated.

  
  

  If other drugs are subsequently introduced, the dose of lamotrigine tablets (chewable, dispersible) may need to be adjusted. In particular, the introduction of valproate requires reduction in the dose of lamotrigine tablets (chewable, dispersible) [see Drug Interactions (7), Clinical Pharmacology (12.3)].
  
  To avoid an increased risk of rash, the recommended initial dose and subsequent dose escalations of lamotrigine tablets (chewable, dispersible) should not be exceeded [see Boxed Warning]. 

  Table 5. Escalation Regimen for Lamotrigine Tablets (Chewable, Dispersible)  in Adults with Bipolar Disorder a  Valproate has been shown to inhibit glucuronidation and decrease the apparent clearance of lamotrigine [see Drug Interactions (7), Clinical Pharmacology (12.3)].
  b Drugs that induce lamotrigine glucuronidation and increase clearance, other than the specified antiepileptic drugs, include estrogen-containing oral contraceptives, rifampin, and the protease inhibitors lopinavir/ritonavir and atazanavir/ritonavir. Dosing recommendations for oral contraceptives and the protease inhibitor atazanavir/ritonavir can be found in General Dosing Considerations [see Dosage and Administration (2.1)]. Patients on rifampin and the protease inhibitor lopinavir/ritonavir should follow the same dosing titration/maintenance regimen used with antiepileptic drugs that induce glucuronidation and increase clearance [see Dosage and Administration (2.1), Drug Interactions (7), and Clinical Pharmacology (12.3)].
   
  In Patients TAKING Valproatea
  In Patients NOT TAKING Carbamazepine, Phenytoin, Phenobarbital, Primidoneb,or Valproatea
  In Patients TAKING Carbamazepine, Phenytoin, Phenobarbital, or Primidoneb and NOT TAKING Valproatea
  Weeks 1 and 2
  25 mg every other day
  25 mg daily
  50 mg daily
  Weeks 3 and 4
  25 mg daily
  50 mg daily
  100 mg daily, in divided doses
  Week 5
  50 mg daily
  100 mg daily
  200 mg daily, in divided doses
  Week 6
  100 mg daily
  200 mg daily
  300 mg daily, in divided doses
  Week 7
  100 mg daily
  200 mg daily
  up to 400 mg daily, in divided doses
  
  Table 6. Dosage Adjustments to Lamotrigine Tablets (Chewable, Dispersible) in Adults with Bipolar Disorder Following Discontinuation of Psychotropic Medications a Valproate has been shown to inhibit glucuronidation and decrease the apparent clearance of lamotrigine [see Drug Interactions (7), Clinical Pharmacology (12.3)].
  b Drugs that induce lamotrigine glucuronidation and increase clearance, other than the specified antiepileptic drugs, include estrogen-containing oral contraceptives, rifampin, and the protease inhibitors lopinavir/ritonavir and atazanavir/ritonavir. Dosing recommendations for oral contraceptives and the protease inhibitor atazanavir/ritonavir can be found in General Dosing Considerations [see Dosage and Administration (2.1)]. Patients on rifampin and the protease inhibitor lopinavir/ritonavir should follow the same dosing titration/maintenance regimen used with antiepileptic drugs that induce glucuronidation and increase clearance [see Dosage and Administration (2.1), Drug Interactions (7), and Clinical Pharmacology (12.3)].
   
  Discontinuation of Psychotropic Drugs (excluding Valproate,a Carbamazepine, Phenytoin, Phenobarbital,  or Primidoneb)
  After Discontinuation of Valproatea
  After Discontinuation of Carbamazepine, Phenytoin, Phenobarbital, or
  Primidoneb
  Current Dose of lamotrigine tablets (chewable, dispersible) (mg/day) 100
  Current Dose of lamotrigine tablets (chewable, dispersible) (mg/day) 400
  Week 1
  Maintain current dose of lamotrigine tablets (chewable, dispersible)
  150
  400
  Week 2
  Maintain current dose of lamotrigine tablets (chewable, dispersible)
  200
  300
  Week 3 onward
  Maintain current dose of lamotrigine tablets (chewable, dispersible)
  200
  200
  2.5 Administration of Lamotrigine Tablets (Chewable, Dispersible)
  

  Lamotrigine tablets (chewable, dispersible) may be swallowed whole, chewed, or dispersed in water or diluted fruit juice. If the tablets are chewed, consume a small amount of water or diluted fruit juice to aid in swallowing.
  
  To disperse lamotrigine tablets (chewable, dispersible), add the tablets to a small amount of liquid (1 teaspoon, or enough to cover the medication). Approximately 1 minute later, when the tablets are completely dispersed, swirl the solution and consume the entire quantity immediately. No attempt should be made to administer partial quantities of the dispersed tablets.

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  2.1 Hypertension

  Dosage must be individualized. The usual starting dose of telmisartan tablets is 40 mg once a day. Blood pressure response is dose-related over the range of 20 mg to 80 mg [see Clinical Studies (14.1)].

  Most of the antihypertensive effect is apparent within 2 weeks and maximal reduction is generally attained after 4 weeks. When additional blood pressure reduction beyond that achieved with 80 mg telmisartan is required, a diuretic may be added.

  No initial dosage adjustment is necessary for elderly patients or patients with renal impairment, including those on hemodialysis. Patients on dialysis may develop orthostatic hypotension; their blood pressure should be closely monitored.

  Telmisartan tablets may be administered with other antihypertensive agents.

  Telmisartan tablets may be administered with or without food.

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  2.1 General Dosing Considerations Rash

  There are suggestions, yet to be proven, that the risk of severe, potentially life threatening rash may be increased by (1) coadministration of lamotrigine tablets with valproate, (2) exceeding the recommended initial dose of lamotrigine tablets, or (3) exceeding the recommended dose escalation for lamotrigine tablets. However, cases have occurred in the absence of these factors [see Boxed Warning]. Therefore, it is important that the dosing recommendations be followed closely.

  The risk of nonserious rash may be increased when the recommended initial dose and/or the rate of dose escalation of lamotrigine tablets are exceeded and in patients with a history of allergy or rash to other AEDs.

  It is recommended that lamotrigine tablets not be restarted in patients who discontinued due to rash associated with prior treatment with lamotrigine, unless the potential benefits clearly outweigh the risks. If the decision is made to restart a patient who has discontinued lamotrigine, the need to restart with the initial dosing recommendations should be assessed. The greater the interval of time since the previous dose, the greater consideration should be given to restarting with the initial dosing recommendations. If a patient has discontinued lamotrigine for a period of more than 5 half-lives, it is recommended that initial dosing recommendations and guidelines be followed. The half-life of lamotrigine is affected by other concomitant medications [see Clinical Pharmacology (12.3)].

  Lamotrigine Tablets Added to Drugs Known to Induce or Inhibit Glucuronidation

  Drugs other than those listed in the Clinical Pharmacology section [see Clinical Pharmacology (12.3)] have not been systematically evaluated in combination with lamotrigine. Because lamotrigine is metabolized predominantly by glucuronic acid conjugation, drugs that are known to induce or inhibit glucuronidation may affect the apparent clearance of lamotrigine and doses of lamotrigine tablets may require adjustment based on clinical response.

  Target Plasma Levels for Patients with Epilepsy or Bipolar Disorder

  A therapeutic plasma concentration range has not been established for lamotrigine. Dosing of lamotrigine tablets should be based on therapeutic response [see Clinical Pharmacology (12.3)].

  Women taking Estrogen-Containing Oral Contraceptives Starting Lamotrigine Tablets in Women taking Estrogen-Containing Oral Contraceptives

  Although estrogen-containing oral contraceptives have been shown to increase the clearance of lamotrigine [see Clinical Pharmacology (12.3)], no adjustments to the recommended dose-escalation guidelines for lamotrigine tablets should be necessary solely based on the use of estrogen-containing oral contraceptives. Therefore, dose escalation should follow the recommended guidelines for initiating adjunctive therapy with lamotrigine tablets based on the concomitant AED or other concomitant medications (see Table 1 or Table 5). See below for adjustments to maintenance doses of lamotrigine tablets in women taking estrogen-containing oral contraceptives.

  Adjustments to the Maintenance Dose of Lamotrigine Tablets in Women taking Estrogen-Containing Oral Contraceptives

  (1) Taking Estrogen-Containing Oral Contraceptives: For women not taking carbamazepine, phenytoin, phenobarbital, primidone or other drugs such as rifampin that induce lamotrigine glucuronidation [see Drug Interactions (7), Clinical Pharmacology (12.3)], the maintenance dose of lamotrigine tablets will in most cases need to be increased, by as much as 2-fold over the recommended target maintenance dose, in order to maintain a consistent lamotrigine plasma level [see Clinical Pharmacology (12.3)].

  (2) Starting Estrogen-Containing Oral Contraceptives: In women taking a stable dose of lamotrigine tablets and not taking carbamazepine, phenytoin, phenobarbital, primidone or other drugs such as rifampin that induce lamotrigine glucuronidation [see Drug Interactions (7), Clinical Pharmacology (12.3)], the maintenance dose will in most cases need to be increased by as much as 2-fold in order to maintain a consistent lamotrigine plasma level. The dose increases should begin at the same time that the oral contraceptive is introduced and continue, based on clinical response, no more rapidly than 50 to 100 mg/day every week. Dose increases should not exceed the recommended rate (see Table 1 or Table 5) unless lamotrigine plasma levels or clinical response support larger increases. Gradual transient increases in lamotrigine plasma levels may occur during the week of inactive hormonal preparation (“pill-free” week), and these increases will be greater if dose increases are made in the days before or during the week of inactive hormonal preparation. Increased lamotrigine plasma levels could result in additional adverse reactions, such as dizziness, ataxia and diplopia. If adverse reactions attributable to lamotrigine tablets consistently occur during the “pill-free” week, dose adjustments to the overall maintenance dose may be necessary. Dose adjustments limited to the “pill-free” week are not recommended. For women taking lamotrigine tablets in addition to carbamazepine, phenytoin, phenobarbital, primidone or other drugs such as rifampin that induce lamotrigine glucuronidation [see Drug Interactions (7), Clinical Pharmacology (12.3)], no adjustment to the dose of lamotrigine tablets should be necessary.

  (3) Stopping Estrogen-Containing Oral Contraceptives: For women not taking carbamazepine, phenytoin, phenobarbital, primidone or other drugs such as rifampin that induce lamotrigine glucuronidation [see Drug Interactions (7), Clinical Pharmacology (12.3)], the maintenance dose of lamotrigine tablets will in most cases need to be decreased by as much as 50% in order to maintain a consistent lamotrigine plasma level. The decrease in dose of lamotrigine tablets should not exceed 25% of the total daily dose per week over a 2-week period, unless clinical response or lamotrigine plasma levels indicate otherwise [see Clinical Pharmacology (12.3)]. For women taking lamotrigine tablets in addition to carbamazepine, phenytoin, phenobarbital, primidone or other drugs such as rifampin that induce lamotrigine glucuronidation [see Drug Interactions (7), Clinical Pharmacology (12.3)], no adjustment to the dose of lamotrigine tablets should be necessary.

  Women and Other Hormonal Contraceptive Preparations or Hormone Replacement Therapy

  The effect of other hormonal contraceptive preparations or hormone replacement therapy on the pharmacokinetics of lamotrigine has not been systematically evaluated. It has been reported that ethinylestradiol, not progestogens, increased the clearance of lamotrigine up to 2-fold, and the progestin-only pills had no effect on lamotrigine plasma levels. Therefore, adjustments to the dosage of lamotrigine tablets in the presence of progestogens alone will likely not be needed.

  Patients with Hepatic Impairment

  Experience in patients with hepatic impairment is limited. Based on a clinical pharmacology study in 24 patients with mild, moderate and severe liver impairment [see Use in Specific Populations (8.6), Clinical Pharmacology (12.3)], the following general recommendations can be made. No dosage adjustment is needed in patients with mild liver impairment. Initial, escalation, and maintenance doses should generally be reduced by approximately 25% in patients with moderate and severe liver impairment without ascites and 50% in patients with severe liver impairment with ascites. Escalation and maintenance doses may be adjusted according to clinical response.

  Patients with Renal Impairment

  Initial doses of lamotrigine tablets should be based on patients' concomitant medications (see Tables 1 to 3 or Table 5); reduced maintenance doses may be effective for patients with significant renal impairment [see Use in Specific Populations (8.7), Clinical Pharmacology (12.3)]. Few patients with severe renal impairment have been evaluated during chronic treatment with lamotrigine tablets. Because there is inadequate experience in this population, lamotrigine tablets should be used with caution in these patients.

  Discontinuation Strategy Epilepsy

  For patients receiving lamotrigine tablets in combination with other AEDs, a reevaluation of all AEDs in the regimen should be considered if a change in seizure control or an appearance or worsening of adverse reactions is observed.

  If a decision is made to discontinue therapy with lamotrigine tablets, a step-wise reduction of dose over at least 2 weeks (approximately 50% per week) is recommended unless safety concerns require a more rapid withdrawal [see Warnings and Precautions (5.10)].

  Discontinuing carbamazepine, phenytoin, phenobarbital, primidone or other drugs such as rifampin that induce lamotrigine glucuronidation should prolong the half-life of lamotrigine; discontinuing valproate should shorten the half-life of lamotrigine.

  Bipolar Disorder

  In the controlled clinical trials, there was no increase in the incidence, type, or severity of adverse reactions following abrupt termination of lamotrigine tablets. In clinical trials in patients with bipolar disorder, two patients experienced seizures shortly after abrupt withdrawal of lamotrigine tablets. However, there were confounding factors that may have contributed to the occurrence of seizures in these bipolar patients. Discontinuation of lamotrigine tablets should involve a step-wise reduction of dose over at least 2 weeks (approximately 50% per week) unless safety concerns require a more rapid withdrawal [see Warnings and Precautions (5.10)].

  2.2 Epilepsy – Adjunctive Therapy

  This section provides specific dosing recommendations for patients greater than 12 years of age and patients 2 to 12 years of age. Within each of these age groups, specific dosing recommendations are provided depending upon concomitant AED or other concomitant medications (Table 1 for patients greater than 12 years of age and Table 2 for patients 2 to 12 years of age). A weight-based dosing guide for patients 2 to 12 years of age on concomitant valproate is provided in Table 3.

  Patients Over 12 Years of Age

  Recommended dosing guidelines are summarized in Table 1.

  Table 1. Escalation Regimen for Lamotrigine Tablets in Patients Over 12 Years of Age with Epilepsy * Valproate has been shown to inhibit glucuronidation and decrease the apparent clearance of lamotrigine [see Drug Interactions (7), Clinical Pharmacology (12.3)]. † These drugs induce lamotrigine glucuronidation and increase clearance [see Drug Interactions (7), Clinical Pharmacology (12.3)]. Other drugs that have similar effects include estrogen-containing oral contraceptives [see Drug Interactions (7), Clinical Pharmacology (12.3)]. Dosing recommendations for oral contraceptives can be found in General Dosing Considerations [see Dosage and Administration (2.1)]. Patients on rifampin, or other drugs that induce lamotrigine glucuronidation and increase clearance, should follow the same dosing titration/maintenance regimen as that used with anticonvulsants that have this effect.

  For Patients TAKING
  Valproate*

  For Patients NOT
  TAKING
  Carbamazepine,
  Phenytoin,
  Phenobarbital,
  Primidone† or
  Valproate*

  For Patients
  TAKING
  Carbamazepine,
  Phenytoin,
  Phenobarbital or
  Primidone† and
  NOT
  TAKING
  Valproate*

  Weeks 1 and 2

  25 mg every other day

  25 mg every day

  50 mg/day

  Weeks 3 and 4

  25 mg every day

  50 mg/day

  100 mg/day
  (in 2 divided doses)

  Week 5 onwards
  to maintenance

  Increase by 25 to 50 mg/day every 1 to 2 weeks

  Increase by 50 mg/day every 1 to 2 weeks

  Increase by 100 mg/day every 1 to 2 weeks

  Usual Maintenance
  Dose

  100 to 200 mg/day with valproate alone
  
  100 to 400 mg/day with valproate and other drugs that induce glucuronidation
  
  (in 1 or 2 divided doses)

  225 to 375 mg/day
  (in 2 divided doses)

  300 to 500 mg/day
  (in 2 divided doses)

  Patients 2 to 12 Years of Age

  Recommended dosing guidelines are summarized in Table 2.

  Smaller starting doses and slower dose escalations than those used in clinical trials are recommended because of the suggestion that the risk of rash may be decreased by smaller starting doses and slower dose escalations. Therefore, maintenance doses will take longer to reach in clinical practice than in clinical trials. It may take several weeks to months to achieve an individualized maintenance dose. Maintenance doses in patients weighing less than 30 kg, regardless of age or concomitant AED, may need to be increased as much as 50%, based on clinical response.

  Table 2. Escalation Regimen for Lamotrigine Tablets in Patients 2 to 12 Years of Age with Epilepsy * Valproate has been shown to inhibit glucuronidation and decrease the apparent clearance of lamotrigine [see Drug Interactions (7), Clinical Pharmacology (12.3)]. † These drugs induce lamotrigine glucuronidation and increase clearance [see Drug Interactions (7), Clinical Pharmacology (12.3)]. Other drugs that have similar effects include estrogen-containing oral contraceptives [see Drug Interactions (7), Clinical Pharmacology (12.3)]. Dosing recommendations for oral contraceptives can be found in General Dosing Considerations [see Dosage and Administration (2.1)]. Patients on rifampin, or other drugs that induce lamotrigine glucuronidation and increase clearance, should follow the same dosing titration/maintenance regimen as that used with anticonvulsants that have this effect.

  For Patients TAKING

  Valproate*

  For Patients NOT
  TAKING
  Carbamazepine,
  Phenytoin, Phenobarbital, Primidone† or Valproate*

  For Patients TAKING
  Carbamazepine,
  Phenytoin,
  Phenobarbital or
  Primidone† and NOT
  TAKING Valproate*

  Weeks
  1 and 2

  0.15 mg/kg/day
  in 1 or 2 divided doses,
  rounded down to the
  nearest whole tablet (see
  Table 3 for weight based
  dosing guide).

  0.3 mg/kg/day
  in 1 or 2 divided doses,
  rounded down to the
  nearest whole tablet.

  0.6 mg/kg/day
  in 2 divided doses,
  rounded down to the
  nearest whole tablet.

  Weeks
  3 and 4

  0.3 mg/kg/day

  in 1 or 2 divided doses,
  rounded down to the
  nearest whole tablet
  (see Table 3 for weight
  based dosing guide).

  0.6 mg/kg/day
  in 2 divided doses,
  rounded down to the
  nearest whole tablet.

  1.2 mg/kg/day
  in 2 divided doses,
  rounded down to the
  nearest whole tablet.

  Week 5
  onwards to
  

  maintenance

  The dose should be
  increased every 1 to
  2 weeks as follows:
  calculate 0.3 mg/kg/day, round this amount down to the nearest whole tablet
  and add this
  amount to the previously
  administered daily dose.

  The dose should be increased every 1 to 2 weeks as follows: calculate 0.6 mg/kg/day,

  round this amount down to the nearest whole tablet and add this amount to the previously administered daily dose.

  The dose should be
  increased every 1 to 2 weeks as follows:
  calculate
  1.2 mg/kg/day, round this amount
  down to the nearest
  whole tablet and
  add this amount to
  the previously
  administered daily
  dose.

  Usual

  Maintenance

  Dose

  1 to 5 mg/kg/day
  (maximum 200 mg/day in
  1 or 2 divided doses).
  1 to 3 mg/kg/day with
  valproate alone.

  4.5 to 7.5 mg/kg/day
  (maximum 300 mg/day in 2 divided doses).

  5 to 15 mg/kg/day
  (maximum 400 mg/day in 2 divided doses).

  Maintenance

  dose in

  patients less

  than 30 kg

  May need to be increased
  by as much as 50%, based
  on clinical response.

  May need to be increased by as much as 50%, based on clinical response.

  May need to be
  increased by as
  much as 50%, based
  on clinical response.

  Note: Only whole tablets should be used for dosing.

  Table 3. The Initial Weight-Based Dosing Guide for Patients 2 to 12 Years of Age taking Valproate (Weeks 1 to 4) with Epilepsy

  If the patient's weight is

  Give this daily dose, using the most appropriate combination of lamotrigine 2 mg and 5 mg tablets

  Greater than

  And less than

  Weeks 1 and 2

  Weeks 3 and 4

  6.7 kg

  14 kg

  2 mg every other day

  2 mg every day

  14.1 kg

  27 kg

  2 mg every day

  4 mg every day

  27.1 kg

  34 kg

  4 mg every day

  8 mg every day

  34.1 kg

  40 kg

  5 mg every day

  10 mg every day

  Usual Adjunctive Maintenance Dose for Epilepsy

  The usual maintenance doses identified in Tables 1 and 2 are derived from dosing regimens employed in the placebo-controlled adjunctive studies in which the efficacy of lamotrigine was established. In patients receiving multidrug regimens employing carbamazepine, phenytoin, phenobarbital or primidone without valproate, maintenance doses of adjunctive lamotrigine tablets as high as 700 mg/day have been used. In patients receiving valproate alone, maintenance doses of adjunctive lamotrigine tablets as high as 200 mg/day have been used. The advantage of using doses above those recommended in Tables 1 through 4 has not been established in controlled trials.

  2.3 Epilepsy – Conversion from Adjunctive Therapy to Monotherapy

  The goal of the transition regimen is to effect the conversion to monotherapy with lamotrigine tablets under conditions that ensure adequate seizure control while mitigating the risk of serious rash associated with the rapid titration of lamotrigine.

  The recommended maintenance dose of lamotrigine tablets as monotherapy is 500 mg/day given in two divided doses.

  To avoid an increased risk of rash, the recommended initial dose and subsequent dose escalations of lamotrigine tablets should not be exceeded [see Boxed Warning].

  Conversion from Adjunctive Therapy with Carbamazepine, Phenytoin, Phenobarbital or Primidone to Monotherapy with Lamotrigine Tablets

  After achieving a dose of 500 mg/day of lamotrigine tablets according to the guidelines in Table 1, the concomitant AED should be withdrawn by 20% decrements each week over a 4-week period. The regimen for the withdrawal of the concomitant AED is based on experience gained in the controlled monotherapy clinical trial.

  Conversion from Adjunctive Therapy with Valproate to Monotherapy with Lamotrigine Tablets

  The conversion regimen involves four steps outlined in Table 4.

  Table 4. Conversion from Adjunctive Therapy with Valproate to Monotherapy with Lamotrigine Tablets in Patients ≥ 16 Years of Age with Epilepsy

  Lamotrigine Tablets

  Valproate

  Step 1

  Achieve a dose of 200 mg/day according to
  guidelines in Table 1 (if not already on

  200 mg/day).

  Maintain previous stable dose.

  Step 2

  Maintain at 200 mg/day.

  Decrease to 500 mg/day by
  decrements no greater than
  500 mg/day/week and then
  maintain the dose of
  500 mg/day for one week.

  Step 3

  Increase to 300 mg/day and maintain
  for one week.

  Simultaneously decrease to
  250 mg/day and maintain for
  one week.

  Step 4

  Increase by 100 mg/day every week to achieve
  maintenance dose of 500 mg/day.

  Discontinue.

  Conversion from Adjunctive Therapy with Antiepileptic Drugs Other than Carbamazepine, Phenytoin, Phenobarbital, Primidone or Valproate to Monotherapy with Lamotrigine Tablets

  No specific dosing guidelines can be provided for conversion to monotherapy with lamotrigine tablets with AEDs other than carbamazepine, phenobarbital, phenytoin, primidone or valproate.

  2.4 Bipolar Disorder

  The goal of maintenance treatment with lamotrigine tablets is to delay the time to occurrence of mood episodes (depression, mania, hypomania, mixed episodes) in patients treated for acute mood episodes with standard therapy. The target dose of lamotrigine tablets is 200 mg/day (100 mg/day in patients taking valproate, which decreases the apparent clearance of lamotrigine and 400 mg/day in patients not taking valproate and taking either carbamazepine, phenytoin, phenobarbital, primidone or other drugs such as rifampin that increase the apparent clearance of lamotrigine). In the clinical trials, doses up to 400 mg/day as monotherapy were evaluated; however, no additional benefit was seen at 400 mg/day compared with 200 mg/day [see Clinical Studies (14.2)]. Accordingly, doses above 200 mg/day are not recommended. Treatment with lamotrigine tablets is introduced, based on concurrent medications, according to the regimen outlined in Table 5. If other psychotropic medications are withdrawn following stabilization, the dose of lamotrigine tablets should be adjusted. For patients discontinuing valproate, the dose of lamotrigine tablets should be doubled over a 2-week period in equal weekly increments (see Table 6). For patients discontinuing carbamazepine, phenytoin, phenobarbital, primidone or other drugs such as rifampin that induce lamotrigine glucuronidation, the dose of lamotrigine tablets should remain constant for the first week and then should be decreased by half over a 2-week period in equal weekly decrements (see Table 6). The dose of lamotrigine tablets may then be further adjusted to the target dose (200 mg) as clinically indicated.

  If other drugs are subsequently introduced, the dose of lamotrigine tablets may need to be adjusted. In particular, the introduction of valproate requires reduction in the dose of lamotrigine tablets [see Drug Interactions (7), Clinical Pharmacology (12.3)].

  To avoid an increased risk of rash, the recommended initial dose and subsequent dose escalations of lamotrigine tablets should not be exceeded [see Boxed Warning].

  Table 5. Escalation Regimen for Lamotrigine Tablets for Patients with Bipolar Disorder * Valproate has been shown to inhibit glucuronidation and decrease the apparent clearance of lamotrigine [see Drug Interactions (7), Clinical Pharmacology (12.3)]. † These drugs induce lamotrigine glucuronidation and increase clearance [see Drug Interactions (7), Clinical Pharmacology (12.3)]. Other drugs that have similar effects include estrogen-containing oral contraceptives [see Drug Interactions (7), Clinical Pharmacology (12.3)]. Dosing recommendations for oral contraceptives can be found in General Dosing Considerations [see Dosage and Administration (2.1)]. Patients on rifampin, or other drugs that induce lamotrigine glucuronidation and increase clearance, should follow the same dosing titration/maintenance regimen as that used with anticonvulsants that have this effect.

  For Patients
  TAKING
  Valproate*

  For Patients NOT
  TAKING
  Carbamazepine,
  Phenytoin,
  Phenobarbital,
  Primidone† or
  Valproate*

  For Patients
  TAKING
  Carbamazepine,
  Phenytoin, Phenobarbital or
  Primidone† and
  NOT TAKING
  Valproate*

  Weeks 1 and 2

  25 mg every other day

  25 mg daily

  50 mg daily

  Weeks 3 and 4

  25 mg daily

  50 mg daily

  100 mg daily, in divided doses

  Week 5

  50 mg daily

  100 mg daily

  200 mg daily, in divided doses

  Week 6

  100 mg daily

  200 mg daily

  300 mg daily, in divided doses

  Week 7

  100 mg daily

  200 mg daily

  up to 400 mg daily, in divided doses

  Table 6. Dosage Adjustments to Lamotrigine Tablets for Patients with Bipolar Disorder Following Discontinuation of Psychotropic Medications * These drugs induce lamotrigine glucuronidation and increase clearance [see Drug Interactions (7), Clinical Pharmacology (12.3)]. Other drugs that have similar effects include estrogen-containing oral contraceptives [see Drug Interactions (7), Clinical Pharmacology (12.3)]. Dosing recommendations for oral contraceptives can be found in General Dosing Considerations [see Dosage and Administration (2.1)]. Patients on rifampin, or other drugs that induce lamotrigine glucuronidation and increase clearance, should follow the same dosing titration/maintenance regimen as that used with anticonvulsants that have this effect. † Valproate has been shown to inhibit glucuronidation and decrease the apparent clearance of lamotrigine [see Drug Interactions (7), Clinical Pharmacology (12.3)].

  Discontinuation of
  Psychotropic Drugs
  (excluding Carbamazepine,
  Phenytoin, Phenobarbital,
  Primidone*
  or Valproate†)

  After
  Discontinuation
  of Valproate†

  After Discontinuation
  of Carbamazepine,
  Phenytoin,
  Phenobarbital or
  Primidone*

  Current dose of lamotrigine tablets (mg/day)
  100

  Current dose of lamotrigine tablets (mg/day)
  400

  Week 1

  Maintain current dose of lamotrigine tablets

  150

  400

  Week 2

  Maintain current dose of lamotrigine tablets

  200

  300

  Week 3 onward

  Maintain current dose of lamotrigine tablets

  200

  200

  The benefit of continuing treatment in patients who had been stabilized in an 8- to 16-week open-label phase with lamotrigine tablets was established in two randomized, placebo-controlled clinical maintenance trials [see Clinical Studies (14.2)]. However, the optimal duration of treatment with lamotrigine tablets has not been established. Thus, patients should be periodically reassessed to determine the need for maintenance treatment.

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  2.1 General Dosing Considerations

  : There are suggestions, yet to be proven, that the risk of severe, potentially life-threatening rash may be increased by (1) coadministration of lamotrigine tablets (chewable, dispersible) with valproate, (2) exceeding the recommended initial dose of lamotrigine tablets (chewable, dispersible), or (3) exceeding the recommended dose escalation for lamotrigine tablets (chewable, dispersible). However, cases have occurred in the absence of these factors [see ]. Therefore, it is important that the dosing recommendations be followed closely. RashBoxed Warning

  The risk of nonserious rash may be increased when the recommended initial dose and/or the rate of dose escalation of lamotrigine tablets (chewable, dispersible) is exceeded and in patients with a history of allergy or rash to other AEDs.

  It is recommended that lamotrigine tablets (chewable, dispersible) not be restarted in patients who discontinued due to rash associated with prior treatment with lamotrigine, unless the potential benefits clearly outweigh the risks. If the decision is made to restart a patient who has discontinued lamotrigine, the need to restart with the initial dosing recommendations should be assessed. The greater the interval of time since the previous dose, the greater consideration should be given to restarting with the initial dosing recommendations. If a patient has discontinued lamotrigine for a period of more than 5 half-lives, it is recommended that initial dosing recommendations and guidelines be followed. The half-life of lamotrigine is affected by other concomitant medications [ ]. see Clinical Pharmacology ( ) 12.3

  : Drugs other than those listed in the Clinical Pharmacology section [ ] have not been systematically evaluated in combination with lamotrigine. Because lamotrigine is metabolized predominantly by glucuronic acid conjugation, drugs that are known to induce or inhibit glucuronidation may affect the apparent clearance of lamotrigine and doses of lamotrigine tablets (chewable, dispersible) may require adjustment based on clinical response. Lamotrigine Added to Drugs Known to Induce or Inhibit Glucuronidationsee Clinical Pharmacology ( ) 12.3

  : A therapeutic plasma concentration range has not been established for lamotrigine. Dosing of lamotrigine tablets (chewable, dispersible) should be based on therapeutic response [ ]. Target Plasma Levels for Patients With Epilepsy or Bipolar Disordersee Clinical Pharmacology ( ) 12.3

  : Although estrogen-containing oral contraceptives have been shown to increase the clearance of lamotrigine [ ], no adjustments to the recommended dose-escalation guidelines for lamotrigine tablets (chewable, dispersible) should be necessary solely based on the use of estrogen-containing oral contraceptives. Therefore, dose escalation should follow the recommended guidelines for initiating adjunctive therapy with lamotrigine tablets (chewable, dispersible) based on the concomitant AED or other concomitant medications (see or ). See below for adjustments to maintenance doses of lamotrigine tablets (chewable, dispersible) in women taking estrogen-containing oral contraceptives. Women Taking Estrogen-Containing Oral ContraceptivesStarting Lamotrigine Tablets (Chewable, Dispersible) in Women Taking Estrogen-Containing Oral Contraceptives:see Clinical Pharmacology ( ) 12.3Table 1Table 5

  Adjustments to the Maintenance Dose of Lamotrigine Tablets (Chewable, Dispersible) in Women Taking Estrogen-Containing Oral Contraceptives:

  For women not taking carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin that induce lamotrigine glucuronidation [ ], the maintenance dose of lamotrigine tablets (chewable, dispersible) will in most cases need to be increased, by as much as 2 fold over the recommended target maintenance dose, in order to maintain a consistent lamotrigine plasma level [ ]. (1) Taking Estrogen-Containing Oral Contraceptives:see Drug Interactions ( ), Clinical Pharmacology ( ) 712.3see Clinical Pharmacology ( ) 12.3

  In women taking a stable dose of lamotrigine tablets (chewable, dispersible) and not taking carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin that induce lamotrigine glucuronidation [ ], the maintenance dose will in most cases need to be increased by as much as 2 fold in order to maintain a consistent lamotrigine plasma level. The dose increases should begin at the same time that the oral contraceptive is introduced and continue, based on clinical response, no more rapidly than 50 to 100 mg/day every week. Dose increases should not exceed the recommended rate (see or ) unless lamotrigine plasma levels or clinical response support larger increases. Gradual transient increases in lamotrigine plasma levels may occur during the week of inactive hormonal preparation (“pill-free” week), and these increases will be greater if dose increases are made in the days before or during the week of inactive hormonal preparation. Increased lamotrigine plasma levels could result in additional adverse reactions, such as dizziness, ataxia, and diplopia. If adverse reactions attributable to lamotrigine tablets (chewable, dispersible) consistently occur during the “pill-free” week, dose adjustments to the overall maintenance dose may be necessary. Dose adjustments limited to the “pill-free” week are not recommended. For women taking lamotrigine tablets (chewable, dispersible) in addition to carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin that induce lamotrigine glucuronidation [ ], no adjustment to the dose of lamotrigine tablets (chewable, dispersible) should be necessary. (2) Starting Estrogen-Containing Oral Contraceptives:see Drug Interactions ( ), Clinical Pharmacology ( ) 712.3Table 1Table 5see Drug Interactions ( ), Clinical Pharmacology ( ) 712.3

  For women not taking carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin that induce lamotrigine glucuronidation [ ], the maintenance dose of lamotrigine tablets (chewable, dispersible) will in most cases need to be decreased by as much as 50% in order to maintain a consistent lamotrigine plasma level. The decrease in dose of lamotrigine tablets (chewable, dispersible) should not exceed 25% of the total daily dose per week over a 2 week period, unless clinical response or lamotrigine plasma levels indicate otherwise [ ]. For women taking lamotrigine tablets (chewable, dispersible) in addition to carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin that induce lamotrigine glucuronidation [ ], no adjustment to the dose of lamotrigine tablets (chewable, dispersible) should be necessary. (3) Stopping Estrogen-Containing Oral Contraceptives:see Drug Interactions ( ), Clinical Pharmacology ( ) 712.3see Clinical Pharmacology ( ) 12.3see Drug Interactions ( ), Clinical Pharmacology ( ) 712.3

  : The effect of other hormonal contraceptive preparations or hormone replacement therapy on the pharmacokinetics of lamotrigine has not been systematically evaluated. It has been reported that ethinylestradiol, not progestogens, increased the clearance of lamotrigine up to 2 fold, and the progestin-only pills had no effect on lamotrigine plasma levels. Therefore, adjustments to the dosage of lamotrigine tablets (chewable, dispersible) in the presence of progestogens alone will likely not be needed. Women and Other Hormonal Contraceptive Preparations or Hormone Replacement Therapy

  : Experience in patients with hepatic impairment is limited. Based on a clinical pharmacology study in 24 patients with mild, moderate, and severe liver impairment [ ], the following general recommendations can be made. No dosage adjustment is needed in patients with mild liver impairment. Initial, escalation, and maintenance doses should generally be reduced by approximately 25% in patients with moderate and severe liver impairment without ascites and 50% in patients with severe liver impairment with ascites. Escalation and maintenance doses may be adjusted according to clinical response. Patients With Hepatic Impairmentsee Use in Specific Populations ( ), Clinical Pharmacology ( ) 8.612.3

  : Initial doses of lamotrigine tablets (chewable, dispersible) should be based on patients' concomitant medications (see to or ); reduced maintenance doses may be effective for patients with significant renal impairment [ ]. Few patients with severe renal impairment have been evaluated during chronic treatment with lamotrigine tablets (chewable, dispersible). Because there is inadequate experience in this population, lamotrigine tablets (chewable, dispersible) should be used with caution in these patients. Patients With Renal ImpairmentTables 13Table 5see Use in Specific Populations ( ), Clinical Pharmacology ( ) 8.712.3

  : For patients receiving lamotrigine tablets (chewable, dispersible) in combination with other AEDs, a reevaluation of all AEDs in the regimen should be considered if a change in seizure control or an appearance or worsening of adverse reactions is observed. Discontinuation StrategyEpilepsy:

  If a decision is made to discontinue therapy with lamotrigine tablets (chewable, dispersible), a step-wise reduction of dose over at least 2 weeks (approximately 50% per week) is recommended unless safety concerns require a more rapid withdrawal [ ]. see Warnings and Precautions ( ) 5.9

  Discontinuing carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin that induce lamotrigine glucuronidation should prolong the half-life of lamotrigine; discontinuing valproate should shorten the half-life of lamotrigine.

  In the controlled clinical trials, there was no increase in the incidence, type, or severity of adverse reactions following abrupt termination of lamotrigine tablets (chewable, dispersible). In clinical trials in patients with Bipolar Disorder, 2 patients experienced seizures shortly after abrupt withdrawal of lamotrigine tablets (chewable, dispersible). However, there were confounding factors that may have contributed to the occurrence of seizures in these bipolar patients. Discontinuation of lamotrigine tablets (chewable, dispersible) should involve a step-wise reduction of dose over at least 2 weeks (approximately 50% per week) unless safety concerns require a more rapid withdrawal [ ]. Bipolar Disorder:see Warnings and Precautions ( ) 5.9

  2.2 Epilepsy – Adjunctive Therapy

  This section provides specific dosing recommendations for patients greater than 12 years of age and patients 2 to 12 years of age. Within each of these age-groups, specific dosing recommendations are provided depending upon concomitant AED or other concomitant medications ( for patients greater than 12 years of age and for patients 2 to 12 years of age). A weight-based dosing guide for patients 2 to 12 years of age on concomitant valproate is provided in . Table 1Table 2Table 3

  Recommended dosing guidelines are summarized in . Patients Over 12 Years of Age:Table 1

  Table 1. Escalation Regimen for Lamotrigine in Patients Over 12 Years of Age With Epilepsy * Valproate has been shown to inhibit glucuronidation and decrease the apparent clearance of lamotrigine [ ]. see Drug Interactions ( ), Clinical Pharmacology ( ) 712.3 † These drugs induce lamotrigine glucuronidation and increase clearance [ ]. Other drugs that have similar effects include estrogen-containing oral contraceptives [ ]. Dosing recommendations for oral contraceptives can be found in General Dosing Considerations [ ]. Patients on rifampin, or other drugs that induce lamotrigine glucuronidation and increase clearance, should follow the same dosing titration/maintenance regimen as that used with anticonvulsants that have this effect. see Drug Interactions ( ), Clinical Pharmacology ( ) 712.3 see Drug Interactions ( ), Clinical Pharmacology ( ) 712.3 see Dosage and Administration ( ) 2.1

  For Patients TAKING Valproate *

  For Patients NOT TAKING Carbamazepine, Phenytoin, Phenobarbital, Primidone, or Valproate †* For Patients TAKING Carbamazepine, Phenytoin, Phenobarbital, or Primidone and NOT TAKING Valproate †* Weeks 1 and 2 25 mg every day other 25 mg every day 50 mg/day Weeks 3 and 4 25 mg every day 50 mg/day (in 2 divided doses) 100 mg/day Week 5 onwards to maintenance Increase by 25 to 50 mg/day every 1 to 2 weeks Increase by 50 mg/day every 1 to 2 weeks Increase by 100 mg/day every 1 to 2 weeks Usual Maintenance Dose

  100 to 200 mg/day with valproate alone

  100 to 400 mg/day with valproate and other drugs that induceglucuronidation

  (in 1 or 2 divided doses)

  225 to 375 mg/day

  (in 2 divided doses)

  300 to 500 mg/day

  (in 2 divided doses)

  Recommended dosing guidelines are summarized in . Patients 2 to 12 Years of Age:Table 2

  Smaller starting doses and slower dose escalations than those used in clinical trials are recommended because of the suggestion that the risk of rash may be decreased by smaller starting doses and slower dose escalations. Therefore, maintenance doses will take longer to reach in clinical practice than in clinical trials. It may take several weeks to months to achieve an individualized maintenance dose. Maintenance doses in patients weighing less than 30 kg, regardless of age or concomitant AED, may need to be increased as much as 50%, based on clinical response.

  [ ]. The smallest available strength of lamotrigine tablets (chewable, dispersible) is 2 mg, and only whole tablets should be administered. If the calculated dose cannot be achieved using whole tablets, the dose should be rounded down to the nearest whole tabletsee How Supplied/Storage and Handling ( ) and 16Medication Guide

  Table 2. Escalation Regimen for Lamotrigine in Patients 2 to 12 Years of Age With Epilepsy * Valproate has been shown to inhibit glucuronidation and decrease the apparent clearance of lamotrigine [ ]. see Drug Interactions ( ), Clinical Pharmacology ( ) 712.3 † These drugs induce lamotrigine glucuronidation and increase clearance [ ]. Other drugs that have similar effects include estrogen-containing oral contraceptives [ ]. Dosing recommendations for oral contraceptives can be found in General Dosing Considerations [ ]. Patients on rifampin, or other drugs that induce lamotrigine glucuronidation and increase clearance, should follow the same dosing titration/maintenance regimen as that used with anticonvulsants that have this effect. see Drug Interactions ( ), Clinical Pharmacology ( ) 712.3 see Drug Interactions ( ), Clinical Pharmacology ( ) 712.3 see Dosage and Administration ( ) 2.1 For Patients TAKING Valproate * For Patients NOT TAKING Carbamazepine, Phenytoin, Phenobarbital, Primidone, or Valproate †* For Patients TAKING Carbamazepine, Phenytoin, Phenobarbital, or Primidone and NOT TAKING Valproate †* Weeks 1 and 2 in 1 or 2 divided doses, rounded down to the nearest whole tablet (see for weight based dosing guide) 0.15 mg/kg/dayTable 3 in 1 or 2 divided doses, rounded down to the nearest whole tablet 0.3 mg/kg/day in 2 divided doses, rounded down to the nearest whole tablet 0.6 mg/kg/day Weeks 3 and 4 in 1 or 2 divided doses, rounded down to the nearest whole tablet (see for weight based dosing guide) 0.3 mg/kg/dayTable 3 in 2 divided doses, rounded down to the nearest whole tablet 0.6 mg/kg/day in 2 divided doses, rounded down to the nearest whole tablet 1.2 mg/kg/day Week 5 onwards to maintenance The dose should be increased every 1 to 2 weeks as follows: calculate 0.3 mg/kg/day, round this amount down to the nearest whole tablet, and add this amount to the previously administered daily dose The dose should be increased every 1 to 2 weeks as follows: calculate 0.6 mg/kg/day, round this amount down to the nearest whole tablet, and add this amount to the previously administered daily dose The dose should be increased every 1 to 2 weeks as follows: calculate 1.2 mg/kg/day, round this amount down to the nearest whole tablet, and add this amount to the previously administered daily dose Usual Maintenance Dose (maximum 200 mg/day in 1 or 2 divided doses) with valproate alone 1 to 5 mg/kg/day1 to 3 mg/kg/day
  (maximum 300 mg/day in 2 divided doses) 4.5 to 7.5 mg/kg/day (maximum 400 mg/day in 2 divided doses) 5 to 15 mg/kg/day Maintenance dose in patients less than 30 kg May need to be increased by as much as 50%, based on clinical response May need to be increased by as much as 50%, based on clinical response May need to be increased by as much as 50%, based on clinical response

  Note: Only whole tablets should be used for dosing.

  Table 3. The Initial Weight-Based Dosing Guide for Patients 2 to 12 Years of Age Taking Valproate (Weeks 1 to 4) With Epilepsy If the patient’s weight is Give this daily dose, using the most appropriate combination of lamotrigine tablets, 2 mg and 5 mg Greater than And less than Weeks 1 and 2 Weeks 3 and 4 6.7 kg 14 kg 2 mg every day other 2 mg every day 14.1 kg 27 kg 2 mg every day 4 mg every day 27.1 kg 34 kg 4 mg every day 8 mg every day 34.1 kg 40 kg 5 mg every day 10 mg every day

  The usual maintenance doses identified in and are derived from dosing regimens employed in the placebo-controlled adjunctive studies in which the efficacy of lamotrigine tablets (chewable, dispersible) was established. In patients receiving multidrug regimens employing carbamazepine, phenytoin, phenobarbital, or primidone , maintenance doses of adjunctive lamotrigine tablets (chewable, dispersible) as high as 700 mg/day have been used. In patients receiving , maintenance doses of adjunctive lamotrigine tablets (chewable, dispersible) as high as 200 mg/day have been used. The advantage of using doses above those recommended in through has not been established in controlled trials. Usual Adjunctive Maintenance Dose for Epilepsy:Tables 12without valproatevalproate aloneTables 14

  2.3 Epilepsy – Conversion From Adjunctive Therapy to Monotherapy

  The goal of the transition regimen is to effect the conversion to monotherapy with lamotrigine tablets (chewable, dispersible) under conditions that ensure adequate seizure control while mitigating the risk of serious rash associated with the rapid titration of lamotrigine tablets (chewable, dispersible).

  The recommended maintenance dose of lamotrigine tablets (chewable, dispersible) as monotherapy is 500 mg/day given in 2 divided doses.

  To avoid an increased risk of rash, the recommended initial dose and subsequent dose escalations of lamotrigine tablets (chewable, dispersible) should not be exceeded [see ]. Boxed Warning

  After achieving a dose of 500 mg/day of lamotrigine tablets (chewable, dispersible) according to the guidelines in , the concomitant AED should be withdrawn by 20% decrements each week over a 4 week period. The regimen for the withdrawal of the concomitant AED is based on experience gained in the controlled monotherapy clinical trial. Conversion From Adjunctive Therapy With Carbamazepine, Phenytoin, Phenobarbital, or Primidone to Monotherapy With Lamotrigine Tablets (Chewable, Dispersible):Table 1

  The conversion regimen involves 4 steps outlined in . Conversion From Adjunctive Therapy With Valproate to Monotherapy With Lamotrigine Tablets (Chewable, Dispersible):Table 4

  Table 4. Conversion From Adjunctive Therapy With Valproate to Monotherapy With Lamotrigine in Patients ≥ 16 Years of Age With Epilepsy Lamotrigine Valproate Step 1 Achieve a dose of 200 mg/day according to guidelines in (if not already on 200 mg/day). Table 1 Maintain previous stable dose. Step 2 Maintain at 200 mg/day. Decrease to 500 mg/day by decrements no greater than 500 mg/day/week and then maintain the dose of 500 mg/day for 1 week. Step 3 Increase to 300 mg/day and maintain for 1 week. Simultaneously decrease to 250 mg/day and maintain for 1 week. Step 4 Increase by 100 mg/day every week to achieve maintenance dose of 500 mg/day. Discontinue.

  No specific dosing guidelines can be provided for conversion to monotherapy with lamotrigine tablets (chewable, dispersible) with AEDs other than carbamazepine, phenobarbital, phenytoin, primidone, or valproate. Conversion From Adjunctive Therapy With Antiepileptic Drugs Other Than Carbamazepine, Phenytoin, Phenobarbital, Primidone, or Valproate to Monotherapy With Lamotrigine Tablets (Chewable, Dispersible):

  2.4 Bipolar Disorder

  The goal of maintenance treatment with lamotrigine tablets (chewable, dispersible) is to delay the time to occurrence of mood episodes (depression, mania, hypomania, mixed episodes) in patients treated for acute mood episodes with standard therapy. The target dose of lamotrigine tablets (chewable, dispersible) is 200 mg/day (100 mg/day in patients taking valproate, which decreases the apparent clearance of lamotrigine, and 400 mg/day in patients not taking valproate and taking either carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin that increase the apparent clearance of lamotrigine). In the clinical trials, doses up to 400 mg/day as monotherapy were evaluated; however, no additional benefit was seen at 400 mg/day compared with 200 mg/day [ ]. Accordingly, doses above 200 mg/day are not recommended. Treatment with lamotrigine tablets (chewable, dispersible) is introduced, based on concurrent medications, according to the regimen outlined in . If other psychotropic medications are withdrawn following stabilization, the dose of lamotrigine tablets (chewable, dispersible) should be adjusted. For patients discontinuing valproate, the dose of lamotrigine tablets (chewable, dispersible) should be doubled over a 2 week period in equal weekly increments (see ). For patients discontinuing carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin that induce lamotrigine glucuronidation, the dose of lamotrigine tablets (chewable, dispersible) should remain constant for the first week and then should be decreased by half over a 2 week period in equal weekly decrements (see ). The dose of lamotrigine tablets (chewable, dispersible) may then be further adjusted to the target dose (200 mg) as clinically indicated. see Clinical Studies ( ) 14.2Table 5Table 6Table 6

  If other drugs are subsequently introduced, the dose of lamotrigine tablets (chewable, dispersible) may need to be adjusted. In particular, the introduction of valproate requires reduction in the dose of lamotrigine tablets (chewable, dispersible) [ ]. see Drug Interactions ( ), Clinical Pharmacology ( ) 712.3

  To avoid an increased risk of rash, the recommended initial dose and subsequent dose escalations of lamotrigine tablets (chewable, dispersible) should not be exceeded [see ]. Boxed Warning

  Table 5. Escalation Regimen for Lamotrigine for Patients With Bipolar Disorder * Valproate has been shown to inhibit glucuronidation and decrease the apparent clearance of lamotrigine [ ]. see Drug Interactions ( ), Clinical Pharmacology ( ) 712.3 † These drugs induce lamotrigine glucuronidation and increase clearance [ ]. Other drugs that have similar effects include estrogen-containing oral contraceptives [ ]. Dosing recommendations for oral contraceptives can be found in General Dosing Considerations [ ]. Patients on rifampin, or other drugs that induce lamotrigine glucuronidation and increase clearance, should follow the same dosing titration/maintenance regimen as that used with anticonvulsants that have this effect. see Drug Interactions ( ), Clinical Pharmacology ( ) 712.3 see Drug Interactions ( ), Clinical Pharmacology ( ) 712.3 see Dosage and Administration ( ) 2.1 For Patients TAKING Valproate * For Patients NOT TAKING Carbamazepine, Phenytoin, Phenobarbital, Primidone, or Valproate †* For Patients TAKING Carbamazepine, Phenytoin, Phenobarbital, or Primidone and NOT TAKING Valproate †* Weeks 1 and 2 25 mg every day other 25 mg daily 50 mg daily Weeks 3 and 4 25 mg daily 50 mg daily 100 mg daily, in divided doses Week 5 50 mg daily 100 mg daily 200 mg daily, in divided doses Week 6 100 mg daily 200 mg daily 300 mg daily, in divided doses Week 7 100 mg daily 200 mg daily up to 400 mg daily, in divided doses Table 6. Dosage Adjustments to Lamotrigine for Patients With Bipolar Disorder Following Discontinuation of Psychotropic Medications * These drugs induce lamotrigine glucuronidation and increase clearance [ ]. Other drugs that have similar effects include estrogen-containing oral contraceptives [ ]. Dosing recommendations for oral contraceptives can be found in General Dosing Considerations [ ]. Patients on rifampin, or other drugs that induce lamotrigine glucuronidation and increase clearance, should follow the same dosing titration/maintenance regimen as that used with anticonvulsants that have this effect. see Drug Interactions ( ), Clinical Pharmacology ( ) 712.3 see Drug Interactions ( ), Clinical Pharmacology ( ) 712.3 see Dosage and Administration ( ) 2.1 † Valproate has been shown to inhibit glucuronidation and decrease the apparent clearance of lamotrigine [ ]. see Drug Interactions ( ), Clinical Pharmacology ( ) 712.3

  Discontinuation of Psychotropic Drugs (excluding Carbamazepine, Phenytoin, Phenobarbital, Primidone, or Valproate ) *†

  After Discontinuation of Valproate † After Discontinuation of Carbamazepine, Phenytoin, Phenobarbital, or Primidone * Current dose of Lamotrigine (mg/day) 100

  Current dose of Lamotrigine (mg/day)

  400

  Week 1 Maintain current dose of lamotrigine 150 400 Week 2 Maintain current dose of lamotrigine 200 300 Week 3 onward Maintain current dose of lamotrigine 200 200

  The benefit of continuing treatment in patients who had been stabilized in an 8 to 16 week open-label phase with lamotrigine tablets (chewable, dispersible) was established in 2 randomized, placebo-controlled clinical maintenance trials [ ]. However, the optimal duration of treatment with lamotrigine tablets (chewable, dispersible) has not been established. Thus, patients should be periodically reassessed to determine the need for maintenance treatment. see Clinical Studies ( ) 14.2

  2.5 Administration of Lamotrigine Tablets (Chewable, Dispersible)

  Lamotrigine tablets (chewable, dispersible) may be swallowed whole, chewed, or dispersed in water or diluted fruit juice. If the tablets are chewed, consume a small amount of water or diluted fruit juice to aid in swallowing.

  To disperse lamotrigine tablets (chewable, dispersible), add the tablets to a small amount of liquid (1 teaspoon, or enough to cover the medication). Approximately 1 minute later, when the tablets are completely dispersed, swirl the solution and consume the entire quantity immediately. No attempt should be made to administer partial quantities of the dispersed tablets.

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  Carvedilol should be taken with food to slow the rate of absorption and reduce the incidence of orthostatic effects.

  2.1 Left Ventricular Dysfunction Following Myocardial Infarction:

  DOSAGE MUST BE INDIVIDUALIZED AND MONITORED DURING UP-TITRATION. Treatment with carvedilol tablets may be started as an inpatient or outpatient and should be started after the patient is hemodynamically stable and fluid retention has been minimized. It is recommended that carvedilol tablets be started at 6.25 mg twice daily and increased after 3 to 10 days, based on tolerability, to 12.5 mg twice daily, then again to the target dose of 25 mg twice daily. A lower starting dose may be used (3.125 mg twice daily) and/or the rate of up-titration may be slowed if clinically indicated (e.g., due to low blood pressure or heart rate, or fluid retention). Patients should be maintained on lower doses if higher doses are not tolerated. The recommended dosing regimen need not be altered in patients who received treatment with an IV or oral β-blocker during the acute phase of the myocardial infarction.

  2.2 Hypertension

  DOSAGE MUST BE INDIVIDUALIZED. The recommended starting dose of carvedilol tablets is 6.25 mg twice daily. If this dose is tolerated, using standing systolic pressure measured about 1 hour after dosing as a guide, the dose should be maintained for 7 to 14 days, and then increased to 12.5 mg twice daily if needed, based on trough blood pressure, again using standing systolic pressure one hour after dosing as a guide for tolerance. This dose should also be maintained for 7 to 14 days and can then be adjusted upward to 25 mg twice daily if tolerated and needed. The full antihypertensive effect of carvedilol tablet is seen within 7 to 14 days. Total daily dose should not exceed 50 mg.

  Concomitant administration with a diuretic can be expected to produce additive effects and exaggerate the orthostatic component of carvedilol action.

  2.3 Hepatic Impairment

  Carvedilol tablets should not be given to patients with severe hepatic impairment [see CONTRAINDICATIONS  (4)].

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  2.1 General Dosing Considerations 

  Rash
  There are suggestions, yet to be proven, that the risk of severe, potentially life-threatening rash may be increased by (1) coadministration of lamotrigine tablets with valproate, (2) exceeding the recommended initial dose of lamotrigine tablets, or (3) exceeding the recommended dose escalation for lamotrigine tablets. However, cases have occurred in the absence of these factors [see Boxed Warning]. Therefore, it is important that the dosing recommendations be followed closely.

  The risk of nonserious rash may be increased when the recommended initial dose and/or the rate of dose escalation for lamotrigine tablets is exceeded and in patients with a history of allergy or rash to other AEDs.

  It is recommended that lamotrigine tablets not be restarted in patients who discontinued due to rash associated with prior treatment with lamotrigine unless the potential benefits clearly outweigh the risks. If the decision is made to restart a patient who has discontinued lamotrigine, the need to restart with the initial dosing recommendations should be assessed. The greater the interval of time since the previous dose, the greater consideration should be given to restarting with the initial dosing recommendations. If a patient has discontinued lamotrigine for a period of more than 5 half-lives, it is recommended that initial dosing recommendations and guidelines be followed. The half-life of lamotrigine is affected by other concomitant medications [see Clinical Pharmacology (12.3)].

  Lamotrigine Added to Drugs Known to Induce or Inhibit Glucuronidation
  Because lamotrigine is metabolized predominantly by glucuronic acid conjugation, drugs that are known to induce or inhibit glucuronidation may affect the apparent clearance of lamotrigine. Drugs that induce glucuronidation include carbamazepine, phenytoin, phenobarbital, primidone, rifampin, estrogen-containing oral contraceptives, and the protease inhibitors lopinavir/ritonavir and atazanavir/ritonavir. Valproate inhibits glucuronidation. For dosing considerations for lamotrigine tablets in patients on estrogen-containing contraceptives and atazanavir/ritonavir, see below and Table 13. For dosing considerations for lamotrigine tablets in patients on other drugs known to induce or inhibit glucuronidation, see Table 1, Table 2, Table 5, Table 6, and Table 13.

  Target Plasma Levels for Patients With Epilepsy or Bipolar Disorder
  A therapeutic plasma concentration range has not been established for lamotrigine. Dosing of lamotrigine tablets should be based on therapeutic response [see Clinical Pharmacology (12.3)].

  Women Taking Estrogen-Containing Oral Contraceptives
  Starting Lamotrigine Tablets in Women Taking Estrogen-Containing Oral Contraceptives: Although estrogen-containing oral contraceptives have been shown to increase the clearance of lamotrigine [see Clinical Pharmacology (12.3)], no adjustments to the recommended dose-escalation guidelines for lamotrigine tablets should be necessary solely based on the use of estrogen-containing oral contraceptives. Therefore, dose escalation should follow the recommended guidelines for initiating adjunctive therapy with lamotrigine tablets based on the concomitant AED or other concomitant medications (see Table 1 or Table 5). See below for adjustments to maintenance doses of lamotrigine tablets in women taking estrogen-containing oral contraceptives.

  Adjustments to the Maintenance Dose of Lamotrigine Tablets in Women Taking Estrogen-Containing Oral Contraceptives:

  (1) Taking Estrogen-Containing Oral Contraceptives: In women not taking carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin and the protease inhibitors lopinavir/ritonavir and atazanavir/ritonavir that induce lamotrigine glucuronidation [see Drug Interactions (7), Clinical Pharmacology (12.3)], the maintenance dose of lamotrigine tablets will in most cases need to be increased by as much as 2 fold over the recommended target maintenance dose to maintain a consistent lamotrigine plasma level.

  (2) Starting Estrogen-Containing Oral Contraceptives: In women taking a stable dose of lamotrigine tablets and not taking carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin and the protease inhibitors lopinavir/ritonavir and atazanavir/ritonavir that induce lamotrigine glucuronidation [see Drug Interactions (7), Clinical Pharmacology (12.3)], the maintenance dose will in most cases need to be increased by as much as 2 fold to maintain a consistent lamotrigine plasma level. The dose increases should begin at the same time that the oral contraceptive is introduced and continue, based on clinical response, no more rapidly than 50 to 100 mg/day every week. Dose increases should not exceed the recommended rate (see Table 1 or Table 5) unless lamotrigine plasma levels or clinical response support larger increases. Gradual transient increases in lamotrigine plasma levels may occur during the week of inactive hormonal preparation (pill-free week), and these increases will be greater if dose increases are made in the days before or during the week of inactive hormonal preparation. Increased lamotrigine plasma levels could result in additional adverse reactions, such as dizziness, ataxia, and diplopia. If adverse reactions attributable to lamotrigine tablets consistently occur during the pill-free week, dose adjustments to the overall maintenance dose may be necessary. Dose adjustments limited to the pill-free week are not recommended. For women taking lamotrigine tablets in addition to carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin and the protease inhibitors lopinavir/ritonavir and atazanavir/ritonavir that induce lamotrigine glucuronidation [see Drug Interactions (7), Clinical Pharmacology (12.3)], no adjustment to the dose of lamotrigine tablets be necessary.

  (3) Stopping Estrogen-Containing Oral Contraceptives: In women not taking carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin and the protease inhibitors lopinavir/ritonavir and atazanavir/ritonavir that induce lamotrigine glucuronidation [see Drug Interactions (7), Clinical Pharmacology (12.3)], the maintenance dose of lamotrigine tablets will in most cases need to be decreased by as much as 50% in order to maintain a consistent lamotrigine plasma level. The decrease in dose of lamotrigine tablets should not exceed 25% of the total daily dose per week over a 2 week period, unless clinical response or lamotrigine plasma levels indicate otherwise [see Clinical Pharmacology (12.3)]. In women taking lamotrigine tablets in addition to carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin and the protease inhibitors lopinavir/ritonavir and atazanavir/ritonavir that induce lamotrigine glucuronidation [see Drug Interactions (7), Clinical Pharmacology (12.3)], no adjustment to the dose of lamotrigine tablets should be necessary.

  Women and Other Hormonal Contraceptive Preparations or Hormone Replacement Therapy
  The effect of other hormonal contraceptive preparations or hormone replacement therapy on the pharmacokinetics of lamotrigine has not been systematically evaluated. It has been reported that ethinylestradiol, not progestogens, increased the clearance of lamotrigine up to 2 fold, and the progestin-only pills had no effect on lamotrigine plasma levels. Therefore, adjustments to the dosage of lamotrigine tablets in the presence of progestogens alone will likely not be needed.

  Patients Taking Atazanavir/Ritonavir
  While atazanavir/ritonavir does reduce the lamotrigine plasma concentration, no adjustments to the recommended dose-escalation guidelines for lamotrigine tablets should be necessary solely based on the use of atazanavir/ritonavir. Dose escalation should follow the recommended guidelines for initiating adjunctive therapy with lamotrigine tablets based on concomitant AED or other concomitant medications (see Tables 1, 2 and 5). In patients already taking maintenance doses of lamotrigine tablets and not taking glucuronidation inducers, the dose of lamotrigine tablets may need to be increased if atazanavir/ritonavir is added, or decreased if atazanavir/ritonavir is discontinued [see Clinical Pharmacology (12.3)].

  Patients With Hepatic Impairment
  Experience in patients with hepatic impairment is limited. Based on a clinical pharmacology study in 24 subjects with mild, moderate, and severe liver impairment [see Use in Specific Populations (8.6), Clinical Pharmacology (12.3)], the following general recommendations can be made. No dosage adjustment is needed in patients with mild liver impairment. Initial, escalation, and maintenance doses should generally be reduced by approximately 25% in patients with moderate and severe liver impairment without ascites and 50% in patients with severe liver impairment with ascites. Escalation and maintenance doses may be adjusted according to clinical response.

  Patients With Renal Impairment
  Initial doses of lamotrigine tablets should be based on patients' concomitant medications (see Tables 1 to 3 or Table 5); reduced maintenance doses may be effective for patients with significant renal impairment [see Use in Specific Populations (8.7), Clinical Pharmacology (12.3)]. Few patients with severe renal impairment have been evaluated during chronic treatment with lamotrigine tablets. Because there is inadequate experience in this population, lamotrigine tablets should be used with caution in these patients.

  Discontinuation Strategy
  Epilepsy: For patients receiving lamotrigine tablets in combination with other AEDs, a re-evaluation of all AEDs in the regimen should be considered if a change in seizure control or an appearance or worsening of adverse reactions is observed.

  If a decision is made to discontinue therapy with lamotrigine tablets, a step-wise reduction of dose over at least 2 weeks (approximately 50% per week) is recommended unless safety concerns require a more rapid withdrawal [see Warnings and Precautions (5.9)].

  Discontinuing carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin and the protease inhibitors lopinavir/ritonavir and atazanavir/ritonavir that induce lamotrigine glucuronidation should prolong the half-life of lamotrigine; discontinuing valproate should shorten the half-life of lamotrigine.

  Bipolar Disorder: In the controlled clinical trials, there was no increase in the incidence, type, or severity of adverse reactions following abrupt termination of lamotrigine tablets. In clinical trials in patients with bipolar disorder, 2 patients experienced seizures shortly after abrupt withdrawal of lamotrigine tablets. However, there were confounding factors that may have contributed to the occurrence of seizures in these patients with bipolar disorder. Discontinuation of lamotrigine tablets should involve a step-wise reduction of dose over at least 2 weeks (approximately 50% per week) unless safety concerns require a more rapid withdrawal [see Warnings and Precautions (5.9)].

  2.2 Epilepsy – Adjunctive Therapy

  This section provides specific dosing recommendations for patients older than 12 years and patients aged 2 to 12 years. Within each of these age-groups, specific dosing recommendations are provided depending upon concomitant AEDs or other concomitant medications (see Table 1 for patients older than 12 years and Table 2for patients aged 2 to 12 years). A weight-based dosing guide for patients aged 2 to 12 years on concomitant valproate is provided in Table 3.

  Patients Older Than 12 Years
  Recommended dosing guidelines are summarized in Table 1.

  Table 1. Escalation Regimen for Lamotrigine in Patients Older Than 12 Years With Epilepsy * Valproate has been shown to inhibit glucuronidation and decrease the apparent clearance of lamotrigine [see Drug Interactions (7), Clinical Pharmacology (12.3)]. † Drugs that induce lamotrigine glucuronidation and increase clearance, other than the specified antiepileptic drugs, include estrogen-containing oral contraceptives, rifampin, and the protease inhibitors lopinavir/ritonavir and atazanavir/ritonavir. Dosing recommendations for oral contraceptives and the protease inhibitor atazanavir/ritonavir can be found in General Dosing Considerations [see Dosage and Administration ( 2.1) ]. Patients on rifampin and the protease inhibitor lopinavir/ritonavir should follow the same dosing titration/maintenance regimen used with antiepileptic drugs that induce glucuronidation and increase clearance [see Dosage and Administration ( 2.1), Drug Interactions (7), and Clinical Pharmacology (12.3) ].

  In Patients TAKING Valproate*

  In Patients NOT TAKING Carbamazepine, Phenytoin, Phenobarbital, Primidone†, or Valproate*

  In Patients TAKING Carbamazepine, Phenytoin, Phenobarbital, or Primidone† and NOT TAKING Valproate*

  Weeks 1 and 2

  25 mg every other day

  25 mg every day

  50 mg/day

  Weeks 3 and 4

  25 mg every day

  50 mg/day

  100 mg/day (in 2 divided doses)

  Week 5 onward to maintenance

  Increase by 25 to 50 mg/day every 1 to 2 weeks

  Increase by 50 mg/day every 1 to 2 weeks

  Increase by 100 mg/day every 1 to 2 weeks

  Usual maintenance dose

  100 to 200 mg/day with valproate alone

  100 to 400 mg/day with valproate and other drugs that induce glucuronidation

  (in 1 or 2 divided doses)

  225 to 375 mg/day (in 2 divided doses)

  300 to 500 mg/day

   (in 2 divided doses)

  Patients Aged 2 to 12 Years
  Recommended dosing guidelines are summarized in Table 2.

  Smaller starting doses and slower dose escalations than those used in clinical trials are recommended because of the suggestion that the risk of rash may be decreased by smaller starting doses and slower dose escalations. Therefore, maintenance doses will take longer to reach in clinical practice than in clinical trials. It may take several weeks to months to achieve an individualized maintenance dose. Maintenance doses in patients weighing less than 30 kg, regardless of age or concomitant AED, may need to be increased as much as 50%, based on clinical response.

  Table 2. Escalation Regimen for Lamotrigine in Patients Aged 2 to 12 Years With Epilepsy * Valproate has been shown to inhibit glucuronidation and decrease the apparent clearance of lamotrigine [see Drug Interactions (7), Clinical Pharmacology (12.3)].

  In Patients TAKING Valproate*

  In Patients NOT TAKING Carbamazepine, Phenytoin, Phenobarbital, Primidone†, or Valproate*

  In Patients TAKING Carbamazepine, Phenytoin, Phenobarbital, or Primidone†and NOT TAKING Valproate*

  Weeks 1 and 2

  0.15 mg/kg/day in 1 or 2 divided doses, rounded down to the nearest whole tablet (see Table 3 for weight-based dosing guide)

  0.3 mg/kg/day in 1 or 2 divided doses, rounded down to the nearest whole tablet

  0.6 mg/kg/day in 2 divided doses, rounded down to the nearest whole tablet

  Weeks 3 and 4

  0.3 mg/kg/day in 1 or 2 divided doses, rounded down to the nearest whole tablet (see Table 3 for weight-based dosing guide)

  0.6 mg/kg/day in 2 divided doses, rounded down to the nearest whole tablet

  1.2 mg/kg/day in 2 divided doses, rounded down to the nearest whole tablet

  Week 5 onward to maintenance

  The dose should be increased every 1 to 2 weeks as follows: calculate 0.3 mg/kg/day, round this amount down to the nearest whole tablet, and add this amount to the previously administered daily dose.

  The dose should be increased every 1 to 2 weeks as follows: calculate 0.6 mg/kg/day, round this amount down to the nearest whole tablet, and add this amount to the previously administered daily dose.

  The dose should be increased every 1 to 2 weeks as follows: calculate 1.2 mg/kg/day, round this amount down to the nearest whole tablet, and add this amount to the previously administered daily dose.

  Usual maintenance dose

  1 to 5 mg/kg/day (maximum 200 mg/day in 1 or 2 divided doses)
  1 to 3 mg/kg/day with valproate alone

  4.5 to 7.5 mg/kg/day (maximum 300 mg/day in 2 divided doses)

  5 to 15 mg/kg/day (maximum 400 mg/day in 2 divided doses)

  Maintenance dose in patients less than 30 kg

  May need to be increased by as much as 50%, based on clinical response.

  May need to be increased by as much as 50%, based on clinical response.

  May need to be increased by as much as 50%, based on clinical response.

  Note: Only whole tablets should be used for dosing.

  Table 3. The Initial Weight-Based Dosing Guide for Patients Aged 2 to 12 Years Taking Valproate (Weeks 1 to 4) With Epilepsy

  If the patient’s weight is

  Give this daily dose, using the most appropriate combination of lamotrigine, 2 and 5 mg tablets

  Greater than

  And less than

  Weeks 1 and 2

  Weeks 3 and 4

  6.7 kg

  14 kg

  2 mg every other day

  2 mg every day

  14.1 kg

  27 kg

  2 mg every day

  4 mg every day

  27.1 kg

  34 kg

  4 mg every day

  8 mg every day

  34.1 kg

  40 kg

  5 mg every day

  10 mg every day

  
  Usual Adjunctive Maintenance Dose for Epilepsy
  The usual maintenance doses identified in Tables 1 and 2 are derived from dosing regimens employed in the placebo-controlled adjunctive trials in which the efficacy of lamotrigine tablets was established. In patients receiving multidrug regimens employing carbamazepine, phenytoin, phenobarbital, or primidone without valproate, maintenance doses of adjunctive lamotrigine tablets as high as 700 mg/day have been used. In patients receiving valproate alone, maintenance doses of adjunctive lamotrigine tablets as high as 200 mg/day have been used. The advantage of using doses above those recommended in Tables 1 through 4 has not been established in controlled trials.

  2.3 Epilepsy – Conversion From Adjunctive Therapy to Monotherapy

  The goal of the transition regimen is to attempt to maintain seizure control while mitigating the risk of serious rash associated with the rapid titration of lamotrigine tablets.

  The recommended maintenance dose of lamotrigine tablets as monotherapy is 500 mg/day given in 2 divided doses.

  To avoid an increased risk of rash, the recommended initial dose and subsequent dose escalations for lamotrigine tablets should not be exceeded [see Boxed Warning].

  Conversion From Adjunctive Therapy With Carbamazepine, Phenytoin, Phenobarbital, or Primidone to Monotherapy With Lamotrigine Tablets
  After achieving a dose of 500 mg/day of lamotrigine tablets using the guidelines in Table 1, the concomitant enzyme-inducing AED should be withdrawn by 20% decrements each week over a 4 week period. The regimen for the withdrawal of the concomitant AED is based on experience gained in the controlled monotherapy clinical trial.

  Conversion From Adjunctive Therapy With Valproate to Monotherapy With Lamotrigine Tablets
  The conversion regimen involves the 4 steps outlined in Table 4.

  Table 4. Conversion From Adjunctive Therapy With Valproate to Monotherapy With Lamotrigine in Patients Aged 16 Years and Older With Epilepsy

   

  Lamotrigine

  Valproate

  Step 1

  Achieve a dose of 200 mg/day according to guidelines in Table 1.

  Maintain established stable dose.

  Step 2

  Maintain at 200 mg/day.

  Decrease dose by decrements no greater than 500 mg/day/week to 500 mg/day and then maintain for 1 week.

  Step 3

  Increase to 300 mg/day and maintain for 1 week.

  Simultaneously decrease to 250 mg/day and maintain for 1 week.

  Step 4

  Increase by 100 mg/day every week to achieve maintenance dose of 500 mg/day.

  Discontinue.

  
  Conversion From Adjunctive Therapy With Antiepileptic Drugs Other Than Carbamazepine, Phenytoin, Phenobarbital, Primidone, or Valproate to Monotherapy With Lamotrigine Tablets
  No specific dosing guidelines can be provided for conversion to monotherapy with lamotrigine tablets with AEDs other than carbamazepine, phenytoin, phenobarbital, primidone, or valproate.

  2.4 Bipolar Disorder

  The goal of maintenance treatment with lamotrigine tablets is to delay the time to occurrence of mood episodes (depression, mania, hypomania, mixed episodes) in patients treated for acute mood episodes with standard therapy. The target dose of lamotrigine tablets is 200 mg/day (100 mg/day in patients taking valproate, which decreases the apparent clearance of lamotrigine, and 400 mg/day in patients not taking valproate and taking either carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin and the protease inhibitor lopinavir/ritonavir that increase the apparent clearance of lamotrigine). In the clinical trials, doses up to 400 mg/day as monotherapy were evaluated; however, no additional benefit was seen at 400 mg/day compared with 200 mg/day [see Clinical Studies (14.2)]. Accordingly, doses above 200 mg/day are not recommended. Treatment with lamotrigine tablets is introduced, based on concurrent medications, according to the regimen outlined in Table 5. If other psychotropic medications are withdrawn following stabilization, the dose of lamotrigine tablets should be adjusted. For patients discontinuing valproate, the dose of lamotrigine tablets should be doubled over a 2 week period in equal weekly increments (see Table 6). For patients discontinuing carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin and the protease inhibitors lopinavir/ritonavir and atazanavir/ritonavir that induce lamotrigine glucuronidation, the dose of lamotrigine tablets should remain constant for the first week and then should be decreased by half over a 2 week period in equal weekly decrements (see Table 6). The dose of lamotrigine tablets may then be further adjusted to the target dose (200 mg) as clinically indicated.

  If other drugs are subsequently introduced, the dose of lamotrigine tablets may need to be adjusted. In particular, the introduction of valproate requires reduction in the dose of lamotrigine tablets [see Drug Interactions (7), Clinical Pharmacology (12.3)].

  To avoid an increased risk of rash, the recommended initial dose and subsequent dose escalations of lamotrigine tablets should not be exceeded [see Boxed Warning].

  Table 5. Escalation Regimen for Lamotrigine in Patients With Bipolar Disorder * Valproate has been shown to inhibit glucuronidation and decrease the apparent clearance of lamotrigine [ see Drug Interactions (7), Clinical Pharmacology (12.3)] . † Valproate has been shown to inhibit glucuronidation and decrease the apparent clearance of lamotrigine [ see Drug Interactions (7), Clinical Pharmacology (12.3)].

  In Patients TAKING Valproate*

  In Patients NOT TAKING Carbamazepine, Phenytoin, Phenobarbital, Primidone†, or Valproate†

  In Patients TAKING Carbamazepine, Phenytoin, Phenobarbital, or Primidone†and NOT TAKING Valproate*

  Weeks 1 and 2

  25 mg every other day

  25 mg daily

  50 mg daily

  Weeks 3 and 4

  25 mg daily

  50 mg daily

  100 mg daily, in divided doses

  Week 5

  50 mg daily

  100 mg daily

  200 mg daily, in divided doses

  Week 6

  100 mg daily

  200 mg daily

  300 mg daily, in divided doses

  Week 7

  100 mg daily

  200 mg daily

  up to 400 mg daily, in divided doses

  Table 6. Dosage Adjustments to Lamotrigine in Patients With Bipolar Disorder Following Discontinuation of Psychotropic Medications

  Discontinuation of Psychotropic Drugs (excluding Valproate*, Carbamazepine, Phenytoin, Phenobarbital, or Primidone†)

  After Discontinuation of Valproate*

  After Discontinuation of Carbamazepine, Phenytoin, Phenobarbital, or Primidone†

  Current dose of Lamotrigine (mg/day) 100

  Current dose of Lamotrigine (mg/day)

  400

  Week 1

  Maintain current dose of lamotrigine

  150

  400

  Week 2

  Maintain current dose of lamotrigine

  200

  300

  Week 3 onward

  Maintain current dose of lamotrigine

  200

  200

  The benefit of continuing treatment in patients who had been stabilized in an 8 to 16 week open-label phase with lamotrigine tablets was established in 2 randomized, placebo-controlled clinical maintenance trials [see Clinical Studies (14.2)]. However, the optimal duration of treatment with lamotrigine tablets has not been established. Thus, patients should be periodically reassessed to determine the need for maintenance treatment.

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  Dosing is based on concomitant medications, indication, and patient age. ( 2.2 , 2.4 ) To avoid an increased risk of rash, the recommended initial dose and subsequent dose escalations should not be exceeded. ( 2.1 ) Do not restart lamotrigine in patients who discontinued due to rash unless the potential benefits clearly outweigh the risks. ( 2.1 ) Adjustments to maintenance doses will in most cases be required in patients starting or stopping estrogen-containing oral contraceptives. ( 2.1 , 5.8 ) Lamotrigine tablets should be discontinued over a period of at least 2 weeks (approximately 50% reduction per week). ( 2.1 , 5.9 )

  Epilepsy

  Adjunctive therapy—See Table 1 for patients >12 years of age and Tables 2 and 3 for patients 2 to 12 years. ( 2.2 ) Conversion to monotherapy—See Table 4. ( 2.3 )

  Bipolar Disorder: See Tables 5 and 6 ( 2.4 )

   

  Rash: There are suggestions, yet to be proven, that the risk of severe, potentially life-threatening rash may be increased by (1) coadministration of lamotrigine tablets with valproate, (2) exceeding the recommended initial dose of lamotrigine tablets, or (3) exceeding the recommended dose escalation for lamotrigine tablets. However, cases have occurred in the absence of these factors [see Boxed Warning ]. Therefore, it is important that the dosing recommendations be followed closely.

  The risk of nonserious rash may be increased when the recommended initial dose and/or the rate of dose escalation of lamotrigine tablet is exceeded and in patients with a history of allergy or rash to other AEDs.

  It is recommended that lamotrigine tablets not be restarted in patients who discontinued due to rash associated with prior treatment with lamotrigine, unless the potential benefits clearly outweigh the risks. If the decision is made to restart a patient who has discontinued lamotrigine, the need to restart with the initial dosing recommendations should be assessed. The greater the interval of time since the previous dose, the greater consideration should be given to restarting with the initial dosing recommendations. If a patient has discontinued lamotrigine for a period of more than 5 half-lives, it is recommended that initial dosing recommendations and guidelines be followed. The half-life of lamotrigine is affected by other concomitant medications [see Clinical Pharmacology (12.3) ].

  Lamotrigine Tablets Added to Drugs Known to Induce or Inhibit Glucuronidation: Drugs other than those listed in the Clinical Pharmacology section [see Clinical Pharmacology (12.3) ] have not been systematically evaluated in combination with lamotrigine. Because lamotrigine is metabolized predominantly by glucuronic acid conjugation, drugs that are known to induce or inhibit glucuronidation may affect the apparent clearance of lamotrigine and doses of lamotrigine tablets may require adjustment based on clinical response.

  Target Plasma Levels for Patients With Epilepsy or Bipolar Disorder: A therapeutic plasma concentration range has not been established for lamotrigine. Dosing of lamotrigine tablets should be based on therapeutic response [see Clinical Pharmacology (12.3) ].

  Women Taking Estrogen-Containing Oral Contraceptives: Starting Lamotrigine Tablets  in Women Taking Estrogen-Containing Oral Contraceptives: Although estrogen-containing oral contraceptives have been shown to increase the clearance of lamotrigine [see Clinical Pharmacology (12.3) ], no adjustments to the recommended dose-escalation guidelines for lamotrigine tablets should be necessary solely based on the use of estrogen-containing oral contraceptives. Therefore, dose escalation should follow the recommended guidelines for initiating adjunctive therapy with lamotrigine tablets based on the concomitant AED or other concomitant medications (see Table 1 or Table 5). See below for adjustments to maintenance doses of lamotrigine tablets in women taking estrogen-containing oral contraceptives.

  Adjustments to the Maintenance Dose of Lamotrigine Tablets In Women Taking Estrogen-Containing Oral Contraceptives:

  (1) Taking Estrogen-Containing Oral Contraceptives: For women not taking carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin that induce lamotrigine glucuronidation [see Drug Interactions (7), Clinical Pharmacology (12.3)], the maintenance dose of lamotrigine  tablets will in most cases need to be increased, by as much as 2-fold over the recommended target maintenance dose, in order to maintain a consistent lamotrigine plasma level [see Clinical Pharmacology (12.3) ].

  (2) Starting Estrogen-Containing Oral Contraceptives: In women taking a stable dose of lamotrigine tablets and not taking carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin that induce lamotrigine glucuronidation [see Drug Interactions (7), Clinical Pharmacology (12.3)], the maintenance dose will in most cases need to be increased by as much as 2-fold in order to maintain a consistent lamotrigine plasma level. The dose increases should begin at the same time that the oral contraceptive is introduced and continue, based on clinical response, no more rapidly than 50 to 100 mg/day every week. Dose increases should not exceed the recommended rate (see Table 1 or Table 5) unless lamotrigine plasma levels or clinical response support larger increases. Gradual transient increases in lamotrigine plasma levels may occur during the week of inactive hormonal preparation ("pill-free" week), and these increases will be greater if dose increases are made in the days before or during the week of inactive hormonal preparation. Increased lamotrigine plasma levels could result in additional adverse reactions, such as dizziness, ataxia, and diplopia. If adverse reactions attributable to lamotrigine tablets consistently occur during the "pill-free" week, dose adjustments to the overall maintenance dose may be necessary. Dose adjustments limited to the "pill-free" week are not recommended. For women taking lamotrigine tablets in addition to carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin that induce lamotrigine glucuronidation [see Drug Interactions (7), Clinical Pharmacology (12.3)], no adjustment to the dose of lamotrigine tablets should be necessary.

  (3) Stopping Estrogen-Containing Oral Contraceptives: For women not taking carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin that induce lamotrigine glucuronidation [see Drug Interactions (7), Clinical Pharmacology (12.3)], the maintenance dose of lamotrigine tablets will in most cases need to be decreased by as much as 50% in order to maintain a consistent lamotrigine plasma level. The decrease in dose of lamotrigine tablets should not exceed 25% of the total daily dose per week over a 2-week period, unless clinical response or lamotrigine plasma levels indicate otherwise [see Clinical Pharmacology (12.3) ]. For women taking lamotrigine tablets in addition to carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin that induce lamotrigine glucuronidation [see Drug Interactions (7), Clinical Pharmacology (12.3)], no adjustment to the dose of lamotrigine tablets should be necessary.

  Women and Other Hormonal Contraceptive Preparations or Hormone Replacement Therapy: The effect of other hormonal contraceptive preparations or hormone replacement therapy on the pharmacokinetics of lamotrigine has not been systematically evaluated. It has been reported that ethinylestradiol, not progestogens, increased the clearance of lamotrigine up to 2-fold, and the progestin-only pills had no effect on lamotrigine plasma levels. Therefore, adjustments to the dosage of lamotrigine tablets in the presence of progestogens alone will likely not be needed.

  Patients With Hepatic Impairment: Experience in patients with hepatic impairment is limited. Based on a clinical pharmacology study in 24 patients with mild, moderate, and severe liver impairment [see Use in Specific Populations (8.6) , Clinical Pharmacology (12.3) ], the following general recommendations can be made. No dosage adjustment is needed in patients with mild liver impairment. Initial, escalation, and maintenance doses should generally be reduced by approximately 25% in patients with moderate and severe liver impairment without ascites and 50% in patients with severe liver impairment with ascites. Escalation and maintenance doses may be adjusted according to clinical response.

  Patients With Renal Impairment: Initial doses of lamotrigine tablets should be based on patients' concomitant medications (see Tables 1-3 or Table 5); reduced maintenance doses may be effective for patients with significant renal impairment [see Use in Specific Populations (8.7) , Clinical Pharmacology (12.3) ]. Few patients with severe renal impairment have been evaluated during chronic treatment with lamotrigine tablets. Because there is inadequate experience in this population, lamotrigine tablets should be used with caution in these patients.

  Discontinuation Strategy:

  Epilepsy: For patients receiving lamotrigine tablets in combination with other AEDs, a reevaluation of all AEDs in the regimen should be considered if a change in seizure control or an appearance or worsening of adverse reactions is observed.

  If a decision is made to discontinue therapy with lamotrigine tablets, a step-wise reduction of dose over at least 2 weeks (approximately 50% per week) is recommended unless safety concerns require a more rapid withdrawal [see Warnings and Precautions (5.9) ].

  Discontinuing carbamazepine, phenytoin, phenobarbital, primidone or other drugs such as rifampin that induce lamotrigine glucuronidation should prolong the half-life of lamotrigine; discontinuing valproate should shorten the half-life of lamotrigine.

  Bipolar Disorder: In the controlled clinical trials, there was no increase in the incidence, type, or severity of adverse reactions following abrupt termination of lamotrigine tablets. In clinical trials in patients with Bipolar Disorder, 2 patients experienced seizures shortly after abrupt withdrawal of lamotrigine tablets. However, there were confounding factors that may have contributed to the occurrence of seizures in these bipolar patients. Discontinuation of lamotrigine tablets should involve a step-wise reduction of dose over at least 2 weeks (approximately 50% per week) unless safety concerns require a more rapid withdrawal [see Warnings and Precautions (5.9) ].

   

  This section provides specific dosing recommendations for patients greater than 12 years of age and patients 2 to 12 years of age. Within each of these age-groups, specific dosing recommendations are provided depending upon concomitant AED or other concomitant medications (Table 1 for patients greater than 12 years of age and Table 2 for patients 2 to 12 years of age). A weight-based dosing guide for patients 2 to 12 years of age on concomitant valproate is provided in Table 3.

  Patients Over 12 Years of Age: Recommended dosing guidelines are summarized in Table 1.

  Table 1. Escalation Regimen for Lamotrigine Tablets in Patients Over 12 Years of Age With Epilepsy
  For 
  For Patients NOT TAKING 
  For Patients 
  
  Patients
  Carbamazepine, 
  TAKING
  
  TAKING
  Phenytoin,
  Carbamazepine,
  
  Valproatea
  Phenobarbital,
  Phenytoin, 
  
  
  or Primidoneb,  
  Phenobarbital,
  
  
  or Valproatea
  or Primidoneb
  
  
  
  and NOT TAKING
  
  
  
  Valproatea
  Weeks 1 and 2
  25 mg every other day
  25 mg every day
  50 mg/day
  Weeks 3 and 4
  25 mg every day
  50 mg/day
  100 mg/day
  (in 2 divided doses)
  Weeks 5 onwards to 
  maintenance
  Increase by 25 to 
  50 mg/day every 1 to 2 weeks
  Increase by 50
  mg/day every 1
  to 2 weeks
  Increase by 
  100 mg/day every 
  1 to 2 weeks.
  Usual maintenance 
  dose
  100 to 200 mg/day
  with valproate alone
  225 to 375 mg/day
  (in 2 divided doses).
  300 to 500 mg/day
  (in 2 divided doses).
  
  100 to 400 mg/day
  with valproate
  and other drugs that induce glucuronidation
  
  
  
  (in 1 or 2 divided doses)
  
  
  

  a Valproate has been shown to inhibit glucuronidation and decrease the apparent clearance of lamotrigine [see Drug Interactions (7), Clinical Pharmacology (12.3)].

  b These drugs induce lamotrigine glucuronidation and increase clearance [see Drug Interactions (7), Clinical Pharmacology (12.3)]. Other drugs that have similar effects include estrogen-containing oral contraceptives [see Drug Interactions (7), Clinical Pharmacology (12.3)]. Dosing recommendations for oral contraceptives can be found in General Dosing Considerations [see Dosage and Administration (2.1)]. Patients on rifampin, or other drugs that induce lamotrigine glucuronidation and increase clearance, should follow the same dosing titration/maintenance regimen as that used with anticonvulsants that have this effect.

  Patients 2 to 12 Years Of Age: Recommended dosing guidelines are summarized in Table 2.

  Smaller starting doses and slower dose escalations than those used in clinical trials are recommended because of the suggestion that the risk of rash may be decreased by smaller starting doses and slower dose escalations. Therefore, maintenance doses will take longer to reach in clinical practice than in clinical trials. It may take several weeks to months to achieve an individualized maintenance dose. Maintenance doses in patients weighing less than 30 kg, regardless of age or concomitant AED, may need to be increased as much as 50%, based on clinical response.

  Table 2. Escalation Regimen for Lamotrigine Tablets in Patients 2 to 12 Years of Age With Epilepsy
  For Patients TAKING 
  Valproatea
  For Patients NOT 
  TAKING Carbamazepine, Phenytoin, 
  Phenobarbital, Primidoneb, or 
  Valproatea
  For Patients TAKING 
  Carbamazepine, Phenytoin, Phenobarbital, or 
  Primidoneb and NOT 
  TAKING Valproatea
  Weeks 1 and 2
  0.15 mg/kg/day
  in 1 or 2 divided doses, rounded down to the 
  nearest whole tablet (see Table 3 for weight 
  based dosing guide).
  0.3 mg/kg/day
  in 1 or 2 divided doses, rounded down to the 
  nearest whole tablet.
  0.6 mg/kg/day
  in 2 divided doses, rounded down to the 
  nearest whole tablet.
  Weeks 3 and 4
  0.3 mg/kg/day
  in 1 or 2 divided doses,
  rounded down to the 
  nearest whole tablet 
  (see Table 3 for weight 
  based dosing guide).
  0.6 mg/kg/day
  in 2 divided doses,
  rounded down to the 
  nearest whole tablet.
  1.2 mg/kg/day
  in 2 divided doses, 
  rounded down to the 
  nearest whole tablet.
  Weeks 5 
  onwards to 
  maintenance
  The dose should be increased every 
  1 to 2 weeks as follows:
  calculate 0.3 mg/kg/day, round this amount 
  down to the nearest whole tablet, and 
  add this amount to the 
  previously administered daily dose.
  The dose should be increased every 
  1 to 2 weeks as follows:
  calculate 0.6 mg/kg/day, round this amount 
  down to the nearest whole tablet, and 
  add this amount to the 
  previously administered daily dose
  The dose should be increased every 
  1 to 2 weeks as follows:
  calculate 1.2 mg/kg/day, round this amount 
  down to the nearest whole tablet, and 
  add this amount to the 
  previously administered daily dose
  Usual 
  Maintenance 
  Dose
  1 to 5 mg/kg/day
  (maximum 200 mg/day 
  in 1 or 2 divided doses).
  1 to 3 mg/kg/day with valproate alone
  4.5 to 7.5 mg/kg/day
  (maximum 300 mg/day 
  in 2 divided doses)
  5 to 15 mg/kg/day
  (maximum 400 mg/day 
  in 2 divided doses)
  Maintenance dose in 
  patients 
  less than 30 kg
  May need to be increased 
  by as much as 50%, 
  based on clinical response
  May need to be increased 
  by as much as 50%, 
  based on clinical response
  May need to be increased 
  by as much as 50%, based 
  on clinical response
  

  Note: Only whole tablets should be used for dosing.

  a Valproate has been shown to inhibit glucuronidation and decrease the apparent clearance of lamotrigine [see Drug Interactions (7), Clinical Pharmacology (12.3)].

  b These drugs induce lamotrigine glucuronidation and increase clearance [see Drug Interactions (7), Clinical Pharmacology (12.3)]. Other drugs which have similar effects include estrogen-containing oral contraceptives [see Drug Interactions (7), Clinical Pharmacology (12.3)]. Dosing recommendations for oral contraceptives can be found in General Dosing Considerations [see Dosage and Administration (2.1)]. Patients on rifampin, or other drugs that induce lamotrigine glucuronidation and increase clearance, should follow the same dosing titration/maintenance regimen as that used with anticonvulsants that have this effect.

  Table 3. The Initial Weight-Based Dosing Guide for Patients 2 to 12 Years Taking Valproate (Weeks 1 to 4) With Epilepsy If the patient’s weight is
  Give this daily dose, using the most appropriate combination of Lamotrigine 2-mg and 5-mg tablets
  Greater than
  And less than
  Weeks 1 and 2
  Weeks 3 and 4
  6.7 kg
  14 kg
  2 mg every other day
  2 mg every day
  14.1 kg
  27 kg
  2 mg every day
  4 mg every day
  27.1 kg
  34 kg
  4 mg every day
  8 mg every day
  34.1 kg
  40 kg
  5 mg every day
  10 mg every day
  

  Usual Adjunctive Maintenance Dose for Epilepsy: The usual maintenance doses identified in Tables 1 and 2 are derived from dosing regimens employed in the placebo-controlled adjunctive studies in which the efficacy of lamotrigine tablets was established. In patients receiving multidrug regimens employing carbamazepine, phenytoin, phenobarbital, or primidone without valproate, maintenance doses of adjunctive lamotrigine tablets as high as 700 mg/day have been used. In patients receiving valproate alone, maintenance doses of adjunctive lamotrigine tablets as high as 200 mg/day have been used. The advantage of using doses above those recommended in Tables 1 through 4 has not been established in controlled trials.

   

  The goal of the transition regimen is to effect the conversion to monotherapy with lamotrigine tablets under conditions that ensure adequate seizure control while mitigating the risk of serious rash associated with the rapid titration of lamotrigine tablets.

  The recommended maintenance dose of lamotrigine tablets as monotherapy is 500 mg/day given in two divided doses.

  To avoid an increased risk of rash, the recommended initial dose and subsequent dose escalations of lamotrigine tablets should not be exceeded [see Boxed Warning].

  Conversion From Adjunctive Therapy With Carbamazepine, Phenytoin, Phenobarbital, or Primidone to Monotherapy With Lamotrigine Tablets: After achieving a dose of 500 mg/day of lamotrigine tablets according to the guidelines in Table 1, the concomitant AED should be withdrawn by 20% decrements each week over a 4-week period. The regimen for the withdrawal of the concomitant AED is based on experience gained in the controlled monotherapy clinical trial.

  Conversion from Adjunctive Therapy With Valproate to Monotherapy With Lamotrigine Tablets:

  The conversion regimen involves 4 steps outlined in Table 4.

  Table 4. Conversion From Adjunctive Therapy With Valproate to Monotherapy With Lamotrigine Tablets in Patients ≥16 Years of Age with Epilepsy
  Lamotrigine Tablets
  Valproate
  Step 1
  Achieve a dose of 200 mg/day according to
  guidelines in Table 1
  (if not already on 200 mg/day).
  Maintain previous stable dose.
  Step 2
  Maintain at 200 mg/day.
  Decrease to 500 mg/day by decrements no greater than
  500 mg/day/week and then maintain the dose of
  500 mg/day for 1 week.
  Step 3
  Increase to 300 mg/day and maintain for 1 week.
  Simultaneously decrease to
  250 mg/day and maintain for 1 week.
  Step 4
  Increase by 100 mg/day every
  week to achieve maintenance dose of 500 mg/day.
  Discontinue.
  

  Conversion from Adjunctive Therapy With AEDs Other Than Carbamazepine, Phenytoin, Phenobarbital, Primidone, or Valproate to Monotherapy With Lamotrigine Tablets: No specific dosing guidelines can be provided for conversion to monotherapy with lamotrigine tablets with AEDs other than carbamazepine, phenobarbital, phenytoin, primidone, or valproate.

   

  The goal of maintenance treatment with lamotrigine tablets is to delay the time to occurrence of mood episodes (depression, mania, hypomania, mixed episodes) in patients treated for acute mood episodes with standard therapy. The target dose of lamotrigine tablets is 200 mg/day (100 mg/day in patients taking valproate, which decreases the apparent clearance of lamotrigine, and 400 mg/day in patients not taking valproate and taking either carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin that increase the apparent clearance of lamotrigine). In the clinical trials, doses up to 400 mg/day as monotherapy were evaluated; however, no additional benefit was seen at 400 mg/day compared with 200 mg/day [see Clinical Studies (14.2) ]. Accordingly, doses above 200 mg/day are not recommended. Treatment with lamotrigine tablets is introduced, based on concurrent medications, according to the regimen outlined in Table 5. If other psychotropic medications are withdrawn following stabilization, the dose of lamotrigine tablets should be adjusted. For patients discontinuing valproate, the dose of lamotrigine tablets should be doubled over a 2-week period in equal weekly increments (see Table 6). For patients discontinuing carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin that induce lamotrigine glucuronidation, the dose of lamotrigine tablets should remain constant for the first week and then should be decreased by half over a 2-week period in equal weekly decrements (see Table 6). The dose of lamotrigine tablets may then be further adjusted to the target dose (200 mg) as clinically indicated.

  If other drugs are subsequently introduced, the dose of lamotrigine tablets may need to be adjusted. In particular, the introduction of valproate requires reduction in the dose of lamotrigine tablets [see Drug Interactions (7) , Clinical Pharmacology (12.3) ].

  To avoid an increased risk of rash, the recommended initial dose and subsequent dose escalations of lamotrigine tablets should not be exceeded [see Boxed Warning ].

  Table 5. Escalation Regimen for Lamotrigine Tablets for Patients With Bipolar Disorder
  For Patients TAKING 
  Valproatea
  For Patients NOT TAKING 
  Carbamazepine, Phenytoin, Phenobarbital, 
  Primidoneb, or Valproatea
  For Patients TAKING 
  Carbamazepine, Phenytoin,
  Phenobarbital, or Primidoneb and NOT TAKING 
  Valproatea
  Weeks 1 and 2
  25 mg every 
  other day
  25 mg daily
  50 mg daily
  Weeks 3 and 4
  25 mg daily
  50 mg daily
  100 mg daily, in divided doses
  Week 5
  50 mg daily
  100 mg daily
  200 mg daily, in divided doses
  Week 6
  100 mg daily
  200 mg daily
  300 mg daily, in divided doses
  Week 7
  100 mg daily
  200 mg daily
  up to 400 mg daily, in divided doses
  

  a Valproate has been shown to inhibit glucuronidation and decrease the apparent clearance of lamotrigine [see Drug Interactions (7), Clinical Pharmacology (12.3)].

  
  

  b These drugs induce lamotrigine glucuronidation and increase clearance [see Drug Interactions (7), Clinical Pharmacology (12.3)]. Other drugs which have similar effects include estrogen-containing oral contraceptives [see Drug Interactions (7), Clinical Pharmacology (12.3)]. Dosing recommendations for oral contraceptives can be found in General Dosing Considerations [see Dosage and Administration (2.1)]. Patients on rifampin, or other drugs that induce lamotrigine glucuronidation and increase clearance, should follow the same dosing titration/maintenance regimen as that used with anticonvulsants that have this effect.

  Table 6. Dosage Adjustments to Lamotrigine Tablets for Patients With Bipolar Disorder Following Discontinuation of Psychotropic Medications
  Discontinuation of Psychotropic Drugs 
  (excluding Carbamazepine, Phenytoin, 
  Phenobarbital, Primidoneb, or 
  Valproatea)
  After Discontinuation of 
  Valproatea
  After Discontinuation of 
  Carbamazepine, Phenytoin, 
  Phenobarbital, or Primidoneb
  
  
  Current dose of lamotrigine tablets
  (mg/day)
  100
  Current dose of lamotrigine tablets
  (mg/day)
  400
  Week 1
  Maintain current dose of lamotrigine tablets
  150
  400
  Week 2
  Maintain current dose of lamotrigine tablets
  200
  300
  Week 3 onward
  Maintain current dose of lamotrigine tablets
  200
  200
  

  The benefit of continuing treatment in patients who had been stabilized in an 8- to 16-week open-label phase with lamotrigine tablets was established in two randomized, placebo-controlled clinical maintenance trials [see Clinical Studies (14.2) ]. However, the optimal duration of treatment with lamotrigine tablets has not been established. Thus, patients should be periodically reassessed to determine the need for maintenance treatment.

   

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  2.1 General Dosing Considerations 

  Rash
  There are suggestions, yet to be proven, that the risk of severe, potentially life-threatening rash may be increased by (1) coadministration of lamotrigine with valproate, (2) exceeding the recommended initial dose of lamotrigine, or (3) exceeding the recommended dose escalation for Lamotrigine. However, cases have occurred in the absence of these factors [see Boxed Warning]. Therefore, it is important that the dosing recommendations be followed closely.

  The risk of nonserious rash may be increased when the recommended initial dose and/or the rate of dose escalation for lamotrigine is exceeded and in patients with a history of allergy or rash to other AEDs.

  It is recommended that lamotrigine not be restarted in patients who discontinued due to rash associated with prior treatment with lamotrigine unless the potential benefits clearly outweigh the risks. If the decision is made to restart a patient who has discontinued Lamotrigine, the need to restart with the initial dosing recommendations should be assessed. The greater the interval of time since the previous dose, the greater consideration should be given to restarting with the initial dosing recommendations. If a patient has discontinued lamotrigine for a period of more than 5 half-lives, it is recommended that initial dosing recommendations and guidelines be followed. The half-life of lamotrigine is affected by other concomitant medications [see Clinical Pharmacology (12.3)].

  Lamotrigine Added to Drugs Known to Induce or Inhibit Glucuronidation
  Because lamotrigine is metabolized predominantly by glucuronic acid conjugation, drugs that are known to induce or inhibit glucuronidation may affect the apparent clearance of lamotrigine. Drugs that induce glucuronidation include carbamazepine, phenytoin, phenobarbital, primidone, rifampin, estrogen-containing oral contraceptives, and the protease inhibitors lopinavir/ritonavir and atazanavir/ritonavir. Valproate inhibits glucuronidation. For dosing considerations for Lamotrigine in patients on estrogen-containing contraceptives and atazanavir/ritonavir, see below and Table 13. For dosing considerations for Lamotrigine in patients on other drugs known to induce or inhibit glucuronidation, see Tables 1, 2, 5-6, and 13.

  Target Plasma Levels for Patients with Epilepsy or Bipolar Disorder
  A therapeutic plasma concentration range has not been established for lamotrigine. Dosing of Lamotrigine should be based on therapeutic response [see Clinical Pharmacology (12.3)].

  Women Taking Estrogen-Containing Oral Contraceptives
  Starting Lamotrigine in Women Taking Estrogen-Containing Oral Contraceptives: Although estrogen-containing oral contraceptives have been shown to increase the clearance of lamotrigine [see Clinical Pharmacology (12.3)], no adjustments to the recommended dose-escalation guidelines for Lamotrigine should be necessary solely based on the use of estrogen-containing oral contraceptives. Therefore, dose escalation should follow the recommended guidelines for initiating adjunctive therapy with Lamotrigine based on the concomitant AED or other concomitant medications (see Tables 1, 5, and 7). See below for adjustments to maintenance doses of Lamotrigine in women taking estrogen-containing oral contraceptives.

  Adjustments to the Maintenance Dose of Lamotrigine in Women Taking Estrogen-Containing Oral Contraceptives:

       (1) Taking Estrogen-Containing Oral Contraceptives: In women not taking carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin and the protease inhibitors lopinavir/ritonavir and atazanavir/ritonavir that induce lamotrigine glucuronidation [see Drug Interactions (7), Clinical Pharmacology (12.3)], the maintenance dose of lamotrigine will in most cases need to be increased by as much as 2-fold over the recommended target maintenance dose to maintain a consistent lamotrigine plasma level.

       (2) Starting Estrogen-Containing Oral Contraceptives: In women taking a stable dose of Lamotrigine and not taking carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin and the protease inhibitors lopinavir/ritonavir and atazanavir/ritonavir that induce lamotrigine glucuronidation [see Drug Interactions (7), Clinical Pharmacology (12.3)], the maintenance dose will in most cases need to be increased by as much as 2-fold to maintain a consistent lamotrigine plasma level. The dose increases should begin at the same time that the oral contraceptive is introduced and continue, based on clinical response, no more rapidly than 50 to 100 mg/day every week. Dose increases should not exceed the recommended rate (see Tables 1 and 5) unless lamotrigine plasma levels or clinical response support larger increases. Gradual transient increases in lamotrigine plasma levels may occur during the week of inactive hormonal preparation (pill-free week), and these increases will be greater if dose increases are made in the days before or during the week of inactive hormonal preparation. Increased lamotrigine plasma levels could result in additional adverse reactions, such as dizziness, ataxia, and diplopia. If adverse reactions attributable to Lamotrigine consistently occur during the pill-free week, dose adjustments to the overall maintenance dose may be necessary. Dose adjustments limited to the pill-free week are not recommended. For women taking Lamotrigine in addition to carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin and the protease inhibitors lopinavir/ritonavir and atazanavir/ritonavir that induce lamotrigine glucuronidation [see Drug Interactions (7), Clinical Pharmacology (12.3)], no adjustment to the dose of Lamotrigine should be necessary.

       (3) Stopping Estrogen-Containing Oral Contraceptives: In women not taking carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin and the protease inhibitors lopinavir/ritonavir and atazanavir/ritonavir that induce lamotrigine glucuronidation [see Drug Interactions (7), Clinical Pharmacology (12.3)], the maintenance dose of lamotrigine will in most cases need to be decreased by as much as 50% in order to maintain a consistent lamotrigine plasma level. The decrease in dose of Lamotrigine should not exceed 25% of the total daily dose per week over a 2-week period, unless clinical response or lamotrigine plasma levels indicate otherwise [see Clinical Pharmacology (12.3)]. In women taking Lamotrigine in addition to carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin and the protease inhibitors lopinavir/ritonavir and atazanavir/ritonavir that induce lamotrigine glucuronidation [see Drug Interactions (7), Clinical Pharmacology (12.3)], no adjustment to the dose of Lamotrigine should be necessary.

  Women and Other Hormonal Contraceptive Preparations or Hormone Replacement Therapy
  The effect of other hormonal contraceptive preparations or hormone replacement therapy on the pharmacokinetics of lamotrigine has not been systematically evaluated. It has been reported that ethinylestradiol, not progestogens, increased the clearance of lamotrigine up to 2-fold, and the progestin-only pills had no effect on lamotrigine plasma levels. Therefore, adjustments to the dosage of Lamotrigine in the presence of progestogens alone will likely not be needed.

  Patients Taking Atazanavir/Ritonavir
  While atazanavir/ritonavir does reduce the lamotrigine plasma concentration, no adjustments to the recommended dose-escalation guidelines for Lamotrigine should be necessary solely based on the use of atazanavir/ritonavir. Dose escalation should follow the recommended guidelines for initiating adjunctive therapy with Lamotrigine based on concomitant AED or other concomitant medications (see Tables 1, 2, and 5). In patients already taking maintenance doses of Lamotrigine and not taking glucuronidation inducers, the dose of Lamotrigine may need to be increased if atazanavir/ritonavir is added, or decreased if atazanavir/ritonavir is discontinued [see Clinical Pharmacology (12.3)].

  Patients with Hepatic Impairment
  Experience in patients with hepatic impairment is limited. Based on a clinical pharmacology study in 24 subjects with mild, moderate, and severe liver impairment [see Use in Specific Populations (8.6), Clinical Pharmacology (12.3)], the following general recommendations can be made. No dosage adjustment is needed in patients with mild liver impairment. Initial, escalation, and maintenance doses should generally be reduced by approximately 25% in patients with moderate and severe liver impairment without ascites and 50% in patients with severe liver impairment with ascites. Escalation and maintenance doses may be adjusted according to clinical response.

  Patients with Renal Impairment
  Initial doses of Lamotrigine should be based on patients' concomitant medications (see Tables 1-3 and 5); reduced maintenance doses may be effective for patients with significant renal impairment [see Use in Specific Populations (8.7), Clinical Pharmacology (12.3)]. Few patients with severe renal impairment have been evaluated during chronic treatment with lamotrigine. Because there is inadequate experience in this population, lamotrigine should be used with caution in these patients.

  Discontinuation Strategy
  Epilepsy: For patients receiving lamotrigine in combination with other AEDs, a re-evaluation of all AEDs in the regimen should be considered if a change in seizure control or an appearance or worsening of adverse reactions is observed.

  If a decision is made to discontinue therapy with lamotrigine, a step-wise reduction of dose over at least 2 weeks (approximately 50% per week) is recommended unless safety concerns require a more rapid withdrawal [see Warnings and Precautions (5.8)].

  Discontinuing carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin and the protease inhibitors lopinavir/ritonavir and atazanavir/ritonavir that induce lamotrigine glucuronidation should prolong the half-life of lamotrigine; discontinuing valproate should shorten the half-life of lamotrigine.

  Bipolar Disorder: In the controlled clinical trials, there was no increase in the incidence, type, or severity of adverse reactions following abrupt termination of lamotrigine. In the clinical development program in adults with bipolar disorder, 2 patients experienced seizures shortly after abrupt withdrawal of lamotrigine. Discontinuation of lamotrigine should involve a step-wise reduction of dose over at least 2 weeks (approximately 50% per week) unless safety concerns require a more rapid withdrawal [see Warnings and Precautions (5.8)].

  2.2 Epilepsy – Adjunctive Therapy

  This section provides specific dosing recommendations for patients older than 12 years and patients aged 2 to 12 years. Within each of these age-groups, specific dosing recommendations are provided depending upon concomitant AEDs or other concomitant medications (see Table 1 for patients older than 12 years and Table 2 for patients aged 2 to 12 years). A weight-based dosing guide for patients aged 2 to 12 years on concomitant valproate is provided in Table 3.

  Patients Older than 12 Years
  
  Recommended dosing guidelines are summarized in Table 1.

  Table 1 Escalation Regimen for Lamotrigine in Patients Older than 12 Years with Epilepsy * Valproate has been shown to inhibit glucuronidation and decrease the apparent clearance of lamotrigine [see Drug Interactions ( 7 ), Clinical Pharmacology  ( 12.3 )]. † Drugs that induce lamotrigine glucuronidation and increase clearance, other than the specified antiepileptic drugs, include estrogen-containing oral contraceptives, rifampin, and the protease inhibitors lopinavir/ritonavir and atazanavir/ritonavir. Dosing recommendations for oral contraceptives and the protease inhibitor atazanavir/ritonavir can be found in General Dosing Considerations [see Dosage and Administration (2.1)]. Patients on rifampin and the protease inhibitor lopinavir/ritonavir should follow the same dosing titration/maintenance regimen used with antiepileptic drugs that induce glucuronidation and increase clearance [see Dosage and Administration (2.1), Drug Interactions (7), and Clinical Pharmacology (12.3)].   In Patients TAKING Valproate* In Patients NOT TAKING Carbamazepine, Phenytoin, Phenobarbital, Primidone†,or Valproate* In Patients TAKING Carbamazepine, Phenytoin, Phenobarbital, or Primidone† and NOT TAKING Valproate* Weeks 1 and 2 25 mg every other day 25 mg every day 50 mg/day Weeks 3 and 4 25 mg every day 50 mg/day 100 mg/day
  (in 2 divided doses) Week 5 onward to maintenance Increase by 25 to 50 mg/day every 1 to 2 weeks. Increase by 50 mg/day
  every 1 to 2 weeks. Increase by 100 mg/day every 1 to 2 weeks. Usual maintenance dose 100 to 200 mg/day with valproate alone
  
  100 to 400 mg/day with valproate and other drugs that induce glucuronidation
  (in 1 or 2 divided doses) 225 to 375 mg/day
  (in 2 divided doses) 300 to 500 mg/day  
  (in 2 divided doses)

  Patients Aged 2 to 12 Years
  Recommended dosing guidelines are summarized in Table 2.

  Lower starting doses and slower dose escalations than those used in clinical trials are recommended because of the suggestion that the risk of rash may be decreased by lower starting doses and slower dose escalations. Therefore, maintenance doses will take longer to reach in clinical practice than in clinical trials. It may take several weeks to months to achieve an individualized maintenance dose. Maintenance doses in patients weighing less than 30 kg, regardless of age or concomitant AED, may need to be increased as much as 50%, based on clinical response.

  Table 2. Escalation Regimen for Lamotrigine in Patients Aged 2 to 12 Years with Epilepsy * Valproate has been shown to inhibit glucuronidation and decrease the apparent clearance of lamotrigine [see Drug Interactions (7), Clinical Pharmacology  (12.3)]. † Drugs that induce lamotrigine glucuronidation and increase clearance, other than the specified antiepileptic drugs, include estrogen-containing oral contraceptives, rifampin, and the protease inhibitors lopinavir/ritonavir and atazanavir/ritonavir. Dosing recommendations for oral contraceptives and the protease inhibitor atazanavir/ritonavir can be found in General Dosing Considerations [see Dosage and Administration (2.1)]. Patients on rifampin and the protease inhibitor lopinavir/ritonavir should follow the same dosing titration/maintenance regimen used with antiepileptic drugs that induce glucuronidation and increase clearance [see Dosage and Administration (2.1), Drug Interactions (7), and Clinical Pharmacology (12.3)].   In Patients TAKING Valproate* In Patients NOT TAKING Carbamazepine, Phenytoin, Phenobarbital,  Primidone† or
   Valproate* In Patients TAKING Carbamazepine, Phenytoin, Phenobarbital, or Primidone† and NOT TAKING Valproate* Weeks 1 and 2 0.15 mg/kg/day
   in 1 or 2 divided doses, rounded down to the nearest whole tablet (see Table 3 for weight-based dosing guide) 0.3 mg/kg/day
  in 1 or 2 divided doses, rounded down to the nearest whole tablet 0.6 mg/kg/day
  in 2 divided doses, rounded down to the nearest whole tablet Weeks 3 and 4 0.3 mg/kg/day
  in 1 or 2 divided doses, rounded down to the nearest whole tablet (see Table 3 for weight-based dosing guide) 0.6 mg/kg/day
   in 2 divided doses, rounded down to the nearest whole tablet 1.2 mg/kg/day
    in 2 divided doses, rounded down to the nearest whole tablet Week 5 onward to maintenance The dose should be increased every 1 to 2 weeks as follows: calculate 0.3 mg/kg/day, round this amount down to the nearest whole tablet, and add this amount to the previously administered daily dose. The dose should be increased every 1 to 2 weeks as follows: calculate 0.6 mg/kg/day, round this amount down to the nearest whole tablet, and add this amount to the previously administered daily dose. The dose should be increased every 1 to 2 weeks as follows: calculate 1.2 mg/kg/day, round this amount down to the nearest whole tablet, and add this amount to the previously administered daily dose. Usual maintenance dose 1 to 5 mg/kg/day
  (maximum 200 mg/day in 1 or 2 divided doses)
   1 to 3 mg/kg/day with valproate alone 4.5 to 7.5 mg/kg/day
  (maximum 300 mg/day in 2 divided doses) 5 to 15 mg/kg/day
  (maximum 400 mg/day in 2 divided doses) Maintenance dose in patients less than 30 kg May need to be increased by as much as 50%, based on clinical response. May need to be increased by as much as 50%, based on clinical response. May need to be increased by as much as 50%, based on clinical response. Note: Only whole tablets should be used for dosing. Table 3. The Initial Weight-Based Dosing Guide for Patients Aged 2 to 12 Years Taking Valproate (Weeks 1 to 4) with Epilepsy If the patient’s weight is Give this daily dose, using the most appropriate combination of Lamotrigine 2-mg and 5-mg tablets Greater than And less than Weeks 1 and 2 Weeks 3 and 4 6.7 kg 14 kg 2 mg every other day 2 mg every day 14.1 kg 27 kg 2 mg every day 4 mg every day 27.1 kg 34 kg 4 mg every day 8 mg every day 34.1 kg 40 kg 5 mg every day 10 mg every day

  Usual Adjunctive Maintenance Dose for Epilepsy
  The usual maintenance doses identified in Tables 1 and 2 are derived from dosing regimens employed in the placebo-controlled adjunctive trials in which the efficacy of lamotrigine was established. In patients receiving multidrug regimens employing carbamazepine, phenytoin, phenobarbital, or primidone without valproate, maintenance doses of adjunctive lamotrigine as high as 700 mg/day have been used. In patients receiving valproate alone, maintenance doses of adjunctive lamotrigine as high as 200 mg/day have been used. The advantage of using doses above those recommended in Tables 1- 4 has not been established in controlled trials.

  2.3 Epilepsy – Conversion from Adjunctive Therapy to Monotherapy

  The goal of the transition regimen is to attempt to maintain seizure control while mitigating the risk of serious rash associated with the rapid titration of lamotrigine.

  The recommended maintenance dose of lamotrigine as monotherapy is 500 mg/day given in 2 divided doses.

  To avoid an increased risk of rash, the recommended initial dose and subsequent dose escalations for lamotrigine should not be exceeded [see Boxed Warning].

  Conversion from Adjunctive Therapy with Carbamazepine, Phenytoin, Phenobarbital, or Primidone to Monotherapy with Lamotrigine  
  
  After achieving a dose of 500 mg/day of lamotrigine using the guidelines in Table 1, the concomitant enzyme-inducing AED should be withdrawn by 20% decrements each week over a 4-week period. The regimen for the withdrawal of the concomitant AED is based on experience gained in the controlled monotherapy clinical trial.

  Conversion from Adjunctive Therapy with Valproate to Monotherapy with Lamotrigine
  
  The conversion regimen involves the 4 steps outlined in Table 4.

  Table 4. Conversion from Adjunctive Therapy with Valproate to Monotherapy with Lamotrigine in Patients Aged 16 Years and Older with Epilepsy  

  Lamotrigine

  Valproate

  Step 1

  Achieve a dose of 200 mg/day according to guidelines in Table 1.

  Maintain established stable dose.

  Step 2

  Maintain at 200 mg/day.

  Decrease dose by decrements no greater than 500 mg/day/week to 500 mg/day and then maintain for 1 week.

  Step 3

  Increase to 300 mg/day and maintain for 1 week.

  Simultaneously decrease to 250 mg/day and maintain for 1 week.

  Step 4

  Increase by 100 mg/day every week to achieve maintenance dose of 500 mg/day.

  Discontinue.

  Conversion from Adjunctive Therapy with Antiepileptic Drugs other than Carbamazepine, Phenytoin, Phenobarbital, Primidone, or Valproate to Monotherapy with Lamotrigine  
  
  No specific dosing guidelines can be provided for conversion to monotherapy with lamotrigine with AEDs other than carbamazepine, phenytoin, phenobarbital, primidone, or valproate.

  2.4 Bipolar Disorder

  The goal of maintenance treatment with lamotrigine is to delay the time to occurrence of mood episodes (depression, mania, hypomania, mixed episodes) in patients treated for acute mood episodes with standard therapy [see Indications and Usage (1)].

  Patients taking Lamotrigine for more than 16 weeks should be periodically reassessed to determine the need for maintenance treatment.

  Adults

  The target dose of lamotrigine is 200 mg/day (100 mg/day in patients taking valproate, which decreases the apparent clearance of lamotrigine, and 400 mg/day in patients not taking valproate and taking either carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin and the protease inhibitor lopinavir/ritonavir that  increase the apparent clearance of lamotrigine). In the clinical trials, doses up to 400 mg/day as monotherapy were evaluated; however, no additional benefit was seen at 400 mg/day compared with 200 mg/day [see Clinical Studies (14.2)]. Accordingly, doses above 200 mg/day are not recommended.

  Treatment with lamotrigine is introduced, based on concurrent medications, according to the regimen outlined in Table 5. If other psychotropic medications are withdrawn following stabilization, the dose of lamotrigine should be adjusted. In patients discontinuing valproate, the dose of lamotrigine should be doubled over a 2-week period in equal weekly increments (see Table 6). In patients discontinuing carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin and the protease inhibitors lopinavir/ritonavir and atazanavir/ritonavir that induce lamotrigine glucuronidation, the dose of lamotrigine should remain constant for the first week and then should be decreased by half over a 2-week period in equal weekly decrements (see Table 6). The dose of lamotrigine may then be further adjusted to the target dose (200 mg) as clinically indicated.

  If other drugs are subsequently introduced, the dose of lamotrigine may need to be adjusted. In particular, the introduction of valproate requires reduction in the dose of lamotrigine [see Drug Interactions (7), Clinical Pharmacology (12.3)].

  To avoid an increased risk of rash, the recommended initial dose and subsequent dose escalations of Lamotrigine should not be exceeded [see Boxed Warning].

  Table 5. Escalation Regimen for Lamotrigine in Adults with Bipolar Disorder * Valproate has been shown to inhibit glucuronidation and decrease the apparent clearance of lamotrigine [see Drug Interactions (7), Clinical Pharmacology (12.3)]. † Drugs that induce lamotrigine glucuronidation and increase clearance, other than the specified antiepileptic drugs, include estrogen-containing oral contraceptives, rifampin, and the protease inhibitors lopinavir/ritonavir and atazanavir/ritonavir. Dosing recommendations for oral contraceptives and the protease inhibitor atazanavir/ritonavir can be found in General Dosing Considerations [see Dosage and Administration (2.1)]. Patients on rifampin and the protease inhibitor lopinavir/ritonavir should follow the same dosing titration/maintenance regimen used with antiepileptic drugs that induce glucuronidation and increase clearance [see Dosage and Administration (2.1), Drug Interactions (7), and Clinical Pharmacology (12.3)].   In Patients TAKING Valproate* In Patients NOT TAKING Carbamazepine, Phenytoin, Phenobarbital, Primidone†, or Valproate* In Patients TAKING Carbamazepine, Phenytoin, Phenobarbital, or Primidone† and NOT TAKING Valproate* Weeks 1 and 2 25 mg every other day 25 mg daily 50 mg daily Weeks 3 and 4 25 mg daily 50 mg daily 100 mg daily, in divided doses Week 5 50 mg daily 100 mg daily 200 mg daily, in divided doses Week 6 100 mg daily 200 mg daily 300 mg daily, in divided doses Week 7 100 mg daily 200 mg daily up to 400 mg daily, in divided doses Table 6. Dosage Adjustments to Lamotrigine in Adults with Bipolar Disorder Following Discontinuation of Psychotropic Medications * Valproate has been shown to inhibit glucuronidation and decrease the apparent clearance of     lamotrigine [see Drug Interactions (7), Clinical Pharmacology (12.3)]. † Drugs that induce lamotrigine glucuronidation and increase clearance, other than the specified antiepileptic drugs, include estrogen-containing oral contraceptives, rifampin, and the protease inhibitors lopinavir/ritonavir and atazanavir/ritonavir. Dosing recommendations for oral contraceptives and the protease inhibitor atazanavir/ritonavir can be found in General Dosing Considerations [see Dosage and Administration (2.1)]. Patients on rifampin and the protease inhibitor lopinavir/ritonavir should follow the same dosing titration/maintenance regimen used with antiepileptic drugs that induce glucuronidation and increase clearance [see Dosage and Administration (2.1), Drug Interactions (7), and Clinical Pharmacology (12.3)].    

  Discontinuation of Psychotropic Drugs (excluding Valproate *Carbamazepine, Phenytoin, Phenobarbital, Primidone†) After Discontinuation of Valproate* After Discontinuation of Carbamazepine, Phenytoin, Phenobarbital, or Primidone† Current dose of lamotrigine (mg/day) 100

  Current dose of lamotrigine (mg/day) 400

  Week 1 Maintain current dose of Lamotrigine 150 400 Week 2 Maintain current dose of Lamotrigine 200 300 Week 3 onward Maintain current dose of Lamotrigine 200 200

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  2.1 General Dosing Considerations Rash

  There are suggestions, yet to be proven, that the risk of severe, potentially life-threatening rash may be increased by (1) coadministration of lamotrigine tablets with valproate, (2) exceeding the recommended initial dose of lamotrigine tablets, or (3) exceeding the recommended dose escalation for lamotrigine tablets. However, cases have occurred in the absence of these factors [see Boxed Warning]. Therefore, it is important that the dosing recommendations be followed closely.

  The risk of nonserious rash may be increased when the recommended initial dose and/or the rate of dose escalation for lamotrigine tablets is exceeded and in patients with a history of allergy or rash to other AEDs.

  It is recommended that lamotrigine tablets not be restarted in patients who discontinued due to rash associated with prior treatment with lamotrigine unless the potential benefits clearly outweigh the risks. If the decision is made to restart a patient who has discontinued lamotrigine tablets, the need to restart with the initial dosing recommendations should be assessed. The greater the interval of time since the previous dose, the greater consideration should be given to restarting with the initial dosing recommendations. If a patient has discontinued lamotrigine tablets for a period of more than 5 half-lives, it is recommended that initial dosing recommendations and guidelines be followed. The half-life of lamotrigine is affected by other concomitant medications [see Clinical Pharmacology (12.3)].

  Lamotrigine Tablets Added to Drugs Known to Induce or Inhibit Glucuronidation

  Because lamotrigine is metabolized predominantly by glucuronic acid conjugation, drugs that are known to induce or inhibit glucuronidation may affect the apparent clearance of lamotrigine. Drugs that induce glucuronidation include carbamazepine, phenytoin, phenobarbital, primidone, rifampin, estrogen-containing oral contraceptives, and the protease inhibitors lopinavir/ritonavir and atazanavir/ritonavir. Valproate inhibits glucuronidation. For dosing considerations for lamotrigine tablets in patients on estrogen-containing contraceptives and atazanavir/ritonavir, see below and Table 13. For dosing considerations for lamotrigine tablets in patients on other drugs known to induce or inhibit glucuronidation, see Table 1, Table 2, Table 5, Table 6, and Table 13.

  Target Plasma Levels for Patients with Epilepsy or Bipolar Disorder

  A therapeutic plasma concentration range has not been established for lamotrigine. Dosing of lamotrigine tablets should be based on therapeutic response [see Clinical Pharmacology (12.3)].

  Women taking Estrogen-Containing Oral Contraceptives Starting Lamotrigine Tablets in Women taking Estrogen-Containing Oral Contraceptives

  Although estrogen-containing oral contraceptives have been shown to increase the clearance of lamotrigine [see Clinical Pharmacology (12.3)], no adjustments to the recommended dose-escalation guidelines for lamotrigine tablets should be necessary solely based on the use of estrogen-containing oral contraceptives. Therefore, dose escalation should follow the recommended guidelines for initiating adjunctive therapy with lamotrigine tablets based on the concomitant AED or other concomitant medications (see Table 1 or Table 5). See below for adjustments to maintenance doses of lamotrigine tablets in women taking estrogen-containing oral contraceptives.

  Adjustments to the Maintenance Dose of Lamotrigine Tablets in Women taking Estrogen-Containing Oral Contraceptives (1) Taking Estrogen-Containing Oral Contraceptives

  In women not taking carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin and the protease inhibitors lopinavir/ritonavir and atazanavir/ritonavir that induce lamotrigine glucuronidation [see Drug Interactions (7), Clinical Pharmacology (12.3)], the maintenance dose of lamotrigine tablets will in most cases need to be increased by as much as 2-fold over the recommended target maintenance dose to maintain a consistent lamotrigine plasma level.

  (2) Starting Estrogen-Containing Oral Contraceptives

  In women taking a stable dose of lamotrigine tablets and not taking carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin and the protease inhibitors lopinavir/ritonavir and atazanavir/ritonavir that induce lamotrigine glucuronidation [see Drug Interactions (7), Clinical Pharmacology (12.3)], the maintenance dose will in most cases need to be increased by as much as 2-fold to maintain a consistent lamotrigine plasma level. The dose increases should begin at the same time that the oral contraceptive is introduced and continue, based on clinical response, no more rapidly than 50 to 100 mg/day every week. Dose increases should not exceed the recommended rate (see Table 1 or Table 5) unless lamotrigine plasma levels or clinical response support larger increases. Gradual transient increases in lamotrigine plasma levels may occur during the week of inactive hormonal preparation (pill-free week), and these increases will be greater if dose increases are made in the days before or during the week of inactive hormonal preparation. Increased lamotrigine plasma levels could result in additional adverse reactions, such as dizziness, ataxia, and diplopia. If adverse reactions attributable to lamotrigine tablets consistently occur during the pill-free week, dose adjustments to the overall maintenance dose may be necessary. Dose adjustments limited to the pill-free week are not recommended. For women taking lamotrigine tablets in addition to carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin and the protease inhibitors lopinavir/ritonavir and atazanavir/ritonavir that induce lamotrigine glucuronidation [see Drug Interactions (7), Clinical Pharmacology (12.3)], no adjustment to the dose of lamotrigine tablets should be necessary.

  (3) Stopping Estrogen-Containing Oral Contraceptives

  In women not taking carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin and the protease inhibitors lopinavir/ritonavir and atazanavir/ritonavir that induce lamotrigine glucuronidation [see Drug Interactions (7), Clinical Pharmacology (12.3)], the maintenance dose of lamotrigine tablets will in most cases need to be decreased by as much as 50% in order to maintain a consistent lamotrigine plasma level. The decrease in dose of lamotrigine tablets should not exceed 25% of the total daily dose per week over a 2-week period, unless clinical response or lamotrigine plasma levels indicate otherwise [see Clinical Pharmacology (12.3)]. In women taking lamotrigine tablets in addition to carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin and the protease inhibitors lopinavir/ritonavir and atazanavir/ritonavir that induce lamotrigine glucuronidation[see Drug Interactions (7), Clinical Pharmacology (12.3)], no adjustment to the dose of lamotrigine tablets should be necessary.

  Women and Other Hormonal Contraceptive Preparations or Hormone Replacement Therapy

  The effect of other hormonal contraceptive preparations or hormone replacement therapy on the pharmacokinetics of lamotrigine has not been systematically evaluated. It has been reported that ethinylestradiol, not progestogens, increased the clearance of lamotrigine up to 2-fold, and the progestin-only pills had no effect on lamotrigine plasma levels. Therefore, adjustments to the dosage of lamotrigine tablets in the presence of progestogens alone will likely not be needed.

  Patients Taking Atazanavir/Ritonavir

  While atazanavir/ritonavir does reduce the lamotrigine plasma concentration, no adjustments to the recommended dose-escalation guidelines for lamotrigine tablets should be necessary solely based on the use of atazanavir/ritonavir. Dose escalation should follow the recommended guidelines for initiating adjunctive therapy with lamotrigine tablets based on concomitant AED or other concomitant medications (see Tables 1, 2, and 5). In patients already taking maintenance doses of lamotrigine tablets and not taking glucuronidation inducers, the dose of lamotrigine tablets may need to be increased if atazanavir/ritonavir is added, or decreased if atazanavir/ritonavir is discontinued [see Clinical Pharmacology (12.3)].

  Patients with Hepatic Impairment

  Experience in patients with hepatic impairment is limited. Based on a clinical pharmacology study in 24 subjects with mild, moderate, and severe liver impairment [see Use in Specific Populations (8.6), Clinical Pharmacology (12.3)], the following general recommendations can be made. No dosage adjustment is needed in patients with mild liver impairment. Initial, escalation, and maintenance doses should generally be reduced by approximately 25% in patients with moderate and severe liver impairment without ascites and 50% in patients with severe liver impairment with ascites. Escalation and maintenance doses may be adjusted according to clinical response.

  Patients with Renal Impairment

  Initial doses of lamotrigine tablets should be based on patients' concomitant medications (see Tables 1 to 3 or Table 5); reduced maintenance doses may be effective for patients with significant renal impairment [see Use in Specific Populations (8.7), Clinical Pharmacology (12.3)]. Few patients with severe renal impairment have been evaluated during chronic treatment with lamotrigine tablets. Because there is inadequate experience in this population, lamotrigine tablets should be used with caution in these patients.

  Discontinuation Strategy Epilepsy

  For patients receiving lamotrigine tablets in combination with other AEDs, a re-evaluation of all AEDs in the regimen should be considered if a change in seizure control or an appearance or worsening of adverse reactions is observed.

  If a decision is made to discontinue therapy with lamotrigine tablets, a step-wise reduction of dose over at least 2 weeks (approximately 50% per week) is recommended unless safety concerns require a more rapid withdrawal [see Warnings and Precautions (5.9)].

  Discontinuing carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin and the protease inhibitors lopinavir/ritonavir and atazanavir/ritonavir that induce lamotrigine glucuronidation should prolong the half-life of lamotrigine; discontinuing valproate should shorten the half-life of lamotrigine.

  Bipolar Disorder

  In the controlled clinical trials, there was no increase in the incidence, type, or severity of adverse reactions following abrupt termination of lamotrigine tablets. In clinical trials in patients with bipolar disorder, two patients experienced seizures shortly after abrupt withdrawal of lamotrigine tablets. However, there were confounding factors that may have contributed to the occurrence of seizures in these patients with bipolar disorder. Discontinuation of lamotrigine tablets should involve a step-wise reduction of dose over at least 2 weeks (approximately 50% per week) unless safety concerns require a more rapid withdrawal [see Warnings and Precautions (5.9)].

  2.2 Epilepsy – Adjunctive Therapy

  This section provides specific dosing recommendations for patients older than 12 years and patients aged 2 to 12 years. Within each of these age-groups, specific dosing recommendations are provided depending upon concomitant AEDs or other concomitant medications (see Table 1 for patients older than 12 years and Table 2 for patients aged 2 to 12 years). A weight-based dosing guide for patients aged 2 to 12 years on concomitant valproate is provided in Table 3.

  Patients Older than 12 Years

  Recommended dosing guidelines are summarized in Table 1.

  Table 1. Escalation Regimen for Lamotrigine Tablets in Patients Older than 12 Years with Epilepsy * Valproate has been shown to inhibit glucuronidation and decrease the apparent clearance of lamotrigine [see Drug Interactions (7), Clinical Pharmacology (12.3)]. † Drugs that induce lamotrigine glucuronidation and increase clearance, other than the specified antiepileptic drugs, include estrogen-containing oral contraceptives, rifampin, and the protease inhibitors lopinavir/ritonavir and atazanavir/ritonavir. Dosing recommendations for oral contraceptives and the protease inhibitor atazanavir/ritonavir can be found in General Dosing Considerations [see Dosage and Administration (2.1)]. Patients on rifampin and the protease inhibitor lopinavir/ritonavir should follow the same dosing titration/maintenance regimen used with antiepileptic drugs that induce glucuronidation and increase clearance [see Dosage and Administration (2.1), Drug Interactions (7), and Clinical Pharmacology (12.3)].

  In Patients TAKING Valproate*

  In Patients NOT TAKING Carbamazepine, Phenytoin, Phenobarbital, Primidone†, or Valproate*

  In Patients TAKING Carbamazepine, Phenytoin, Phenobarbital, or Primidone† and NOT TAKING Valproate*

  Weeks 1 and 2

  25 mg every other day

  25 mg every day

  50 mg/day

  Weeks 3 and 4

  25 mg every day

  50 mg/day

  100 mg/day
  (in 2 divided doses)

  Week 5 onward

  to maintenance

  Increase by 25 to
  50 mg/day every
  1 to 2 weeks.

  Increase by
  50 mg/day every
  1 to 2 weeks.

  Increase by
  100 mg/day every
  1 to 2 weeks.

  Usual maintenance
  dose

  100 to 200 mg/day with valproate alone
  
  100 to 400 mg/day with valproate and other drugs that induce glucuronidation

  (in 1 or 2 divided doses)

  225 to 375 mg/day
  (in 2 divided doses)

  300 to 500 mg/day
  (in 2 divided doses)

  Patients Aged 2 to 12 Years

  Recommended dosing guidelines are summarized in Table 2.

  Smaller starting doses and slower dose escalations than those used in clinical trials are recommended because of the suggestion that the risk of rash may be decreased by smaller starting doses and slower dose escalations. Therefore, maintenance doses will take longer to reach in clinical practice than in clinical trials. It may take several weeks to months to achieve an individualized maintenance dose. Maintenance doses in patients weighing less than 30 kg, regardless of age or concomitant AED, may need to be increased as much as 50%, based on clinical response.

  Table 2. Escalation Regimen for Lamotrigine Tablets in Patients Aged 2 to 12 Years with Epilepsy Note: Only whole tablets should be used for dosing. * Valproate has been shown to inhibit glucuronidation and decrease the apparent clearance of lamotrigine [see Drug Interactions (7), Clinical Pharmacology (12.3)]. † Drugs that induce lamotrigine glucuronidation and increase clearance, other than the specified antiepileptic drugs, include estrogen-containing oral contraceptives, rifampin, and the protease inhibitors lopinavir/ritonavir and atazanavir/ritonavir. Dosing recommendations for oral contraceptives and the protease inhibitor atazanavir/ritonavir can be found in General Dosing Considerations [see Dosage and Administration (2.1)]. Patients on rifampin and the protease inhibitor lopinavir/ritonavir should follow the same dosing titration/maintenance regimen used with antiepileptic drugs that induce glucuronidation and increase clearance [see Dosage and Administration (2.1), Drug Interactions (7), and Clinical Pharmacology (12.3)].

  In Patients TAKING

  Valproate*

  In Patients NOT TAKING Carbamazepine, Phenytoin, Phenobarbital, Primidone†, or Valproate*

  In Patients TAKING Carbamazepine, Phenytoin, Phenobarbital, or Primidone† and NOT TAKING Valproate*

  Weeks 1 and 2

  0.15 mg/kg/day
  in 1 or 2 divided doses, rounded down to the nearest whole tablet (see Table 3 for weight-based dosing guide)

  0.3 mg/kg/day
  in 1 or 2 divided doses, rounded down to the nearest whole tablet

  0.6 mg/kg/day
  in 2 divided doses, rounded down to the nearest whole tablet

  Weeks 3 and 4

  0.3 mg/kg/day

  in 1 or 2 divided doses, rounded down to the nearest whole tablet (see Table 3 for weight-based dosing guide)

  0.6 mg/kg/day
  in 2 divided doses, rounded down to the nearest whole tablet

  1.2 mg/kg/day
  in 2 divided doses, rounded down to the nearest whole tablet

  Week 5

  onward to

  maintenance

  The dose should be increased every 1 to 2 weeks as follows: calculate 0.3 mg/kg/day, round this amount down to the nearest whole tablet, and add this amount to the previously administered daily dose.

  The dose should be increased every 1 to 2 weeks as follows: calculate 0.6 mg/kg/day, round this amount down to the nearest whole tablet, and add this amount to the previously administered daily dose.

  The dose should be increased every 1 to 2 weeks as follows: calculate 1.2 mg/kg/day, round this amount down to the nearest whole tablet, and add this amount to the previously administered daily dose.

  Usual

  maintenance

  dose

  1 to 5 mg/kg/day
  (maximum 200 mg/day in 1 or 2 divided doses)
  1 to 3 mg/kg/day with valproate alone

  4.5 to 7.5 mg/kg/day
  (maximum 300 mg/day in 2 divided doses)

  5 to 15 mg/kg/day
  (maximum 400 mg/day in 2 divided doses)

  Maintenance

  dose in

  patients less

  than 30 kg

  May need to be increased by as much as 50%, based
  on clinical response.

  May need to be increased by as much as 50%, based on clinical response.

  May need to be increased by as much as 50%, based on clinical response.

  Table 3. The Initial Weight-Based Dosing Guide for Patients Aged 2 to 12 Years Taking Valproate (Weeks 1 to 4) with Epilepsy

  If the patient’s weight is

  Give this daily dose, using the most appropriate combination of lamotrigine 2 mg and 5 mg tablets

  Greater than

  And less than

  Weeks 1 and 2

  Weeks 3 and 4

  6.7 kg

  14 kg

  2 mg every other day

  2 mg every day

  14.1 kg

  27 kg

  2 mg every day

  4 mg every day

  27.1 kg

  34 kg

  4 mg every day

  8 mg every day

  34.1 kg

  40 kg

  5 mg every day

  10 mg every day

        

  Usual Adjunctive Maintenance Dose for Epilepsy

  The usual maintenance doses identified in Tables 1 and 2 are derived from dosing regimens employed in the placebo-controlled adjunctive trials in which the efficacy of lamotrigine tablets was established. In patients receiving multidrug regimens employing carbamazepine, phenytoin, phenobarbital, or primidone without valproate, maintenance doses of adjunctive lamotrigine tablets as high as 700 mg/day have been used. In patients receiving valproate alone, maintenance doses of adjunctive lamotrigine tablets as high as 200 mg/day have been used. The advantage of using doses above those recommended in Tables 1 through 4 has not been established in controlled trials.

  2.3 Epilepsy – Conversion from Adjunctive Therapy to Monotherapy

  The goal of the transition regimen is to attempt to maintain seizure control while mitigating the risk of serious rash associated with the rapid titration of lamotrigine tablets.

  The recommended maintenance dose of lamotrigine tablets as monotherapy is 500 mg/day given in two divided doses.

  To avoid an increased risk of rash, the recommended initial dose and subsequent dose escalations for lamotrigine tablets should not be exceeded [see Boxed Warning].

  Conversion from Adjunctive Therapy with Carbamazepine, Phenytoin, Phenobarbital, or Primidone to Monotherapy with Lamotrigine Tablets

  After achieving a dose of 500 mg/day of lamotrigine tablets using the guidelines in Table 1, the concomitant enzyme-inducing AED should be withdrawn by 20% decrements each week over a 4-week period. The regimen for the withdrawal of the concomitant AED is based on experience gained in the controlled monotherapy clinical trial.

  Conversion from Adjunctive Therapy with Valproate to Monotherapy with Lamotrigine Tablets

  The conversion regimen involves the four steps outlined in Table 4.

  Table 4. Conversion from Adjunctive Therapy with Valproate to Monotherapy with Lamotrigine Tablets in Patients Aged 16 Years and Older with Epilepsy

  Lamotrigine Tablets

  Valproate

  Step 1

  Achieve a dose of 200 mg/day according to guidelines in Table 1.

  Maintain established stable dose.

  Step 2

  Maintain at 200 mg/day.

  Decrease dose by decrements no greater than 500 mg/day/week to 500 mg/day and then maintain for one week.

  Step 3

  Increase to 300 mg/day and maintain for one week.

  Simultaneously decrease to 250 mg/day and maintain for one week.

  Step 4

  Increase by 100 mg/day every week to achieve maintenance dose of 500 mg/day.

  Discontinue.

       

  Conversion from Adjunctive Therapy with Antiepileptic Drugs Other than Carbamazepine, Phenytoin, Phenobarbital, Primidone, or Valproate to Monotherapy with Lamotrigine Tablets

  No specific dosing guidelines can be provided for conversion to monotherapy with lamotrigine tablets with AEDs other than carbamazepine, phenytoin, phenobarbital, primidone, or valproate.

  2.4 Bipolar Disorder

  The goal of maintenance treatment with lamotrigine tablets is to delay the time to occurrence of mood episodes (depression, mania, hypomania, mixed episodes) in patients treated for acute mood episodes with standard therapy. The target dose of lamotrigine tablets is 200 mg/day (100 mg/day in patients taking valproate, which decreases the apparent clearance of lamotrigine, and 400 mg/day in patients not taking valproate and taking either carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin and the protease inhibitor lopinavir/ritonavir that increase the apparent clearance of lamotrigine). In the clinical trials, doses up to 400 mg/day as monotherapy were evaluated; however, no additional benefit was seen at 400 mg/day compared with 200 mg/day [see Clinical Studies (14.2)]. Accordingly, doses above 200 mg/day are not recommended. Treatment with lamotrigine tablets is introduced, based on concurrent medications, according to the regimen outlined in Table 5. If other psychotropic medications are withdrawn following stabilization, the dose of lamotrigine tablets should be adjusted. For patients discontinuing valproate, the dose of lamotrigine tablets should be doubled over a 2-week period in equal weekly increments (see Table 6). For patients discontinuing carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin and the protease inhibitors lopinavir/ritonavir and atazanavir/ritonavir that induce lamotrigine glucuronidation, the dose of lamotrigine tablets should remain constant for the first week and then should be decreased by half over a 2-week period in equal weekly decrements (see Table 6). The dose of lamotrigine tablets may then be further adjusted to the target dose (200 mg) as clinically indicated.

  If other drugs are subsequently introduced, the dose of lamotrigine tablets may need to be adjusted. In particular, the introduction of valproate requires reduction in the dose of lamotrigine tablets [see Drug Interactions (7), Clinical Pharmacology (12.3)].

  To avoid an increased risk of rash, the recommended initial dose and subsequent dose escalations of lamotrigine tablets should not be exceeded [see Boxed Warning].

  Table 5. Escalation Regimen for Lamotrigine Tablets in Patients with Bipolar Disorder * Valproate has been shown to inhibit glucuronidation and decrease the apparent clearance of lamotrigine [see Drug Interactions (7), Clinical Pharmacology (12.3)]. † Drugs that induce lamotrigine glucuronidation and increase clearance, other than the specified antiepileptic drugs, include estrogen-containing oral contraceptives, rifampin, and the protease inhibitors lopinavir/ritonavir and atazanavir/ritonavir. Dosing recommendations for oral contraceptives and the protease inhibitor atazanavir/ritonavir can be found in General Dosing Considerations [see Dosage and Administration (2.1)]. Patients on rifampin and the protease inhibitor lopinavir/ritonavir should follow the same dosing titration/maintenance regimen used with antiepileptic drugs that induce glucuronidation and increase clearance [see Dosage and Administration (2.1), Drug Interactions (7), and Clinical Pharmacology (12.3)].

  In Patients TAKING Valproate*

  In Patients NOT TAKING Carbamazepine, Phenytoin, Phenobarbital, Primidone†, or Valproate*

  In Patients TAKING Carbamazepine, Phenytoin, Phenobarbital, or Primidone† and NOT TAKING Valproate*

  Weeks 1 and 2

  25 mg every other day

  25 mg daily

  50 mg daily

  Weeks 3 and 4

  25 mg daily

  50 *mg daily

  100 mg daily, in divided doses

  Week 5

  50 mg daily

  100 mg daily

  200 mg daily, in divided doses

  Week 6

  100 mg daily

  200 mg daily

  300 mg daily, in divided doses

  Week 7

  100 mg daily

  200 mg daily

  up to 400 mg daily, in divided doses

  Table 6. Dosage Adjustments to Lamotrigine Tablets in Patients with Bipolar Disorder Following Discontinuation of Psychotropic Medications * Valproate has been shown to inhibit glucuronidation and decrease the apparent clearance of lamotrigine [see Drug Interactions (7), Clinical Pharmacology (12.3)]. † Drugs that induce lamotrigine glucuronidation and increase clearance, other than the specified antiepileptic drugs, include estrogen-containing oral contraceptives, rifampin, and the protease inhibitors lopinavir/ritonavir and atazanavir/ritonavir. Dosing recommendations for oral contraceptives and the protease inhibitor atazanavir/ritonavir can be found in General Dosing Considerations [see Dosage and Administration (2.1)]. Patients on rifampin and the protease inhibitor lopinavir/ritonavir should follow the same dosing titration/maintenance regimen used with antiepileptic drugs that induce glucuronidation and increase clearance [see Dosage and Administration (2.1), Drug Interactions (7), and Clinical Pharmacology (12.3)].

  Discontinuation of Psychotropic Drugs (excluding Valproate*, Carbamazepine, Phenytoin, Phenobarbital, or Primidone†)

  After Discontinuation of Valproate*

  After Discontinuation of Carbamazepine, Phenytoin, Phenobarbital, or Primidone†

  Current dose of lamotrigine tablets (mg/day) 100

  Current dose of lamotrigine tablets (mg/day)

  400

  Week 1

  Maintain current dose of lamotrigine tablets

  150

  400

  Week 2

  Maintain current dose of lamotrigine tablets

  200

  300

  Week 3 onward

  Maintain current dose of lamotrigine tablets

  200

  200

  The benefit of continuing treatment in patients who had been stabilized in an 8- to 16-week open-label phase with lamotrigine tablets was established in two randomized, placebo-controlled clinical maintenance trials [see Clinical Studies (14.2)]. However, the optimal duration of treatment with lamotrigine tablets has not been established. Thus, patients should be periodically reassessed to determine the need for maintenance treatment.

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  Lamotrigine extended-release tablets are taken once daily, with or without food. Tablets must be swallowed whole and must not be chewed, crushed, or divided.

  2.1 General Dosing Considerations

           Rash: There are suggestions, yet to be proven, that the risk of severe, potentially life-threatening rash may be increased by (1) coadministration of lamotrigine extended-release tablets with valproate, (2) exceeding the recommended initial dose of lamotrigine extended-release tablets, or (3) exceeding the recommended dose escalation for lamotrigine extended-release tablets. However, cases have occurred in the absence of these factors [see Boxed Warning]. Therefore, it is important that the dosing recommendations be followed closely.

           The risk of nonserious rash may be increased when the recommended initial dose and/or the rate of dose escalation for lamotrigine extended-release tablets is exceeded and in patients with a history of allergy or rash to other AEDs.

           It is recommended that lamotrigine extended-release tablets not be restarted in patients who discontinued due to rash associated with prior treatment with lamotrigine, unless the potential benefits clearly outweigh the risks. If the decision is made to restart a patient who has discontinued lamotrigine extended-release tablets, the need to restart with the initial dosing recommendations should be assessed. The greater the interval of time since the previous dose, the greater consideration should be given to restarting with the initial dosing recommendations. If a patient has discontinued lamotrigine for a period of more than 5 half-lives, it is recommended that initial dosing recommendations and guidelines be followed. The half-life of lamotrigine is affected by other concomitant medications [see Clinical Pharmacology (12.3)].

           Lamotrigine Extended-Release Tablets Added to Drugs Known to Induce or Inhibit Glucuronidation: Drugs other than those listed in the Clinical Pharmacology section [see Clinical Pharmacology (12.3)] have not been systematically evaluated in combination with lamotrigine. Because lamotrigine is metabolized predominantly by glucuronic acid conjugation, drugs that are known to induce or inhibit glucuronidation may affect the apparent clearance of lamotrigine and doses of lamotrigine extended-release tablets may require adjustment based on clinical response.

           Target Plasma Levels: A therapeutic plasma concentration range has not been established for lamotrigine. Dosing of lamotrigine extended-release tablets should be based on therapeutic response [see Clinical Pharmacology (12.3)].

           Women Taking Estrogen-Containing Oral Contraceptives: Starting Lamotrigine Extended-Release Tablets in Women Taking Estrogen-Containing Oral Contraceptives: Although estrogen-containing oral contraceptives have been shown to increase the clearance of lamotrigine [see Clinical Pharmacology (12.3)], no adjustments to the recommended dose-escalation guidelines for lamotrigine extended-release tablets should be necessary solely based on the use of estrogen-containing oral contraceptives. Therefore, dose escalation should follow the recommended guidelines for initiating adjunctive therapy with lamotrigine extended-release tablets based on the concomitant AED or other concomitant medications (see Table 1). See below for adjustments to maintenance doses of lamotrigine extended-release tablets in women taking estrogen-containing oral contraceptives.

                    Adjustments to the Maintenance Dose of Lamotrigine Extended-Release Tablets in Women Taking Estrogen-Containing Oral Contraceptives:

                     (1) Taking Estrogen-Containing Oral Contraceptives: For women not taking carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin that induce lamotrigine glucuronidation [see Drug Interactions (7), Clinical Pharmacology (12.3)], the maintenance dose of lamotrigine extended-release tablets will in most cases need to be increased by as much as 2-fold over the recommended target maintenance dose in order to maintain a consistent lamotrigine plasma level [see Clinical Pharmacology (12.3)].

                     (2) Starting Estrogen-Containing Oral Contraceptives: In women taking a stable dose of lamotrigine extended-release tablets and not taking carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin that induce lamotrigine glucuronidation [see Drug Interactions (7), Clinical Pharmacology (12.3)], the maintenance dose will in most cases need to be increased by as much as 2-fold in order to maintain a consistent lamotrigine plasma level. The dose increases should begin at the same time that the oral contraceptive is introduced and continue, based on clinical response, no more rapidly than 50 to 100 mg/day every week. Dose increases should not exceed the recommended rate (see Table 1) unless lamotrigine plasma levels or clinical response support larger increases. Gradual transient increases in lamotrigine plasma levels may occur during the week of inactive hormonal preparation (pill-free week), and these increases will be greater if dose increases are made in the days before or during the week of inactive hormonal preparation. Increased lamotrigine plasma levels could result in additional adverse reactions, such as dizziness, ataxia, and diplopia. If adverse reactions attributable to lamotrigine extended-release tablets consistently occur during the pill-free week, dose adjustments to the overall maintenance dose may be necessary. Dose adjustments limited to the pill-free week are not recommended. For women taking lamotrigine extended-release tablets in addition to carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin that induce lamotrigine glucuronidation [see Drug Interactions (7), Clinical Pharmacology (12.3)], no adjustment to the dose of lamotrigine extended-release tablets should be necessary.

                     (3) Stopping Estrogen-Containing Oral Contraceptives: For women not taking carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin that induce lamotrigine glucuronidation [see Drug Interactions (7), Clinical Pharmacology (12.3)], the maintenance dose of lamotrigine extended-release tablets will in most cases need to be decreased by as much as 50% in order to maintain a consistent lamotrigine plasma level. The decrease in dose of lamotrigine extended-release tablets should not exceed 25% of the total daily dose per week over a 2-week period, unless clinical response or lamotrigine plasma levels indicate otherwise [see Clinical Pharmacology (12.3)]. For women taking lamotrigine extended-release tablets in addition to carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin that induce lamotrigine glucuronidation [see Drug Interactions (7), Clinical Pharmacology (12.3)], no adjustment to the dose of lamotrigine extended-release tablets should be necessary.

           Women and Other Hormonal Contraceptive Preparations or Hormone Replacement Therapy: The effect of other hormonal contraceptive preparations or hormone replacement therapy on the pharmacokinetics of lamotrigine has not been systematically evaluated. It has been reported that ethinylestradiol, not progestogens, increased the clearance of lamotrigine up to 2-fold, and the progestin-only pills had no effect on lamotrigine plasma levels. Therefore, adjustments to the dosage of lamotrigine extended-release tablets in the presence of progestogens alone will likely not be needed.

           Patients With Hepatic Impairment: Experience in patients with hepatic impairment is limited. Based on a clinical pharmacology study in 24 patients with mild, moderate, and severe liver impairment [see Use in Specific Populations (8.6), Clinical Pharmacology (12.3)], the following general recommendations can be made. No dosage adjustment is needed in patients with mild liver impairment. Initial, escalation, and maintenance doses should generally be reduced by approximately 25% in patients with moderate and severe liver impairment without ascites and 50% in patients with severe liver impairment with ascites. Escalation and maintenance doses may be adjusted according to clinical response.

           Patients With Renal Impairment: Initial doses of lamotrigine extended-release tablets should be based on patients' concomitant medications (see Table 1); reduced maintenance doses may be effective for patients with significant renal impairment [see Use in Specific Populations (8.7), Clinical Pharmacology (12.3)]. Few patients with severe renal impairment have been evaluated during chronic treatment with immediate-release lamotrigine. Because there is inadequate experience in this population, lamotrigine extended-release tablets should be used with caution in these patients.

           Discontinuation Strategy: For patients receiving lamotrigine extended-release tablets in combination with other AEDs, a re-evaluation of all AEDs in the regimen should be considered if a change in seizure control or an appearance or worsening of adverse reactions is observed.

           If a decision is made to discontinue therapy with lamotrigine extended-release tablets, a step-wise reduction of dose over at least 2 weeks (approximately 50% per week) is recommended unless safety concerns require a more rapid withdrawal [see Warnings and Precautions (5.8)].

           Discontinuing carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin that induce lamotrigine glucuronidation should prolong the half-life of lamotrigine; discontinuing valproate should shorten the half-life of lamotrigine.

  2.2 Adjunctive Therapy for Primary Generalized Tonic-Clonic and Partial Onset Seizures

              This section provides specific dosing recommendations for patients ≥13 years of age. Specific dosing recommendations are provided depending upon concomitant AED or other concomitant medications.

  Table 1. Escalation Regimen for Lamotrigine Extended-Release Tablets in Patients ≥13 Years of Age

  aValproate has been shown to inhibit glucuronidation and decrease the apparent clearance of lamotrigine [see Drug Interactions (7), Clinical Pharmacology (12.3)].
  

  bThese drugs induce lamotrigine glucuronidation and increase clearance [see Drug Interactions (7), Clinical Pharmacology (12.3)]. Other drugs that have similar effects include estrogen-containing oral contraceptives [see Drug Interactions (7), Clinical Pharmacology (12.3)]. Dosing recommendations for oral contraceptives can be found in General Dosing Considerations [see Dosage and Administration (2.1)]. Patients on rifampin, or other drugs that induce lamotrigine glucuronidation and increase clearance, should follow the same dosing titration/maintenance regimen as that used with anticonvulsants that have this effect.
  

  cDose increases at week 8 or later should not exceed 100 mg daily at weekly intervals.
  

  
  For Patients 
  TAKING Valproatea
  For Patients NOT TAKING Carbamazepine,
  Phenytoin,
  Phenobarbital,
  Primidone,b or
  Valproatea
  For Patients TAKING Carbamazepine,
  Phenytoin,
  Phenobarbital, or
  Primidoneb and 
  NOT TAKING Valproatea
  Weeks 1 and 2
  25 mg every other day
  25 mg every day
  50 mg every day
  Weeks 3 and 4
  25 mg every day
  50 mg every day
  100 mg every day
  Week 5
  50 mg every day
  100 mg every day
  200 mg every day
  Week 6
  100 mg every day
  150 mg every day
  300 mg every day
  Week 7
  150 mg every day
  200 mg every day
  400 mg every day
  Maintenance range
  (week 8 and onward)
  200 to 250 mg every dayc
  300 to 400 mg every dayc
  400 to 600 mg every dayc
  2.3 Conversion From Adjuctive Therapy to Monotherapy

  The goal of the transition regimen is to attempt to maintain seizure control while mitigating the risk of serious rash associated with the rapid titration of lamotrigine extended-release tablets.

  The recommended maintenance dosage range of lamotrigine extended-release tablets as monotherapy is 250 to 300 mg given once daily.

  The recommended initial dose and subsequent dose escalations for lamotrigine extended-release tablets should not be exceeded [see Boxed Warning].

  Conversion From Adjunctive Therapy With Carbamazepine, Phenytoin, Phenobarbital, or Primidone to Monotherapy With Lamotrigine Extended-Release Tablets: After achieving a dosage of 500 mg/day of lamotrigine extended-release tablets using the guidelines in Table 1, the concomitant enzyme-inducing AED should be withdrawn by 20% decrements each week over a 4-week period. Two weeks after completion of withdrawal of the enzyme-inducing AED, the dosage of lamotrigine extended-release tablets may be decreased no faster than 100 mg/day each week to achieve the monotherapy maintenance dosage range of 250 to 300 mg/day.

  The regimen for the withdrawal of the concomitant AED is based on experience gained in the controlled monotherapy clinical trial using immediate-release lamotrigine.

  Conversion From Adjunctive Therapy With Valproate to Monotherapy With Lamotrigine Extended-Release Tablets: The conversion regimen involves the 4 steps outlined in Table 2.

  Table 2. Conversion From Adjunctive Therapy With Valproate to Monotherapy With Lamotrigine Extended-Release Tablets in Patients ≥13 Years of Age With Epilepsy
  Lamotrigine extended-release tablets
  Valproate 
  Step 1
  Achieve a dosage of 150 mg/day according to guidelines in Table 1. 
  Maintain established stable dose. 
  Step 2
  Maintain at 150 mg/day1
  Decrease dosage by decrements no greater than 500 mg/day/week to 500 mg/day and then maintain for 1 week. 
  Step 3
  Increase to 200 mg/day. 
  Simultaneously decrease to 250 mg/day and maintain for 1 week. 
  Step 4
  Increase to 250 or 300 mg/day. 
  Discontinue. 
  

  Conversion From Adjunctive Therapy With Antiepileptic Drugs Other Than Carbamazepine, Phenytoin, Phenobarbital, Primidone, or Valproate to Monotherapy With Lamotrigine Extended-Release Tablets: After achieving a dosage of 250 to 300 mg/day of lamotrigine extended-release tablets using the guidelines in Table 1, the concomitant AED should be withdrawn by 20% decrements each week over a 4-week period. No adjustment to the monotherapy dose of lamotrigine extended-release tablets is needed.

  2.4 Conversion From Immediate-Release Lamotrigine Tablets to Lamotrigine Extended-Release Tablets

              Patients may be converted directly from immediate-release lamotrigine to lamotrigine extended-release tablets. The initial dose of lamotrigine extended-release tablets should match the total daily dose of immediate-release lamotrigine. However, some subjects on concomitant enzyme-inducing agents may have lower plasma levels of lamotrigine on conversion and should be monitored [see Clinical Pharmacology (12.3)].

              Following conversion to lamotrigine extended-release tablets, all patients (but especially those on drugs that induce lamotrigine glucuronidation) should be closely monitored for seizure control [see Drug Interactions (7)]. Depending on the therapeutic response after conversion, the total daily dose may need to be adjusted within the recommended dosing instructions (Table 1).

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  • do not take more than directed (see overdose warning)

  adults and children 12 years and over

  • take 2 caplets every 6 hours while symptoms last • do not take more than 6 caplets in 24 hours, unless directed by a doctor • do not use for more than 10 days unless directed by a doctor

  children under 12 years

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  2.1 General Dosing Considerations

  There are suggestions, yet to be proven, that the risk of severe, potentially life-threatening rash may be increased by (1) coadministration of lamotrigine tablets with valproate, (2) exceeding the recommended initial dose of lamotrigine tablets, or (3) exceeding the recommended dose escalation for lamotrigine tablets. However, cases have occurred in the absence of these factors Therefore, it is important that the dosing recommendations be followed closely. Rash:[see ]. Boxed Warning

  The risk of nonserious rash may be increased when the recommended initial dose and/or the rate of dose escalation of lamotrigine tablet is exceeded and in patients with a history of allergy or rash to other AEDs.

  It is recommended that lamotrigine tablets not be restarted in patients who discontinued due to rash associated with prior treatment with lamotrigine, unless the potential benefits clearly outweigh the risks. If the decision is made to restart a patient who has discontinued lamotrigine, the need to restart with the initial dosing recommendations should be assessed. The greater the interval of time since the previous dose, the greater consideration should be given to restarting with the initial dosing recommendations. If a patient has discontinued lamotrigine for a period of more than 5 half-lives, it is recommended that initial dosing recommendations and guidelines be followed. The half-life of lamotrigine is affected by other concomitant medications [see ]. Clinical Pharmacology (12.3)

  Drugs other than those listed in the Clinical Pharmacology section have not been systematically evaluated in combination with lamotrigine. Because lamotrigine is metabolized predominantly by glucuronic acid conjugation, drugs that are known to induce or inhibit glucuronidation may affect the apparent clearance of lamotrigine and doses of lamotrigine tablets may require adjustment based on clinical response. Lamotrigine Tablets Added to Drugs Known to Induce or Inhibit Glucuronidation:[see ] Clinical Pharmacology (12.3)

  A therapeutic plasma concentration range has not been established for lamotrigine. Dosing of lamotrigine tablets should be based on therapeutic response Target Plasma Levels for Patients With Epilepsy or Bipolar Disorder:[see ]. Clinical Pharmacology (12.3)

  Although estrogen-containing oral contraceptives have been shown to increase the clearance of lamotrigine no adjustments to the recommended dose-escalation guidelines for lamotrigine tablets should be necessary solely based on the use of estrogen-containing oral contraceptives. Therefore, dose escalation should follow the recommended guidelines for initiating adjunctive therapy with lamotrigine tablets based on the concomitant AED or other concomitant medications (see Table 1 or Table 5). See below for adjustments to maintenance doses of lamotrigine tablets in women taking estrogen-containing oral contraceptives. Women Taking Estrogen-Containing Oral Contraceptives:Starting Lamotrigine Tablets  in Women Taking Estrogen-Containing Oral Contraceptives:[see ], Clinical Pharmacology (12.3)

  Adjustments to the Maintenance Dose of Lamotrigine Tablets In Women Taking Estrogen-Containing Oral Contraceptives:

  For women not taking carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin that induce lamotrigine glucuronidation the maintenance dose of lamotrigine  tablets will in most cases need to be increased, by as much as 2-fold over the recommended target maintenance dose, in order to maintain a consistent lamotrigine plasma level (1) Taking Estrogen-Containing Oral Contraceptives:[see , ], Drug Interactions (7)Clinical Pharmacology (12.3)[see ]. Clinical Pharmacology (12.3)

  In women taking a stable dose of lamotrigine tablets and not taking carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin that induce lamotrigine glucuronidation the maintenance dose will in most cases need to be increased by as much as 2-fold in order to maintain a consistent lamotrigine plasma level. The dose increases should begin at the same time that the oral contraceptive is introduced and continue, based on clinical response, no more rapidly than 50 to 100 mg/day every week. Dose increases should not exceed the recommended rate (see Table 1 or Table 5) unless lamotrigine plasma levels or clinical response support larger increases. Gradual transient increases in lamotrigine plasma levels may occur during the week of inactive hormonal preparation ("pill-free" week), and these increases will be greater if dose increases are made in the days before or during the week of inactive hormonal preparation. Increased lamotrigine plasma levels could result in additional adverse reactions, such as dizziness, ataxia, and diplopia. If adverse reactions attributable to lamotrigine tablets consistently occur during the "pill-free" week, dose adjustments to the overall maintenance dose may be necessary. Dose adjustments limited to the "pill-free" week are not recommended. For women taking lamotrigine tablets in addition to carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin that induce lamotrigine glucuronidation no adjustment to the dose of lamotrigine tablets should be necessary. (2) Starting Estrogen-Containing Oral Contraceptives:[see , ], Drug Interactions (7)Clinical Pharmacology (12.3)[see , ], Drug Interactions (7)Clinical Pharmacology (12.3)

  For women not taking carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin that induce lamotrigine glucuronidation the maintenance dose of lamotrigine tablets will in most cases need to be decreased by as much as 50% in order to maintain a consistent lamotrigine plasma level. The decrease in dose of lamotrigine tablets should not exceed 25% of the total daily dose per week over a 2-week period, unless clinical response or lamotrigine plasma levels indicate otherwise For women taking lamotrigine tablets in addition to carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin that induce lamotrigine glucuronidation no adjustment to the dose of lamotrigine tablets should be necessary. (3) Stopping Estrogen-Containing Oral Contraceptives:[see , ], Drug Interactions (7)Clinical Pharmacology (12.3)[see ]. Clinical Pharmacology (12.3)[see , ], Drug Interactions (7)Clinical Pharmacology (12.3)

  The effect of other hormonal contraceptive preparations or hormone replacement therapy on the pharmacokinetics of lamotrigine has not been systematically evaluated. It has been reported that ethinylestradiol, not progestogens, increased the clearance of lamotrigine up to 2-fold, and the progestin-only pills had no effect on lamotrigine plasma levels. Therefore, adjustments to the dosage of lamotrigine tablets in the presence of progestogens alone will likely not be needed. Women and Other Hormonal Contraceptive Preparations or Hormone Replacement Therapy:

  Experience in patients with hepatic impairment is limited. Based on a clinical pharmacology study in 24 patients with mild, moderate, and severe liver impairment the following general recommendations can be made. No dosage adjustment is needed in patients with mild liver impairment. Initial, escalation, and maintenance doses should generally be reduced by approximately 25% in patients with moderate and severe liver impairment without ascites and 50% in patients with severe liver impairment with ascites. Escalation and maintenance doses may be adjusted according to clinical response. Patients With Hepatic Impairment:[see , ], Use in Specific Populations (8.6)Clinical Pharmacology (12.3)

  Initial doses of lamotrigine tablets should be based on patients' concomitant medications (see Tables 1-3 or Table 5); reduced maintenance doses may be effective for patients with significant renal impairment Few patients with severe renal impairment have been evaluated during chronic treatment with lamotrigine tablets. Because there is inadequate experience in this population, lamotrigine tablets should be used with caution in these patients. Patients With Renal Impairment:[see , ]. Use in Specific Populations (8.7)Clinical Pharmacology (12.3)

  Discontinuation Strategy:

  For patients receiving lamotrigine tablets in combination with other AEDs, a reevaluation of all AEDs in the regimen should be considered if a change in seizure control or an appearance or worsening of adverse reactions is observed. Epilepsy:

  If a decision is made to discontinue therapy with lamotrigine tablets, a step-wise reduction of dose over at least 2 weeks (approximately 50% per week) is recommended unless safety concerns require a more rapid withdrawal [see ]. Warnings and Precautions (5.9)

  Discontinuing carbamazepine, phenytoin, phenobarbital, primidone or other drugs such as rifampin that induce lamotrigine glucuronidation should prolong the half-life of lamotrigine; discontinuing valproate should shorten the half-life of lamotrigine.

  In the controlled clinical trials, there was no increase in the incidence, type, or severity of adverse reactions following abrupt termination of lamotrigine tablets. In clinical trials in patients with Bipolar Disorder, 2 patients experienced seizures shortly after abrupt withdrawal of lamotrigine tablets. However, there were confounding factors that may have contributed to the occurrence of seizures in these bipolar patients. Discontinuation of lamotrigine tablets should involve a step-wise reduction of dose over at least 2 weeks (approximately 50% per week) unless safety concerns require a more rapid withdrawal Bipolar Disorder:[see ]. Warnings and Precautions (5.9)

  2.2 Epilepsy – Adjunctive Therapy

  This section provides specific dosing recommendations for patients greater than 12 years of age and patients 2 to 12 years of age. Within each of these age-groups, specific dosing recommendations are provided depending upon concomitant AED or other concomitant medications (Table 1 for patients greater than 12 years of age and Table 2 for patients 2 to 12 years of age). A weight-based dosing guide for patients 2 to 12 years of age on concomitant valproate is provided in Table 3.

  Recommended dosing guidelines are summarized in Table 1. Patients Over 12 Years of Age:

  Table 1. Escalation Regimen for Lamotrigine Tablets in Patients Over 12 Years of Age With Epilepsy

  a Valproate has been shown to inhibit glucuronidation and decrease the apparent clearance of lamotrigine [see  , ]. Drug Interactions (7)Clinical Pharmacology (12.3)

  b These drugs induce lamotrigine glucuronidation and increase clearance [see  , ]. Other drugs that have similar effects include estrogen-containing oral contraceptives [see , ]. Dosing recommendations for oral contraceptives can be found in General Dosing Considerations [see ]. Patients on rifampin, or other drugs that induce lamotrigine glucuronidation and increase clearance, should follow the same dosing titration/maintenance regimen as that used with anticonvulsants that have this effect. Drug Interactions (7)Clinical Pharmacology (12.3)Drug Interactions (7)Clinical Pharmacology (12.3)Dosage and Administration (2.1)

  
  For 
  For Patients NOT TAKING 
  For Patients 
  
  Patients
  Carbamazepine, 
  TAKING
  
  TAKING
  Phenytoin,
  Carbamazepine,
  
  Valproate a
  Phenobarbital,
  Phenytoin, 
  
  
  or Primidone b,  
  Phenobarbital,
  
  
  or Valproate a
  or Primidone b
  
  
  
  and NOT TAKING
  
  
  
  Valproate a
  Weeks 1 and 2
  25 mg every other day
  25 mg every day
  50 mg/day
  Weeks 3 and 4
  25 mg every day
  50 mg/day
  (in 2 divided doses) 100 mg/day
  
  Weeks 5 onwards to  maintenance
  
  Increase by 25 to  50 mg/day every 1 to 2 weeks
  
  Increase by 50 mg/day every 1 to 2 weeks
  
  
  Increase by  100 mg/day every  1 to 2 weeks.
  
  
  Usual maintenance  dose
  
  100 to 200 mg/day
  with valproate alone
  (in 2 divided doses). 225 to 375 mg/day
  
  (in 2 divided doses). 300 to 500 mg/day
  
  
  100 to 400 mg/day
  with valproate
  and other drugs that induce glucuronidation
  
  
  
  (in 1 or 2 divided doses)
  
  
  

  Recommended dosing guidelines are summarized in Table 2. Patients 2 to 12 Years Of Age:

  Smaller starting doses and slower dose escalations than those used in clinical trials are recommended because of the suggestion that the risk of rash may be decreased by smaller starting doses and slower dose escalations. Therefore, maintenance doses will take longer to reach in clinical practice than in clinical trials. It may take several weeks to months to achieve an individualized maintenance dose. Maintenance doses in patients weighing less than 30 kg, regardless of age or concomitant AED, may need to be increased as much as 50%, based on clinical response.

  Table 2. Escalation Regimen for Lamotrigine Tablets in Patients 2 to 12 Years of Age With Epilepsy

  Note:Onlywholetabletsshouldbeusedfordosing.

  a Valproate has been shown to inhibit glucuronidation and decrease the apparent clearance of lamotrigine [see  , ]. Drug Interactions (7)Clinical Pharmacology (12.3)

  b These drugs induce lamotrigine glucuronidation and increase clearance [see  , ]. Other drugs which have similar effects include estrogen-containing oral contraceptives [see , ]. Dosing recommendations for oral contraceptives can be found in General Dosing Considerations [see ]. Patients on rifampin, or other drugs that induce lamotrigine glucuronidation and increase clearance, should follow the same dosing titration/maintenance regimen as that used with anticonvulsants that have this effect. Drug Interactions (7)Clinical Pharmacology (12.3)Drug Interactions (7)Clinical Pharmacology (12.3)Dosage and Administration (2.1)

  
  For Patients TAKING 
  Valproate a
  For Patients NOT 
  TAKING Carbamazepine, Phenytoin, 
  Phenobarbital, Primidone b, or 
  Valproate a
  For Patients TAKING 
  Carbamazepine, Phenytoin, Phenobarbital, or 
  Primidone   band NOT 
  TAKING Valproate a
  Weeks 1 and 2
  in 1 or 2 divided doses, rounded down to the  nearest whole tablet (see Table 3 for weight  based dosing guide). 0.15 mg/kg/day
  
  
  
  in 1 or 2 divided doses, rounded down to the  nearest whole tablet. 0.3 mg/kg/day
  
  
  in 2 divided doses, rounded down to the  nearest whole tablet. 0.6 mg/kg/day
  
  
  Weeks 3 and 4
  in 1 or 2 divided doses, rounded down to the  nearest whole tablet  (see Table 3 for weight  based dosing guide). 0.3 mg/kg/day
  
  
  
  
  
  in 2 divided doses, rounded down to the  nearest whole tablet. 0.6 mg/kg/day
  
  
  
  in 2 divided doses,  rounded down to the  nearest whole tablet. 1.2 mg/kg/day
  
  
  
  Weeks 5  onwards to  maintenance
  
  
  The dose should be increased every  1 to 2 weeks as follows: calculate 0.3 mg/kg/day, round this amount  down to the nearest whole tablet, and  add this amount to the  previously administered daily dose.
  
  
  
  
  
  The dose should be increased every  1 to 2 weeks as follows: calculate 0.6 mg/kg/day, round this amount  down to the nearest whole tablet, and  add this amount to the  previously administered daily dose
  
  
  
  
  
  The dose should be increased every  1 to 2 weeks as follows: calculate 1.2 mg/kg/day, round this amount  down to the nearest whole tablet, and  add this amount to the  previously administered daily dose
  
  
  
  
  
  Usual  Maintenance  Dose
  
  
  (maximum 200 mg/day  in 1 or 2 divided doses). with valproate alone 1 to 5 mg/kg/day
  
  
  1 to 3 mg/kg/day 
  (maximum 300 mg/day  in 2 divided doses) 4.5 to 7.5 mg/kg/day
  
  
  (maximum 400 mg/day  in 2 divided doses) 5 to 15 mg/kg/day
  
  
  Maintenance dose in  patients  less than 30 kg
  
  
  May need to be increased  by as much as 50%,  based on clinical response
  
  
  May need to be increased  by as much as 50%,  based on clinical response
  
  
  May need to be increased  by as much as 50%, based  on clinical response
  
  
  Table 3. The Initial Weight-Based Dosing Guide for Patients 2 to 12 Years Taking Valproate (Weeks 1 to 4) With Epilepsy If the patient’s weight is
  Give this daily dose, using the most appropriate combination of Lamotrigine 2-mg and 5-mg tablets
  Greater than
  And less than
  Weeks 1 and 2
  Weeks 3 and 4
  6.7 kg
  14 kg
  2 mg every  day other 
  2 mg every day
  14.1 kg
  27 kg
  2 mg every day
  4 mg every day
  27.1 kg
  34 kg
  4 mg every day
  8 mg every day
  34.1 kg
  40 kg
  5 mg every day
  10 mg every day
  

  The usual maintenance doses identified in Tables 1 and 2 are derived from dosing regimens employed in the placebo-controlled adjunctive studies in which the efficacy of lamotrigine tablets was established. In patients receiving multidrug regimens employing carbamazepine, phenytoin, phenobarbital, or primidone , maintenance doses of adjunctive lamotrigine tablets as high as 700 mg/day have been used. In patients receiving , maintenance doses of adjunctive lamotrigine tablets as high as 200 mg/day have been used. The advantage of using doses above those recommended in Tables 1 through 4 has not been established in controlled trials. Usual Adjunctive Maintenance Dose for Epilepsy:without valproatevalproate alone

  2.3 Epilepsy – Conversion From Adjunctive Therapy to Monotherapy

  The goal of the transition regimen is to effect the conversion to monotherapy with lamotrigine tablets under conditions that ensure adequate seizure control while mitigating the risk of serious rash associated with the rapid titration of lamotrigine tablets.

  The recommended maintenance dose of lamotrigine tablets as monotherapy is 500 mg/day given in two divided doses.

  To avoid an increased risk of rash, the recommended initial dose and subsequent dose escalations of lamotrigine tablets should not be exceeded [see ]. Boxed Warning

  After achieving a dose of 500 mg/day of lamotrigine tablets according to the guidelines in Table 1, the concomitant AED should be withdrawn by 20% decrements each week over a 4-week period. The regimen for the withdrawal of the concomitant AED is based on experience gained in the controlled monotherapy clinical trial. Conversion From Adjunctive Therapy With Carbamazepine, Phenytoin, Phenobarbital, or Primidone to Monotherapy With Lamotrigine Tablets:

  Conversion from Adjunctive Therapy With Valproate to Monotherapy With Lamotrigine Tablets:

  The conversion regimen involves 4 steps outlined in Table 4.

  Table 4. Conversion From Adjunctive Therapy With Valproate to Monotherapy With Lamotrigine Tablets in Patients ≥16 Years of Age with Epilepsy
  Lamotrigine Tablets
  Valproate
  Step 1
  Achieve a dose of 200 mg/day according to guidelines in Table 1 (if not already on 200 mg/day).
  
  
  Maintain previous stable dose.
  Step 2
  Maintain at 200 mg/day.
  Decrease to 500 mg/day by decrements no greater than 500 mg/day/week and then maintain the dose of 500 mg/day for 1 week.
  
  
  Step 3
  Increase to 300 mg/day and maintain for 1 week.
  Simultaneously decrease to 250 mg/day and maintain for 1 week.
  
  Step 4
  Increase by 100 mg/day every week to achieve maintenance dose of 500 mg/day.
  
  Discontinue.
  

  No specific dosing guidelines can be provided for conversion to monotherapy with lamotrigine tablets with AEDs other than carbamazepine, phenobarbital, phenytoin, primidone, or valproate. Conversion from Adjunctive Therapy With AEDs Other Than Carbamazepine, Phenytoin, Phenobarbital, Primidone, or Valproate to Monotherapy With Lamotrigine Tablets:

  2.4 Bipolar Disorder

  The goal of maintenance treatment with lamotrigine tablets is to delay the time to occurrence of mood episodes (depression, mania, hypomania, mixed episodes) in patients treated for acute mood episodes with standard therapy. The target dose of lamotrigine tablets is 200 mg/day (100 mg/day in patients taking valproate, which decreases the apparent clearance of lamotrigine, and 400 mg/day in patients not taking valproate and taking either carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin that increase the apparent clearance of lamotrigine). In the clinical trials, doses up to 400 mg/day as monotherapy were evaluated; however, no additional benefit was seen at 400 mg/day compared with 200 mg/day Accordingly, doses above 200 mg/day are not recommended. Treatment with lamotrigine tablets is introduced, based on concurrent medications, according to the regimen outlined in Table 5. If other psychotropic medications are withdrawn following stabilization, the dose of lamotrigine tablets should be adjusted. For patients discontinuing valproate, the dose of lamotrigine tablets should be doubled over a 2-week period in equal weekly increments (see Table 6). For patients discontinuing carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin that induce lamotrigine glucuronidation, the dose of lamotrigine tablets should remain constant for the first week and then should be decreased by half over a 2-week period in equal weekly decrements (see Table 6). The dose of lamotrigine tablets may then be further adjusted to the target dose (200 mg) as clinically indicated. [see ]. Clinical Studies (14.2)

  If other drugs are subsequently introduced, the dose of lamotrigine tablets may need to be adjusted. In particular, the introduction of valproate requires reduction in the dose of lamotrigine tablets [see , ]. Drug Interactions (7)Clinical Pharmacology (12.3)

  To avoid an increased risk of rash, the recommended initial dose and subsequent dose escalations of lamotrigine tablets should not be exceeded [see ]. Boxed Warning

  Table 5. Escalation Regimen for Lamotrigine Tablets for Patients With Bipolar Disorder

  a Valproate has been shown to inhibit glucuronidation and decrease the apparent clearance of lamotrigine [see  , ]. Drug Interactions (7)Clinical Pharmacology (12.3)

  
  

  b These drugs induce lamotrigine glucuronidation and increase clearance [see  , ]. Other drugs which have similar effects include estrogen-containing oral contraceptives [see , ]. Dosing recommendations for oral contraceptives can be found in General Dosing Considerations [see ]. Patients on rifampin, or other drugs that induce lamotrigine glucuronidation and increase clearance, should follow the same dosing titration/maintenance regimen as that used with anticonvulsants that have this effect. Drug Interactions (7)Clinical Pharmacology (12.3)Drug Interactions (7)Clinical Pharmacology (12.3)Dosage and Administration (2.1)

  
  For Patients TAKING 
  Valproate a
  For Patients NOT TAKING 
  Carbamazepine, Phenytoin, Phenobarbital, 
  Primidone b, or Valproate a
  For Patients TAKING 
  Carbamazepine, Phenytoin,
  Phenobarbital, or Primidone b and NOT TAKING 
  Valproate a
  Weeks 1 and 2
  25 mg every  day
  other 
  25 mg daily
  50 mg daily
  Weeks 3 and 4
  25 mg daily
  50 mg daily
  100 mg daily, in divided doses
  Week 5
  50 mg daily
  100 mg daily
  200 mg daily, in divided doses
  Week 6
  100 mg daily
  200 mg daily
  300 mg daily, in divided doses
  Week 7
  100 mg daily
  200 mg daily
  up to 400 mg daily, in divided doses
  Table 6. Dosage Adjustments to Lamotrigine Tablets for Patients With Bipolar Disorder Following Discontinuation of Psychotropic Medications
  Discontinuation of Psychotropic Drugs 
  (excluding Carbamazepine, Phenytoin, 
  Phenobarbital, Primidone b, or 
  Valproate a)
  After Discontinuation of 
  Valproate a
  After Discontinuation of 
  Carbamazepine, Phenytoin, 
  Phenobarbital, or Primidone b
  
  
  Current dose of lamotrigine tablets
  (mg/day)
  100
  Current dose of lamotrigine tablets
  (mg/day)
  400
  

  a Valproate has been shown to inhibit glucuronidation and decrease the apparent clearance of lamotrigine [see  , ]. Drug Interactions (7)Clinical Pharmacology (12.3)

  
  

  b These drugs induce lamotrigine glucuronidation and increase clearance [see  , ]. Other drugs which have similar effects include estrogen-containing oral contraceptives [see , ]. Dosing recommendations for oral contraceptives can be found in General Dosing Considerations [see ]. Patients on rifampin, or other drugs that induce lamotrigine glucuronidation and increase clearance, should follow the same dosing titration/maintenance regimen as that used with anticonvulsants that have this effect. Drug Interactions (7)Clinical Pharmacology (12.3)Drug Interactions (7)Clinical Pharmacology (12.3)Dosage and Administration (2.1)

  Week 1
  Maintain current dose of lamotrigine tablets
  150
  400
  Week 2
  Maintain current dose of lamotrigine tablets
  200
  300
  Week 3 onward
  Maintain current dose of lamotrigine tablets
  200
  200
  

  The benefit of continuing treatment in patients who had been stabilized in an 8- to 16-week open-label phase with lamotrigine tablets was established in two randomized, placebo-controlled clinical maintenance trials However, the optimal duration of treatment with lamotrigine tablets has not been established. Thus, patients should be periodically reassessed to determine the need for maintenance treatment. [see ]. Clinical Studies (14.2)

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  The volume and concentration of OMNIPAQUE 300 to be administered will depend on the degree and extent of contrast required in the area(s) under examination and on the equipment and technique employed.

  OMNIPAQUE 300 at a concentration of 300 mgI/mL is recommended for the examination of the lumbar, thoracic, and cervical regions in adults by lumbar or direct cervical injection and is slightly hypertonic to CSF.

  A total dose of 3060 mg iodine or a concentration of 300 mgI/mL should not be exceeded in adults in a single myelographic examination. This is based on clinical trial evaluation to date. As in all diagnostic procedures, the minimum volume and dose to produce adequate visualization should be used. Most procedures do not require either maximum dose or concentration.

  Anesthesia is not necessary. Premedication sedatives or tranquilizers are usually not needed (see PRECAUTIONS). Patients should be well hydrated prior to and following contrast administration.

  Seizure-prone patients should be maintained on anticonvulsant medication.

  Many radiopaque contrast agents are incompatible in vitro with some antihistamines and many other drugs; therefore, concurrent drugs should not be physically admixed with contrast agents.

  Rate of Injection

  To avoid excessive mixing with CSF and consequent dilution of contrast, injection should be made slowly over 1 to 2 minutes.

  Depending on the estimated volume of contrast medium which may be required for the procedure a small amount of CSF may be removed to minimize distention of the subarachnoid spaces.

  The lumbar or cervical puncture needle may be removed immediately following injection since it is not necessary to remove OMNIPAQUE after injection into the subarachnoid space.

  Adults

  The usual recommended total doses for use in lumbar, thoracic, cervical, and total columnar myelography in adults are 1.2 gI to 3.0 gI as follows:

  Procedure Formulations Concentration
  (mgI/mL) Volume
  (mL) Dose
  (gI) Thoracic Myelography (via lumbar injection) OMNIPAQUE 300 300 6-10 1.8-3.0 Cervical Myelography (via lumbar injection) OMNIPAQUE 300 300 6-10 1.8-3.0 Cervical Myelography (via C1-2 injection OMNIPAQUE 300 300 4-10 1.2-3.0 Total Columnar Myelography (via lumbar injection OMNIPAQUE 300 300 6-10 1.8-3.0

  Refer to DIRECTIONS FOR PROPER USE OF OMNIPAQUE PHARMACY BULK PACKAGE section for instructions.

  Parenteral products should be inspected visually for particulate matter or discoloration prior to administration. If particulate matter or discoloration is present, do not use.

  Repeat Procedures

  If in the clinical judgment of the physician sequential or repeat examinations are required, a suitable interval of time between administrations should be observed to allow for normal clearance of the drug from the body. An interval of at least 48 hours should be allowed before repeat examination; however, whenever possible, 5 to 7 days is recommended.

  As with all radiopaque contrast agents, the lowest dose of OMNIPAQUE necessary to obtain adequate visualization should be used. A lower dose may reduce the possibility of an adverse reaction. Most procedures do not require use of either the maximum volume or the highest concentration of OMNIPAQUE. The combination of volume and concentration of OMNIPAQUE to be used should be carefully individualized accounting for factors such as age, body weight, size of the vessel and the rate of blood flow within the vessel. Other factors such as anticipated pathology, degree and extent of opacification required, structure(s) or area to be examined, disease processes affecting the patient, and equipment and technique to be employed should be considered.

  Sterile technique must be used in all vascular injections involving contrast media.

  Refer to DIRECTIONS FOR PROPER USE OF OMNIPAQUE PHARMACY BULK PACKAGE section for instructions.

  If nondisposable equipment is used, scrupulous care should be taken to prevent residual contamination with traces of cleansing agents.

  It may be desirable that solutions of radiopaque diagnostic agents be used at body temperature when injected.

  Parenteral products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit. Solutions of OMNIPAQUE should be used only if clear and within the normal colorless to pale yellow range. If particulate matter or discoloration is present, do not use.

  Dosage and Administration

  The individual dose or volume is determined by the size of the structure to be visualized, the anticipated degree of hemodilution, and valvular competence. Weight is a minor consideration in adults, but must be considered in infants and young children. The volume of each individual injection is a more important consideration than the total dosage used. When large individual volumes are administered, as in ventriculography and aortography, it has been suggested that several minutes be permitted to elapse between each injection to allow for subsidence of possible hemodynamic disturbances.

  The recommended single injection volume of OMNIPAQUE 350 for angiocardiographic procedures in adults and the recommended single injection volumes of OMNIPAQUE 350 and OMNIPAQUE 300 for angiographic procedures in children are as follows:

  Ventriculography Adults

  The usual adult volume for a single injection is 40 mL with a range of 30 mL to 60 mL. This may be repeated as necessary. When combined with selective coronary arteriography, the total administered volume should not exceed 250 mL (87.5 gI).

  Pediatrics

  The usual single injection dose of OMNIPAQUE 350 is 1.25 mL/kg of body weight with a range of 1.0 mL/kg to 1.5 mL/kg. For OMNIPAQUE 300 the usual single injection dose is 1.75 mL/kg with a range of 1.5 mL/kg to 2.0 mL/kg. When multiple injections are given, the total administered dose should not exceed 5 mL/kg up to a total volume of 250 mL of OMNIPAQUE 350 or up to a total volume of 291 mL of OMNIPAQUE 300.

  Selective Coronary Arteriography

  The usual adult volume for right or left coronary arteriography is 5 mL (range 3 mL to 14 mL) per injection.

  Aortic Root and Arch Study When Used Alone

  The usual adult single injection volume is 50 mL, with a range of 20 mL to 75 mL.

  Pulmonary Angiography Pediatrics

  The usual single injection dose is 1.0 mL/kg of OMNIPAQUE 350.

  Combined Angiocardiographic Procedures Multiple Procedures Adults

  The visualization of multiple vascular systems and target organs is possible during a single radiographic examination of the patient.

  Large doses of OMNIPAQUE 350 were well tolerated in angiographic procedures requiring multiple injections.

  The maximum total volume for multiple procedures should not exceed 250 mL of 350 mgI/mL (87.5 gI).

  Pediatrics

  Visualization of multiple vascular systems and target organs is possible during a single radiographic examination of the patient.

  The maximum total dose for multiple injection procedures should not exceed 5.0 mL/kg up to a total volume of 250 mL of OMNIPAQUE 350 or 6.0 mL/kg up to a total volume of 291 mL of OMNIPAQUE 300.

  Dosage and Administration Adults

  The usual adult volume as a single injection is 50 mL to 80 mL for the aorta, 30 mL to 60 mL for major branches including celiac and mesenteric arteries, and 5 mL to 15 mL for renal arteries. Repeated injections may be performed if indicated, but the total volume should not exceed 291 mL of OMNIPAQUE 300 or 250 mL of OMNIPAQUE 350 (87.5 gI).

  Pediatrics

  The usual single injection dose is 1.0 mL/kg of OMNIPAQUE 350 and should not exceed 5.0 mL/kg up to a total volume of 250 mL of OMNIPAQUE 350.

  Dosage and Administration

  OMNIPAQUE 300 is recommended for cerebral arteriography at the following volumes: common carotid artery (6 mL to 12 mL), internal carotid artery (8 mL to 10 mL), external carotid artery (6 mL to 9 mL), and vertebral artery (6 mL to 10 mL).

  Dosage and Administration

  The concentration and volume required will depend on the equipment and imaging technique used.

  Dosage and Administration

  The usual injection volume of OMNIPAQUE 350 for the intravenous digital technique is 30 mL to 50 mL of a 350 mgI/mL solution. This is administered as a bolus at 7.5 to 30 mL/second using a pressure injector. The volume and rate of injection will depend primarily on the type of equipment and technique used.

  Frequently three or more injections may be required, up to a total volume not to exceed 250 mL (87.5 gI).

  Dosage and Administration

  The volume required will depend on the size, flow rate, and disease state of the injected vessel and on the size and condition of the patient, as well as the imaging technique used.

  The dosage recommended for use in peripheral angiography is as follows:

  Aortofemoral runoffs: 20 mL to 70 mL of OMNIPAQUE 350 (350 mgI/mL)
  30 mL to 90 mL of OMNIPAQUE 300 (300 mgI/mL) Selective arteriograms: (femoral/iliac) 10 mL to 30 mL of OMNIPAQUE 350 (350 mgI/mL)
  10 mL to 60 mL of OMNIPAQUE 300 (300 mgI/mL) Venography (per leg): 40 mL to 100 mL of OMNIPAQUE 300 (300 mgI/mL) Dosage and Administration Adults

  OMNIPAQUE 300 and OMNIPAQUE 350 at dosages from 200 mgI/kg body weight to 350 mgI/kg body weight have produced diagnostic opacification of the excretory system in patients with normal renal function.

  See SECTION II, DOSAGE AND ADMINISTRATION—General.

  Dosage and Administration Adults

  The recommended dosage of undiluted OMNIPAQUE 350 at a concentration of 350 mgI/mL for oral pass-thru examination of the gastrointestinal tract in adults is 50 mL to 100 mL depending on the nature of the examination and the size of the patient.

  The recommended oral dosage of OMNIPAQUE diluted to concentrations of 6 mgI/mL to 9 mgI/mL for contrast enhanced computed tomography of the abdomen in adults is 500 mL to 1000 mL. Smaller administered volumes are needed as the concentration of the final solution is increased (see Table below). In conjunction with dilute oral administration, the recommended dosage of OMNIPAQUE 300 administered intravenously is 100 mL to 150 mL. The oral dose is administered about 20 to 40 minutes prior to the intravenous dose and image acquisition.

  Children

  The dosage of undiluted OMNIPAQUE 300 at a concentration of 300 mgI/mL, is dependent on the nature of the examination and the size of the patient. Based on clinical experience, it is recommended that OMNIPAQUE 180 (available in single use vials), be used in children less than 3 months of age. OMNIPAQUE 300 may be used in children 3 months of age and older. The following dosage guidelines are recommended:

  Age Volume of OMNIPAQUE Less than 3 months 5 — 30 mL Three months to 3 years Up to 60 mL Four years to 10 years Up to 80 mL Greater than 10 years Up to 100 mL

  When given rectally, larger volumes may be used.

  The recommended oral dosage of OMNIPAQUE diluted to concentrations of 9 mgI/mL to 21 mgI/mL for contrast enhanced computed tomography of the abdomen in children is 180 mL to 750 mL. Smaller administered volumes are needed as the concentration of the final solution is increased (see Table below). The total oral dose in grams of iodine should generally not exceed 5 gI for children under 3 years of age and 10 gI for children from 3 to 18 years of age. The oral dosage may be given all at once or over a period of 30 to 45 minutes if there is difficulty in consuming the required volume.

  In conjunction with dilute oral administration the recommended dosage of OMNIPAQUE 300 is 2.0 mL/kg when administered intravenously with a range of 1.0 mL/kg to 2.0 mL/kg. Dosage for infants and children should be administered in proportion to age and body weight. The total intravenously administered dose should not exceed 3 mL/kg. The oral dose is administered about 30 to 60 minutes prior to the intravenous dose and image acquisition.

  OMNIPAQUE may be diluted with water or beverage as follows:

  To Achieve Add To One Liter of Contrast Medium at A Final Concentration
  (mgI/mL) of Stock Concentration of OMNIPAQUE
  (mgI/mL) Volume
  (mL) Water, Carbonated Beverage, Milk, or Juice
  (mL) 6 300 20 980 350 17 983 9 300 30 970 350 26 974 12 300 40 960 350 35 965 15 300 50 950 350 43 957 18 300 60 940 350 52 948 21 300 70 930 350 60 940

  Dilutions of OMNIPAQUE should be prepared just prior to use and any unused portion discarded after the procedure.

  Dosage and Administration

  OMNIPAQUE may be diluted, utilizing aseptic technique, with Sterile Water for Injection to a concentration of 50 mgI/mL to 100 mgI/mL for voiding cystourethrography. The concentration may vary depending upon the patient's size and age and also with the technique and equipment used. Sufficient volume of contrast medium should be administered to adequately fill the bladder. The usual volume ranges from 50 mL to 300 mL of OMNIPAQUE at a concentration of 100 mgI/mL and 50 mL to 600 mL of OMNIPAQUE at a concentration of 50 mgI/mL.

  OMNIPAQUE may be diluted with Sterile Water for Injection as indicated in the table below:

  To Achieve Add To A Final Concentration Each 100 mL of OMNIPAQUE Sterile Water for Injection, USP (mL) (mgI/mL) OMNIPAQUE 300 OMNIPAQUE 350 100 200 250 90 233 289 80 275 338 70 330 400 60 400 483 50 500 600

  Dilutions of OMNIPAQUE should be prepared just prior to use and any unused portion discarded after the procedure.

  Dosage and Administration

  Arthrography is usually performed under local anesthesia. The amount of OMNIPAQUE injected is dependent on the size of the joint to be examined and the technique employed. Lower volumes of contrast medium are usually injected for knee and shoulder arthrography when double-contrast examinations using 15 mL to 100 mL of air are performed.

  The following concentrations and volumes are recommended for normal adult knee, shoulder, and temporomandibular joints but should serve as guidelines since joints may require more or less contrast medium for optimal visualization.

  KNEE Lower volumes recommended for double-contrast examinations; higher volumes recommended for single-contrast examinations. OMNIPAQUE 300 5 mL to 15 mL OMNIPAQUE 350 5 mL to 10 mL SHOULDER OMNIPAQUE 300 10 mL TEMPOROMANDIBULAR OMNIPAQUE 300 0.5 mL to 1.0 mL

  Passive or active manipulation is used to disperse the medium throughout the joint space.

  Dosage and Administration

  The recommended dosage of OMNIPAQUE 300 is 15 mL to 20 mL but will vary depending on individual anatomy and/or disease state.

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  Lamotrigine | Northstar Rxllc

  

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  2.1. General Dosing Considerations

  Rash
  There are suggestions, yet to be proven, that the risk of severe, potentially life-threatening rash may be increased by (1) coadministration of lamotrigine tablets with valproate, (2) exceeding the recommended initial dose of lamotrigine tablets, or (3) exceeding the recommended dose escalation for lamotrigine tablets. However, cases have occurred in the absence of these factors [see Boxed Warning]. Therefore, it is important that the dosing recommendations be followed closely.

  
  

  The risk of nonserious rash may be increased when the recommended initial dose and/or the rate of dose escalation for lamotrigine tablets are exceeded and in patients with a history of allergy or rash to other AEDs. 

  
  

  It is recommended that lamotrigine tablets not be restarted in patients who discontinued due to rash associated with prior treatment with lamotrigine, unless the potential benefits clearly outweigh the risks. If the decision is made to restart a patient who has discontinued lamotrigine, the need to restart with the initial dosing recommendations should be assessed. The greater the interval of time since the previous dose, the greater consideration should be given to restarting with the initial dosing recommendations. If a patient has discontinued lamotrigine for a period of more than 5 half-lives, it is recommended that initial dosing recommendations and guidelines be followed. The half-life of lamotrigine is affected by other concomitant medications [see Clinical Pharmacology (12.3)].

  
  

  Lamotrigine Tablets Added to Drugs Known to Induce or Inhibit Glucuronidation
  Because lamotrigine is metabolized predominantly by glucuronic acid conjugation, drugs that are known to induce or inhibit glucuronidation may affect the apparent clearance of lamotrigine. Drugs that induce glucuronidation include carbamazepine, phenytoin, phenobarbital, primidone, rifampin, estrogen-containing oral contraceptives, and the protease inhibitors lopinavir/ritonavir and atazanavir/ritonavir. Valproate inhibits glucuronidation. For dosing considerations for lamotrigine tablets in patients on estrogen-containing contraceptives and atazanavir/ritonavir, see below and Table 13. For dosing considerations for lamotrigine tablets in patients on other drugs known to induce or inhibit glucuronidation, see Tables 1, 2, 5 to 6, and 13.

  
  

  Target Plasma Levels for Patients with Epilepsy or Bipolar Disorder
  A therapeutic plasma concentration range has not been established for lamotrigine. Dosing of lamotrigine tablets should be based on therapeutic response [see Clinical Pharmacology (12.3)].

   

  Women Taking Estrogen-Containing Oral Contraceptives
  Starting Lamotrigine Tablets in Women Taking Estrogen-Containing Oral Contraceptives: Although estrogen-containing oral contraceptives have been shown to increase the clearance of lamotrigine [see Clinical Pharmacology (12.3)], no adjustments to the recommended dose-escalation guidelines for lamotrigine tablets should be necessary solely based on the use of estrogen-containing oral contraceptives. Therefore, dose escalation should follow the recommended guidelines for initiating adjunctive therapy with lamotrigine tablets based on the concomitant AED or other concomitant medications (see Table 1, 5 and 7). See below for adjustments to maintenance  doses of lamotrigine tablets in women taking estrogen-containing oral contraceptives.  

  Adjustments to the Maintenance Dose of Lamotrigine Tablets in Women Taking Estrogen-Containing Oral Contraceptives 

  1)      Taking Estrogen-Containing Oral Contraceptives:In women not taking carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin and the  protease inhibitors lopinavir/ritonavir and atazanavir/ritonavir  that induce lamotrigine glucuronidation [see Drug Interactions (7), Clinical Pharmacology (12.3)], the maintenance dose of lamotrigine tablets will in most cases need to be increased by as much as 2-fold over the recommended target maintenance dose to maintain a consistent lamotrigine plasma level

  
  

  2)      Starting Estrogen-Containing Oral Contraceptives:In women taking a stable dose of lamotrigine tablets and not taking carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin and the  protease inhibitors lopinavir/ritonavir and atazanavir/ritonavir  that induce lamotrigine glucuronidation [see Drug Interactions (7), Clinical Pharmacology (12.3)], the maintenance dose will in most cases need to be increased by as much as 2-fold to maintain a consistent lamotrigine plasma level. The dose increases should begin at the same time that the oral contraceptive is introduced and continue, based on clinical response, no more rapidly than 50 to 100 mg/day every week. Dose increases should not exceed the recommended rate (see Tables 1 and 5) unless lamotrigine plasma levels or clinical response support larger increases. Gradual transient increases in lamotrigine plasma levels may occur during the week of inactive hormonal preparation (pill-free week), and these increases will be greater if dose increases are made in the days before or during the week of inactive hormonal preparation. Increased lamotrigine plasma levels could result in additional adverse reactions, such as dizziness, ataxia, and diplopia. If adverse reactions attributable to lamotrigine tablets consistently occur during the pill-free week, dose adjustments to the overall maintenance dose may be necessary. Dose adjustments limited to the pill-free week are not recommended. For women taking lamotrigine tablets in addition to carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin and the  protease inhibitors lopinavir/ritonavir and atazanavir/ritonavir that induce lamotrigine glucuronidation [see Drug Interactions (7), Clinical Pharmacology (12.3)], no adjustment to the dose of lamotrigine should be necessary.

  
  

  3)      Stopping Estrogen-Containing Oral Contraceptives:In women not taking carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin and the  protease inhibitors lopinavir/ritonavir and atazanavir/ritonavir  that induce lamotrigine glucuronidation [see Drug Interactions (7), Clinical Pharmacology (12.3)], the maintenance dose of lamotrigine tablets will in most cases need to be decreased by as much as 50%, in order to maintain a consistent lamotrigine plasma level. The decrease in dose of lamotrigine tablets should not exceed 25% of the total daily dose per week over a 2-week period, unless clinical response or lamotrigine plasma levels indicate otherwise [see Clinical Pharmacology (12.3)]. In women taking lamotrigine tablets in addition to carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin and the  protease inhibitors lopinavir/ritonavir and atazanavir/ritonavir  that induce lamotrigine glucuronidation [see Drug Interactions (7), Clinical Pharmacology (12.3)], no adjustment to the dose of lamotrigine tablets should be necessary.  

  Women and Other Hormonal Contraceptive Preparations or Hormone Replacement Therapy
  The effect of other hormonal contraceptive preparations or hormone replacement therapy on the pharmacokinetics of lamotrigine has not been systematically evaluated. It has been reported that ethinylestradiol, not progestogens, increased the clearance of lamotrigine up to 2-fold, and the progestin-only pills had no effect on lamotrigine plasma levels. Therefore, adjustments to the dosage of lamotrigine tablets in the presence of progestogens alone will likely not be needed.  

  Patients Taking Atazanavir/Ritonavir
  While atazanavir/ritonavir does reduce the lamotrigine plasma concentration, no adjustments to the recommended dose-escalation guidelines for lamotrigine tablets should be necessary solely based on the use of atazanavir/ritonavir. Dose escalation should follow the recommended guidelines for initiating adjunctive therapy with lamotrigine tablets based on concomitant AED or other concomitant medications (see Tables 1, 2, and 5). In patients already taking maintenance doses of lamotrigine tablets and not taking glucuronidation inducers, the dose of lamotrigine tablets may need to be increased if atazanavir/ritonavir is added, or decreased if atazanavir/ritonavir is discontinued [see Clinical Pharmacology (12.3)]. 

  Patients with Hepatic Impairment
  Experience in patients with hepatic impairment is limited. Based on a clinical pharmacology study in 24 subjects with mild, moderate, and severe liver impairment  [see Use in Specific Populations (8.6), Clinical Pharmacology (12.3)],

  the following general recommendations can be made. No dosage adjustment is needed in patients with mild liver impairment. Initial, escalation, and maintenance doses should generally be reduced by approximately 25% in patients with moderate and severe liver impairment without ascites and 50% in patients with severe liver impairment with ascites. Escalation and maintenance doses may be adjusted according to clinical response. 

  Patients with Renal Impairment
  Initial doses of lamotrigine tablets should be based on patients’ concomitant medications (see Tables 1 to 3, and  5); reduced maintenance doses may be effective for patients with significant renal impairment [see Use in Specific Populations (8.7), Clinical Pharmacology (12.3)]. Few patients with severe renal impairment have been evaluated during chronic treatment with lamotrigine tablets. Because there is inadequate experience in this population, lamotrigine tablets should be used with caution in these patients. 

  Discontinuation Strategy
  Epilepsy: For patients receiving lamotrigine tablets in combination with other AEDs, a re-evaluation of all AEDs in the regimen should be considered if a change in seizure control or an appearance or worsening of adverse reactions is observed.  

  If a decision is made to discontinue therapy with lamotrigine tablets, a step-wise reduction of dose over at least 2 weeks (approximately 50% per week) is recommended unless safety concerns require a more rapid withdrawal [see Warnings and Precautions (5.8)].  

  Discontinuing carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin and the  protease inhibitors lopinavir/ritonavir and atazanavir/ritonavir that induce lamotrigine glucuronidation should prolong the half-life of lamotrigine; discontinuing valproate should shorten the half-life of lamotrigine. 

  
  

  Bipolar Disorder: In the controlled clinical trials, there was no increase in the incidence, type, or severity of adverse reactions following abrupt termination of lamotrigine tablets. In the clinical development program in adults with bipolar disorder, 2 patients experienced seizures shortly after abrupt withdrawal of lamotrigine tablets. Discontinuation of lamotrigine tablets should involve a step-wise reduction of dose over at least 2 weeks (approximately 50% per week) unless safety concerns require a more rapid withdrawal [see Warnings and Precautions (5.8)]. 

  
  2.2. Epilepsy - Adjunctive Therapy
  

  This section provides specific dosing recommendations for patients older than 12 years and patients aged 2 to 12 years. Within each of these age-groups, specific dosing recommendations are provided depending upon concomitant AEDs or other concomitant medications (see Table 1 for patients older than 12 years and Table 2 for patients aged 2 to 12 years). A weight-based dosing guide for patients aged 2 to 12 years on concomitant valproate is provided in Table 3.

  
  

  Patients Older than 12 Years
  Recommended dosing guidelines are summarized in Table 1.

  
  
  

                                                                                    Table 1

           Escalation Regimen for Lamotrigine Tablets in Patients Older than 12 Years with Epilepsy

  
   
  In Patients TAKING Valproatea
  In Patients NOT TAKING Carbamazepine, Phenytoin, Phenobarbital, Primidoneb, or Valproatea
  In Patients TAKING Carbamazepine, Phenytoin, Phenobarbital, or Primidoneband NOT TAKING Valproatea
  Weeks 1 and 2
  25 mg every other day
  25 mg every day
  50 mg/day
  Weeks 3 and 4
  25 mg every day
  50 mg/day
  100 mg/day
  (in 2 divided doses)
  Week 5 onwards to maintenance
  Increase by 25 to 50 mg/day every 1 to 2 weeks
  Increase by 50 mg/day every 1 to 2 weeks
  Increase by 100 mg/day every 1 to 2 weeks.
  Usual Maintenance Dose
  100 to 200 mg/day with valproate alone
   
  100 to 400 mg/day
  with valproate and other drugs that induce glucuronidation
  ( in 1 or 2 divided doses)
  225 to 375 mg/day
  (in 2 divided doses)
  300 to 500 mg/day
  (in 2 divided doses)
  
  

  a Valproate has been shown to inhibit glucuronidation and decrease the apparent clearance of lamotrigine [see Drug Interactions (7), Clinical Pharmacology (12.3)].

  
  

  b Drugs that induce lamotrigine glucuronidation and increase clearance, other than the specified antiepileptic drugs, include estrogen-containing oral contraceptives, rifampin, and the protease inhibitors lopinavir/ritonavir and atazanavir/ritonavir. Dosing recommendations for oral contraceptives and the protease inhibitor atazanavir/ritonavir can be found in General Dosing Considerations [see Dosage and Administration (2.1)]. Patients on rifampin and the protease inhibitor lopinavir/ritonavir should follow the same dosing titration/maintenance regimen used with antiepileptic drugs that induce glucuronidation and increase clearance [see Dosage and Administration (2.1), Drug Interactions (7), and Clinical Pharmacology (12.3)].

  
  

   
  Patients Aged 2 to 12 Years
  Recommended dosing guidelines are summarized in Table 2.

  Lower starting doses and slower dose escalations than those used in clinical trials are recommended because of the suggestion that the risk of rash may be decreased by lower  starting doses and slower dose escalations. Therefore, maintenance doses will take longer to reach in clinical practice than in clinical trials. It may take several weeks to months to achieve an individualized maintenance dose. Maintenance doses in patients weighing less than 30 kg, regardless of age or concomitant AED, may need to be increased as much as 50%, based on clinical response.

                                                                   Table 2

  Escalation Regimen for Lamotrigine Tablets in Patients Aged 2 to 12 Years with Epilepsy  

  
  
  
   
  In Patients TAKING Valproatea
  In Patients
  NOT TAKING Carbamazepine,
  Phenytoin,
  Phenobarbital,
  Primidoneb, or  Valproatea
  For Patients TAKING Carbamazepine, Phenytoin, Phenobarbital, or Primidoneband NOT TAKING Valproatea
  Weeks 1 and 2
  0.15 mg/kg/day
  in 1 or 2 divided doses, rounded down to the nearest whole tablet (see Table 3 for weight-based dosing guide).
  0.3 mg/kg/day
  in 1 or 2 divided doses, rounded down to the nearest whole tablet.
  0.6 mg/kg/day
  in 2 divided doses, rounded down to the nearest whole tablet.
  Weeks 3 and 4
  0.3 mg/kg/day
  in 1 or 2 divided doses, rounded down to the nearest whole tablet (see Table 3 for weight-based dosing guide).
  0.6 mg/kg/day
  in 2 divided doses, rounded down to the nearest whole tablet.
  1.2 mg/kg/day
  in 2 divided doses, rounded down to the nearest whole tablet.
  Week 5 onwards to maintenance
  The dose should be increased every 1 to 2 weeks as follows: calculate 0.3 mg/kg/day, round this amount down to the nearest whole tablet, and add this amount to the previously administered daily dose.
  The dose should be increased every 1 to 2 weeks as follows: calculate 0.6 mg/kg/day, round this amount down to the nearest whole tablet, and add this amount to the previously administered daily dose
  The dose should be increased every 1 to 2 weeks as follows: calculate 1.2 mg/kg/day, round this amount down to the nearest whole tablet, and add this amount to the previously administered daily dose
  Usual maintenance dose
  1 to 5 mg/kg/day(maximum 200 mg/day in 1 or 2 divided doses).
  1 to 3 mg/kg/day with valproate alone
  4.5 to 7.5 mg/kg/day
  (maximum 300 mg/day in 2 divided doses)
  5 to 15 mg/kg/day(maximum 400 mg/day in 2 divided doses)
  Maintenance dose in patients less than 30 kg
  May need to be increased by as much as 50%, based on clinical response
  May need to be increased by as much as 50%, based on clinical response
  May need to be increased by as much as 50%, based on clinical response
  
  
  

  Note: Only whole tablets should be used for dosing
  
  a Valproate has been shown to inhibit glucuronidation and decrease the apparent clearance of lamotrigine [see Drug Interactions (7), Clinical Pharmacology (12.3)].

  
  
  

  b Drugs that induce lamotrigine glucuronidation and increase clearance, other than the specified antiepileptic drugs, include estrogen-containing oral contraceptives, rifampin, and the protease inhibitors lopinavir/ritonavir and atazanavir/ritonavir. Dosing recommendations for oral contraceptives and the protease inhibitor atazanavir/ritonavir can be found in General Dosing Considerations [see Dosage and Administration (2.1)]. Patients on rifampin and the protease inhibitor lopinavir/ritonavir should follow the same dosing titration/maintenance regimen used with antiepileptic drugs that induce glucuronidation and increase clearance [see Dosage and Administration (2.1), Drug Interactions (7), and Clinical Pharmacology (12.3)].

                                                                Table 3

  The Initial Weight-Based Dosing Guide for Patients Aged 2 to 12 Years Taking Valproate (Weeks 1 to 4) with Epilepsy 

  
  If the patient’s weight is
  Give this daily dose, using the most appropriate combination of lamotrigine tablets 2- and 5-mg tablets
  Greater than
  And less than
  Weeks 1 and 2
  Weeks 3 and 4
  6.7 kg
  14 kg
  2 mg every other day
  2 mg every day
  14.1 kg
  27 kg
  2 mg every day
  4 mg every day
  27.1 kg
  34 kg
  4 mg every day
  8 mg every day
  34.1 kg
  40 kg
  5 mg every day
  10 mg every day
  
  
  

  Usual Adjunctive Maintenance Dose for Epilepsy
  The usual maintenance doses identified in Tables 1 and 2 are derived from dosing regimens employed in the placebo-controlled adjunctive trials  in which the efficacy of lamotrigine tablets were established. In patients receiving multidrug regimens employing carbamazepine, phenytoin, phenobarbital, or primidone without valproate , maintenance doses of adjunctive lamotrigine tablets as high as 700 mg/day have been used. In patients receiving valproate alone , maintenance doses of adjunctive lamotrigine tablets as high as 200 mg/day have been used. The advantage of using doses above those recommended in Tables 1 to 4 has not been established in controlled trials.

  2.3. Epilepsy - Conversion from Adjunctive Therapy to Monotherapy

  The goal of the transition regimen is to attempt to maintain seizure control while mitigating the risk of serious rash associated with the rapid titration of lamotrigine tablets.

  The recommended maintenance dose of lamotrigine tablets as monotherapy is 500 mg/day given in 2 divided doses.

  To avoid an increased risk of rash, the recommended initial dose and subsequent dose escalations for lamotrigine tablets should not be exceeded [see Boxed Warning].

  
  

  Conversion from Adjunctive Therapy with Carbamazepine, Phenytoin, Phenobarbital, or Primidone to Monotherapy with Lamotrigine Tablets
  After achieving a dose of 500 mg/day of lamotrigine tablets using the guidelines in Table 1, the concomitant  enzyme-inducing AED should be withdrawn by 20% decrements each week over a 4-week period. The regimen for the withdrawal of the concomitant AED is based on experience gained in the controlled monotherapy clinical trial.

  
  

  Conversion from Adjunctive Therapy with Valproate to Monotherapy with Lamotrigine Tablets
  The conversion regimen involves the 4 steps outlined in Table 4.

  
  Table 4

  
  
  

  Conversion from Adjunctive Therapy with Valproate to Monotherapy with Lamotrigine Tablets in Patients  Aged 16 Years and Older with Epilepsy 

  
   
  Lamotrigine Tablets
  Valproate
  Step 1
  Achieve a dose of 200 mg/day according to guidelines in Table 1
  Maintain established stable dose.
  Step 2
  Maintain at 200 mg/day.
  Decrease dose by decrements no greater than 500 mg/day/ week to 500 mg/day and then maintain  for 1 week.
  Step 3
  Increase to 300 mg/day and maintain for 1 week.
  Simultaneously decrease to 250 mg/day and maintain for 1 week.
  Step 4
  Increase by 100 mg/day every week to achieve maintenance dose of 500 mg/day.
  Discontinue.
  
  

  Conversion from Adjunctive Therapy with Antiepileptic Drugs other than Carbamazepine, Phenytoin, Phenobarbital, Primidone, or Valproate to Monotherapy with Lamotrigine Tablets
  No specific dosing guidelines can be provided for conversion to monotherapy with lamotrigine tablets with AEDs other than carbamazepine, phenytoin, phenobarbital,  primidone, or valproate.

  2.4. Bipolar Disorder
  

  The goal of maintenance treatment with lamotrigine tablets are to delay the time to occurrence of mood episodes (depression, mania, hypomania, mixed episodes) in patients treated for acute mood episodes with standard therapy therapy [see Indications and Usage (1)].
  Patients taking lamotrigine tablets for more than 16 weeks should be periodically reassessed to determine the need for maintenance treatment.
  Adults
  The target dose of lamotrigine tablets are 200 mg/day (100 mg/day in patients taking valproate, which decreases the apparent clearance of lamotrigine, and 400 mg/day in patients not taking valproate and taking either carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin and the  protease inhibitors lopinavir/ritonavir that increase the apparent clearance of lamotrigine). In the clinical trials, doses up to 400 mg/day as monotherapy were evaluated; however, no additional benefit was seen at 400 mg/day compared with 200 mg/day [see Clinical Studies (14.2)]. Accordingly, doses above 200 mg/day are not recommended.
  Treatment with lamotrigine tablets are introduced, based on concurrent medications, according to the regimen outlined in Table 5. If other psychotropic medications are withdrawn following stabilization, the dose of lamotrigine tablets should be adjusted. In  patients discontinuing valproate, the dose of lamotrigine tablets should be doubled over a 2-week period in equal weekly increments (see Table 6). In  patients discontinuing carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin and the  protease inhibitors lopinavir/ritonavir that induce lamotrigine glucuronidation, the dose of lamotrigine tablets should remain constant for the first week and then should be decreased by half over a 2-week period in equal weekly decrements (see Table 6). The dose of lamotrigine tablets may then be further adjusted to the target dose (200 mg) as clinically indicated.
  
  If other drugs are subsequently introduced, the dose of lamotrigine tablets may need to be adjusted. In particular, the introduction of valproate requires reduction in the dose of lamotrigine tablets [see Drug Interactions (7), Clinical Pharmacology (12.3)].
  
  To avoid an increased risk of rash, the recommended initial dose and subsequent dose escalations of lamotrigine tablets should not be exceeded [see Boxed Warning].
  
  Table 5
  Escalation Regimen for Lamotrigine Tablets in Adults with Bipolar Disorder

   
  In Patients TAKING Valproatea
  In Patients NOT TAKING Carbamazepine, Phenytoin, Phenobarbital, Primidoneb, or Valproatea
  For Patients TAKING Carbamazepine, Phenytoin, Phenobarbital, or Primidoneb and NOT TAKING Valproatea
  Weeks 1 and 2
  25 mg every other day
  25 mg daily
  50 mg daily
  Weeks 3 and 4
  25 mg daily
  50 mg daily
  100 mg daily, in divided doses
  Week 5
  50 mg daily
  100 mg daily
  200 mg daily, in divided doses
  Week 6
  100 mg daily
  200 mg daily
  300 mg daily, in divided doses
  Week 7
  100 mg daily
  200 mg daily
  up to 400 mg daily, in divided doses
  
  

  a Valproate has been shown to inhibit glucuronidation and decrease the apparent clearance of lamotrigine [see Drug Interactions (7), Clinical Pharmacology (12.3)].

  
  

  b Drugs that induce lamotrigine glucuronidation and increase clearance, other than the specified antiepileptic drugs, include estrogen-containing oral contraceptives, rifampin, and the protease inhibitors lopinavir/ritonavir and atazanavir/ritonavir. Dosing recommendations for oral contraceptives and the protease inhibitor atazanavir/ritonavir can be found in General Dosing Considerations [see Dosage and Administration (2.1)]. Patients on rifampin and the protease inhibitor lopinavir/ritonavir should follow the same dosing titration/maintenance regimen used with antiepileptic drugs that induce glucuronidation and increase clearance [see Dosage and Administration (2.1), Drug Interactions (7), and Clinical Pharmacology(12.3)].

  
  Table 6

  
  

  Dosage Adjustments to Lamotrigine Tablets in Adults with Bipolar Disorder Following
  Discontinuation of Psychotropic Medications  

  
   
  Discontinuation of Psychotropic Drugs (excluding Carbamazepine, Phenytoin, Phenobarbital Primidoneb)
  After Discontinuation of Valproatea
  After Discontinuation of Carbamazepine, Phenytoin, Phenobarbital, or Primidoneb
  Current Dose of Lamotrigine Tablets (mg/day) 100
  Current Dose of Lamotrigine Tablets (mg/day) 400
  Week 1
  Maintain current dose of Lamotrigine Tablets
  150
  400
  Week 2
  Maintain current dose of Lamotrigine Tablets
  200
  300
  Week 3 onward
  Maintain current dose of Lamotrigine Tablets
  200
  200
  
  

  a Valproate has been shown to inhibit glucuronidation and decrease the apparent clearance of lamotrigine [see Drug Interactions (7), Clinical Pharmacology (12.3)].

  
  

  b Drugs that induce lamotrigine glucuronidation and increase clearance, other than the specified antiepileptic drugs, include estrogen-containing oral contraceptives, rifampin, and the protease inhibitors lopinavir/ritonavir and atazanavir/ritonavir. Dosing recommendations for oral contraceptives and the protease inhibitor atazanavir/ritonavir can be found in General Dosing Considerations [see Dosage and Administration (2.1)]. Patients on rifampin and the protease inhibitor lopinavir/ritonavir should follow the same dosing titration/maintenance regimen used with antiepileptic drugs that induce glucuronidation and increase clearance [see Dosage and Administration (2.1), Drug Interactions (7), and Clinical Pharmacology (12.3)].

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  Lamotrigine | Teva Pharmaceuticals Usa Inc

  

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  Hypertension

  The recommended initial dosage of trandolapril tablets for patients not receiving a diuretic is 1 mg once daily in non-black patients and 2 mg in black patients. Dosage should be adjusted according to the blood pressure response. Generally, dosage adjustments should be made at intervals of at least 1 week. Most patients have required dosages of 2 to 4 mg once daily. There is little clinical experience with doses above 8 mg.

  Patients inadequately treated with once-daily dosing at 4 mg may be treated with twice-daily dosing. If blood pressure is not adequately controlled with trandolapril tablets monotherapy, a diuretic may be added.

  In patients who are currently being treated with a diuretic, symptomatic hypotension occasionally can occur following the initial dose of trandolapril tablets. To reduce the likelihood of hypotension, the diuretic should, if possible, be discontinued two to three days prior to beginning therapy with trandolapril tablets. (See WARNINGS.) Then, if blood pressure is not controlled with trandolapril tablets alone, diuretic therapy should be resumed. If the diuretic cannot be discontinued, an initial dose of 0.5 mg trandolapril tablets should be used with careful medical supervision for several hours until blood pressure has stabilized. The dosage should subsequently be titrated (as described above) to the optimal response. (See WARNINGS and PRECAUTIONS, Drug Interactions.)

  Concomitant administration of trandolapril tablets with potassium supplements, potassium salt substitutes, or potassium sparing diuretics can lead to increases of serum potassium. (See PRECAUTIONS.)

  Heart Failure Post Myocardial Infarction or Left-Ventricular Dysfunction Post Myocardial Infarction

  The recommended starting dose is 1 mg, once daily. Following the initial dose, all patients should be titrated (as tolerated) toward a target dose of 4 mg, once daily. If a 4 mg dose is not tolerated, patients can continue therapy with the greatest tolerated dose.

  Dosage Adjustment in Renal Impairment or Hepatic Cirrhosis

  For patients with a creatinine clearance < 30 mL/min. or with hepatic cirrhosis, the recommended starting dose, based on clinical and pharmacokinetic data, is 0.5 mg daily. Patients should subsequently have their dosage titrated (as described above) to the optimal response.

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