Terbinafine Hydrochloride
FDA Label NDC 21695-630

Terbinafine Hydrochloride Tablets contain the synthetic allylamine antifungal compound terbinafine hydrochloride USP.

Chemically, terbinafine hydrochloride is (E)-

N

-(6,6-dimethyl-2-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:

Chemical Structure (Dfb8fc2d 4899 4891 A985 755fbdf1d525 01)

Terbinafine hydrochloride USP 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.

Each tablet contains:

Active Ingredients:

 Terbinafine hydrochloride USP (equivalent to 250 mg base)

Inactive Ingredients:

  Microcrystalline cellulose, sodium starch glycolate, colloidal silicon dioxide, hypromellose, magnesium stearate

INDICATIONS AND USAGE

section:

Trichophyton mentagrophytes

Trichophyton rubrum

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:

Candida albicans
Epidermophyton floccosum
Scopulariopsis brevicaulis

Terbinafine hydrochloride 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

).

Prior to initiating treatment, appropriate nail specimens for laboratory testing (KOH preparation, fungal culture, or nail biopsy) should be obtained to confirm the diagnosis of onychomycosis.

Terbinafine hydrochloride tablets are contraindicated in individuals with hypersensitivity to terbinafine or to any other ingredients of the formulation.

Rare cases of liver failure, some leading to death or liver transplant, have occurred with the use of terbinafine hydrochloride 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 terbinafine hydrochloride use, the patients had serious underlying systemic conditions and an uncertain causal association with terbinafine hydrochloride. The severity of hepatic events and/or their outcome may be worse in patients with active or chronic liver disease (see

PRECAUTIONS

). Treatment with terbinafine hydrochloride 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 syndrome and toxic epidermal necrolysis). If progressive skin rash occurs, treatment with terbinafine hydrochloride should be discontinued.

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 terbinafine hydrochloride has not been adequately studied, and therefore, is not recommended (see

CLINICAL PHARMACOLOGY, Pharmacokinetics

).

During post-marketing experience, precipitation and exacerbation of cutaneous and systemic lupus erythematosus have been reported infrequently in patients taking terbinafine hydrochloride. Terbinafine hydrochloride 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 terbinafine hydrochloride 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 terbinafine hydrochloride-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 terbinafine hydrochloride therapy for greater than six weeks.

Isolated cases of severe neutropenia have been reported. These were reversible upon discontinuation of terbinafine hydrochloride, 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

, terbinafine hydrochloride should be discontinued and supportive management started.

In vivo

studies have shown that terbinafine is an inhibitor of the CYP450 2D6 isozyme. Drugs predominantly metabolized by the CYP450 2D6 isozyme include the following drug classes: tricyclic antidepressants, selective serotonin reuptake inhibitors, beta-blockers, antiarrhythmics class 1C (e.g., flecainide and propafenone) and monoamine oxidase inhibitors Type B. Coadministration of terbinafine hydrochloride should be done with careful monitoring and may require a reduction in dose of the 2D6-metabolized drug. In a study to assess the effects of terbinafine on desipramine in healthy volunteers characterized as normal metabolizers, the administration of terbinafine resulted in a 2-fold increase in C

_max

and a 5-fold increase in AUC. In this study, these effects were shown to persist at the last observation at 4 weeks after discontinuation of terbinafine hydrochloride.

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 healthy volunteer subjects showed that terbinafine does not affect the clearance of antipyrine or digoxin.

Terbinafine decreases the clearance of caffeine by 19%. Terbinafine increases the clearance of cyclosporine by 15%.

There have been spontaneous reports of increase or decrease in prothrombin times in patients concomitantly taking oral terbinafine and warfarin, however, a causal relationship between terbinafine hydrochloride

tablets and these changes has not been established.

Terbinafine clearance is increased 100% by rifampin, a CYP450 enzyme inducer, and decreased 33% by cimetidine, a CYP450 enzyme inhibitor. 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, and calcium channel blockers.

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 [2 x 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 12 x 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 Category B

Oral reproduction studies have been performed in rabbits and rats at doses up to 300 mg/kg/day (12 x to 23 x 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 terbinafine hydrochloride 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 terbinafine hydrochloride is not recommended in nursing mothers.

The safety and efficacy of terbinafine hydrochloride 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.

Adverse events, based on worldwide experience with terbinafine hydrochloride tablets use, include: idiosyncratic and symptomatic hepatic injury and more rarely, cases of liver failure, some leading to death or liver transplant, (see

WARNINGS

 and

PRECAUTIONS

), serious skin reactions (see

WARNINGS

), severe neutropenia (see

PRECAUTIONS

), thrombocytopenia, angioedema and allergic reactions (including anaphylaxis). Psoriasiform eruptions or exacerbation of psoriasis, acute generalized exanthematous pustulosis and precipitation and exacerbation of cutaneous and systemic lupus erythematosus have been reported in patients taking terbinafine hydrochloride tablets. Terbinafine hydrochloride tablets may cause taste disturbance (including taste loss) which usually recovers within several weeks after discontinuation of the drug. There have been reports of prolonged (greater than one year) taste disturbance. Taste disturbances associated with oral terbinafine have been reported to be severe enough to result in decreased food intake leading to significant and unwanted weight loss.

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 terbinafine hydrochloride tablets and agranulocytosis (rare).

Clinical experience regarding overdose with terbinafine hydrochloride 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.

Terbinafine hydrochloride tablets, one 250 mg tablet, should be taken once daily for 6 weeks by patients with fingernail onychomycosis. Terbinafine hydrochloride tablets, 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.