Lamotrigine

LAMOTRIGINE- lamotrigine tablet
Hikma Pharmaceutical

HIGHLIGHTS OF PRESCRIBING INFORMATION

HIGHLIGHTS OF PRESCRIBING INFORMATION

These highlights do not include all the information needed to use lamotrigine safely and effectively. See full prescribing information for lamotrigine.

Lamotrigine Tablets, USP

Initial U.S. Approval: 1994

———————-RECENT MAJOR CHANGES——————-­

Warnings and Precautions, Multiorgan Hypersensitivity July 2011

Reactions and Organ Failure (5.2)

Warnings and Precautions, Aseptic Meningitis (5.6) October 2010

————————— INDICATIONS AND USAGE ——————-­

Lamotrigine is an antiepileptic drug (AED) indicated for:

Epilepsyadjunctive therapy in patients ≥2 years of age: (1.1)

• partial seizures.

• primary generalized tonic-clonic seizures.

• generalized seizures of Lennox-Gastaut syndrome.

Epilepsy—monotherapy in patients16 years of age: conversion to monotherapy in patients with partial seizures who are receiving treatment with carbamazepine, phenobarbital, phenytoin, primidone, or valproate as the single AED. (1.1)

Bipolar Disorder in patients18 years of age: maintenance treatment of Bipolar I Disorder to delay the time to occurrence of mood episodes in patients treated for acute mood episodes with standard therapy. (1.2)

——————-DOSAGE AND ADMINISTRATION —————­

· Dosing is based on concomitant medications, indication, and patient age. (2.2, 2.4)

· To avoid an increased risk of rash, the recommended initial dose and subsequent dose escalations should not be exceeded.

· Do not restart lamotrigine in patients who discontinued due to rash unless the potential benefits clearly outweigh the risks. (2.1)

· Adjustments to maintenance doses will in most cases be required in patients starting or stopping estrogen-containing oral contraceptives. (2.1, 5.8)

· Lamotrigine should be discontinued over a period of at least 2 weeks (approximately 50% reduction per week). (2.1, 5.9)

Epilepsy

· Adjunctive therapy—See Table 1 for patients >12 years of age and Tables 2 and 3 for patients 2 to 12 years. (2.2)

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

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

——————DOSAGE FORMS AND STRENGTHS ————-­

Tablets: 25 mg, 100 mg, 150 mg, and 200 mg scored. (3.1, 16)

———————–CONTRAINDICATIONS———————–­

Hypersensitivity to the drug or its ingredients. (Boxed Warning, 4)

—————-WARNINGS AND PRECAUTIONS —————­

· Life-threatening serious rash and/or rash-related death may result. (Boxed Warning, 5.1)

· Fatal or life-threatening hypersensitivity reaction: Multiorgan hypersensitivity reactions, also known as Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) 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. (5.2)

· Blood dyscrasias (e.g., neutropenia, thrombocytopenia, pancytopenia: May occur, either with or without an associated hypersensitivity syndrome. (5.3)

· Suicidal behavior and ideation. (5.4)

· Clinical worsening, emergence of new symptoms, and suicidal ideation/behaviors may be associated with treatment of bipolar disorder. Patients should be closely monitored, particularly early in treatment or during dosage changes. (5.5)

· Aseptic meningitis reported in pediatric and adult patients. (5.6)

· Medication errors involving lamotrigine have occurred. In particular the name lamotrigine can be confused with names of other commonly used medications. (3.4, 5.7, 16, 17.10)

—————————ADVERSE REACTIONS ———————-­

· Most common adverse reactions (incidence ≥10%) in adult epilepsy clinical studies were dizziness, headache, diplopia, ataxia, nausea, blurred vision, somnolence, rhinitis, and rash. Additional adverse reactions (incidence ≥10%) reported in children in epilepsy clinical studies included vomiting, infection, fever, accidental injury, pharyngitis, abdominal pain, and tremor. (6.1)

· Most common adverse reactions (incidence >5%) in adult bipolar clinical studies were nausea, insomnia, somnolence, back pain, fatigue, rash, rhinitis, abdominal pain, and xerostomia. (6.1)

To report SUSPECTED ADVERSE REACTIONS, contact West-Ward Pharmaceuticals Corp. at 1-877-233-2001, or the FDA at 1-800-FDA-1088 or www.fda.gov/medwatch .

—————————DRUG INTERACTIONS———————–­

· Valproate increases lamotrigine concentrations more than 2-fold. (7, 12.3)

· Carbamazepine, phenytoin, phenobarbital, and primidone decrease lamotrigine concentrations by approximately 40%. (7, 12.3)

· Oral estrogen-containing contraceptives and rifampin also decrease lamotrigine concentrations by approximately 50%. (7, 12.3)

———————–USE IN SPECIFIC POPULATIONS —————­

· Hepatic impairment: Dosage adjustments required. (2.1)

· 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)

· Efficacy of lamotrigine, used as adjunctive treatment for partial seizures, was not demonstrated in a small randomized, double-blind, placebo-controlled study in very young pediatric patients (1 to 24 months). (8.4)

See 17 for PATIENT COUNSELING INFORMATION and Medication Guide.

BOXED WARNING

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):

· coadministration with valproate

· exceeding recommended initial dose of lamotrigine.

· exceeding recommended dose escalation of lamotrigine

Benign rashes are also caused by lamotrigine; however, it is not possible to predict which rashes will prove to be serious or life-threatening. Lamotrigine should be discontinued at the first sign of rash, unless the rash is clearly not drug-related. (5.1)

5 WARNINGS AND PRECAUTIONS

5.1 Serious Skin Rashes [see Boxed Warning]

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 16 years) with epilepsy receiving adjunctive therapy 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.

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 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 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 of lamotrigine is exceeded and in patients with a history of allergy or rash to other AEDs.

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