The following prescribing information is based on official labeling in effect July 2000.
Lamisil® (terbinafine hydrochloride tablets) Tablets contain the synthetic allylamine antifungal compound terbinafine hydrochloride.
Chemically, terbinafine hydrochloride is (E)- N -(6,6-dimethyl2-hepten-4-ynyl)- N -methyl-1-naphthalenemethanamine hydrochloride. The empirical formula C 21 H 26 CIN with a molecular weight of 327.90, and the following structural formula:
Terbinafine hydrochloride is a white to off-white fine crystalline powder. It is freely soluble in methanol and methylene chloride, soluble in ethanol, and slightly soluble in water.
Active Ingredients: terbinafine hydrochloride (equivalent to 250 mg base)
Inactive Ingredients: colloidal silicon dioxide, NF; hydroxypropyl methylcellulose, USP; magnesium stearate, NF; microcrystalline cellulose, NF; sodium starch glycolate, NF
Following oral administration, terbinafine is well absorbed (>70%) and the bioavailability of Lamisil® (terbinafine hydrochloride tablets) Tablets as a result of first-pass metabolism is approximately 40%. Peak plasma concentrations of 1 µg/mL appear within 2 h after a single 250 mg dose; the AUC (area under the curve) is approximately 4.56 µg·h/mL. An increase in the AUC of terbinafine of less than 20% is observed when Lamisil® is administered with food. No clinically relevant age-dependent changes in steady-state plasma concentrations of terbinafine have been reported. In patients with renal impairment (creatinine clearance </=50 mL/min) or hepatic cirrhosis, the clearance of terbinafine is decreased by approximately 50% compared to normal volunteers. No effect of gender on the blood levels of terbinafine was detected in clinical trials. In plasma, terbinafine is >99% bound to plasma proteins and there are no specific binding sites. At steady-state, in comparison to a single dose, the peak concentration of terbinafine is 25% higher and plasma AUC increases by a factor of 2.5; the increase in plasma AUC is consistent with an effective half-life of ~36 hours. Terbinafine is distributed to the sebum and skin. A terminal half-life of 200-400 h may represent the slow elimination of terbinafine from tissues such as skin and adipose. Prior to excretion, terbinafine is extensively metabolized. No metabolites have been identified that have antifungal activity similar to terbinafine. Approximately 70% of the administered dose is eliminated in the urine.
Terbinafine hydrochloride is a synthetic allylamine derivative. Terbinafine hydrochloride is hypothesized to act by inhibiting squalene epoxidase, thus blocking the biosynthesis of ergosterol, an essential component of fungal cell membranes. In vitro , mammalian squalene epoxidase is only inhibited at higher (4000 fold) concentrations than is needed for inhibition of the dermatophyte enzyme. Depending on the concentration of the drug and the fungal species test in vitro , terbinafine hydrochloride may be fungicidal. However, the clinical significance of in vitro data is unknown.
Terbinafine has been shown to be active against most strains of the following microorganisms both in vitro and in clinical infections as described in the section
The following in vitro data are available, but their clinical significance is unknown. In vitro , terbinafine exhibits satisfactory MIC's against most strains of the following microorganisms; however, the safety and efficacy of terbinafine in treating clinical infections due to these microorganisms have not been established in adequate and well-controlled clinical trials:
The efficacy of Lamisil® (terbinafine hydrochloride tablets) Tablets in the treatment of onychomycosis is illustrated by the response of patients with toenail and/or fingernail infections who participated in three US/Canadian placebocontrolled clinical trials.
Results of the first toenail study, as assessed at week 48 (12 weeks of treatment with 36 weeks follow-up after completion of therapy), demonstrated mycological cure, defined as simultaneous occurrence of negative KOH plus negative culture, in 70% of patients. Fifty-nine percent (59%) of patients experienced effective treatment (mycological cure plus 0% nail involvement or >5mm of new unaffected nail growth); 38% of patients demonstrated mycological cure plus clinical cure (0% nail involvement).
In a second toenail study of dermatophytic onychomycosis, in which non-dermatophytes were also cultured, similar efficacy against the dermatophytes was demonstrated. The pathogenic role of the non-dermatophytes cultured in the presence of dermatophytic onychomycosis has not been established. The clinical significance of this association is unknown.
Results of the fingernail study, as assessed at week 24 (6 weeks of treatment with 18 weeks follow-up after completion of therapy), demonstrated mycological cure in 79% of patients, effective treatment in 75% of the patients, and mycological cure plus clinical cure in 59% of the patients.
The mean time to overall success was approximately 10 months for the first toenail study and 4 months for the fingernail study. In the first toenail study, for patients evaluated at least six months after achieving clinical cure and at least one year after completing Lamisil® therapy, the clinical relapse rate was approximately 15%.
Lamisil® (terbinafine hydrochloride tablets) Tablets are indicated for the treatment of onychomycosis of the toenail or fingernail due to dermatophytes (tinea unguium) (see DOSAGE AND ADMINISTRATION and CLINICAL STUDIES ).
Lamisil® (terbinafine hydrochloride tablets) Tablets are contraindicated in individuals with hypersensitivity to terbinafine or to any other ingredients of the formulation.
Rare cases of symptomatic hepatobiliary dysfunction including cholestatic hepatitis have been reported. Treatment with Lamisil® (terbinafine hydrochloride tablets) Tablets should be discontinued if hepatobiliary dysfunction develops (see PRECAUTIONS and ADVERSE REACTIONS ). There have been isolated reports of serious skin reactions (e.g., Stevens-Johnson Syndrome and toxic epidermal necrolysis). If progressive skin rash occurs, treatment with Lamisil® should be discontinued.
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.
Hepatic function (hepatic enzyme) tests are recommended in patients administered Lamisil® (terbinafine hydrochloride tablets) Tablets for more than six weeks or in those who develop unexplained persistent nausea, anorexia, or fatigue or jaundice, dark urine, or pale stools (see ).
In patients with either pre-existing liver disease or renal impairment (creatinine clearance </=50 mL/min), the use of Lamisil® has not been adequately studied, and therefore, is not recommended (see , ).
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/mm 3 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/mm 3 , Lamisil® should be discontinued and supportive management started.
In vitro studies with human liver microsomes showed that terbinafine does not inhibit the metabolism of tolbutamide, ethinylestradiol, ethoxycoumarin, and cyclosporine. In vivo drug-drug interaction studies conducted in normal volunteer subjects showed that terbinafine does not affect the clearance of antipyrine, digoxin, and the antihistamine terfenadine. Terbinafine decreases the clearance of intravenously administered caffeine by 19%. Terbinafine increases the clearance of cyclosporine by 15%.
Terbinafine clearance is increased 100% by rifampin, a CyP450 enzyme inducer, and decreased 33% by cimetidine, a CyP450 enzyme inhibitor. Terbinafine exposure (AUC) is increased 16% by terfenadine. Terbinafine clearance is unaffected by cyclosporine.
There is no information available from adequate drug-drug interaction studies with the following classes of drugs: oral contraceptives, hormone replacement therapies, hypoglycemics, theophyllines, phenytoins, thiazide diuretics, beta blockers, and calcium channel blockers.
In a 28-month oral carcinogenicity study in rats, a marginal increase in the incidence of liver tumors was observed in males at the highest dose level, 69 mg/kg/day [3.6 × the Maximum Recommended Human Dose (MRHD) based on body surface area (BSA)]. There was no dose-related trend and the mid-dose male rats (20 mg/kg/day; 1.0 × the MRHD based on BSA) did not have any tumors. No increased incidence in liver tumors was noted in female rats at dose levels up to 97 mg/kg/day (4.5 × the MRHD based on BSA) or in male or female mice treated orally for 23 months at doses up to 156 mg/kg/day (3.9 × the MRHD based on BSA).
A wide range of in vivo studies in mice, rats, dogs, and monkeys, and in vitro studies using rat, monkey, and human hepatocytes suggest that the development of liver tumors in the high-dose male rats may be associated with peroxisome proliferation, and support the conclusion that this is a rat-specific finding. In vivo investigations included evaluations of the effects of Lamisil® on liver weight, morphology, and ultrastructure; hepatic cytochrome P450; and peroxisome proliferation assessed morphologically and biochemically (peroxisomal enzymes) in mice, rats, dogs, and monkeys. The effects of Lamisil® and two known metabolites on hepatic morphology and peroxisomal and P450 enzyme activities were also evaluated in vivo in male rats and in vitro in primary hepatocyte cultures from male rats and humans and from monkeys. The results of the in vivo investigations indicated that oral administration of Lamisil® (500 mg/kg/day) resulted in peroxisome proliferation in rats, and that these effects did not occur in mice, dogs, or monkeys. Further, in vitro studies indicated that peroxisome proliferation occurred in rat hepatocytes, but not in monkey or human hepatocytes.
Systemic exposure to Lamisil®, assessed by the steady-state plasma unbound fraction area under the curve (AUC) for terbinafine and metabolites, was 7.7 and 9.7 µg·h/mL for male and female rats, respectively, and 11.2 and 13.1 µg·h/mL for male and female mice, respectively, at doses comparable to the high doses in the carcinogenicity studies. In human subjects at the MRHD (a daily dose of 250 mg of Lamisil®), the unbound AUC was 0.466 µg·h/mL. The resulting safety margins for humans, based on relative systemic exposure (AUC unbound), in rats and mice were 17 to 21 and 24 to 28, respectively.
The results of a variety of in vitro (mutations in E. coli and Salmonella , 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 and demonstrated the absence of tumor-initiating or cell-proliferating activity.
Oral reproduction studies in rats at doses up to 300 mg/kg/day (approximately 12 × the MRHD based on 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 Category B: Oral reproduction studies have been performed in rabbits and rats at doses up to 300 mg/kg/day (9 × to 12 × 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.
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.
The safety and efficacy of Lamisil® have not been established in pediatric patients.
The most frequently reported adverse events observed in the three US/Canadian placebo-controlled trials are listed in the table below. The adverse events reported encompass gastrointestinal symptoms (including diarrhea, dyspepsia, and abdominal pain), liver test abnormalities, rashes, urticaria, pruritus, and taste disturbances. In general, the adverse events were mild, transient, and did not lead to discontinuation from study participation.
Rare adverse events, based on worldwide experience with Lamisil® (terbinafine hydrochloride tablets) Tablets use, include: symptomatic idiosyncratic hepatobiliary dysfunction (including cholestatic hepatitis and very rarely liver failure) (see and PRECAUTIONS ), serious skin reactions (see ), severe neutropenia (see PRECAUTIONS ), thrombocytopenia and allergic reactions (including anaphylaxis). Uncommonly, Lamisil® may cause taste disturbance (including taste loss) which usually recovers within several weeks after discontinuation of the drug.
Other adverse reactions which have been reported include malaise, fatigue, vomiting, arthralgia, myalgia, and hair loss.
Clinical adverse effects reported spontaneously since the drug was marketed include altered prothrombin time (prolongation and reduction) in patients concomitantly treated with warfarin and Lamisil® (terbinafine hydrochloride tablets) Tablets and agranulocytosis (very rare).
Clinical experience regarding overdose with Lamisil® (terbinafine hydrochloride tablets) Tablets is limited. Doses up to 5 grams (20 times the therapeutic daily dose) have been taken without inducing serious adverse reactions. The symptoms of overdose included nausea, vomiting, abdominal pain, dizziness, rash, frequent urination, and headache.
Lamisil® (terbinafine hydrochloride tablets) Tablets, one 250 mg tablet, should be taken once daily for 6 weeks by patients with fingernail onychomycosis. Lamisil®, one 250 mg tablet, should be taken once daily for 12 weeks by patients with toenail onychomycosis. The optimal clinical effect is seen some months after mycological cure and cessation of treatment. This is related to the period required for outgrowth of healthy nail.
(terbinafine hydrochloride tablets)
Supplied as white to yellow-tinged white circular, bi-convex, bevelled tablets containing 250 mg of terbinafine imprinted with "LAMISIL" in circular form on one side and code "250" on the other.
Bottles of 100 tablets
Bottles of 30 tablets
Store tablets below 25°C (77°F); in a tight container. Protect from light.
Novartis Pharmaceuticals Canada, Inc.
Dorval (Québec), Canada H9S 1A9
Novartis Pharmaceuticals Corporation
East Hanover, New Jersey 07936
REV: NOVEMBER 1999 T1999-71