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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  Lamotrigine | Unit Dose Services

  

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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 glucur