Rare cases of liver failure, some leading to death or liver transplant, have occurred with the use of LAMISIL® (terbinafine hydrochloride tablets) Tablets for the treatment of onychomycosis in individuals with and without pre-existing liver disease.

In the majority of liver cases reported in association with LAMISIL® use, the patients had serious underlying systemic conditions and an uncertain causal association with LAMISIL®. The severity of hepatic events and/or their outcome may be worse in patients with active or chronic liver disease (see PRECAUTIONS). Treatment with LAMISIL® Tablets should be discontinued if biochemical or clinical evidence of liver injury develops (see PRECAUTIONS below).

There have been isolated reports of serious skin reactions (e.g., Stevens-Johnson Ssyndrome and toxic epidermal necrolysis). If progressive skin rash occurs, treatment with LAMISIL® should be discontinued.

General

LAMISIL® (terbinafine hydrochloride tablets) Tablets are not recommended for patients with chronic or active liver disease. Before prescribing LAMISIL® Tablets, pre-existing liver disease should be assessed. Hepatotoxicity may occur in patients with and without pre-existing liver disease. Pretreatment serum transaminase (ALT and AST) tests are advised for all patients before taking LAMISIL® Tablets. Patients prescribed LAMISIL® Tablets should be warned to report immediately to their physician any symptoms of persistent nausea, anorexia, fatigue, vomiting, right upper abdominal pain or jaundice, dark urine or pale stools (see WARNINGS). Patients with these symptoms should discontinue taking oral terbinafine, and the patient's liver function should be immediately evaluated.

In patients with renal impairment (creatinine clearance <50 mL/ min), the use of LAMISIL® has not been adequately studied, and therefore, is not recommended (see CLINICAL PHARMACOLOGY, Pharmacokinetics).

During postmarketing experience, precipitation and exacerbation of cutaneous and systemic lupus erythematosus have been reported infrequently in patients taking LAMISIL®. LAMISIL® therapy should be discontinued in patients with clinical signs and symptoms suggestive of lupus erythematosus.

Changes in the ocular lens and retina have been reported following the use of LAMISIL® (terbinafine hydrochloride tablets) Tablets in controlled trials. The clinical significance of these changes is unknown.

Transient decreases in absolute lymphocyte counts (ALC) have been observed in controlled clinical trials. In placebo-controlled trials, 8/465 LAMISIL®-treated patients (1.7%) and 3/137 placebo-treated patients (2.2%) had decreases in ALC to below 1000/mm³ on two or more occasions. The clinical significance of this observation is unknown. However, in patients with known or suspected immunodeficiency, physicians should consider monitoring complete blood counts in individuals using LAMISIL® therapy for greater than six weeks.

Isolated cases of severe neutropenia have been reported. These were reversible upon discontinuation of LAMISIL®, with or without supportive therapy. If clinical signs and symptoms suggestive of secondary infection occur, a complete blood count should be obtained. If the neutrophil count is ≤ 1,000 cells/mm³, LAMISIL® should be discontinued and supportive management started.

Carcinogenesis, Mutagenesis, Impairment of Fertility

In a 28-month oral carcinogenicity study in rats, an increase in the incidence of liver tumors was observed in males at the highest dose tested, 69 mg/kg/day [2x the Maximum Recommended Human Dose (MRHD) based on AUC comparisons of the parent terbinafine]; however, even though dose-limiting toxicity was not achieved at the highest tested dose, higher doses were not tested.

The results of a variety of in vitro (mutations in E. coli and S. typhimurium, DNA repair in rat hepatocytes, mutagenicity in Chinese hamster fibroblasts, chromosome aberration and sister chromatid exchanges in Chinese hamster lung cells), and in vivo (chromosome aberration in Chinese hamsters, micronucleus test in mice) genotoxicity tests gave no evidence of a mutagenic or clastogenic potential. Oral reproduction studies in rats at doses up to 300 mg/kg/day (approximately 12x the MRHD based on body surface area comparisons, BSA) did not reveal any specific effects on fertility or other reproductive parameters. Intravaginal application of terbinafine hydrochloride at 150 mg/day in pregnant rabbits did not increase the incidence of abortions or premature deliveries nor affect fetal parameters.

Pregnancy

Pregnancy Category B: Oral reproduction studies have been performed in rabbits and rats at doses up to 300 mg/kg/day (12x to 23x the MRHD, in rabbits and rats, respectively, based on BSA) and have revealed no evidence of impaired fertility or harm to the fetus due to terbinafine. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, and because treatment of onychomycosis can be postponed until after pregnancy is completed, it is recommended that LAMISIL® not be initiated during pregnancy.

Nursing Mothers

After oral administration, terbinafine is present in breast milk of nursing mothers. The ratio of terbinafine in milk to plasma is 7:1. Treatment with LAMISIL® is not recommended in nursing mothers.

Pediatric Use

The safety and efficacy of LAMISIL® have not been established in pediatric patients.

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