Lamotrigine: uses, appearance and warnings

Lamotrigine extended-release tablets are indicated for: adjunctive therapy for primary generalized tonic-clonic seizures (PGTC) and partial-onset seizures with or without secondary generalization in patients aged 13 years and older. (1.1) conversion to monotherapy in patients aged 13 years and older with partial-onset seizures who are receiving treatment with a single antiepileptic drug (AED). (1.2) Limitation of use: Safety and effectiveness in patients younger than 13 years have not been established. (1.3) 1.1 Adjunctive Therapy Lamotrigine extended-release tablets are indicated as adjunctive therapy for primary generalized tonic-clonic (PGTC) seizures and partial-onset seizures with or without secondary generalization in patients aged 13 years and older. 1.2 Monotherapy Lamotrigine extended-release tablets are indicated for conversion to monotherapy in patients aged 13 years and older with partial-onset seizures who are receiving treatment with a single antiepileptic drug (AED). Safety and effectiveness of lamotrigine extended-release tablets have not been established (1) as initial monotherapy or (2) for simultaneous conversion to monotherapy from 2 or more concomitant AEDs. 1.3 Limitation of Use Safety and effectiveness of lamotrigine extended-release tablets for use in patients younger than 13 years have not been established.

Extended-release tablets: 25 mg, 50 mg, 100 mg, 200 mg, 250 mg and 300 mg. (3.1, 16) 3.1 Extended-Release Tablets Lamotrigine extended-release tablets USP, 25 mg, are yellow, round shaped, film-coated tablets debossed with “A” above “949” on one side and plain on the other side. Lamotrigine extended-release tablets USP, 50 mg, are green, round shaped, film-coated tablets debossed with “A” above “956” on one side and plain on the other side. Lamotrigine extended-release tablets USP, 100 mg, are beige, round shaped, film-coated tablets debossed with “A” above “958” on one side and plain on the other side. Lamotrigine extended-release tablets USP, 200 mg, are blue, round shaped, film-coated tablets debossed with “A” above “986” on one side and plain on the other side. Lamotrigine extended-release tablets USP, 250 mg, are purple, capsule shaped, film-coated tablets debossed with “AN 988” on one side and plain on the other side. Lamotrigine extended-release tablets USP, 300 mg, are gray, capsule shaped, film-coated tablets debossed with “AN 990” on one side and plain on the other side.

Lamotrigine extended-release tablets USP, 25 mg, are supplied as yellow, round shaped, film-coated tablets debossed with “A” above “949” on one side and plain on the other side. They are available as follows: Bottles of 30: NDC 65162-949-03 Bottles of 90: NDC 65162-949-09 Lamotrigine extended-release tablets USP, 50 mg, are supplied as green, round shaped, film-coated tablets debossed with “A” above “956” on one side and plain on the other side. They are available as follows: Bottles of 30: NDC 65162-956-03 Bottles of 90: NDC 65162-956-09 Lamotrigine extended-release tablets USP, 100 mg, are supplied as beige, round shaped, film-coated tablets debossed with “A” above “958” on one side and plain on the other side. They are available as follows: Bottles of 30: NDC 65162-958-03 Bottles of 90: NDC 65162-958-09 Lamotrigine extended-release tablets USP, 200 mg, are supplied as blue, round shaped, film-coated tablets debossed with “A” above “986” on one side and plain on the other side. They are available as follows: Bottles of 30: NDC 65162-986-03 Bottles of 90: NDC 65162-986-09 Lamotrigine extended-release tablets USP, 250 mg, are supplied as purple, capsule shaped, film-coated tablets debossed with “AN 988” on one side and plain on the other side. They are available as follows: Bottles of 30: NDC 65162-988-03 Bottles of 90: NDC 65162-988-09 Lamotrigine extended-release tablets USP, 300 mg, are supplied as gray, capsule shaped, film-coated tablets debossed with “AN 990” on one side and plain on the other side. They are available as follows: Bottles of 30: NDC 65162-990-03 Bottles of 90: NDC 65162-990-09 Storage Store at 20° to 25°C (68° to 77°F); excursions permitted between 15° to 30°C (59° to 86°F) [see USP Controlled Room Temperature].

Lamotrigine extended-release tablets are 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, 5.3) ] . Hypersensitivity to the drug or its ingredients. (Boxed Warning, 4)

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 extended-release 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 (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 extended-release 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 extended-release could cause serious arrhythmias and/or death in patients with certain underlying cardiac disorders or arrhythmias. Any expected or observed benefit of lamotrigine extended-release 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 [see Boxed Warning] The risk of serious rash caused by treatment with lamotrigine extended-release is not expected to differ from that with immediate-release lamotrigine [see Boxed Warning ] . However, the relatively limited treatment experience with lamotrigine extended-release makes it difficult to characterize the frequency and risk of serious rashes caused by treatment with lamotrigine extended-release. 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, 1 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 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, 1.2% (6 of 482) experienced a serious rash compared with 0.6% (6 of 952) patients not taking valproate. Lamotrigine extended-release is not approved in patients younger than 13 years. 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 those associated with multiorgan hypersensitivity [see Warnings and Precautions (5.3) ] . Risk Factors Concomitant Use of Valproate 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 The risk of rash may be increased in patients with a history of allergy or rash to other AEDs. Not Adhering to the Recommended Dosage The risk of rash is increased by both exceeding the recommended initial dose of lamotrigine extended-release and exceeding the recommended dose escalation for lamotrigine extended-release. Patients with Genetic Variant Human Leukocyte Antigen (HLA)-B*1502 Allele Retrospective case-control studies in patients of certain Asian ancestry (e.g., Han Chinese and Thai) suggest that the HLA-B*1502 allele is associated with an increased risk (approximately 2 to 3 times higher) of developing Stevens-Johnson syndrome (SJS)/toxic epidermal necrolysis (TEN) in patients using lamotrigine. The risks and benefits of therapy should be weighed when considering use of lamotrigine extended-release in patients known to be positive for HLA-B*1502. Application of HLA genotyping as a screening tool has important limitations and must never substitute for appropriate clinical vigilance and patient management. …

The following serious adverse reactions are described in more detail in the Warnings and Precautions section of the labeling: Serious Skin Rashes [see Warnings and Precautions (5.1) ] Hemophagocytic Lymphohistiocytosis [see Warnings and Precautions (5.2) ] Multiorgan Hypersensitivity Reactions and Organ Failure [see Warnings and Precautions (5.3) ] Cardiac Rhythm and Conduction Abnormalities [see Warnings and Precautions (5.4) ] Blood Dyscrasias [see Warnings and Precautions (5.5) ] Suicidal Behavior and Ideation [see Warnings and Precautions (5.6) ] Aseptic Meningitis [see Warnings and Precautions (5.7) ] Withdrawal Seizures [see Warnings and Precautions (5.10) ] Status Epilepticus [see Warnings and Precautions (5.11) ] Most common adverse reactions with use as adjunctive therapy (treatment difference between lamotrigine extended-release and placebo ≥4%) were dizziness, tremor/intention …

Significant drug interactions with lamotrigine are summarized in this section. Additional details of these drug interaction studies, which were conducted using immediate-release lamotrigine, are provided in the Clinical Pharmacology section [see Clinical Pharmacology (12.3) ] . Uridine 5´-diphospho-glucuronyl transferases (UGT) have been identified as the enzymes responsible for metabolism of lamotrigine. Drugs that induce or inhibit glucuronidation may, therefore, affect the apparent clearance of lamotrigine. Strong or moderate inducers of the cytochrome P450 3A4 (CYP3A4) enzyme, which are also known to induce UGT, may also enhance the metabolism of lamotrigine. Those drugs that have been demonstrated to have a clinically significant impact on lamotrigine metabolism are outlined in Table 13. …