CLINICAL PHARMACOLOGY
Pharmacokinetics
Following oral administration, terbinafine is well absorbed (>70%) and the bioavailability of LAMISIL® (terbinafine hydrochloride) Tablets as a result of first-pass metabolism is approximately 40%. Peak plasma concentrations of 1 µg/mL appear within 2 hours 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 hours 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.
Microbiology
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
ANIMAL TOXICOLOGY
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 2-3x those seen in humans at the MRHD. Higher doses were not tested.
Distributed by:
Novartis Pharmaceuticals Corporation
East Hanover, New Jersey 07936
REV: NOVEMBER 2005 T2005-69
5000561
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