Lamisil (Terbinafine)

LAMISIL®

Novartis Pharmaceuticals

Terbinafine HCl

Antifungal

Action And Clinical Pharmacology: Terbinafine is an allylamine which has a broad spectrum of antifungal activity. At low concentrations terbinafine is fungicidal against dermatophytes, molds and certain dimorphic fungi. The activity against yeasts is fungicidal or fungistatic, depending on the species.

Terbinafine interferes specifically with fungal sterol biosynthesis by inhibition of squalene epoxidase in the fungal cell membrane. This leads to a deficiency in ergosterol and to an intracellular accumulation of squalene, resulting in fungal cell death. The enzyme squalene epoxidase is not linked to the cytochrome P450 system, hence terbinafine does not influence the metabolism of hormones or other drugs. When given orally, the drug concentrates rapidly in skin, hair and nails at levels associated with fungicidal activity.

The cream has a rapid onset of action and can be effective with a short duration of treatment.

Pharmacokinetics: Oral: A single oral dose of 250 mg terbinafine results in peak plasma concentrations of 0.97 g/mL within 2 hours after administration. The absorption half-life is 0.8 hour and the distribution half-life is 4.6 hours. The bioavailability of terbinafine is moderately increased by a fat-rich meal, but not sufficiently to require dosing adjustments.

Terbinafine binds strongly to plasma proteins (99%). It rapidly diffuses through the dermis and concentrates in the lipophilic stratum corneum. Terbinafine is also secreted in sebum, thus achieving high concentrations in hair follicles, hair and in sebum-rich skin. There is also evidence that terbinafine is distributed into the nail plate within the first few weeks of commencing therapy, resulting in a rapid onset of action.

Biotransformation results in metabolites with no antifungal activity, which are excreted predominantly in the urine. The terminal elimination half-life is 17 hours. There is no evidence of accumulation. No age-dependent changes in pharmacokinetics have been observed but the elimination rate may be reduced in patients with renal or hepatic impairment, resulting in higher blood levels of terbinafine (see Warnings).

Topical: Less than 5% of the dose is absorbed after topical application to humans; systemic exposure is thus very slight.

Indications And Clinical Uses: The treatment of fungal infections of the skin and nails caused by dermatophytes such as Trichophyton (e.g., T. rubrum, T. mentagrophytes, T. verrucosum, T. violaceum), M. canis and E. floccosum.

Oral: Oral terbinafine is indicated in the treatment of onychomycosis (fungal infection of the nail) caused by dermatophyte fungi. Where oral therapy is considered appropriate owing to the site, severity or extent of the infection, terbinafine tablets may also be indicated in the treatment of tineal skin infections (tinea corporis, tinea cruris and tinea pedis).

Note: Oral terbinafine is not effective in pityriasis versicolor.

Topical: Cream: Topical terbinafine is indicated in the treatment of fungal infections of the skin caused by dermatophytes such as Trichophyton, as well as yeast infections of the skin, principally those caused by the genus Candida (e.g., Candida albicans). The cream is also indicated in the treatment of pityriasis (tinea) versicolor due to P. orbiculare (also known as M. furfur).

Spray: The spray is indicated in the treatment of fungal infections of the skin caused by dermatophytes such as trichophyton. The spray is also indicated in the treatment of pityriasis (tinea) versicolor due to P. orbiculare (also known as M. furfur).

Note: Topical terbinafine is not effective in onychomycosis.

Contra-Indications: In patients with a hypersensitivity to terbinafine or any of the excipients (see Supplied).

Manufacturers’ Warnings In Clinical States: Clinical studies in patients with liver dysfunction and impaired renal function suggest that the elimination rate of orally administered terbinafine may be reduced in these patients. Consequently, patients with pre-existing stable chronic liver dysfunction or impaired renal function (creatinine clearance less than 50 mL/minute or serum creatinine of more than 300 mol/L) should receive half the regular dose of oral terbinafine and be carefully monitored (see Precautions and Dosage).

Cases of significant hepatobiliary dysfunction as well as isolated cases of blood dyscrasias have been reported in patients treated with oral terbinafine (see Precautions and Adverse Effects).

Precautions: General: Terbinafine should be kept out of the reach of children.

Terbinafine cream and spray are for external use only. Contact with the eyes should be avoided. The spray should not be used on the face. In case of accidental contact with the eyes, rinse eyes thoroughly with running water and consult a physician if any symptoms persist. In case of accidental inhalation, patients should be advised to consult a physician if any symptoms develop and persist.

The spray should be used with caution in patients with lesions where alcohol could be irritating.

Patients should report any signs and symptoms which may suggest hepatobiliary dysfunction or a blood dyscrasia so that terbinafine treatment can be discontinued and/or appropriate laboratory testing can be done. Such signs and symptoms would include unusual fatigue, anorexia, jaundice, dark urine, pale stools and pruritus, or sore throat and fever.

In those patients at a higher risk for developing hepatic dysfunction (e.g., those receiving terbinafine concomitantly with potentially hepatotoxic drugs; those with a history of significant alcohol intake or suspicion of liver disorder) performing liver function tests at baseline and periodically during terbinafine treatment may be of value.

Pregnancy and Lactation: Fetal toxicity and fertility studies in animals suggest no adverse effects.

There is very limited clinical experience with terbinafine in pregnant women; therefore, unless the potential benefits outweigh any potential risks, terbinafine tablets should not be used during pregnancy.

Terbinafine is excreted in breast milk; therefore, mothers receiving oral treatment with terbinafine should not breast-feed. However, with the cream and spray treatment, the small amounts absorbed through the skin are unlikely to affect the infant.

Geriatrics: There is no evidence to suggest that healthy elderly patients require different dosages or experience adverse effects different from those of younger patients. The possibility of pre-existing impairment of liver or kidney function should be considered in this age group (see Warnings).

Children: There is limited experience with terbinafine in children.

Drug Interactions: Tablets: According to the results from studies undertaken in vitro and in healthy volunteers, terbinafine shows negligible potential to inhibit or induce the clearance of drugs that are metabolized via the cytochrome P450 system (e.g., cyclosporine, tolbutamide or oral contraceptives). Some cases of menstrual irregularities have been reported in patients taking terbinafine concomitantly with oral contraceptives, although the incidence of these disorders remains within the background incidence of patients taking oral contraceptives alone. On the other hand, the plasma clearance of terbinafine may be accelerated by drugs which induce metabolism (such as rifampicin) and may be reduced by drugs which inhibit cytochrome P450 (such as cimetidine). Where coadministration of such agents is necessary the dosage of terbinafine may need to be adjusted accordingly.

Cream and Spray: No drug interactions are known to date.

Carcinogenesis: An increase in liver tumors was observed in male rats at the highest dose level (69 mg/kg) during the life-time (123 weeks) carcinogenicity study. The changes included increased enzyme activity, peroxisome proliferation and altered triglyceride metabolism. The changes have been shown to be species specific since they were not seen in mice or monkeys.

Adverse Reactions: Tablets: In general terbinafine is well tolerated. Side effects are mild to moderate in severity, and transient. The most common are gastrointestinal symptoms (fullness, loss of appetite, dyspepsia, nausea, mild abdominal pain, diarrhea) or nonserious forms of skin reactions (rash, urticaria).

There have been isolated reports of serious skin reactions (e.g., Stevens-Johnson Syndrome, Toxic Epidermal Necrolysis). If progressive skin rash occurs, treatment with terbinafine should be discontinued.

A few cases of hair loss have been reported, although a clear causal relationship remains to be established.

Rarely, terbinafine may cause taste disturbances, including taste loss, which usually recover within several weeks after discontinuation of the drug.

Oral terbinafine has been rarely associated with systemic allergic reactions, including urticaria, angioedema, arthralgia, arthritis, serum-sickness like reactions and anaphylactoid reactions.

Hepatobiliary dysfunction has been rarely reported in association with terbinafine treatment. Liver function tests should be performed if a patient develops unexplained nausea, anorexia or tiredness. If liver function tests are found to be abnormal in a patient, or if a patient presents with overt symptoms of liver dysfunction, terbinafine should be discontinued.

The estimated reporting incidence of the development of clinically significant signs and symptoms of hepatobiliary dysfunction for which no other cause was apparent, and in which terbinafine was considered the possible causative agent is approximately 1:45 000. Extremely rare cases (less than 1:1 000 000 exposed patients) of liver failure with fatal outcome have been reported following treatment with oral terbinafine. A causal relationship has not been established.

Worldwide, of the estimated 4.7 million patients treated with terbinafine as of August 1996, there have been 8 cases of agranulocytosis, 1 case of pancytopenia and 10 cases of thrombocytopenia, which are possibly related to terbinafine. One case of thrombotic thrombocytopenic purpura (TTP) has been reported. The mechanism of TTP and its induction are not completely known. The role of terbinafine in the development of TTP in the reported case cannot be established.

In clinical trials adverse events occurred in 10.4% of patients receiving the recommended dose. Of these, 5% were mild to moderate gastrointestinal events, 3% were skin reactions (rash or urticaria) and the remainder were miscellaneous nonspecific events such as malaise or tiredness.

Cream and Spray: Redness, itching or stinging occasionally occur at the site of application; however, treatment rarely has to be discontinued for this reason. These symptoms should be distinguished from allergic reactions which are rare but require discontinuation of the drug. In clinical trials, adverse reactions were recorded in 33 of the 1 757 (1.8%) patients who received terbinafine cream and in 39 of the 898 (4.3%) patients who received the terbinafine spray.

Symptoms And Treatment Of Overdose: Symptoms and Treatment: A few cases of accidental overdosage of up to 5 g have been reported. After intake, the patients presented with headache, nausea, epigastric pain and dizziness. The recommended treatment of overdosage consists of eliminating the drug primarily by the administration of activated charcoal and, if needed, of symptomatic supportive therapy.

No case of overdoage has been reported with terbinafine cream or spray. Should, however, terbinafine cream or spray be inadvertently ingested, adverse effects similar to those observed with an overdosage of terbinafine tablets are to be expected. The alcohol content (23.5%) of the spray has to be taken into account.

Dosage And Administration: Tablets: The bioavailability of terbinafine is moderately increased by a fat-rich meal, but not sufficiently to require dosing adjustments.

Adults: 250 mg daily.

Note: In tineal skin infections, terbinafine tablets should be used when oral therapy is considered appropriate owing to the site, severity or extent of the infection.

Patients with Renal or Hepatic Impairment: The elimination rate may be reduced in patients with renal or hepatic impairment. The dose should be reduced by half in these patients (see Warnings and Precautions).

Cream: The cream can be applied once or twice daily. The affected areas should be cleansed and dried thoroughly before application of terbinafine cream. The cream should be applied to the affected skin and surrounding area in a thin layer and rubbed in lightly. In the case of intertriginous infections (submammary, interdigital, intergluteal, inguinal) the application may be covered with a gauze strip, especially at night.

Many patients treated with shorter durations of therapy (1 to 2 weeks) continue to improve during the 2 to 4 weeks after therapy has been completed. As a consequence, patients should not be considered therapeutic failures until they have been observed for a period of 2 to 4 weeks after cessation of treatment.

Relief of clinical symptoms usually occurs within a few days. Irregular use or premature discontinuation of treatment increases the risk of recurrence. If there are no signs of improvement after 2 weeks, the diagnosis should be verified.

Spray: The spray is applied once or twice daily, depending on the indication. The affected areas should be cleansed and dried thoroughly before application of the spray. A sufficient amount of solution should be applied to wet the treatment area(s) thoroughly, and to cover the affected skin and surrounding area.

Relief of clinical symptoms usually occurs within a few days. Irregular use or premature discontinuation of treatment increases the risk of recurrence. If there are no signs of improvement after 2 weeks the diagnosis should be verified.

Availability And Storage: Cream: Each g of white, smooth, glossy cream contains: terbinafine HCl 10 mg. Nonmedicinal ingredients: benzyl alcohol, cetyl alcohol, cetyl palmitate, isopropyl myristate, polysorbate 60, purified water, sodium hydroxide, sorbitan monostearate and stearyl alcohol. Tubes of 30 g. Store at temperatures between 15 and 30°C.

Spray: Each g of clear solution contains: terbinafine HCl 10 mg. Nonmedicinal ingredients: cetomacrogol 1 000, ethanol, propylene glycol and water. Alcohol: 23.5% w/w. Bottles of 30 mL. Store at temperatures between 15 and 30°C.

Tablets: Each round, whitish/yellow uncoated tablet, scored on one side and embossed “Lamisil 250”, contains: terbinafine 250 mg, present as the hydrochloride salt. Nonmedicinal ingredients: cellulose microcrystalline, magnesium stearate, methylhydroxypropylcellulose, silica, colloidal anhydrous and sodium carboxymethyl starch. Blister strips of 14, cartons of 14 and 28. Store at temperatures between 15 and 30°C. Protect from light.

LAMISIL® Novartis Pharmaceuticals Terbinafine HCl Antifungal

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