1 INDICATIONS AND USAGE

1.1 Adjunctive Therapy

LAMICTAL XR is indicated as adjunctive therapy for primary generalized tonic-clonic (PGTC) seizures and partial onset seizures with or without secondary generalization in patients ≥13 years of age.

 1.2 Monotherapy

 LAMICTAL XR is indicated for conversion to monotherapy in patients ≥13 years of age with partial seizures who are receiving treatment with a single antiepileptic drug (AED).

 Safety and effectiveness of LAMICTAL XR have not been established (1) as initial monotherapy or (2) for simultaneous conversion to monotherapy from two or more concomitant AEDs.

1.3 Limitation of Use

Safety and effectiveness of LAMICTAL XR for use in patients less than 13 years of age have not been established.

2 DOSAGE AND ADMINISTRATION

LAMICTAL XR Extended-Release Tablets are taken once daily, with or without food. Tablets must be swallowed whole and must not be chewed, crushed, or divided.

2.1 General Dosing Considerations

Rash: There are suggestions, yet to be proven, that the risk of severe, potentially life-threatening rash may be increased by (1) coadministration of LAMICTAL XR with valproate, (2) exceeding the recommended initial dose of LAMICTAL XR, or (3) exceeding the recommended dose escalation for LAMICTAL XR. 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 LAMICTAL XR is exceeded and in patients with a history of allergy or rash to other AEDs.

LAMICTAL XR Patient Titration Kits provide LAMICTAL XR at doses consistent with the recommended titration schedule for the first 5 weeks of treatment, based upon concomitant medications for patients with partial onset seizures, and are intended to help reduce the potential for rash. The use of LAMICTAL XR Patient Titration Kits is recommended for appropriate patients who are starting or restarting LAMICTAL XR [see How Supplied/Storage and Handling (16)].

It is recommended that LAMICTAL XR 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 LAMICTAL XR, 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)].

LAMICTAL XR Added to Drugs Known to Induce or Inhibit Glucuronidation: Drugs other than those listed in the Clinical Pharmacology section [seeClinical Pharmacology(12.3)] have not been systematically eva luated 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 LAMICTAL XR may require adjustment based on clinical response.

Target Plasma Levels: A therapeutic plasma concentration range has not been established for lamotrigine. Dosing of LAMICTAL XR should be based on therapeutic response [see Clinical Pharmacology (12.3)].

Women Taking Estrogen-Containing Oral Contraceptives:Starting LAMICTAL XR 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 LAMICTAL XR 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 LAMICTAL XR based on the concomitant AED or other concomitant medications (see Table 1). See below for adjustments to maintenance doses of LAMICTAL XR in women taking estrogen-containing oral contraceptives.

Adjustments to the Maintenance Dose of LAMICTAL XR 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 LAMICTAL XR 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 LAMICTAL XR and not taking carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin that induce lamotrigine glucuronidation [see Drug Interactions (7), Clinical Pharmacology (12.3)], the maintenance dose will in most cases need to be increased by as much as 2-fold in order to maintain a consistent lamotrigine plasma level. The dose increases should begin at the same time that the oral contraceptive is introduced and continue, based on clinical response, no more rapidly than 50 to 100 mg/day every week. Dose increases should not exceed the recommended rate (see Table 1) unless lamotrigine plasma levels or clinical response support larger increases. Gradual transient increases in lamotrigine plasma levels may occur during the week of inactive hormonal preparation (pill-free week), and these increases will be greater if dose increases are made in the days before or during the week of inactive hormonal preparation. Increased lamotrigine plasma levels could result in additional adverse reactions, such as dizziness, ataxia, and diplopia. If adverse reactions attributable to LAMICTAL XR 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 LAMICTAL XR 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 LAMICTAL XR 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 LAMICTAL XR 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 LAMICTAL XR 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 LAMICTAL XR 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 LAMICTAL XR 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 eva luated. 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 LAMICTAL XR 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 LAMICTAL XR should be based on patients’ concomitant medications (see Table 1); reduced maintenance doses may be effective for patients with significant renal impairment [see Use in Specific Populations (8.7), Clinical Pharmacology (12.3)]. Few patients with severe renal impairment have been eva luated during chronic treatment with immediate-release lamotrigine. Because there is inadequate experience in this population, LAMICTAL XR should be used with caution in these patients.

Discontinuation Strategy: For patients receiving LAMICTAL XR in combination with other AEDs, a re-eva luation 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 LAMICTAL XR, 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.

2.2 Adjunctive Therapy for Primary Generalized Tonic-Clonic and Partial Onset Seizures

This section provides specific dosing recommendations for patients ≥13 years of age. Specific dosing recommendations are provided depending upon concomitant AED or other concomitant medications.

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

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

cDose increases at week 8 or later should not exceed 100 mg daily at weekly intervals.

 2.3 Conversion From Adjunctive Therapy to Monotherapy

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

 The recommended maintenance dosage range of LAMICTAL XR as monotherapy is 250 to 300 mg given once daily.

 The recommended initial dose and subsequent dose escalations for LAMICTAL XR should not be exceeded [see Boxed Warning].

 Conversion From Adjunctive Therapy With Carbamazepine, Phenytoin, Phenobarbital, or Primidone to Monotherapy With LAMICTAL XR: After achieving a dosage of 500 mg/day of LAMICTAL XR using the guidelines in Table 1, the concomitant enzyme-inducing AED should be withdrawn by 20% decrements each week over a 4-week period. Two weeks after completion of withdrawal of the enzyme-inducing AED, the dosage of LAMICTAL XR may be decreased no faster than 100 mg/day each week to achieve the monotherapy maintenance dosage range of 250 to 300 mg/day.

 The regimen for the withdrawal of the concomitant AED is based on experience gained in the controlled monotherapy clinical trial using immediate-release lamotrigine.

 Conversion From Adjunctive Therapy With Valproate to Monotherapy With LAMICTAL XR: The conversion regimen involves the 4 steps outlined in Table 2.

 Conversion From Adjunctive Therapy With Antiepileptic Drugs Other Than Carbamazepine, Phenytoin, Phenobarbital, Primidone, or Valproate to Monotherapy With LAMICTAL XR: After achieving a dosage of 250 to 300 mg/day of LAMICTAL XR using the guidelines in Table 1, the concomitant AED should be withdrawn by 20% decrements each week over a 4-week period. No adjustment to the monotherapy dose of LAMICTAL XR is needed.

2.4 Conversion From Immediate-Release Lamotrigine Tablets to LAMICTAL XR

Patients may be converted directly from immediate-release lamotrigine to LAMICTAL XR Extended-Release Tablets. The initial dose of LAMICTAL XR should match the total daily dose of immediate-release lamotrigine. However, some subjects on concomitant enzyme-inducing agents may have lower plasma levels of lamotrigine on conversion and should be monitored [see Clinical Pharmacology (12.3)].

Following conversion to LAMICTAL XR, all patients (but especially those on drugs that induce lamotrigine glucuronidation) should be closely monitored for seizure control [see Drug Interactions (7)]. Depending on the therapeutic response after conversion, the total daily dose may need to be adjusted within the recommended dosing instructions (Table 1).

3 DOSAGE FORMS AND STRENGTHS

3.1 Extended-Release Tablets

25 mg, yellow with white center, round, biconvex, film-coated tablets printed with “LAMICTAL” and “XR 25.”

50 mg, green with white center, round, biconvex, film-coated tablets printed with “LAMICTAL” and “XR 50.”

100 mg, orange with white center, round, biconvex, film-coated tablets printed with “LAMICTAL” and “XR 100.”

200 mg, blue with white center, round, biconvex, film-coated tablets printed with “LAMICTAL” and “XR 200.”

300 mg, gray with white center, caplet-shaped, film-coated tablets printed with “LAMICTAL” and “XR 300.”

3.2 Potential Medication Errors

Patients should be strongly advised to visually inspect their tablets to verify that they are receiving LAMICTAL XR, as opposed to other medications, and that they are receiving the correct formulation of lamotrigine each time they fill their prescription. Depictions of the LAMICTAL XR tablets can be found in the Medication Guide.

4 CONTRAINDICATIONS

LAMICTAL XR is contraindicated in patients who have demonstrated hypersensitivity (e.g., rash, angioedema, acute urticaria, extensive pruritus, mucosal ulceration) to the drug or its ingredients [see Boxed Warning, Warnings and Precautions (5.1, 5.2)].

5 WARNINGS AND PRECAUTIONS

5.1 Serious Skin Rashes

The risk of serious rash caused by treatment with LAMICTAL XR is not expected to differ from that with immediate-release lamotrigine [see Boxed Warning]. However, the relatively limited treatment experience with LAMICTAL XR makes it difficult to characterize the frequency and risk of serious rashes caused by treatment with LAMICTAL XR.

Pediatric Population: The incidence of serious rash associated with hospitalization and discontinuation of immediate-release lamotrigine in a prospectively followed cohort of pediatric patients (aged 2 to 16 years) with epilepsy receiving adjunctive therapy with immediate-release lamotrigine was approximately 0.8% (16 of 1,983).  When 14 of these cases were reviewed by 3 expert dermatologists, there was considerable disagreement as to their proper classification. To illustrate, one dermatologist considered none of the cases to be Stevens-Johnson syndrome; another assigned 7 of the 14 to this diagnosis. There was 1 rash-related death in this 1,983-patient cohort. Additionally, there have been rare cases of toxic epidermal necrolysis with and without permanent sequelae and/or death in US 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, 1.2% (6 of 482) experienced a serious rash compared with 0.6% (6 of 952) patients not taking valproate.

LAMICTAL XR is not approved in patients less than 13 years of age.

Adult Population: Serious rash associated with hospitalization and discontinuation of immediate-release lamotrigine occurred in 0.3% (11 of 3,348) of adult patients who received immediate-release lamotrigine in premarketing clinical trials of epilepsy. 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 a rash associated with a variable number of the following systemic manifestations: fever, lymphadenopathy, facial swelling, and hematologic and hepatologic abnormalities.

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 immediate-release 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 immediate-release lamotrigine in the absence of valproate were hospitalized.

Patients With History of Allergy or Rash to Other Antiepileptic Drugs: