LAMOTRIGINE- lamotrigine tablet
Rebel Distributors Corp
LAMOTRIGINE 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 LAMOTRIGINE as adjunctive therapy for epilepsy and 0.3% (3 per 1,000) in adults on adjunctive therapy for epilepsy. In clinical trials of bipolar and other mood disorders, the rate of serious rash was 0.08% (0.8 per 1,000) in adult patients receiving LAMOTRIGINE as initial monotherapy and 0.13% (1.3 per 1,000) in adult patients receiving LAMOTRIGINE as adjunctive therapy. In a prospectively followed cohort of 1,983 pediatric patients (2 to 16 years of age) with epilepsy taking adjunctive LAMOTRIGINE, there was 1 rash-related death. 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.
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 LAMOTRIGINE. There are suggestions, yet to be proven, that the risk of rash may also be increased by (1) coadministration of LAMOTRIGINE with valproate (includes valproic acid and divalproex sodium), (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. Nearly all cases of life-threatening rashes caused by LAMOTRIGINE 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 LAMOTRIGINE, it is not possible to predict reliably which rashes will prove to be serious or life-threatening. Accordingly, LAMOTRIGINE 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)].
Adjunctive Therapy: LAMOTRIGINE is indicated as adjunctive therapy for the following seizure types in patients ≥2 years of age:
- partial seizures
- generalized seizures of Lennox-Gastaut syndrome
Monotherapy: LAMOTRIGINE is indicated for conversion to monotherapy in adults (≥16 years of age) with partial seizures who are receiving treatment with carbamazepine, phenytoin, phenobarbital, primidone, or valproate as the single antiepileptic drug (AED).
Safety and effectiveness of LAMOTRIGINE have not been established (1) as initial monotherapy; (2) for conversion to monotherapy from AEDs other than carbamazepine, phenytoin, phenobarbital, primidone, or valproate; or (3) for simultaneous conversion to monotherapy from 2 or more concomitant AEDs.
LAMOTRIGINE is indicated for the maintenance treatment of Bipolar I Disorder to delay the time to occurrence of mood episodes (depression, mania, hypomania, mixed episodes) in adults (≥18 years of age) treated for acute mood episodes with standard therapy. The effectiveness of LAMOTRIGINE in the acute treatment of mood episodes has not been established.
The effectiveness of LAMOTRIGINE as maintenance treatment was established in 2 placebo-controlled trials in patients with Bipolar I Disorder as defined by DSM-IV [see Clinical Studies (14.2)]. The physician who elects to prescribe LAMOTRIGINE for periods extending beyond 16 weeks should periodically re-evaluate the long-term usefulness of the drug for the individual patient.
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 of LAMOTRIGINE is exceeded and in patients with a history of allergy or rash to other AEDs.
LAMOTRIGINE Starter Kits provide LAMOTRIGINE at doses consistent with the recommended titration schedule for the first 5 weeks of treatment, based upon concomitant medications for patients with epilepsy (>12 years of age) and Bipolar I Disorder (≥18 years of age) and are intended to help reduce the potential for rash. The use of LAMOTRIGINE Starter Kits is recommended for appropriate patients who are starting or restarting LAMOTRIGINE [see How Supplied/Storage and Handling (16)].
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)].
LAMOTRIGINE 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 evaluated 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 LAMOTRIGINE may require adjustment based on clinical response.
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 LAMOTRIGINE 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 or Table 5). 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: For women not taking carbamazepine, phenytoin, phenobarbital, primidone, or rifampin, 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, 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 LAMOTRIGINE and not taking carbamazepine, phenytoin, phenobarbital, primidone, or rifampin, 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 or Table 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 rifampin, no adjustment should be necessary to the dose of LAMOTRIGINE.
(3) Stopping Estrogen-Containing Oral Contraceptives: For women not taking carbamazepine, phenytoin, phenobarbital, primidone, or rifampin, 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)]. For women taking LAMOTRIGINE in addition to carbamazepine, phenytoin, phenobarbital, primidone, or rifampin, 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 LAMOTRIGINE 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 LAMOTRIGINE should be based on patients’ concomitant medications (see Tables 1-3 or Table 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 re-evaluation 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 (5.9)].
Discontinuing carbamazepine, phenytoin, phenobarbital, or primidone 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 clinical trials in patients with Bipolar Disorder, 2 patients experienced seizures shortly after abrupt withdrawal of LAMOTRIGINE. However, there were confounding factors that may have contributed to the occurrence of seizures in these bipolar patients. 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 (5.9)].
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