Terbinafine Hydrochloride (Page 3 of 4)

8.6 Renal Impairment

In patients with renal impairment (creatinine clearance less than or equal to 50 mL/min), the use of terbinafine tablets has not been adequately studied.

8.7 Hepatic Impairment

Terbinafine tablets are contraindicated for patients with chronic or active liver disease [see Contraindications (4) and Warnings and Precautions (5.1)]. Cases of liver failure, some leading to liver transplant or death, have occurred with the use of terbinafine tablets in individuals with and without preexisting liver disease. The severity of hepatic events and/or their outcome may be worse in patients with active or chronic liver disease.

10 OVERDOSAGE

Clinical experience regarding overdose with oral terbinafine 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.

11 DESCRIPTION

Terbinafine tablets, USP contain the synthetic allylamine antifungal compound terbinafine hydrochloride, USP.

Chemically, terbinafine hydrochloride, USP is (E)-N -(6,6-dimethyl-2-hepten-4-ynyl)-N -methyl-1-naphthalenemethanamine hydrochloride. The empirical formula C21 H26 ClN with a molecular weight of 327.90, and the following structural formula:

structure

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 Ingredient: terbinafine hydrochloride, USP (equivalent to 250 mg terbinafine)

Inactive Ingredients: colloidal silicon dioxide, ferric oxide, hypromellose, magnesium stearate, microcrystalline cellulose, and sodium starch glycolate.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Terbinafine is an allylamine antifungal [see Clinical Pharmacology (12.4) ].

12.2 Pharmacodynamics

The pharmacodynamics of terbinafine tablets is unknown.

12.3 Pharmacokinetics

Following oral administration, terbinafine is well absorbed (greater than 70%) and the bioavailability of terbinafine tablets as a result of first-pass metabolism is approximately 40%. Peak plasma concentrations of 1 mcg/mL appear within 2 hours after a single 250 mg dose; the AUC is approximately 4.56 mcg.h/mL. An increase in the AUC of terbinafine of less than 20% is observed when terbinafine tablets are administered with food.

In plasma, terbinafine is greater than 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 to 400 hours may represent the slow elimination of terbinafine from tissues such as skin and adipose. Prior to excretion, terbinafine is extensively metabolized by at least 7 CYP isoenzymes with major contributions from CYP2C9, CYP1A2, CYP3A4, CYP2C8, and CYP2C19. No metabolites have been identified that have antifungal activity similar to terbinafine. Approximately 70% of the administered dose is eliminated in the urine.

In patients with renal impairment (creatinine clearance less than or equal to 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. No clinically relevant age-dependent changes in steady-state plasma concentrations of terbinafine have been reported.

12.4 Microbiology

Terbinafine, an allylamine antifungal, inhibits biosynthesis of ergosterol, an essential component of fungal cell membrane, via inhibition of squalene epoxidase enzyme. This results in fungal cell death primarily due to the increased membrane permeability mediated by the accumulation of high concentrations of squalene but not due to ergosterol deficiency. 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:

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

13 NONCLINICAL TOXICOLOGY

13.1 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 (2 times the 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 (12 times the MRHD based on BSA comparisons) 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.

13.2 Animal Toxicology and/or Pharmacology

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 peroxisome proliferation in the liver is a rat-specific finding. However, other effects, including increased liver weights and APTT, occurred in dogs and monkeys at doses giving Css trough levels of the parent terbinafine 2 to 3 times those seen in humans at the MRHD. In a 52 week oral toxicology study conducted in juvenile maturing dogs, increased heart and liver weights were noted in males and signs of CNS disturbance including 3 cases of single episodes of seizures were noted in females at the highest dose tested, 100 mg/kg/day [19 times (males) and 10 times (females) the MRHD based on AUC comparisons of the parent terbinafine]. No treatment related findings were noted at 30 mg/kg/day [1.6 times (males) and 1.9 times (females) the MRHD based on AUC comparisons of the parent terbinafine] in this study.

14 CLINICAL STUDIES

The efficacy of terbinafine tablets in the treatment of onychomycosis is illustrated by the response of subjects with toenail and/or fingernail infections who participated in 3 US/Canadian placebo-controlled clinical trials.

Results of the first toenail trial, 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 subjects. Fifty-nine percent (59%) of subjects experienced effective treatment (mycological cure plus 0% nail involvement or greater than 5mm of new unaffected nail growth); 38% of subjects demonstrated mycological cure plus clinical cure (0% nail involvement).

In a second toenail trial of dermatophytic onychomycosis, in which nondermatophytes were also cultured, similar efficacy against the dermatophytes was demonstrated. The pathogenic role of the nondermatophytes cultured in the presence of dermatophytic onychomycosis has not been established. The clinical significance of this association is unknown.

Results of the fingernail trial, as assessed at week 24 (6 weeks of treatment with 18 weeks follow-up after completion of therapy), demonstrated mycological cure in 79% of subjects, effective treatment in 75% of the subjects, and mycological cure plus clinical cure in 59% of the subjects.

The mean time to overall success was approximately 10 months for the first toenail trial and 4 months for the fingernail trial. In the first toenail trial, for subjects evaluated at least 6 months after achieving clinical cure and at least 1 year after completing therapy with terbinafine tablets, the clinical relapse rate was approximately 15%.

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