Some cases of menstrual irregularities have been reported in patients taking Lamisil 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 that induce metabolism (such as rifampicin) and may be inhibited by drugs which inhibit cytochrome P450 (such as cimetidine). Where co-administration of such agents is necessary, the dosage of Lamisil may need to be adjusted accordingly.

Adverse Effects

Frequency estimate: very common ≥ 10%, common ≥ 1% to < 10%, uncommon ≥ 0.1% to < 1%, rare ≥ 0.01% to < 0.1%, very rare < 0.01%.

In general Lamisil tablets are well tolerated. Side effects are usually mild to moderate and transient. The most common are gastrointestinal symptoms (feeling of fullness, loss of appetite, dyspepsia, nausea, mild abdominal pain, diarrhoea), non-serious forms of skin reactions (rash, urticaria), musculoskeletal reactions (arthralgia, myalgia).

Uncommon: taste disturbances, including taste loss, which usually recover within several weeks after discontinuation of the drug.

Rare: hepatobiliary dysfunction (primarily cholestatic in nature) has been reported in association with Lamisil treatment, including very rare cases of liver failure (see Special warnings and special precautions for use).

Very rare: serious skin reactions (e.g. Stevens-Johnson syndrome, toxic epidermal necrolysis) and anaphylactoid reactions have been reported. If progressive skin rash occurs, Lamisil treatment should be discontinued.

Very rare: haematological disorders such as neutropenia, agranulocytosis or thrombocytopenia have been reported.

Very rare: hair loss has been reported, although a causal relationship has not been established.

Overdose

A few cases of overdosage (up to 5g) have been reported, giving rise to headache, nausea, epigastric pain and dizziness.

The recommended treatment of overdosage consists in eliminating the drug, primarily by the administration of activated charcoal, and giving symptomatic supportive therapy, if needed.

Pharmacological Properties

Pharmacodynamic Properties

Pharmacotherapeutic group: Oral antifungal agent (ATC code D01B A02)

Terbinafine is an allylamine which has a broad spectrum of activity against fungal pathogens of the skin, hair and nails including dermatophytes such as Trichophyton (e.g. T. rubrum, T. mentagrophytes, T. verrucosum, T. tonsurans, T. violaceum), Microsporum (e.g. M.canis), Epidermophyton floccosum, and yeasts of the genera Candida (e.g. C. albicans) and Pityrosporum. At low concentrations terbinafine is fungicidal against dermatophytes, moulds and certain dimorphic fungi. Its activity against yeasts is fungicidal or fungistatic, depending on the species.

Terbinafine interferes specifically with fungal sterol biosynthesis at an early step. This leads to a deficiency in ergosterol and to an intracellular accumulation of squalene, resulting in fungal cell death. Terbinafine acts by inhibition of squalene epoxidase in the fungal cell membrane. The enzyme squalene epoxidase is not linked to the cytochrome P450 system. Terbinafine does not influence the metabolism of hormones or other drugs.

When given orally, the drug concentrates in skin, hair and nails at levels associated with fungicidal activity.

Pharmacokinetic Properties

A single oral dose of 250 mg terbinafine results in peak plasma concentrations of 0.97 mcg/mL within 2 hours of administration. The absorption half-life is 0.8 hours and the distribution half-life is 4.6 hours. The bioavailability of terbinafine is moderately affected by food, but not sufficiently to require dose 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 sebum-rich skin. There is also evidence that terbinafine is distributed into the nail plate within the first few weeks after commencing therapy.

Terbinafine is metabolised rapidly and extensively by at least seven CYP isoenzymes with major contributions from CYP2C9, CYP1A2, CYP3A4, and CYP2C8 and CYP2C19. 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 steady-state plasma concentrations of terbinafine have been observed, but the elimination rate may be reduced in patients with renal or hepatic impairment, resulting in higher blood levels of terbinafine.

Single dose pharmacokinetic studies in patients with pre-existing liver disease have shown that the clearance of Lamisil may be reduced by about 50%.

Preclinical Safety Data

In long-term studies (up to 1 year) in rats and dogs no marked toxic effects were seen in either species up to oral doses of about 100 mg/kg a day. At high oral doses, the liver and possibly also the kidneys were identified as potential target organs.

In a two-year oral carcinogenicity study in mice, no neoplastic or other abnormal findings attributable to treatment were made up to doses of 130 (males) and 156 (females) mg/kg a day. In a two-year oral carcinogenicity study in rats, an increased incidence of liver tumours was observed in males at the highest dose level of 69 mg/kg a day. The changes which may be associated with peroxisome proliferation have been shown to be species-specific since they were not seen in the carcinogenicity study in mice or in other studies in mice, dogs or monkeys.

During high-dose studies in monkeys, refractile irregularities were observed in the retina at the higher doses (non-toxic effect level 50 mg/kg). These irregularities were associated with the presence of a terbinafine metabolite in ocular tissue and disappeared after drug discontinuation. They were not associated with histological changes.

A standard battery of in vitro and in vivo genotoxicity tests revealed no evidence of mutagenic or clastogenic potential.

No adverse effects on fertility or other reproduction parameters were observed in studies in rats or rabbits.

Pharmaceutical Particulars

List of excipients

250 mg: magnesium stearate; colloidal anhydrous silica; methylhydroxypropylcellulose; microcrystalline cellulose; sodium carboxymethyl starch.

Incompatibilities

None known.

Shelf life

250 mg tablets: 5 years

Special Precautions for Storage

Protect from light.

Lamisil should be kept out of the reach of children.

Nature and Content of Container

250 mg tablets: the dosage form is packed in polyvinyl chloride (PVC) blister packs consisting of an aluminium foil coated on one side with a heat sealable lacquer and a PVC film or in polypropylene (PP) blister packs consisting of a lacquered aluminium foil coated on one side with a heat sealable lacquer and a PP film. The different packaging materials in contact with the tablets comply with the requirements of both Ph.Eur. and USP.