2.1 General Dosing Considerations
Rash
There are suggestions, yet to be proven, that the risk of severe, potentially life threatening rash may be increased by (1) coadministration of lamotrigine tablets with valproate, (2) exceeding the recommended initial dose of lamotrigine tablets, or (3) exceeding the recommended dose escalation for lamotrigine tablets. However, cases have occurred in the absence of these factors [see Boxed Warning]. Therefore, it is important that the dosing recommendations be followed closely.
The risk of nonserious rash may be increased when the recommended initial dose and/or the rate of dose escalation of lamotrigine tablets are exceeded and in patients with a history of allergy or rash to other AEDs.
It is recommended that lamotrigine tablets not be restarted in patients who discontinued due to rash associated with prior treatment with lamotrigine, unless the potential benefits clearly outweigh the risks. If the decision is made to restart a patient who has discontinued lamotrigine, the need to restart with the initial dosing recommendations should be assessed. The greater the interval of time since the previous dose, the greater consideration should be given to restarting with the initial dosing recommendations. If a patient has discontinued lamotrigine for a period of more than 5 half-lives, it is recommended that initial dosing recommendations and guidelines be followed. The half-life of lamotrigine is affected by other concomitant medications [see Clinical Pharmacology (12.3)].
Lamotrigine Tablets Added to Drugs Known to Induce or Inhibit Glucuronidation
Drugs other than those listed in the Clinical Pharmacology section [see Clinical Pharmacology (12.3)] have not been systematically evaluated in combination with lamotrigine. Because lamotrigine is metabolized predominantly by glucuronic acid conjugation, drugs that are known to induce or inhibit glucuronidation may affect the apparent clearance of lamotrigine and doses of lamotrigine tablets may require adjustment based on clinical response.
Target Plasma Levels for Patients with Epilepsy or Bipolar Disorder
A therapeutic plasma concentration range has not been established for lamotrigine. Dosing of lamotrigine tablets should be based on therapeutic response [see Clinical Pharmacology (12.3)].
Women taking Estrogen-Containing Oral Contraceptives
Starting Lamotrigine Tablets in Women taking Estrogen-Containing Oral Contraceptives
Although estrogen-containing oral contraceptives have been shown to increase the clearance of lamotrigine [see Clinical Pharmacology (12.3)], no adjustments to the recommended dose-escalation guidelines for lamotrigine tablets should be necessary solely based on the use of estrogen-containing oral contraceptives. Therefore, dose escalation should follow the recommended guidelines for initiating adjunctive therapy with lamotrigine tablets based on the concomitant AED or other concomitant medications (see Table 1 or Table 5). See below for adjustments to maintenance doses of lamotrigine tablets in women taking estrogen-containing oral contraceptives.
Adjustments to the Maintenance Dose of Lamotrigine Tablets in Women taking Estrogen-Containing Oral Contraceptives
(1) Taking Estrogen-Containing Oral Contraceptives: For women not taking carbamazepine, phenytoin, phenobarbital, primidone or other drugs such as rifampin that induce lamotrigine glucuronidation [see Drug Interactions (7), Clinical Pharmacology (12.3)], the maintenance dose of lamotrigine tablets will in most cases need to be increased, by as much as 2-fold over the recommended target maintenance dose, in order to maintain a consistent lamotrigine plasma level [see Clinical Pharmacology (12.3)].
(2) Starting Estrogen-Containing Oral Contraceptives: In women taking a stable dose of lamotrigine tablets and not taking carbamazepine, phenytoin, phenobarbital, primidone or other drugs such as rifampin that induce lamotrigine glucuronidation [see Drug Interactions (7), Clinical Pharmacology (12.3)], the maintenance dose will in most cases need to be increased by as much as 2-fold in order to maintain a consistent lamotrigine plasma level. The dose increases should begin at the same time that the oral contraceptive is introduced and continue, based on clinical response, no more rapidly than 50 to 100 mg/day every week. Dose increases should not exceed the recommended rate (see Table 1 or Table 5) unless lamotrigine plasma levels or clinical response support larger increases. Gradual transient increases in lamotrigine plasma levels may occur during the week of inactive hormonal preparation (“pill-free” week), and these increases will be greater if dose increases are made in the days before or during the week of inactive hormonal preparation. Increased lamotrigine plasma levels could result in additional adverse reactions, such as dizziness, ataxia and diplopia. If adverse reactions attributable to lamotrigine tablets consistently occur during the “pill-free” week, dose adjustments to the overall maintenance dose may be necessary. Dose adjustments limited to the “pill-free” week are not recommended. For women taking lamotrigine tablets in addition to carbamazepine, phenytoin, phenobarbital, primidone or other drugs such as rifampin that induce lamotrigine glucuronidation [see Drug Interactions (7), Clinical Pharmacology (12.3)], no adjustment to the dose of lamotrigine tablets should be necessary.
(3) Stopping Estrogen-Containing Oral Contraceptives: For women not taking carbamazepine, phenytoin, phenobarbital, primidone or other drugs such as rifampin that induce lamotrigine glucuronidation [see Drug Interactions (7), Clinical Pharmacology (12.3)], the maintenance dose of lamotrigine tablets will in most cases need to be decreased by as much as 50% in order to maintain a consistent lamotrigine plasma level. The decrease in dose of lamotrigine tablets should not exceed 25% of the total daily dose per week over a 2-week period, unless clinical response or lamotrigine plasma levels indicate otherwise [see Clinical Pharmacology (12.3)]. For women taking lamotrigine tablets in addition to carbamazepine, phenytoin, phenobarbital, primidone or other drugs such as rifampin that induce lamotrigine glucuronidation [see Drug Interactions (7), Clinical Pharmacology (12.3)], no adjustment to the dose of lamotrigine tablets should be necessary.
Women and Other Hormonal Contraceptive Preparations or Hormone Replacement Therapy
The effect of other hormonal contraceptive preparations or hormone replacement therapy on the pharmacokinetics of lamotrigine has not been systematically evaluated. It has been reported that ethinylestradiol, not progestogens, increased the clearance of lamotrigine up to 2-fold, and the progestin-only pills had no effect on lamotrigine plasma levels. Therefore, adjustments to the dosage of lamotrigine tablets in the presence of progestogens alone will likely not be needed.
Patients with Hepatic Impairment
Experience in patients with hepatic impairment is limited. Based on a clinical pharmacology study in 24 patients with mild, moderate and severe liver impairment [see Use in Specific Populations (8.6), Clinical Pharmacology (12.3)], the following general recommendations can be made. No dosage adjustment is needed in patients with mild liver impairment. Initial, escalation, and maintenance doses should generally be reduced by approximately 25% in patients with moderate and severe liver impairment without ascites and 50% in patients with severe liver impairment with ascites. Escalation and maintenance doses may be adjusted according to clinical response.
Patients with Renal Impairment
Initial doses of lamotrigine tablets should be based on patients' concomitant medications (see Tables 1 to 3 or Table 5); reduced maintenance doses may be effective for patients with significant renal impairment [see Use in Specific Populations (8.7), Clinical Pharmacology (12.3)]. Few patients with severe renal impairment have been evaluated during chronic treatment with lamotrigine tablets. Because there is inadequate experience in this population, lamotrigine tablets should be used with caution in these patients.
Discontinuation Strategy
Epilepsy
For patients receiving lamotrigine tablets in combination with other AEDs, a reevaluation of all AEDs in the regimen should be considered if a change in seizure control or an appearance or worsening of adverse reactions is observed.
If a decision is made to discontinue therapy with lamotrigine tablets, a step-wise reduction of dose over at least 2 weeks (approximately 50% per week) is recommended unless safety concerns require a more rapid withdrawal [see Warnings and Precautions (5.10)].
Discontinuing carbamazepine, phenytoin, phenobarbital, primidone or other drugs such as rifampin that induce lamotrigine glucuronidation should prolong the half-life of lamotrigine; discontinuing valproate should shorten the half-life of lamotrigine.
Bipolar Disorder
In the controlled clinical trials, there was no increase in the incidence, type, or severity of adverse reactions following abrupt termination of lamotrigine tablets. In clinical trials in patients with bipolar disorder, two patients experienced seizures shortly after abrupt withdrawal of lamotrigine tablets. However, there were confounding factors that may have contributed to the occurrence of seizures in these bipolar patients. Discontinuation of lamotrigine tablets should involve a step-wise reduction of dose over at least 2 weeks (approximately 50% per week) unless safety concerns require a more rapid withdrawal [see Warnings and Precautions (5.10)].
2.2 Epilepsy – Adjunctive Therapy
This section provides specific dosing recommendations for patients greater than 12 years of age and patients 2 to 12 years of age. Within each of these age groups, specific dosing recommendations are provided depending upon concomitant AED or other concomitant medications (Table 1 for patients greater than 12 years of age and Table 2 for patients 2 to 12 years of age). A weight-based dosing guide for patients 2 to 12 years of age on concomitant valproate is provided in Table 3.
Patients Over 12 Years of Age
Recommended dosing guidelines are summarized in Table 1.
Table 1. Escalation Regimen for Lamotrigine Tablets in Patients Over 12 Years of Age with Epilepsy
*
Valproate has been shown to inhibit glucuronidation and decrease the apparent clearance of lamotrigine
[see Drug Interactions (7), Clinical Pharmacology (12.3)].
†
These drugs induce lamotrigine glucuronidation and increase clearance
[see Drug Interactions (7), Clinical Pharmacology (12.3)]. Other drugs that have similar effects include estrogen-containing oral contraceptives
[see Drug Interactions (7), Clinical Pharmacology (12.3)]. Dosing recommendations for oral contraceptives can be found in General Dosing Considerations
[see Dosage and Administration (2.1)]. Patients on rifampin, or other drugs that induce lamotrigine glucuronidation and increase clearance, should follow the same dosing titration/maintenance regimen as that used with anticonvulsants that have this effect.
For Patients TAKINGValproate*
For Patients NOTTAKINGCarbamazepine,Phenytoin, Phenobarbital,Primidone† orValproate*
For PatientsTAKINGCarbamazepine,Phenytoin,Phenobarbital orPrimidone† andNOTTAKINGValproate*
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 onwardsto 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 MaintenanceDose
100 to 200 mg/day with valproate alone 100 to 400 mg/day with valproate and other drugs that induce glucuronidation (in 1 or 2 divided doses)
225 to 375 mg/day (in 2 divided doses)
300 to 500 mg/day (in 2 divided doses)
Patients 2 to 12 Years of Age
Recommended dosing guidelines are summarized in Table 2.
Smaller starting doses and slower dose escalations than those used in clinical trials are recommended because of the suggestion that the risk of rash may be decreased by smaller starting doses and slower dose escalations. Therefore, maintenance doses will take longer to reach in clinical practice than in clinical trials. It may take several weeks to months to achieve an individualized maintenance dose. Maintenance doses in patients weighing less than 30 kg, regardless of age or concomitant AED, may need to be increased as much as 50%, based on clinical response.
Table 2. Escalation Regimen for Lamotrigine Tablets in Patients 2 to 12 Years of Age with Epilepsy
*
Valproate has been shown to inhibit glucuronidation and decrease the apparent clearance of lamotrigine
[see Drug Interactions (7), Clinical Pharmacology (12.3)].
†
These drugs induce lamotrigine glucuronidation and increase clearance
[see Drug Interactions (7), Clinical Pharmacology (12.3)]. Other drugs that have similar effects include estrogen-containing oral contraceptives
[see Drug Interactions (7), Clinical Pharmacology (12.3)]. Dosing recommendations for oral contraceptives can be found in General Dosing Considerations
[see Dosage and Administration (2.1)]. Patients on rifampin, or other drugs that induce lamotrigine glucuronidation and increase clearance, should follow the same dosing titration/maintenance regimen as that used with anticonvulsants that have this effect.
For Patients TAKING
Valproate*
For Patients NOTTAKINGCarbamazepine,Phenytoin, Phenobarbital, Primidone† or Valproate*
For Patients TAKINGCarbamazepine,Phenytoin,Phenobarbital orPrimidone† and NOTTAKING Valproate*
Weeks 1 and 2
0.15 mg/kg/day in 1 or 2 divided doses,rounded down to thenearest whole tablet (seeTable 3 for weight baseddosing guide).
0.3 mg/kg/day in 1 or 2 divided doses,rounded down to thenearest whole tablet.
0.6 mg/kg/day in 2 divided doses,rounded down to thenearest whole tablet.
Weeks 3 and 4
0.3 mg/kg/day
in 1 or 2 divided doses,rounded down to thenearest whole tablet (see Table 3 for weight based dosing guide).
0.6 mg/kg/day in 2 divided doses,rounded down to thenearest whole tablet.
1.2 mg/kg/day in 2 divided doses,rounded down to thenearest whole tablet.
Week 5onwards to
maintenance
The dose should beincreased every 1 to 2 weeks as follows: calculate 0.3 mg/kg/day, round this amount down to the nearest whole tablet and add thisamount to the previouslyadministered 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 beincreased every 1 to 2 weeks as follows:calculate 1.2 mg/kg/day, round this amountdown to the nearestwhole tablet andadd this amount tothe previouslyadministered dailydose.
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 withvalproate 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 increasedby as much as 50%, basedon clinical response.
May need to be increased by as much as 50%, based on clinical response.
May need to beincreased by asmuch as 50%, basedon clinical response.
Note: Only whole tablets should be used for dosing.
Table 3. The Initial Weight-Based Dosing Guide for Patients 2 to 12 Years of Age taking Valproate (Weeks 1 to 4) with Epilepsy
If the patient's weight is
Give this daily dose, using the most appropriate combination of lamotrigine 2 mg and 5 mg tablets
Greater than
And less than
Weeks 1 and 2
Weeks 3 and 4
6.7 kg
14 kg
2 mg every other day
2 mg every day
14.1 kg
27 kg
2 mg every day
4 mg every day
27.1 kg
34 kg
4 mg every day
8 mg every day
34.1 kg
40 kg
5 mg every day
10 mg every day
Usual Adjunctive Maintenance Dose for Epilepsy
The usual maintenance doses identified in Tables 1 and 2 are derived from dosing regimens employed in the placebo-controlled adjunctive studies in which the efficacy of lamotrigine was established. In patients receiving multidrug regimens employing carbamazepine, phenytoin, phenobarbital or primidone without valproate, maintenance doses of adjunctive lamotrigine tablets as high as 700 mg/day have been used. In patients receiving valproate alone, maintenance doses of adjunctive lamotrigine tablets as high as 200 mg/day have been used. The advantage of using doses above those recommended in Tables 1 through 4 has not been established in controlled trials.
2.3 Epilepsy – Conversion from Adjunctive Therapy to Monotherapy
The goal of the transition regimen is to effect the conversion to monotherapy with lamotrigine tablets under conditions that ensure adequate seizure control while mitigating the risk of serious rash associated with the rapid titration of lamotrigine.
The recommended maintenance dose of lamotrigine tablets as monotherapy is 500 mg/day given in two divided doses.
To avoid an increased risk of rash, the recommended initial dose and subsequent dose escalations of lamotrigine tablets should not be exceeded [see Boxed Warning].
Conversion from Adjunctive Therapy with Carbamazepine, Phenytoin, Phenobarbital or Primidone to Monotherapy with Lamotrigine Tablets
After achieving a dose of 500 mg/day of lamotrigine tablets according to the guidelines in Table 1, the concomitant AED should be withdrawn by 20% decrements each week over a 4-week period. The regimen for the withdrawal of the concomitant AED is based on experience gained in the controlled monotherapy clinical trial.
Conversion from Adjunctive Therapy with Valproate to Monotherapy with Lamotrigine Tablets
The conversion regimen involves four steps outlined in Table 4.
Table 4. Conversion from Adjunctive Therapy with Valproate to Monotherapy with Lamotrigine Tablets in Patients ≥ 16 Years of Age with Epilepsy
Lamotrigine Tablets
Valproate
Step 1
Achieve a dose of 200 mg/day according toguidelines 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 bydecrements no greater than500 mg/day/week and thenmaintain the dose of 500 mg/day for one week.
Step 3
Increase to 300 mg/day and maintainfor one week.
Simultaneously decrease to250 mg/day and maintain forone week.
Step 4
Increase by 100 mg/day every week to achievemaintenance dose of 500 mg/day.
Discontinue.
Conversion from Adjunctive Therapy with Antiepileptic Drugs Other than Carbamazepine, Phenytoin, Phenobarbital, Primidone or Valproate to Monotherapy with Lamotrigine Tablets
No specific dosing guidelines can be provided for conversion to monotherapy with lamotrigine tablets with AEDs other than carbamazepine, phenobarbital, phenytoin, primidone or valproate.
2.4 Bipolar Disorder
The goal of maintenance treatment with lamotrigine tablets is to delay the time to occurrence of mood episodes (depression, mania, hypomania, mixed episodes) in patients treated for acute mood episodes with standard therapy. The target dose of lamotrigine tablets is 200 mg/day (100 mg/day in patients taking valproate, which decreases the apparent clearance of lamotrigine and 400 mg/day in patients not taking valproate and taking either carbamazepine, phenytoin, phenobarbital, primidone or other drugs such as rifampin that increase the apparent clearance of lamotrigine). In the clinical trials, doses up to 400 mg/day as monotherapy were evaluated; however, no additional benefit was seen at 400 mg/day compared with 200 mg/day [see Clinical Studies (14.2)]. Accordingly, doses above 200 mg/day are not recommended. Treatment with lamotrigine tablets is introduced, based on concurrent medications, according to the regimen outlined in Table 5. If other psychotropic medications are withdrawn following stabilization, the dose of lamotrigine tablets should be adjusted. For patients discontinuing valproate, the dose of lamotrigine tablets should be doubled over a 2-week period in equal weekly increments (see Table 6). For patients discontinuing carbamazepine, phenytoin, phenobarbital, primidone or other drugs such as rifampin that induce lamotrigine glucuronidation, the dose of lamotrigine tablets should remain constant for the first week and then should be decreased by half over a 2-week period in equal weekly decrements (see Table 6). The dose of lamotrigine tablets may then be further adjusted to the target dose (200 mg) as clinically indicated.
If other drugs are subsequently introduced, the dose of lamotrigine tablets may need to be adjusted. In particular, the introduction of valproate requires reduction in the dose of lamotrigine tablets [see Drug Interactions (7), Clinical Pharmacology (12.3)].
To avoid an increased risk of rash, the recommended initial dose and subsequent dose escalations of lamotrigine tablets should not be exceeded [see Boxed Warning].
Table 5. Escalation Regimen for Lamotrigine Tablets for Patients with Bipolar Disorder
*
Valproate has been shown to inhibit glucuronidation and decrease the apparent clearance of lamotrigine
[see Drug Interactions (7), Clinical Pharmacology (12.3)].
†
These drugs induce lamotrigine glucuronidation and increase clearance
[see Drug Interactions (7), Clinical Pharmacology (12.3)]. Other drugs that have similar effects include estrogen-containing oral contraceptives
[see Drug Interactions (7), Clinical Pharmacology (12.3)]. Dosing recommendations for oral contraceptives can be found in General Dosing Considerations
[see Dosage and Administration (2.1)]. Patients on rifampin, or other drugs that induce lamotrigine glucuronidation and increase clearance, should follow the same dosing titration/maintenance regimen as that used with anticonvulsants that have this effect.
For Patients TAKINGValproate*
For Patients NOT TAKING Carbamazepine, Phenytoin, Phenobarbital, Primidone† or Valproate*
For Patients TAKING Carbamazepine, Phenytoin, Phenobarbital or Primidone† and NOT TAKING Valproate*
Weeks 1 and 2
25 mg every other day
25 mg daily
50 mg daily
Weeks 3 and 4
25 mg daily
50 mg daily
100 mg daily, in divided doses
Week 5
50 mg daily
100 mg daily
200 mg daily, in divided doses
Week 6
100 mg daily
200 mg daily
300 mg daily, in divided doses
Week 7
100 mg daily
200 mg daily
up to 400 mg daily, in divided doses
Table 6. Dosage Adjustments to Lamotrigine Tablets for Patients with Bipolar Disorder Following Discontinuation of Psychotropic Medications
*
These drugs induce lamotrigine glucuronidation and increase clearance
[see Drug Interactions (7), Clinical Pharmacology (12.3)]. Other drugs that have similar effects include estrogen-containing oral contraceptives
[see Drug Interactions (7), Clinical Pharmacology (12.3)]. Dosing recommendations for oral contraceptives can be found in General Dosing Considerations
[see Dosage and Administration (2.1)]. Patients on rifampin, or other drugs that induce lamotrigine glucuronidation and increase clearance, should follow the same dosing titration/maintenance regimen as that used with anticonvulsants that have this effect.
†
Valproate has been shown to inhibit glucuronidation and decrease the apparent clearance of lamotrigine
[see Drug Interactions (7), Clinical Pharmacology (12.3)].
Discontinuation of Psychotropic Drugs (excluding Carbamazepine, Phenytoin, Phenobarbital, Primidone* or Valproate†)
After Discontinuation of Valproate†
After Discontinuation of Carbamazepine, Phenytoin, Phenobarbital or Primidone*
Current dose of lamotrigine tablets (mg/day) 100
Current dose of lamotrigine tablets (mg/day) 400
Week 1
Maintain current dose of lamotrigine tablets
150
400
Week 2
Maintain current dose of lamotrigine tablets
200
300
Week 3 onward
Maintain current dose of lamotrigine tablets
200
200
The benefit of continuing treatment in patients who had been stabilized in an 8- to 16-week open-label phase with lamotrigine tablets was established in two randomized, placebo-controlled clinical maintenance trials [see Clinical Studies (14.2)]. However, the optimal duration of treatment with lamotrigine tablets has not been established. Thus, patients should be periodically reassessed to determine the need for maintenance treatment.