Terbinafine

Following oral administration, terbinafine is rapidly absorbed and widely distributed to body tissues including the poorly perfused nail matrix. Nail terbinafine concentrations are detected within 1 week after starting therapy and persist for at least 30 weeks after the completion of treatment.

Randomized, double-blind trials showed oral terbinafine 250 mg/day for 12 or 16 weeks was more efficacious than itraconazole, fluconazole and griseofulvin in dermatophyte onychomycosis of the toenails. In particular, at 72 weeks’ follow-up, the multicenter, multinational, L.I.ON. (Lamisil® vs Itraconazole in ONychomycosis) study found that mycologic cure rates (76 vs 38% of patients after 12 weeks’ treatment; 81 vs 49% of recipients after 16 weeks’ therapy) and complete cure rates were approximately twice as high after terbinafine treatment than after itraconazole (3 or 4 cycles of 400 mg/day for 1 week repeated every 4 weeks) in patients with toenail mycosis. Furthermore, the L.I.ON. Icelandic Extension study demonstrated that terbinafine was more clinically effective than intermittent itraconazole to a statistically significant extent at 5-year follow-up. Terbinafine produced a superior complete cure rate (35 vs 14%), mycologic cure rate (46 vs 13%) and clinical cure rate (42 vs 18%) to that of itraconazole. The mycologic and clinical relapse rates were 23% and 21% in the terbinafine group, respectively, compared with 53% and 48% in the itraconazole group.

In comparative clinical trials, oral terbinafine had a better tolerability profile than griseofulvin and a comparable profile to that of itraconazole or fluconazole. Post marketing surveillance confirmed terbinafine’s good tolerability profile. Adverse events were experienced by 10.5% of terbinafine recipients, with gastrointestinal complaints being the most common. Unlike the azoles, terbinafine has a low potential for drug-drug interactions.

Most pharmacoeconomic evaluations have shown that the greater clinical effectiveness of oral terbinafine in dermatophyte onychomycosis translates into a cost-effectiveness ratio superior to that of itraconazole, fluconazole and griseofulvin.

Terbinafine is an orally and topically active, synthetic, allylamine, which passively diffuses into the poorly perfused target tissues of the nail matrix. Terbinafine inhibits the biosynthesis of the principal sterol in fungi, ergosterol, at the level of squalene epoxidase. Squalene epoxidase inhibition results in ergosterol-depleted fungal cell membranes (fungistatic effect) and the toxic accumulation of intracellular squalene (fungicidal effect). Terbinafine is selectively toxic because fungal squalene epoxidase is at least 1000 times more sensitive than the mammalian counterpart.

Despite the use of many in vitro techniques, terbinafine has consistently produced excellent in vitro activity against a wide range of dermatophytes with minimum inhibitory concentration (MIC) values typically ranging from 0.0015 to 0.01 mg/L (112 isolates). Terbinafine exhibited a primarily fungicidal effect on 39 dermatophytes with a geometric mean MIC and minimum fungicidal concentration value of 0.004 mg/L (MIC range 0.003 to 0.006 mg/L).

The MIC ranges of terbinafine against a range of non-dermatophyte molds were as follows: Scytalidium dimidiatum, 0.06 to 0.12 mg/L; S. hyalinum, 0.25 mg/L; Scopulariopsis brevicaulis, 0.5 to 2.0 mg/L; Acremonium spp., 0.25 to 8.0 mg/L; and Aspergillus spp., 0.03 to 0.25 mg/L.

In healthy volunteers and patients with onychomycosis, oral terbinafine (250 mg/day) exhibits predictable pharmacokinetics that can be described by a three-compartment model. A single dose of terbinafine 250mg achieves peak plasma concentrations (C_max) of ≈0.8 to 1.5 mg/L within 1.3 to 2 hours (t_max). The concomitant intake of food delayed t_max and slightly elevated C_max, resulting in a modestly increased area under the plasma concentration-time curve (AUC). In healthy volunteers and patients with onychomycosis, a multiple-dosage regimen of terbinafine 250 mg/day increased C_max values by ≈25% and AUC values by ≈ 2-fold at steady state.

Terbinafine is rapidly delivered to the poorly perfused tissues of the nail, stratum corneum, hair and dermisepidermis. Nail terbinafine concentrations are detected within 1 week after starting therapy and persist for at least 30 weeks after the completion of treatment.

Terbinafine undergoes extensive hepatic biotransformations, primarily phase I oxidation reactions. Phase II conjugation reactions render the oxidated metabolites more hydrophilic and facilitate elimination by urinary excretion. Compared with azole metabolism, terbinafine metabolism utilizes a small fraction of hepatic cytochrome P450 (CYP) capacity (>60 vs ≤5%). The initial elimination half-life (t_1/2ß ≈ 16 to 26 hours) is shorter than the terminal elimination half-life (t_1/2γ ≈90 hours) after a single dose. t_1/2γ was 22 days in patients who received 4 weeks of terbinafine 250 mg/day. Approximately 70 to 80% of a terbinafine dose is excreted in the urine (as metabolites) with the remainder being eliminated via the feces. Total plasma clearance of terbinafine is 76 L/h in healthy volunteers.

Unlike the azoles, terbinafine has a low potential for affecting the metabolism of other drugs because it has affinity for ≤5% of liver CYP. However, terbinafine is a potent CYP2D6 inhibitor and will affect the pharmacokinetic profile of other drugs that are substrates for this enzyme (e.g. thioridazine, desipramine, nortriptyline, paroxetine, venlafaxine, codeine and dextromethorphan) and the cardiovascular drugs metoprolol, encainide, flecainide, propafenone and mexilitine. In an open-label, randomized, crossover study involving 12 healthy volunteers, pretreatment with oral terbinafine (250 mg/day for 4 days) increased the AUC of theophylline (after a 5 mg/kg oral dose) by 16% (p = 0.03). Post marketing surveillance could not detect any drug interaction signals with oral antidiabetic agents, astemizole, terfenadine and cimetidine. Individual volunteer studies have failed to detect clinically significant interactions between oral terbinafine 250mg and warfarin 30mg, digoxin 0.75mg or terfenadine 60mg twice daily. In contrast to the azoles, terbinafine 250mg does not affect the time course of midazolam or triazolam or interact with protease inhibitors. Studies in healthy male volunteers (n = 20) and organ transplant recipients with tinea unguium (n = 11) suggest that the coadministration of terbinafine 250 mg/day has little effect on cyclosporin pharmacokinetics. Terbinafine clearance may be decreased when coadministered with cimetidine and increased by rifampin (rifampicin).

Randomized, double-blind trials have shown oral terbinafine (250 mg/day for 12 or 16 weeks) to be more effective than intermittent (3 or 4 cycles of 400 mg/day for 1 week every 4 weeks) or continuous (200 mg/day for 12 or 16 weeks) itraconazole and fluconazole (150 mg/week for 12 or 24 weeks) in dermatophyte onychomycosis of the toenails. Importantly, the complete, mycologic and clinical cure rates of terbinafine continued to increase after the completion of therapy.

The multicenter, multinational, L.I.ON. (Lamisil® vs Itraconazole in ONychomycosis) study found that the 12-week (and 16-week) terbinafine treatment regimen achieved complete and mycologic cure rates of 46% (55%) and 76% (81%), respectively, at the 72-week follow-up. The corresponding rates in the 3-month (and 4-month) itraconazole treatment group (400 mg/day for 1 week repeated every 4 weeks) were 23% (26%) and 38% (49%). All cure rates were higher in the terbinafine group than in the itraconazole group to a statistically significant extent (p < 0.01 for all comparisons).

In addition, the randomized, double-blind, L.I.ON. (Lamisil® vs Itraconazole in ONychomycosis) Icelandic Extension study (L.I.ON.I.E.S.) found that terbinafine produced a greater complete cure rate (35 vs 14%, p < 0.005), mycologic cure rate (46 vs 13%, p < 0.001) and clinical cure rate (42 vs 18%, p < 0.0024) than intermittent itraconazole in the treatment of dermatophyte onychomycosis at 5-year follow-up. The mycologic relapse rates were 23% in the terbinafine group compared with 53% in the itraconazole group (p < 0.01). The clinical relapse rate was 21% and 48% in the terbinafine and itraconazole groups, respectively (p < 0.05). All patients (n = 72) in the L.I.ON.I.E.S. who required a second treatment course received terbinafine, irrespective of whether they had received terbinafine or itraconazole initially. Importantly, 72% of these recipients achieved a complete cure. A meta-analysis of 26 published articles reported that oral terbinafine produced a disease-free toenail (normal-appearing nail plus mycologic cure) in approximately 35 to 50% of patients with onychomycosis compared with 25 to 40% of itraconazole recipients. Limited data suggest that oral terbinafine has good efficacy in the treatment of dermatophyte onychomycosis in patients with concomitant systemic disease.

Terbinafine is not well studied in onychomycosis involving yeasts and non-dermatophyte molds; notably though, ≈90% of fungal nail infections are caused by dermatophyte infections. Comparative (placebo-controlled) and noncomparative data suggest that terbinafine has efficacy in non-dermatophyte onychomycosis but further comparative studies involving the azoles are required to confirm these observations.

In comparative studies, oral terbinafine had a better tolerability profile than griseofulvin and a comparable profile to that of itraconazole or fluconazole. There is a rare incidence (<1 in 1000 and >1 in 10 000 exposures) of serious hepatic reactions and a very rare incidence (<1 in 10 000 exposures) of serious hematologic and dermatologic reactions associated with oral terbinafine treatment.

Oral terbinafine 250 mg/day was well tolerated in a large post marketing surveillance study involving >25 000 recipients treated for a median duration of 12 weeks. The percentage of patients who experienced adverse events was 10.5%; 4.9, 2.3 and 3.3% of patients experienced gastrointestinal, dermatologic and other events, respectively. Slightly more than half (55.9%) of all adverse events were considered by investigators to be possibly or probably related to terbinafine treatment. The adverse events tended to be reversible. The study found that approximately half of those who reported adverse events terminated terbinafine treatment prematurely (5.3% of patients). Treatment terminations were primarily due to gastrointestinal disorders (2.7% of patients).

Most pharmacoeconomic evaluations have shown that the greater clinical effectiveness of oral terbinafine in treating dermatophyte onychomycosis translates into a cost-effectiveness ratio superior to that of itraconazole, fluconazole and griseofulvin. In particular, pharmacoeconomic analysis based on clinical results of a randomized, double-blind trial showed that terbinafine had a lower cost-per-patient-cured ratio and produced a greater number of disease-free days than intermittent itraconazole despite the tolerability comparison being skewed in favor of itraconazole (1998 costs).

Terbinafine hydrochloride tablets are indicated for the treatment of onychomycosis of the toenail or fingernail due to dermatophytes (tinea unguium) and for the treatment of other superficial mycoses.

The usual adult dosage of terbinafine for the treatment of tinea unguium of the fingernail and toenail is 250 mg/day for 6 and 12 weeks, respectively. In most countries, terbinafine has not been licensed to treat onychomycosis in children. Terbinafine is not recommended in patients with chronic or active liver disease. There is no evidence to suggest that dosage adjustment is required in the elderly. However, a dosage adjustment may be required in patients who receive concomitant cimetidine or rifampin. Fingernails are usually re-evaluated 18 weeks or longer, and toenails are re-evaluated 6 to 9 months or longer, after completion of therapy. Clinical benefit is optimal some months after the completion of treatment and corresponds to the time required for healthy nail outgrowth. Some patients may benefit from extended and/or repeated courses of terbinafine therapy.