Lamisil (Terbinafine)

Terbinafine is a systemic (oral) allylamine antifungal agent that inhibits squalene epoxidase, resulting in ergosterol biosynthesis inhibition and accumulation of squalene within the fungal cell, leading to fungal cell death. Terbinafine (Lamisil) 250 mg tablets are indicated for the treatment of onychomycosis of the toenail or fingernail due to dermatophytes.

Terbinafine (Lamisil) 250 mg tablets are a synthetic allylamine antifungal, structurally similar to naftifine.

Terbinafine (Lamisil) 250 mg tablets are well absorbed (>70%), but bioavailability is approximately 40% due to first-pass metabolism. In plasma, terbinafine is greater than 99% bound to plasma proteins. An effective half-life is ~36 hours; a terminal half-life of 200 to 400 hours may represent slow elimination from tissues such as skin and adipose. Terbinafine is distributed to the sebum and skin.

LAMISIL Tablets are contraindicated in patients with chronic or active liver disease. Use has not been adequately studied in patients with renal impairment (creatinine clearance ≤ 50 mL/min). Rifampin increases terbinafine clearance and cimetidine decreases terbinafine clearance. The drug is generally well tolerated; rare but serious adverse reactions can include hepatotoxicity, severe neutropenia, Stevens-Johnson syndrome, toxic epidermal necrolysis, and other serious skin reactions.

Available human data are insufficient to evaluate a drug-associated risk in pregnancy; because treatment of onychomycosis can usually be postponed, discuss use during pregnancy with a healthcare provider.

Terbinafine (Lamisil) 250 mg is given as one 250 mg tablet once daily. Fingernail onychomycosis: 6 weeks. Toenail onychomycosis: 12 weeks. The optimal clinical effect is typically seen several months after mycologic cure and completion of treatment as healthy nail grows out. In the US, oral terbinafine tablets are FDA-approved for onychomycosis; use for other fungal infections may be used off-label.

Terbinafine Hydrochloride: Uses

Onychomycosis

Terbinafine is used orally in the treatment of dermatophytic infections of the toenail or fingernail (onychomycosis, tinea unguium) caused by susceptible fungi. Prior to administration of oral terbinafine, appropriate nail specimens for microbiologic studies (e.g., potassium hydroxide [KOH] preparation, fungal culture, or nail biopsy) should be obtained to confirm the diagnosis of onychomycosis. The optimal clinical effect of terbinafine in the treatment of onychomycoses is seen several months after mycologic cure and completion of treatment, and is related to the period required for outgrowth of healthy nail.

Because terbinafine is highly lipophilic and keratophilic, the drug distributes in high concentrations into the stratum corneum, sebum, hair, and nail matrix, bed, and plate, persisting in these tissues for several weeks to months after discontinuance of the drug. Toenail infections generally require more prolonged terbinafine therapy than do fingernail infections.

Efficacy of terbinafine has been established in uncontrolled and placebo- or comparative drug-controlled studies in patients with toenail or fingernail onychomycosis. In these studies, patients were assessed for mycologic cure (negative observation of fungus in lesion scrapings prepared with potassium hydroxide, and negative culture of lesion scrapings), effective treatment (mycologic cure and either no nail involvement or more than 5 mm of unaffected new nail growth), or mycologic and clinical (no nail involvement) cure. Terbinafine has been shown to be active against most strains of Trichophyton rubrum and T. mentagrophytes both in vitro and in clinical infections of the nail. Although terbinafine is active in vitro against most strains of Epidermophyton floccosum, Candida albicans, and Scopulariopsis brevicaulis, efficacy of the drug in the treatment of onychomycosis caused by these organisms remains to be established in controlled clinical studies.

In the toenail studies, 12 weeks of oral therapy with terbinafine 250 mg daily was more effective than placebo or itraconazole 200 mg daily, and 16 weeks of oral terbinafine therapy at this dosage was more effective than up to 52 weeks of oral griseofulvin 500 mg daily. In these studies, 70-88% of patients experienced mycologic cure, 59% experienced effective treatment, and 38-57% experienced mycologic and clinical cure when evaluated 36-48 weeks after completion of terbinafine treatment; the clinical relapse rate was about 15% in those evaluated at least 6 months after experiencing clinical cure and at least 1 year after completion of terbinafine treatment.

In a study comparing 4 months of continuous (250 mg daily) or intermittent (500 mg daily for 1 week each month) oral terbinafine or intermittent (400 mg daily for 1 week each month) oral itraconazole, a trend favoring continuous terbinafine therapy was observed, but statistically significant differences in cure rates among the regimens were not observed. In a treatment duration-ranging study comparing 6-, 12-, and 24-weeks of terbinafine therapy in patients with toenail infections, mycologic cure rates were substantially greater for the 12- or 24-week regimens compared with the 6-week regimen, but the 24-week regimen was not substantially more effective than the 12-week regimen. However, some patients who do not respond to an initial 12-week course of terbinafine therapy may respond to a second course with the drug.

In the fingernail studies, 75% of patients experienced effective treatment, and 59-90% of patients experienced mycologic and clinical cure when evaluated 18-42 weeks after completion of treatment with oral terbinafine 250 mg daily for 6 weeks. Extending the course of terbinafine therapy to 12 weeks in patients with fingernail infections does not appear to improve response substantially. In a study in patients with fingernail onychomycosis who received oral terbinafine 250 mg daily for 2 or 4 weeks, 65% exhibited mycologic and clinical cure 6 months after completion of therapy; the cure rate in those who received only 2 weeks of therapy was 45%.

However, liver failure (sometimes leading to death or liver transplant) has occurred rarely in patients with or without preexisting liver disease who were receiving terbinafine for the treatment of onychomycosis. Prior to administration of oral terbinafine, presence of liver disease should be assessed; pretreatment determination of serum concentrations of ALT (SGPT) and AST (SGOT) is advised for all patients.

Terbinafine should be discontinued if biochemical or clinical signs of liver injury develop during therapy. Patients should be instructed to report any signs or symptoms of liver dysfunction, such as persistent nausea, anorexia, fatigue, vomiting, right upper abdominal pain or jaundice, dark urine, pale stools; patients with these signs/symptoms should discontinue terbinafine and have their liver function immediately evaluated.

Other uses

In the US, terbinafine tablets are FDA-approved for onychomycosis; use for other fungal infections may be used off-label and should be directed by a healthcare provider. Safety and efficacy of LAMISIL Tablets have not been established in pediatric patients.

Terbinafine: Organs and Systems

Sensory systems

Taste disturbance is a rare adverse effect of terbinafine. It is usually reversible, with a median time to recovery of 42 days. However, prolonged or persistent taste disturbances have been reported.

Hematologic

Pancytopenia has been reported.

Leukocytes

Neutropenia has been reported in patients taking terbinafine.

• A 55-year-old woman who was taking terbinafine and paroxetine presented with fever, diarrhea, and vomiting. A bone marrow biopsy showed overall reduced cellularity, and the aspirate showed a profound shift toward the production of immature myeloid cells, consistent with maturation arrest. Treatment consisted of withdrawal of all outpatient medications, hydration, intravenous fluids, broad-spectrum antibiotics, and G-CSF 5 µg/kg for 5 days. Mature granulocytes appeared in the peripheral blood on the fifth day in hospital, and she was discharged on the seventh hospital day with an absolute neutrophil count of 6.2 x 10⁹/L. Paroxetine was resumed weeks after discharge from hospital without hematological toxicity over 6 months.
• A 60-year-old man presented with fever, oral mucositis, pedal cellulitis, and bacteremia after a 6-week course of terbinafine 250 mg. He was taking concurrent yohimbine for impotence. Bone marrow examination showed a hypocellular marrow with myeloid maturation arrest. Treatment consisted of withdrawal of outpatient medications, broad-spectrum antibiotics, hydration, and G-CSF, and was ultimately successful. Yohimbine was resumed later without any adverse effects.
• A 42-year-old man presented with fever and granulocytopenia (absolute neutrophil count: 340 x 10⁶/L; temperature: 39.5°C / 103.1°F) after a 30-day course of oral terbinafine 250 mg/day for presumed onychomycosis. The granulocyte count recovered promptly after withdrawal of the drug and administration of G-CSF for 2 days.
• Agranulocytosis occurred in a 15-year-old who took terbinafine 250 mg/day for toenail onychomycosis and tinea pedis. This effect was noted 4 weeks after starting terbinafine and resolved within 1 week after its withdrawal.

Platelets

Thrombocytopenia has been attributed to terbinafine.

• A 25-year-old Yemeni woman with familial-ethnic leukopenia developed thrombocytopenia with epistaxis after taking terbinafine 250 mg for 4 weeks. The platelet count recovered from a nadir of 63 x 10⁹/L to 314 x 10⁹/L after drug withdrawal.
• A 53-year-old woman developed severe thrombocytopenia after a 6-week course of terbinafine (250 mg/day) for onychomycosis. A bone marrow aspirate showed a normocellular marrow. She received a platelet transfusion and recovered after a short course of prednisolone.

Mouth

• A 38-year-old man presented with acute right otitis media and unrelated painless bilateral enlargement of the parotid glands 15 days after taking oral terbinafine for tinea cruris. He stopped taking terbinafine and 12 days later the swelling had significantly abated and completely disappeared 4 weeks later.

Liver

Minor abnormalities in liver function tests have been reported in patients taking oral terbinafine. Terbinafine can cause hepatitis and rare cases of liver failure have been reported.

Skin

Cutaneous adverse effects reportedly occur in patients taking terbinafine. The majority of these reactions consist of mild to moderate macular exanthemas.

Generalized rashes, fixed drug eruptions, toxic epidermolysis, and erythema exudativum multiforme have all been reported in association with terbinafine.

Storage

Store below 25°C / 77°F in a tightly closed container. Protect from light.