Terbinafine

Summary

Synopsis

Terbinafine is an orally and topically active allylamine antifungal agent with a primarily fungicidal action in vitro. Its spectrum of in vitro activity includes a broad range of dermatophyte, filamentous, dimorphic and dematiaceous fungi, and some yeast species. In clinical trials, mycological and overall efficacy rates of around 90 and 80%, respectively, have been achieved in cutaneous dermatophyte infections (tinea corporis/cruris and tinea pedis) with terbinafine, administered either orally (250 or 500 mg/day) or topically (a 1% cream applied twice daily). Similar rates of cure have been obtained with oral terbinafine in dermatophyte nail infections after relatively short treatment periods ranging from 3 to 12 months. Topical terbinafine has been effective in approximately 80% of patients with cutaneous candidiasis or pityriasis versicolor. Few comparative data have been published, but generally oral terbinafine appeared to be at least as effective as oral griseofulvin or ketoconazole in tinea corporis/cruris and more effective than griseofulvin in tinea pedis. Both oral and topical terbinafine have been very well tolerated in clinical trials to date, with only minor adverse effects reported.

Although further research is required to establish the efficacy of terbinafine in comparison with other available therapies, as well as to fully clarify its tolerability profile, the early results obtained with terbinafine in superficial fungal infections are very encouraging. Terbinafine appears likely to become a first-line therapy for dermatophyte infections, particularly those affecting the nails.

Pharmacodynamic Properties

Terbinafine is an allylamine antifungal agent which appears to act by preventing fungal ergosterol biosynthesis via specific and selective inhibition of fungal squalene epoxidase.

In standard in vitro susceptibility tests terbinafine has demonstrated activity against a wide range of dermatophyte, filamentous, dimorphic and dematiaceous fungi, as well as yeasts. Terbinafine shows primarily fungicidal activity against dermatophytes, Aspergillus species, Scopulariopsis brevicaulis, Blastomyces dermatitidis, Histoplasma capsulatum and Candida parapsilosis at concentrations similar to MIC values, but is only fungistatic against C. albicans. In comparative in vitro tests, terbinafine was generally more active against dermatophytes and Aspergillus species than naftifine, ketoconazole, itraconazole, clotrimazole, econazole, griseofulvin, or amphotericin B, but was less active than the azole antifungal drugs against yeast species. Terbinafine also inhibits growth of the protozoan species Trypanosoma cruzi and Leishmania mexicana mexicana, in vitro.

Orally or topically administered terbinafine was effective in curing experimental cutaneous infections in animals caused by Trichophyton mentagrophytes or M. canis and topical terbinafine cured experimental cutaneous or vaginal C. albicans infections. However, the drug was ineffective in murine models of systemic sporotrichosis, candidiasis, phaeohyphomycosis, pulmonary aspergillosis and cryptococcal lung infection, despite showing good in vitro activity against the causative organisms.

In contrast to azole antifungal drugs, terbinafine is only weakly bound to cytochrome P450 and therefore does not interfere with steroid hormone production in the host and has little potential for interaction with other medications. Moreover, mammalian squalene epoxidase is considerably less sensitive than the fungal enzyme to inhibition by terbinafine.

Terbinafine inhibited platelet-derived growth factor-induced mitogenesis in smooth muscle cells and fibroblasts in vitro and reduced injury-induced neointimal thickening in the carotid artery in rats, suggesting in vivo inhibition of smooth muscle cell proliferation.

Pharmacokinetic Properties

Maximum plasma concentrations of approximately 0.8 and 1.7 to 2.0 mg/L are achieved within 2 hours of oral administration of terbinafine 250mg and 500mg, respectively. Steady-state plasma concentrations are reached in 10 to 14 days. The drug is extensively distributed to body tissues, with mean volumes of distribution of 220.6 and 726.9L for the central and peripheral compartments, respectively. Terbinafine rapidly accumulates in sebum, maintains high concen-trations in the stratum corneum and hair during oral administration and appears to diffuse readily into formed nail plate. Terbinafine is strongly bound to plasma proteins, including albumin and lipoprotein fractions. Because of the lipophilic properties of terbinafine, its elimination from adipose tissue occurs more slowly than from other tissues. The drug is also secreted into breast milk. Terbinafine undergoes extensive hepatic metabolism and is excreted primarily in the urine (approximately 80% of a dose), with the remainder in the faeces. Total plasma clearance of ter-binafine is approximately 75 L/h (1250 ml/min), and plasma elimination half-life values of 11 to 16 hours have been reported following administration of unlabelled drug, with an additional elimination phase of 90 to 100 hours being apparent following administration of radiolabelled terbinafine.

The pharmacokinetics of terbinafine in elderly subjects were similar to those in healthy young volunteers, but excretion of the drug was considerably slower in patients with impaired hepatic or renal function, resulting in markedly increased AUC values.

Following topical administration, penetration of terbinafine into the systemic circulation is minimal (> 5% of a dose).

Therapeutic Use

Clinical trials have demonstrated that terbinafine, administered either orally (250 or 500 mg/ day) or as a 1% topical cream (twice daily), is extremely effective in the treatment of dermatophyte infections of the skin, producing mycological cure in approximately 90% of patients with tinea corporis/cruris and tinea pedis (including chronic and/or recurrent infections), with an associated clinical cure in approximately 80% of cases. Oral terbinafine has also achieved similar rates of cure in dermatophyte fingernail and toenail infections after 3 to 12 months’ treatment.

Topical terbinafine has been effective in approximately 80% of patients with cutaneous candidiasis, with a mycological cure rate of 93%. Oral terbinafine is ineffective in the treatment of pityriasis versicolor, but topical therapy with the drug produces clinical and mycological cure in approximately 80% of patients.

The usual duration of treatment for fungal or yeast skin infections has been 2 to 4 weeks (topical therapy) or 3 to 6 weeks (oral therapy), but shorter courses of topical terbinafine (1 to 2 weeks) were as effective as standard-duration therapy in dermatomycoses.

Cure rates are generally higher at follow-up than at the end of terbinafine therapy and relapse rates are low (0% in the first month after treatment and 6 to 10% at 15 months), suggesting a residual, and possibly fungicidal, effect of the drug in the tissues.

Comparative data are limited, but oral terbinafine generally appeared to be at least as effective as oral griseofulvin or ketoconazole in tinea corporis (depending on the dosages compared) and considerably more effective than griseofulvin in tinea pedis, while topical terbinafine was more effective than topical clotrimazole in tinea pedis. Moreover, the rates of cure achieved with terbinafine in dermatophyte onychomycosis are markedly higher than would be expected with gri-seofulvin and the treatment period can be shortened considerably.

Tolerability

Adverse effects occurred in 10.4 and 11.5% of patients receiving terbinafine 250 and 500 mg/ day, respectively. These consisted mostly of gastrointestinal or cutaneous symptoms, or nonspecific effects such as tiredness or malaise.

Terbinafine cream 1 % has also been well tolerated in clinical trials, with only 2% of patients experiencing adverse effects (local irritation, erythema, burning and dryness).

Dosage and Administration

The recommended adult dosage of oral terbinafine is 250mg daily (as a single or divided dose), for 2 to 4 weeks (tinea corporis/cruris infections and cutaneous candidiasis), 2 to 6 weeks (tinea pedis) or 6 weeks to 12 months (fungal nail infections). Following mycological cure, complete clinical resolution may not be seen for several weeks in skin infections and several months in fungal nail infections. Dosage adjustment is required in those with severe hepatic or renal impairment (creatinine clearance < 3 L/h or serum creatinine > 300 µmol/L) and those receiving cimetidine or rifampicin.

For topical therapy of fungal skin infections, terbinafine 1% cream should be applied once or twice daily, for 1 to 2 weeks (tinea corporis/cruris and cutaneous candidiasis), 2 weeks (pityriasis versicolor) or 2 to 4 weeks (tinea pedis).