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HIGHLIGHTS OF PRESCRIBING INFORMATION |
These highlights do not include all the information needed to use LAMICTAL XR safely and effectively. See full prescribing information for LAMICTAL XR.
LAMICTAL XR (lamotrigine) Extended-Release Tablets
Initial U.S. Approval: 1994
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WARNING: SERIOUS SKIN RASHES
See full prescribing information for complete boxed warning.
Cases of life-threatening serious rashes, including Stevens-Johnson syndrome, toxic-epidermal necrolysis, and/or rash-related death, have been caused by lamotrigine. The rate of serious rash is greater in pediatric patients than in adults. Additional factors that may increase the risk of rash include (5.1):
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coadministration with valproate
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exceeding recommended initial dose of LAMICTAL XR
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exceeding recommended dose escalation of LAMICTAL XR
Benign rashes are also caused by lamotrigine; however, it is not possible to predict which rashes will prove to be serious or life-threatening. LAMICTAL XR should be discontinued at the first sign of rash unless the rash is clearly not drug-related. (5.1)
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INDICATIONS AND USAGE
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LAMICTAL XR is an antiepileptic drug (AED) indicated as adjunctive therapy for partial onset seizures with or without secondary generalization in patients ≥13 years of age. (1.1)
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DOSAGE AND ADMINISTRATION
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Doses are administered once daily. Dose escalation and maintenance doses are based on concomitant medications. (2.1, 2.2)
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To avoid an increased risk of rash, the recommended initial dose and subsequent dose escalations should not be exceeded. LAMICTAL XR Patient Titration Kits are available for the first 5 weeks of treatment. (2.1, 16)
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For patients being converted from immediate-release lamotrigine to LAMICTAL XR, the initial dose of LAMICTAL XR should match the total daily dose of the immediate-release lamotrigine. Patients should be closely monitored for seizure control after conversion to LAMICTAL XR. (2.3)
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Do not restart LAMICTAL XR in patients who discontinued due to rash unless the potential benefits clearly outweigh the risks. (2.1, 5.1)
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Adjustments to maintenance doses will in most cases be required in patients starting or stopping estrogen-containing oral contraceptives. (2.1, 5.7)
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LAMICTAL XR should be discontinued over a period of at least 2 weeks (approximately 50% reduction per week). (2.1, 5.8)
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DOSAGE FORMS AND STRENGTHS
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Extended-Release Tablets: 25 mg, 50 mg, 100 mg, and 200 mg. (3.1, 16)
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CONTRAINDICATIONS
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Hypersensitivity to the drug or its ingredients. (Boxed Warning, 4)
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WARNINGS AND PRECAUTIONS
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Life-threatening serious rash, and/or rash-related death, may result. (Boxed Warning, 5.1)
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Hypersensitivity reaction may be fatal or life-threatening. Early signs of hypersensitivity (e.g., fever, lymphadenopathy) may present without rash; if signs present, patient should be eva luated immediately.
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LAMICTAL XR should be discontinued if alternate etiology for hypersensitivity signs is not found. (5.2)
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Acute multiorgan failure has resulted (some cases fatal). (5.3)
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Blood dyscrasias (e.g., neutropenia, thrombocytopenia, pancytopenia) may result, either with or without an associated hypersensitivity syndrome. (5.4)
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Suicidal behavior and ideation. (5.5)
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Medication errors involving LAMICTAL have occurred. In particular, the names LAMICTAL or lamotrigine can be confused with the names of other commonly used medications. Medication errors may also occur between the different formulations of LAMICTAL. (3.2, 5.6, 16, 17.9)
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ADVERSE REACTIONS
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Most common adverse reactions (treatment difference ≥4%, LAMICTAL XR - Placebo) are dizziness, tremor/intention tremor, cerebellar coordination/balance disorder, nausea, asthenic conditions (asthenia, fatigue, malaise), vertigo/positional vertigo, and diplopia. (6.1)
To report SUSPECTED ADVERSE REACTIONS, contact GlaxoSmithKline at 1-888-825-5249 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch
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DRUG INTERACTIONS
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Valproate increases lamotrigine concentrations more than 2-fold. (7, 12.3)
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Carbamazepine, phenytoin, phenobarbital, and primidone decrease lamotrigine concentrations by approximately 40%. (7, 12.3)
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Oral estrogen-containing contraceptives and rifampin also decrease lamotrigine concentrations by approximately 50%. (7, 12.3)
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USE IN SPECIFIC POPULATIONS
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Pediatric use: Safety and effectiveness in patients below the age of 13 have not been established. (8.4)
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Effectiveness of lamotrigine, used as adjunctive treatment for partial seizures, was not demonstrated in a small randomized, double-blind, placebo-controlled, withdrawal study in very young pediatric patients (1 to 24 months). (8.4)
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Hepatic impairment: Dosage adjustments required. (2.1)
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Healthcare professionals can enroll patients in the Lamotrigine Pregnancy Registry (1-800-336-2176). Patients can enroll themselves in the North American Antiepileptic Drug Pregnancy Registry (1-888-233-2334). (8.1)
September 2009
LXR:2PI
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See 17 for PATIENT COUNSELING INFORMATION and the FDA-approved Medication Guide |
Revised: 01/2010 |
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FULL PRESCRIBING INFORMATION: CONTENTS* |
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FULL PRESCRIBING INFORMATION
WARNING: SERIOUS SKIN RASHES
LAMICTAL® XR™ can cause serious rashes requiring hospitalization and discontinuation of treatment. The incidence of these rashes, which have included Stevens-Johnson syndrome, is approximately 0.8% (8 per 1,000) in pediatric patients (2 to 16 years of age) receiving the immediate-release formulation of LAMICTAL as adjunctive therapy for epilepsy and 0.3% (3 per 1,000) in adults on adjunctive therapy for epilepsy. In a prospectively followed cohort of 1,983 pediatric patients (2 to 16 years of age) with epilepsy taking the adjunctive immediate-release formulation of LAMICTAL, there was 1 rash-related death. LAMICTAL XR is not approved for patients under the age of 13 years. In worldwide postmarketing experience, rare cases of toxic epidermal necrolysis and/or rash-related death have been reported in adult and pediatric patients, but their numbers are too few to permit a precise estimate of the rate.
The risk of serious rash caused by treatment with LAMICTAL XR is not expected to differ from that with the immediate-release formulation of LAMICTAL. 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.
Other than age, there are as yet no factors identified that are known to predict the risk of occurrence or the severity of rash caused by LAMICTAL XR. There are suggestions, yet to be proven, that the risk of rash may also be increased by (1) coadministration of LAMICTAL XR with valproate (includes valproic acid and divalproex sodium), (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.
Nearly all cases of life-threatening rashes caused by the immediate-release formulation of LAMICTAL have occurred within 2 to 8 weeks of treatment initiation. However, isolated cases have occurred after prolonged treatment (e.g., 6 months). Accordingly, duration of therapy cannot be relied upon as means to predict the potential risk heralded by the first appearance of a rash.
Although benign rashes are also caused by LAMICTAL XR, it is not possible to predict reliably which rashes will prove to be serious or life-threatening. Accordingly, LAMICTAL XR should ordinarily be discontinued at the first sign of rash, unless the rash is clearly not drug-related. Discontinuation of treatment may not prevent a rash from becoming life-threatening or permanently disabling or disfiguring [see Warnings and Precautions (5.1)].
1 INDICATIONS AND USAGE
LAMICTAL XR is indicated as adjunctive therapy for partial onset seizures with or without secondary generalization in patients ≥13 years of age.
Safety and effectiveness of LAMICTAL XR for use in patients below the age of 13 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 of 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 [see Clinical 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
