Mechanism of Action

Terbinafine is an allylamine antifungal.

Pharmacodynamics

The pharmacodynamics of Lamisil (terbinafine) is unknown.

Pharmacokinetics

Following oral administration, terbinafine is well absorbed ( > 70%) and the bioavailability of Lamisil (terbinafine) 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 (terbinafine) Tablets are administered with food.

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 by at least seven 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 ≤ 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.

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

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 2-3x those seen in humans at the MRHD. Higher doses were not tested.

Clinical Studies

The efficacy of Lamisil (terbinafine) Tablets in the treatment of onychomycosis is illustrated by the response of patients with toenail and/or fingernail infections who participated in three US/Canadian placebo-controlled clinical trials.

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

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

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

The mean time to overall success was approximately 10 months for the first toenail study and 4 months for the fingernail study. In the first toenail study, for patients evaluated at least six months after achieving clinical cure and at least one year after completing Lamisil (terbinafine) therapy, the clinical relapse rate was approximately 15%.

Patient Counseling Information

[See FDA-Approved Patient Labeling (PATIENT INFORMATION)]

Patients taking Lamisil (terbinafine) Tablets should receive the following information and instructions:

• Patients should take one 250 mg tablet once daily for 6 weeks for treatment of fingernail onychomycosis or once daily for 12 weeks for treatment of toenail onychomycosis. The optimal clinical effect is seen some months after mycological cure and cessation of treatment due to the time period required for outgrowth of healthy nail.
• Patients should be advised to immediately report to their physician any symptoms of persistent nausea, anorexia, fatigue, vomiting, right upper abdominal pain, jaundice, dark urine or pale stools. Lamisil (terbinafine) Tablets treatment should be discontinued.
• Patients should be advised to report to their physician any signs of taste disturbance, smell disturbance and/or depressive symptoms. Lamisil (terbinafine) Tablets treatment should be discontinued.
• Patients should be advised to immediately report to their physician or get emergency help if they experience any of the following symptoms: hives, mouth sores, blistering and peeling of skin, swelling of face, lips, tongue, or throat, difficulty swallowing or breathing. Lamisil (terbinafine) Tablets treatment should be discontinued.
• Patients should be advised to report to their physician any symptoms of new onset or worsening lupus erythematosus. Symptoms can include erythema, scaling, loss of pigment, and unusual photosensitivity that can result in a rash. Lamisil (terbinafine) treatment should be discontinued.
• Measurement of serum transaminases (ALT and AST) is advised for all patients before taking Lamisil (terbinafine) Tablets.
• Patients should be advised that if they forget to take Lamisil (terbinafine) Tablets, to take their tablets as soon as they remember, unless it is less than four hours before the next dose is due. Patients should also be advised that if they take too many Lamisil (terbinafine) Tablets they should call their physician.

Last reviewed on RxList: 5/19/2011
This monograph has been modified to include the generic and brand name in many instances.