Terbinafine Hydrochloride Tablets

Following oral administration, terbinafine is well absorbed (>70%) and the bioavailability of Terbinafine Hydrochloride 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 terbinafine hydrochloride 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 ≤ 50mL/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 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 not recommended for patients with chronic or active liver disease. Before prescribing Terbinafine Hydrochloride 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 Terbinafine Hydrochloride Tablets. Patients prescribed Terbinafine Hydrochloride 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 terbinafine hydrochloride 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 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/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 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/mm³, 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 Tablets 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 [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.

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 Tablets have not been established in pediatric patients.

Store between 20°–25°C (68°–77°F) (See USP Controlled Room Temperature); in a tight container.

Protect from light.