lamotrigine (lamotrigine 25 mg) Dailymed

2. Dosage And Administration

·    Dosing is based on concomitant medications, indication, and patient age. (2.1, 2.2, 2.3, 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, 5.1)

·    Adjustments to maintenance doses will be necessary in most patients starting or stopping estrogen-containing oral contraceptives. (2.1, 5.9)

·    Discontinuation: Taper over a period of at least 2 weeks (approximately 50% dose reduction per week). (2.1, 5.10)

Epilepsy:  

·    Adjunctive therapy - See Table 1 for patients older than 12 years and Tables 2 and 3 for patients aged 2 to 12 years. (2.2)

·    Conversion to monotherapy - See Table 4. (2.3)

Bipolar disorder:  See Tables 5 and 6. (2.4)

2.1. General Dosing Considerations

Rash There are suggestions, yet to be proven, that the risk of severe, potentially life-threatening rash may be increased by (1) coadministration of lamotrigine with valproate, (2) exceeding the recommended initial dose of lamotrigine, or (3) exceeding the recommended dose escalation for lamotrigine. However, cases have occurred in the absence of these factors [see Boxed Warning]. Therefore, it is important that the dosing recommendations be followed closely. The risk of nonserious rash may be increased when the recommended initial dose and/or the rate of dose escalation for lamotrigine is exceeded and in patients with a history of allergy or rash to other AEDs. It is recommended that lamotrigine not be restarted in patients who discontinued due to rash associated with prior treatment with lamotrigine, unless the potential benefits clearly outweigh the risks. If the decision is made to restart a patient who has discontinued lamotrigine, the need to restart with the initial dosing recommendations should be assessed. The greater the interval of time since the previous dose, the greater consideration should be given to restarting with the initial dosing recommendations. If a patient has discontinued lamotrigine for a period of more than 5 half-lives, it is recommended that initial dosing recommendations and guidelines be followed. The half-life of lamotrigine is affected by other concomitant medications [see Clinical Pharmacology (12.3)]. L amotrigine 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, 2, 5, 6, and 13. Target Plasma Levels for Patients with Epilepsy or Bipolar Disorder A therapeutic plasma concentration range has not been established for lamotrigine. Dosing of lamotrigine should be based on therapeutic response [see Clinical Pharmacology (12.3)]. Women Taking Estrogen-Containing Oral Contraceptives Starting L amotrigine 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, 5, and 7). See below for adjustments to maintenance doses of lamotrigine in women taking estrogen-containing oral contraceptives. Adjustments to the Maintenance Dose of Lamotrigine in Women Taking Estrogen-Containing Oral Contraceptives: (1)      Taking Estrogen-Containing Oral Contraceptives:In women not taking carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin and the  protease inhibitors lopinavir/ritonavir and atazanavir/ritonavir that induce lamotrigine glucuronidation [see Drug Interactions (7), Clinical Pharmacology (12.3)], the maintenance dose of lamotrigine will in most cases need to be increased  by as much as 2-fold over the recommended target maintenance dose to maintain a consistent lamotrigine plasma level. (2)      Starting Estrogen-Containing Oral Contraceptives:In women taking a stable dose of lamotrigine and not taking carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin and the  protease inhibitors lopinavir/ritonavir and atazanavir/ritonavir that induce lamotrigine glucuronidation [see Drug Interactions (7), Clinical Pharmacology (12.3)], the maintenance dose will in most cases need to be as much as 2-fold, to maintain a consistent lamotrigine plasma level. The dose increases should begin at the same time that the oral contraceptive is introduced and continue, based on clinical response, no more rapidly than 50 to 100 mg/day every week. Dose increases should not exceed the recommended rate (see Tables 1 and  5) unless lamotrigine plasma levels or clinical response support larger increases. Gradual transient increases in lamotrigine plasma levels may occur during the week of inactive hormonal preparation (pill-free week), and these increases will be greater if dose increases are made in the days before or during the week of inactive hormonal preparation. Increased lamotrigine plasma levels could result in additional adverse reactions, such as dizziness, ataxia, and diplopia. If adverse reactions attributable to lamotrigine consistently occur during the pill-free week, dose adjustments to the overall maintenance dose may be necessary. Dose adjustments limited to the pill-free week are not recommended. For women taking lamotrigine in addition to carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin and the  protease inhibitors lopinavir/ritonavir and atazanavir/ritonavir that induce lamotrigine glucuronidation [see Drug Interactions (7), Clinical Pharmacology (12.3)], no adjustment to the dose of lamotrigine should be necessary. (3)      Stopping Estrogen-Containing Oral Contraceptives: In women not taking carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin and the  protease inhibitors lopinavir/ritonavir and atazanavir/ritonavir that induce lamotrigine glucuronidation [see Drug Interactions (7), Clinical Pharmacology (12.3)], the maintenance dose of lamotrigine will in most cases need to be decreased by as much as 50%, in order to maintain a consistent lamotrigine plasma level. The decrease in dose of lamotrigine should not exceed 25% of the total daily dose per week over a 2-week period, unless clinical response or lamotrigine plasma levels indicate otherwise [see Clinical Pharmacology (12.3)]. In women taking lamotrigine in addition to carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin and the  protease inhibitors lopinavir/ritonavir and atazanavir/ritonavir that induce lamotrigine glucuronidation [see Drug Interactions (7), Clinical Pharmacology (12.3)], no adjustment to the dose of lamotrigine should be necessary. Women and Other Hormonal Contraceptive Preparations or Hormone Replacement Therapy The effect of other hormonal contraceptive preparations or hormone replacement therapy on the pharmacokinetics of lamotrigine has not been systematically evaluated. It has been reported that ethinylestradiol, not progestogens, increased the clearance of lamotrigine up to 2-fold, and the progestin-only pills had no effect on lamotrigine plasma levels. Therefore, adjustments to the dosage of lamotriginein 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 to 3, and  5); reduced maintenance doses may be effective for patients with significant renal impairment [see Use in Specific Populations (8.7), Clinical Pharmacology (12.3)]. Few patients with severe renal impairment have been evaluated during chronic treatment with lamotrigine. 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 and the  protease inhibitors lopinavir/ritonavir and atazanavir/ritonavir that induce lamotrigine glucuronidation  should prolong the half-life of lamotrigine; discontinuing valproate should shorten the half-life of lamotrigine. Bipolar Disorder: In the controlled clinical trials, there was no increase in the incidence, type, or severity of adverse reactions following abrupt termination of lamotrigine. In the  clinical   development program  in adults  with bipolar disorder, 2 patients experienced seizures shortly after abrupt withdrawal of lamotrigine.  Discontinuation of lamotrigine should involve a step-wise reduction of dose over at least 2 weeks (approximately 50% per week) unless safety concerns require a more rapid withdrawal [see Warnings and Precautions (5.10)].

2.2. Epilepsy-Adjunctive Therapy

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

Patients Older than 12 Years  

Recommended dosing guidelines are summarized in Table 1. Table 1. Escalation Regimen for Lamotrigine in Patients Older than 12 Years with Epilepsy 

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

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

^b Drugs that induce lamotrigine glucuronidation and increase clearance, other than the specified antiepileptic drugs, include estrogen-containing oral contraceptives, rifampin, and the protease inhibitors lopinavir/ritonavir and atazanavir/ritonavir. Dosing recommendations for oral contraceptives and the protease inhibitor atazanavir/ritonavir can be found in General Dosing Considerations [see Dosage and Administration (2.1)]. Patients on rifampin and the protease inhibitor lopinavir/ritonavir should follow the same dosing titration/maintenance regimen used with antiepileptic drugs that induce glucuronidation and increase clearance [see Dosage and Administration (2.1), Drug Interactions (7), Clinical Pharmacology (12.3)].

Patients Aged 2 to 12 Years Recommended dosing guidelines are summarized in Table 2.Lower  starting doses and slower dose escalations than those used in clinical trials are recommended because of the suggestion that the risk of rash may be decreased by lower  starting doses and slower dose escalations. Therefore, maintenance doses will take longer to reach in clinical practice than in clinical trials. It may take several weeks to months to achieve an individualized maintenance dose. Maintenance doses in patients weighing <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 for oral suspension is 2 mg, and only whole tablets should be administered. If the calculated dose cannot be achieved using whole tablets, the dose should be rounded down to the nearest whole tablet    [see How Supplied/Storage and Handling (16) and Medication Guide]. Table 2. Escalation Regimen for Lamotrigine in Patients Aged 2 to 12 Years with Epilepsy 

	In Patients TAKING Valproatea	In Patients NOT TAKING Carbamazepine, Phenytoin, Phenobarbital, Primidoneb, 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/daywith 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  <30 kg	May need to be increased by as much as 50%, based on clinical response.	May need to be increased by as much as 50%, based on clinical response.	May need to be increased by as much as 50%, based on clinical response.

Note: Only whole tablets should be used for dosing.

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

^b Drugs that induce lamotrigine glucuronidation and increase clearance, other than the specified antiepileptic drugs, include estrogen-containing oral contraceptives, rifampin, and the protease inhibitors lopinavir/ritonavir and atazanavir/ritonavir. Dosing recommendations for oral contraceptives and the protease inhibitor atazanavir/ritonavir can be found in General Dosing Considerations [see Dosage and Administration (2.1)]. Patients on rifampin and the protease inhibitor lopinavir/ritonavir should follow the same dosing titration/maintenance regimen used with antiepileptic drugs that induce glucuronidation and increase clearance [see Dosage and Administration (2.1), Drug Interactions (7), Clinical Pharmacology (12.3)].

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

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

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

2.3. Epilepsy-Conversion from Adjunctive Therapy to Monotherapy

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

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

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

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

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

 

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

	Lamotrigine	Valproate
Step 1	Achieve a dose of 200 mg/day according to guidelines in Table 1.	Maintain established stable dose.
Step 2	Maintain at 200 mg/day.	Decrease dose by decrements no greater than 500 mg/day/week to 500 mg/day and then maintain for 1 week.
Step 3	Increase to 300 mg/day and maintain for 1 week.	Simultaneously decrease to 250 mg/day and maintain for 1 week.
Step 4	Increase by 100 mg/day every week to achieve maintenance dose of 500 mg/day.	Discontinue.

Conversion from Adjunctive Therapy with 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 lamotriginewith AEDs other than carbamazepine, phenytoin, phenobarbital, primidone, or valproate.

2.4. Bipolar Disorder

The goal of maintenance treatment with lamotrigine is to delay the time to occurrence of mood episodes (depression, mania, hypomania, mixed episodes) in patients treated for acute mood episodes with standard therapy [see Indications and Usage (1.2)].

Patients taking lamotrigine for more than 16 weeks should be periodically reassessed to determine the need for maintenance treatment.

Adults

The target dose of lamotrigine is 200 mg/day (100 mg/day in patients taking valproate, which decreases the apparent clearance of lamotrigine, and 400 mg/day in patients not taking valproate and taking either carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin and the  protease inhibitor lopinavir/ritonavir that increase the apparent clearance of lamotrigine). In the clinical trials, doses up to 400 mg/day as monotherapy were evaluated; however, no additional benefit was seen at 400 mg/day compared with 200 mg/day [see Clinical Studies (14.2)] . Accordingly, doses above 200 mg/day are not recommended.

Treatment with lamotrigine is introduced, based on concurrent medications, according to the regimen outlined in Table 5. If other psychotropic medications are withdrawn following stabilization, the dose of lamotrigine should be adjusted. In patients  discontinuing valproate, the dose of lamotrigine should be doubled over a 2-week period in equal weekly increments (see Table 6). In patients discontinuing carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin and the protease inhibitors lopinavir/ritonavir and atazanavir/ritonavir that induce lamotrigine glucuronidation, the dose of lamotrigine should remain constant for the first week and then should be decreased by half over a 2-week period in equal weekly decrements (see Table 6). The dose of lamotrigine may then be further adjusted to the target dose (200 mg) as clinically indicated.

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

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

Table 5. Escalation Regimen for Lamotrigine in Adults with Bipolar Disorder

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

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

^b Drugs that induce lamotrigine glucuronidation and increase clearance, other than the specified antiepileptic drugs, include estrogen-containing oral contraceptives, rifampin, and the protease inhibitors lopinavir/ritonavir and atazanavir/ritonavir. Dosing recommendations for oral contraceptives and the protease inhibitor atazanavir/ritonavir can be found in General Dosing Considerations [see Dosage and Administration (2.1)]. Patients on rifampin and the protease inhibitor lopinavir/ritonavir should follow the same dosing titration/maintenance regimen used with antiepileptic drugs that induce glucuronidation and increase clearance [see Dosage and Administration (2.1), Drug Interactions (7), Clinical Pharmacology (12.3)].

Table 6. Dosage Adjustments to Lamotrigine in Adults with Bipolar Disorder Following Discontinuation of Psychotropic Medications

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

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

^b Drugs that induce lamotrigine glucuronidation and increase clearance, other than the specified antiepileptic drugs, include estrogen-containing oral contraceptives, rifampin, and the protease inhibitors lopinavir/ritonavir and atazanavir/ritonavir. Dosing recommendations for oral contraceptives and the protease inhibitor atazanavir/ritonavir can be found in General Dosing Considerations [see Dosage and Administration (2.1)]. Patients on rifampin and the protease inhibitor lopinavir/ritonavir should follow the same dosing titration/maintenance regimen used with antiepileptic drugs that induce glucuronidation and increase clearance [see Dosage and Administration (2.1), Drug Interactions (7), Clinical Pharmacology (12.3)].

2.5. Administration of Lamotrigine Tablets for Oral Suspension

Lamotrigine tablets for oral suspension 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 for oral suspension, 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.

Phenylketonurics:Phenylalanine is a component of aspartame. Each lamotrigine tablets for oral suspension 5 mg and 25 mg contains 1.4 mg and 0.98 mg of phenylalanine, respectively.


• Life-threatening serious rash and/or rash-related death: Discontinue at the first sign of rash, unless the rash is clearly not drug related. (Boxed Warning, 5.1) • Hemophagocytic lymphohistiocytosis: Consider this diagnosis and evaluate patients immediately if they develop signs or symptoms of systemic inflammation. Discontinue lamotrigine if an alternative etiology is not established. (5.2) • Fatal or life-threatening hypersensitivity reaction: Multiorgan hypersensitivity reactions, also known as drug reaction with eosinophilia and systemic symptoms, may be fatal or life threatening. Early signs may include rash, fever, and lymphadenopathy. These reactions may be associated with other organ involvement, such as hepatitis, hepatic failure, blood dyscrasias, or acute multiorgan failure. Lamotrigine should be discontinued if alternate etiology for this reaction is not found. (5.3)

• Cardiac rhythm and conduction abnormalities: Based on in vitro findings, lamotrigine could cause serious arrhythmias and/or death in patients with certain underlying cardiac disorders or arrhythmias. Any expected or observed benefit of lamotrigine in an individual patient with clinically important structural or functional heart disease must be carefully weighed against the risk for serious arrythmias and/or death for that patient. (5.4)

• Blood dyscrasias (e.g., neutropenia, thrombocytopenia, pancytopenia): May occur, either with or without an associated hypersensitivity syndrome. Monitor for signs of anemia, unexpected infection, or bleeding. (5.5) • Suicidal behavior and ideation: Monitor for suicidal thoughts or behaviors. (5.6) • Aseptic meningitis: Monitor for signs of meningitis. (5.7) • Medication errors due to product name confusion: Strongly advise patients to visually inspect tablets to verify the received drug is correct. (5.8, 16, 17)

5.1. Serious Skin Rashes

Pediatric Population

The incidence of serious rash associated with hospitalization and discontinuation of lamotrigine in a prospectively followed cohort of pediatric patients (aged 2 to 17 years)is approximately 0.3% to 0.8%. One rash-related death was reported in a prospectively followed cohort of 1,983 pediatric patients (aged 2 to 16 years) with epilepsy taking lamotrigine as adjunctive therapy. Additionally, there have been rare cases of toxic epidermal necrolysis with and without permanent sequelae and/or death in U.S. and foreign postmarketing experience.

There is evidence that the inclusion of valproate in a multidrug regimen increases the risk of serious, potentially life-threatening rash in pediatric patients. In pediatric patients who used valproate concomitantly for epilepsy, 1.2% (6 of 482) experienced a serious rash compared with 0.6% (6 of 952) patients not taking valproate.

Adult Population Serious rash associated with hospitalization and discontinuation of lamotrigine occurred in 0.3% (11 of 3,348) of adult patients who received lamotrigine in premarketing clinical trials of epilepsy. In the bipolar and other mood disorders clinical trials, the rate of serious rash was 0.08% (1 of 1,233) of adult patients who received lamotrigine as initial monotherapy and 0.13% (2 of 1,538) of adult patients who received lamotrigine as adjunctive therapy. No fatalities occurred among these individuals. However, in worldwide postmarketing experience, rare cases of rash-related death have been reported, but their numbers are too few to permit a precise estimate of the rate.

Among the rashes leading to hospitalization were Stevens-Johnson syndrome, toxic epidermal necrolysis, angioedema, and those associated with multiorgan hypersensitivity [see Warnings and Precautions (5.3)]. 

There is evidence that the inclusion of valproate in a multidrug regimen increases the risk of serious, potentially life-threatening rash in adults. Specifically, of 584 patients administered lamotrigine with valproate in epilepsy clinical trials, 6 (1%) were hospitalized in association with rash; in contrast, 4 (0.16%) of 2,398 clinical trial patients and volunteers administered lamotrigine in the absence of valproate were hospitalized.

Patients with History of Allergy or Rash to Other Antiepileptic Drugs

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.  

5.2. Hemophagocytic Lymphohistiocytosis

Hemophagocytic lymphohistiocytosis (HLH) has occurred in pediatric and adult patients taking lamotrigine for various indications. HLH is a life-threatening syndrome of pathologic immune activation characterized by clinical signs and symptoms of extreme systemic inflammation. It is associated with high mortality rates if not recognized early and treated. Common findings include fever, hepatosplenomegaly, rash, lymphadenopathy, neurologic symptoms, cytopenias, high serum ferritin, hypertriglyceridemia, and liver function and coagulation abnormalities. In cases of HLH reported with lamotrigine, patients have presented with signs of systemic inflammation (fever, rash, hepatosplenomegaly, and organ system dysfunction) and blood dyscrasias. Symptoms have been reported to occur within 8 to 24 days following the initiation of treatment. Patients who develop early manifestations of pathologic immune activation should be evaluated immediately, and a diagnosis of HLH should be considered. Lamotrigine should be discontinued if an alternative etiology for the signs or symptoms cannot be established.

5.3. Multiorgan Hypersensitivity Reactions and Organ Failure

Multiorgan hypersensitivity reactions, also known as drug reaction with eosinophilia and systemic symptoms (DRESS) have occurred with lamotrigine. Some have been fatal or life-threatening. DRESS typically, although not exclusively, presents with fever, rash, and/or lymphadenopathy in association with other organ system involvement, such as hepatitis, nephritis, hematologic abnormalities, myocarditis, or myositis, sometimes resembling an acute viral infection. Eosinophilia is often present. This disorder is variable in its expression, and other organ systems not noted here may be involved. Fatalities associated with acute multiorgan failure and various degrees of hepatic failure have been reported in 2 of 3,796 adult patients and 4 of 2,435 pediatric patients who received lamotrigine in epilepsy clinical trials. Rare fatalities from multiorgan failure have also been reported in postmarketing use. Isolated liver failure without rash or involvement of other organs has also been reported with lamotrigine. It is important to note that early manifestations of hypersensitivity (e.g., fever, lymphadenopathy) may be present even though a rash is not evident. If such signs or symptoms are present, the patient should be evaluated immediately. Lamotrigine  should be discontinued if an alternative etiology for the signs or symptoms cannot be established. Prior to initiation of treatment with lamotrigine, the patient should be instructed that a rash or other signs or symptoms of hypersensitivity (e.g., fever, lymphadenopathy) may herald a serious medical event and that the patient should report any such occurrence to a healthcare provider immediately.

5.4 Cardiac Rhythm and Conduction Abnormalities

In vitro testing showed that lamotrigine exhibits Class IB antiarrhythmic activity at therapeutically relevant concentrations [see Clinical Pharmacology (12.2)]. Based on these in vitro findings, lamotrigine could slow ventricular conduction (widen QRS) and induce proarrhythmia, which can lead to sudden death, in patients with clinically important structural or functional heart disease (i.e., patients with heart failure, valvular heart disease, congenital heart disease, conduction system disease, ventricular arrhythmias, cardiac channelopathies [e.g., Brugada syndrome], clinically important ischemic heart disease, or multiple risk factors for coronary artery disease). Any expected or observed benefit of lamotrigine in an individual patient with clinically important structural or functional heart disease must be carefully weighed against the risks for serious arrythmias and/or death for that patient. Concomitant use of other sodium channel blockers may further increase the risk of proarrhythmia.

5.5. Blood Dyscrasias

There have been reports of blood dyscrasias that may or may not be associated with multiorgan hypersensitivity (also known as DRESS) [see Warnings and Precautions (5.3)]. These have included neutropenia, leukopenia, anemia, thrombocytopenia, pancytopenia, and, rarely, aplastic anemia and pure red cell aplasia.

5.6. Suicidal Behavior and Ideation

AEDs, including lamotrigine, increase the risk of suicidal thoughts or behavior in patients taking these drugs for any indication. Patients treated with any AED for any indication should be monitored for the emergence or worsening of depression, suicidal thoughts or behavior, and/or any unusual changes in mood or behavior.

Pooled analyses of 199 placebo-controlled clinical trials (monotherapy and adjunctive therapy) of 11 different AEDs showed that patients randomized to one of the AEDs had approximately twice the risk (adjusted Relative Risk 1.8, 95% CI:1.2, 2.7) of suicidal thinking or behavior compared with patients randomized to placebo. In these trials, which had a median treatment duration of 12 weeks, the estimated incidence of suicidal behavior or ideation among 27,863 AED-treated patients was 0.43%, compared with 0.24% among 16,029 placebo-treated patients, representing an increase of approximately 1 case of suicidal thinking or behavior for every 530 patients treated. There were 4 suicides in drug-treated patients in the trials and none in placebo-treated patients, but the number of events is too small to allow any conclusion about drug effect on suicide.

The increased risk of suicidal thoughts or behavior with AEDs was observed as early as 1 week after starting treatment with AEDs and persisted for the duration of treatment assessed. Because most trials included in the analysis did not extend beyond 24 weeks, the risk of suicidal thoughts or behavior beyond 24 weeks could not be assessed.

The risk of suicidal thoughts or behavior was generally consistent among drugs in the data analyzed. The finding of increased risk with AEDs of varying mechanism of action and across a range of indications suggests that the risk applies to all AEDs used for any indication. The risk did not vary substantially by age (5 to 100 years) in the clinical trials analyzed.

Table 7 shows absolute and relative risk by indication for all evaluated AEDs.

Table 7.   Risk by Indication for Antiepileptic Drugs in the Pooled Analysis 

Indication	Placebo Patients with Events per 1,000 Patients	Drug Patients with Events per 1,000 Patients	Relative Risk: Incidence of Events in Drug Patients / Incidence in Placebo Patients	Risk Difference: Additional Drug Patients with Events per 1,000 Patients
Epilepsy	1	3.4	3.5	2.4
Psychiatric	5.7	8.5	1.5	2.9
Other	1	1.8	1.9	0.9
Total	2.4	4.3	1.8	1.9

The relative risk for suicidal thoughts or behavior was higher in clinical trials for epilepsy than in clinical trials for psychiatric or other conditions, but the absolute risk differences were similar for the epilepsy and psychiatric indications. Anyone considering prescribing lamotrigine or any other AED must balance the risk of suicidal thoughts or behavior with the risk of untreated illness. Epilepsy and many other illnesses for which AEDs are prescribed are themselves associated with morbidity and mortality and an increased risk of suicidal thoughts and behavior. Should suicidal thoughts and behavior emerge during treatment, the prescriber needs to consider whether the emergence of these symptoms in any given patient may be related to the illness being treated. Patients, their caregivers, and families should be informed that AEDs increase the risk of suicidal thoughts and behavior and should be advised of the need to be alert for the emergence or worsening of the signs and symptoms of depression, any unusual changes in mood or behavior, the emergence of suicidal thoughts or suicidal  behavior, or thoughts about self-harm. Behaviors of concern should be reported immediately to healthcare providers.

5.7. Aseptic Meningitis

Therapy with lamotrigine increases the risk of developing aseptic meningitis. Because of the potential for serious outcomes of untreated meningitis due to other causes, patients should also be evaluated for other causes of meningitis and treated as appropriate. Postmarketing cases of aseptic meningitis have been reported in pediatric and adult patients taking lamotrigine for various indications. Symptoms upon presentation have included headache, fever, nausea, vomiting, and nuchal rigidity. Rash, photophobia, myalgia, chills, altered consciousness, and somnolence were also noted in some cases. Symptoms have been reported to occur within 1 day to one and a half months following the initiation of treatment. In most cases, symptoms were reported to resolve after discontinuation of lamotrigine. Re-exposure resulted in a rapid return of symptoms (from within 30 minutes to 1 day following reinitiation of treatment) that were frequently more severe. Some of the patients treated with lamotrigine who developed aseptic meningitis had underlying diagnoses of systemic lupus erythematosus or other autoimmune diseases. Cerebrospinal fluid (CSF) analyzed at the time of clinical presentation in reported cases was characterized by a mild to moderate pleocytosis, normal glucose levels, and mild to moderate increase in protein. CSF white blood cell count differentials showed a predominance of neutrophils in a majority of the cases, although a predominance of lymphocytes was reported in approximately one third of the cases. Some patients also had new onset of signs and symptoms of involvement of other organs (predominantly hepatic and renal involvement), which may suggest that in these cases the aseptic meningitis observed was part of a hypersensitivity reaction [see Warnings and Precautions (5.3)].

5.8. Potential Medication Errors

Medication errors involving lamotrigine have occurred. In particular, the name lamotrigine can be confused with the names of other commonly used medications. Medication errors may also occur between the different formulations of lamotrigine. To reduce the potential of medication errors, write and say lamotrigine clearly. Depictionsof the lamotrigine tablets for oral suspension, can be found in the Medication Guide that accompanies the product to highlight the distinctive markings, colors, and shapes that serve to identify the different presentations of the drug and thus may help reduce the risk of medication errors. To avoid the medication error of using the wrong drug or formulation, patients should be strongly advised to visually inspect their tablets to verify that they are lamotrigine, as well as the correct formulation of lamotrigine, each time they fill their prescription.

5.9. Concomitant Use with Oral Contraceptives

Some estrogen-containing oral contraceptives have been shown to decrease serum concentrations of lamotrigine [see Clinical Pharmacology (12.3)]. Dosage adjustments will be necessary in most patients who start or stop estrogen-containing oral contraceptives while taking lamotrigine [see Dosage and Administration (2.1)] . During the week of inactive hormone preparation (pill-free week) of oral contraceptive therapy, plasma lamotrigine levels are expected to rise, as much as doubling at the end of the week. Adverse reactions consistent with elevated levels of lamotrigine, such as dizziness, ataxia, and diplopia, could occur. 

5.10. Withdrawal Seizures

As with other AEDs, lamotrigine should not be abruptly discontinued. In patients with epilepsy there is a possibility of increasing seizure frequency. In clinical trials in adults  with bipolar disorder, 2 patients experienced seizures shortly after abrupt withdrawal of lamotrigine. Unless safety concerns require a more rapid withdrawal, the dose of lamotrigine should be tapered over a period of at least 2 weeks (approximately 50% reduction per week) [see Dosage and Administration (2.1)].

5.11. Status Epilepticus

Valid estimates of the incidence of treatment-emergent status epilepticus among patients treated with lamotrigine are difficult to obtain because reporters participating in clinical trials did not all employ identical rules for identifying cases. At a minimum, 7 of 2,343 adult patients had episodes that could unequivocally be described as status epilepticus. In addition, a number of reports of variably defined episodes of seizure exacerbation (e.g., seizure clusters, seizure flurries) were made.

5.12. Sudden Unexplained Death in Epilepsy (SUDEP)

During the premarketing development of lamotrigine, 20 sudden and unexplained deaths were recorded among a cohort of 4,700 patients with epilepsy (5,747 patient-years of exposure).

Some of these could represent seizure-related deaths in which the seizure was not observed, e.g., at night. This represents an incidence of 0.0035 deaths per patient-year. Although this rate exceeds that expected in a healthy population matched for age and sex, it is within the range of estimates for the incidence of sudden unexplained death in epilepsy (SUDEP)  in patients not receiving lamotrigine (ranging from 0.0005 for the general population of patients with epilepsy, to 0.004 for a recently studied clinical trial population similar to that in the clinical development program for lamotrigine, to 0.005 for patients with refractory epilepsy). Consequently, whether these figures are reassuring or suggest concern depends on the comparability of the populations reported upon with the cohort receiving lamotrigine and the accuracy of the estimates provided. Probably most reassuring is the similarity of estimated SUDEP rates in patients receiving lamotrigine and those receiving other AEDs, chemically unrelated to each other, that underwent clinical testing in similar populations. This evidence suggests, although it certainly does not prove, that the high SUDEP rates reflect population rates, not a drug effect.

5.13. Addition of Lamotrigine to a Multidrug Regimen that Includes Valproate

Because valproate reduces the clearance of lamotrigine, the dosage of lamotrigine in the presence of valproate is less than half of that required in its absence [see Dosage and Administration (2.2, 2.3, 2.4), Drug Interactions (7)].

5.14. Binding in the Eye and Other Melanin-Containing Tissues

Because lamotrigine binds to melanin, it could accumulate in melanin-rich tissues over time. This raises the possibility that lamotrigine may cause toxicity in these tissues after extended use. Although ophthalmological testing was performed in 1 controlled clinical trial, the testing was inadequate to exclude subtle effects or injury occurring after long-term exposure. Moreover, the capacity of available tests to detect potentially adverse consequences, if any, of lamotrigine’s binding to melanin is unknown [see Clinical Pharmacology (12.2)]. Accordingly, although there are no specific recommendations for periodic ophthalmological monitoring, prescribers should be aware of the possibility of long-term ophthalmologic effects.

5.15. Laboratory Tests

False-Positive Drug Test Results

Lamotrigine has been reported to interfere with the assay used in some rapid urine drug screens, which can result in false-positive readings, particularly for phencyclidine (PCP). A more specific analytical method should be used to confirm a positive result.

Plasma Concentrations of Lamotrigine 

The value of monitoring plasma concentrations of lamotrigine in patients treated with lamotrigine has not been established. Because of the possible pharmacokinetic interactions between lamotrigine and other drugs including AEDs (see Table 13), monitoring of the plasma levels of lamotrigine and concomitant drugs may be indicated, particularly during dosage adjustments. In general, clinical judgment should be exercised regarding monitoring of plasma levels of lamotrigine and other drugs and whether or not dosage adjustments are necessary.