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Uses
1.1 Epilepsy
Adjunctive Therapy:
Lamotrigine tablets are indicated as adjunctive therapy for the following seizure types in patients ≥ 2 years of age:
partial seizures
primary generalized tonic-clonic seizures
generalized seizures of Lennox-Gastaut syndrome
Monotherapy:
Lamotrigine tablets are indicated for conversion to monotherapy in adults (≥16 years of age) with partial seizures who are receiving treatment with carbamazepine, phenytoin, phenobarbital, primidone, or valproate as the single antiepileptic drug (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.
1.2 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 adults (≥18 years of age) treated for acute mood episodes with standard therapy. The effectiveness of lamotrigine tablets in the acute treatment of mood episodes has not been established.
The effectiveness of lamotrigine tablets as maintenance treatment was established in 2 placebo-controlled trials in patients with Bipolar I Disorder as defined by DSM-IV [see Clinical Studies (14.2)]. The physician who elects to prescribe lamotrigine tablets for periods extending beyond 16 weeks should periodically re-evaluate the long-term usefulness of the drug for the individual patient.
History
There is currently no drug history available for this drug.
Other Information
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Lamotrigine, an AED of the phenyltriazine class, is chemically unrelated to existing AEDs. Its chemical name is 3,5-diamino-6-(2,3-dichlorophenyl)-as-triazine, its molecular formula is C9H7N5Cl2, and its molecular weight is 256.09. Lamotrigine is a white to pale cream-colored powder and has a pKa of 5.7. Lamotrigine is very slightly soluble in water (0.17 mg/mL at 25°C) and slightly soluble in 0.1 M HCl (4.1 mg/mL at 25°C). The structural formula is:
Lamotrigine tablets USP are supplied for oral administration as 25 mg, 100 mg, 150 mg or 200 mg tablets. Each tablet contains the labeled amount of lamotrigine and the following inactive ingredients: lactose monohydrate, magnesium stearate, microcrystalline cellulose, povidone and sodium starch glycolate. In addition, the 200 mg tablets contain FD&C Blue No. 2 Lake.
Sources
Lamotrigine Manufacturers
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Direct Rx
Lamotrigine | Direct Rx
2.1 General Dosing ConsiderationsRash: 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 TherapyThis 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 Epilepsya 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 EpilepsyNote: 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 dayUsual 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 MonotherapyThe 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 DisorderThe 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 Disordera 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)
400a 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 200The 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.
-
Avpak
Lamotrigine | Avpak
2.1 General Dosing ConsiderationsRash: 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 TherapyThis 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 dayUsual 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 MonotherapyThe 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 EpilepsyLamotrigine
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 DisorderThe 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].
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 200The 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.
-
Proficient Rx Lp
Lamotrigine | Proficient Rx Lp
2.1 General Dosing ConsiderationsRash: 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 TherapyThis 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
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 200 mg/day
with valproate alone225 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
ValproateaFor Patients NOT
TAKING Carbamazepine, Phenytoin,
Phenobarbital, Primidoneb, or
ValproateaFor Patients TAKING
Carbamazepine, Phenytoin, Phenobarbital, or
Primidoneb and NOT
TAKING ValproateaWeeks 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
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
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
by as much as 50%, based
on clinical response
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 MonotherapyThe 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 EpilepsyLamotrigine 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 DisorderThe 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
ValproateaFor Patients NOT TAKING
Carbamazepine, Phenytoin, Phenobarbital,
Primidoneb, or ValproateaFor Patients TAKING
Carbamazepine, Phenytoin,
Phenobarbital, or Primidoneb and NOT TAKING
ValproateaWeeks 1 and 2
25 mg every
other day25 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.
-
Remedyrepack Inc.
Lamotrigine | Remedyrepack Inc.
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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Global Pharmaceuticals, Division Of Impax Laboratories Inc.
Lamotrigine | Global Pharmaceuticals, Division Of Impax Laboratories Inc.
2.1 General Dosing ConsiderationsRash: 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 TherapyThis 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 dayUsual 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 MonotherapyThe 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 DisorderThe 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 200The 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 TabletsLamotrigine 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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Direct Rx
Lamotrigine | Direct Rx
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 Epilepsya 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 EpilepsyNote: 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 dayUsual 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 Disordera 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)
400a 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 200The 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.
-
State Of Florida Doh Central Pharmacy
Lamotrigine | State Of Florida Doh Central Pharmacy
2.1 General Dosing ConsiderationsRash: 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 TherapyThis 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 Epilepsya 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 EpilepsyNote: 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 MonotherapyThe 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 DisorderThe 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 Disordera 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.
-
State Of Florida Doh Central Pharmacy
Lamotrigine | State Of Florida Doh Central Pharmacy
2.1 General Dosing ConsiderationsRash: 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 TherapyThis 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 Epilepsya 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 EpilepsyNote: 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 MonotherapyThe 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 DisorderThe 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 Disordera 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 Medicationsa 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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State Of Florida Doh Central Pharmacy
Lamotrigine | State Of Florida Doh Central Pharmacy
2.1 General Dosing ConsiderationsRash: 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 TherapyThis 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 responseDosing 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 dayUsual 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 MonotherapyThe 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 DisorderThe 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 200The 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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Sandoz Inc
Lamotrigine | Sandoz Inc
2.1 General Dosing ConsiderationsRash: 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 TherapyThis 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 WithFor Patients Taking
Valproate *For Patients Taking
AEDs Other Than
Carbamazepine,
Phenytoin,
Phenobarbital, or
Primidone†, and Not
Taking ValproateFor 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/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 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 ValproateFor Patients Taking
Carbamazepine,
Phenytoin,
Phenobarbital, or
Primidone† and Not
Taking Valproate Weeks 1 and 20.15 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 tablet0.6mg/kg/day
in 2 divided doses,
rounded down to the
nearest whole tablet Weeks 3 and 40.3mg/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 tablet1.2mg/kg/day
in 2 divided doses,
rounded down to the
nearest whole tabletWeeks 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 doseThe 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 5mg/kg/day
(maximum
200 mg/day in 1 or
2 divided doses).
1 to 3mg/kg/day with
valproate alone4.5 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 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.
* 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 dayUsual 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 MonotherapyThe 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 DisorderThe 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)
100Current dose of
lamotrigine (mg/day)
400 Week1Maintain current dose of
lamotrigine 150 400 Week 2Maintain current dose of
lamotrigine 200 300Week 3
onwardMaintain 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 ValproateWeeks 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
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
Table 10. The Initial Weight-Based Dosing Guide for Patients 2 to 12 Years Taking Valproate (Weeks 1 to 4) With Epilepsy
much as 50%, based on
clinical responseIf the patient’s weight is
Give this daily dose, using the most appropriate
combination of lamotrigine 2-mg and 5-mg tabletsGreater 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
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 ValproateWeeks 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
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/daywith valproate alone225 to 375 mg/day
(in 2 divided doses).300 to 500 mg/day
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:
(in 2 divided doses).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 EpilepsyLamotrigine
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) 400Week 1
Maintain current
Lamotrigine dose150
400
Week 2
Maintain current
Lamotrigine dose200
300
Week 3 onward
Maintain current
Lamotrigine dose200
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 ConsiderationsRash: 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 TherapyThis 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 MonotherapyThe 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 DisorderThe 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 ConsiderationsRash: 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 TherapyThis 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 Dose100 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 responseNote: 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 dayUsual 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 MonotherapyThe 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 DisorderThe 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].
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 200The 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.
-
Pd-rx Pharmaceuticals, Inc.
Lamotrigine | Pd-rx Pharmaceuticals, Inc.
2.1 General Dosing ConsiderationsRash: 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 TherapyThis 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 EpilepsyNote: 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 MonotherapyThe 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 DisorderThe 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.
-
Pd-rx Pharmaceuticals, Inc.
Lamotrigine | Pd-rx Pharmaceuticals, Inc.
2.1 General Dosing ConsiderationsRash: 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 TherapyThis 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 EpilepsyNote: 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 MonotherapyThe 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 DisorderThe 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.
-
Pd-rx Pharmaceuticals, Inc.
Lamotrigine | Pd-rx Pharmaceuticals, Inc.
2.1 General Dosing ConsiderationsRash: 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 TherapyThis 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 EpilepsyNote: 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 MonotherapyThe 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 DisorderThe 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.
-
Pd-rx Pharmaceuticals, Inc.
Lamotrigine | Pd-rx Pharmaceuticals, Inc.
2.1 General Dosing ConsiderationsRash: 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 TherapyThis 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 EpilepsyNote: 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 MonotherapyThe 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 DisorderThe 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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Lamotrigine | Remedyrepack Inc.
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.
-
Remedyrepack Inc.
Lamotrigine | Remedyrepack Inc.
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.
-
Remedyrepack Inc.
Lamotrigine | Remedyrepack Inc.
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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Remedyrepack Inc.
Lamotrigine | Remedyrepack Inc.
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.
-
Remedyrepack Inc.
Lamotrigine | Remedyrepack Inc.
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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West-ward Pharmaceutical Corp
Lamotrigine | West-ward Pharmaceutical Corp
2.1 General Dosing ConsiderationsRash: 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 TherapyThis 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/day100 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 dose100 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 20.15 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 40.3 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 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 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 responseNote: 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 dayUsual 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 MonotherapyThe 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 DisorderThe 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 dosesaValproate 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 PrimidonebCurrent dose of LAMICTAL (mg/day)
100Current 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 200aValproate 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.
-
Hikma Pharmaceutical
Lamotrigine | Hikma Pharmaceutical
2.1 General Dosing ConsiderationsRash: 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 TherapyThis 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/day100 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 dose100 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 20.15 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 40.3 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 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 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 responseNote: 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 dayUsual 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 MonotherapyThe 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 DisorderThe 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 dosesaValproate 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 PrimidonebCurrent dose of LAMICTAL (mg/day)
100Current 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 200aValproate 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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Ncs Healthcare Of Ky, Inc Dba Vangard Labs
Lamotrigine | Ncs Healthcare Of Ky, Inc Dba Vangard Labs
2.1 General Dosing ConsiderationsRash: 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 TherapyThis 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 Dose100 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 responseNote: 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 dayUsual 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 MonotherapyThe 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 DisorderThe 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) 100Current 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 200The 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 | Remedyrepack Inc.
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 ConsiderationsRash: 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 TherapyThis 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 responseDosing 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 dayUsual 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 MonotherapyThe 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 DisorderThe 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 200The 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 ConsiderationsRash: 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 TherapyThis 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 responseDosing 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 dayUsual 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 MonotherapyThe 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 DisorderThe 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 200The 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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Mylan Pharmaceuticals Inc.
Lamotrigine | Mylan Pharmaceuticals Inc.
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 PopulationsElderly 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 InsufficiencyPatients 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 InsufficiencyNo 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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Cadila Healthcare Limited
Lamotrigine | Cadila Healthcare Limited
2.1 General Dosing ConsiderationsRash
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 TherapyThis 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 MonotherapyThe 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 DisorderThe 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.
-
Unichem Pharmaceuticals (Usa), Inc.
Lamotrigine | Unichem Pharmaceuticals (usa), Inc.
2.1 General Dosing ConsiderationsRash: 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 TherapyThis 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 Epilepsya 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 EpilepsyNote: 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 MonotherapyThe 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 DisorderThe 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 Disordera 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.
-
Cardinal Health
Lamotrigine | Cardinal Health
2.1 General Dosing ConsiderationsRash: 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 TherapyThis 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 Dose100 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 responseNOTE: 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 dayUsual 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 MonotherapyThe 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 DisorderThe 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].
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 200The 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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Unit Dose Services
Lamotrigine | Unit Dose Services
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