Lamisil® Tablets 250mg

Terbinafine 250mg Tablets

Each tablet contains 281.25mg terbinafine hydrochloride, equivalent to 250mg terbinafine.

Tablets for oral administration.

LAMISIL Tablets 250mg:

Whitish to yellow tinged white, circular, biconvex tablets, scored on one side and coded LAMISIL 250 on the other.

Terbinafine 250mg Tablets:

Whitish to yellow tinged white, circular, biconvex tablets, coded T on one side.

Fungal infections of the skin and nails caused by Trichophyton (eg. T. rubrum, T.mentagrophytes, T. verrucosum, T. violaceum), Microsporum canis and Epidermophyton floccosum.

1. Oral Lamisil is indicated in the treatment of ringworm (tinea corporis, tinea cruris and tinea pedis) where oral therapy is considered appropriate due to the site, severity or extent of the infection.

2. Oral Lamisil is indicated in the treatment of onychomycosis.

Adults

250mg once daily.

The duration of treatment varies according to the indication and the severity of the infection.

Skin infections

Likely durations of treatment are as follows:

Onychomycosis

The duration of treatment for most patients is between 6 weeks and 3 months. Treatment periods of less than 3 months can be anticipated in patients with fingernail infection, toenail infection other than of the big toe, or patients of younger age. In the treatment of toenail infections, 3 months is usually sufficient although a few patients may require treatment of 6 months or longer. Poor nail outgrowth during the first weeks of treatment may enable identification of those patients in whom longer therapy is required.

Complete resolution of the signs and symptoms of infection may not occur until several weeks after mycological cure.

Additional information on special population

Liver impairment

Lamisil tablets are not recommended for patients with chronic or active liver disease (see section 4.4 Special warnings and precautions for use).

Renal impairment

The use of Lamisil tablets has not been adequately studied in patients with renal impairment and is therefore not recommended in this population (see section 4.4 Special warnings and precautions for use and section 5.2 Pharmacokinetic properties).

Children

A review of safety experience with oral LAMISIL in children, which includes 314 patients involved in the UK LAMISIL Post Marketing Surveillance study, has shown that the adverse event profile in children is similar to that seen in adults. No evidence of any new, unusual or more severe reactions to those seen in the adult population have been noted. However, as data is still limited its use is not recommended.

Elderly

There is no evidence to suggest that elderly patients require different dosages or experience side-effects different to those of younger patients. The possibility of impairment of liver or kidney function should be considered in this age group (see Precautions).

Method of administration

Via the oral route.

Hypersensitivity to Lamisil

Liver Function

Lamisil tablets are not recommended for patients with chronic or active liver disease. Before prescribing Lamisil tablets, any pre-existing liver disease should be assessed.

Hepatotoxicity may occur in patients with and without pre-existing liver disease.

Very rare cases of serious liver failure (some with a fatal outcome, or requiring liver transplant) have been reported in patients treated with Lamisil tablets. In the majority of liver failure cases the patients had serious underlying systemic conditions and a causal association with the intake of Lamisil tablets was uncertain (see section 4.8 Undesirable effects).

Patients prescribed Lamisil tablets should be instructed to report immediately any signs or symptoms suggestive of liver dysfunction such as pruritus, unexplained persistent nausea, anorexia or tiredness, or jaundice, vomiting, fatigue, abdominal pain or dark urine, or pale stools. Patients with these symptoms should discontinue taking oral terbinafine and the patient's liver function should be immediately evaluated.

Dermatological effects

Serious skin reactions (e.g. Stevens-Johnson syndrome, toxic epidermal necrolysis) have been very rarely reported in patients taking Lamisil tablets. If progressive skin rash occurs, Lamisil tablets treatment should be discontinued.

Haematological effects

Very rare cases of blood dyscrasias (neutropenia, agranulocytosis, thrombocytopenia, pancytopenia) have been reported in patients treated with Lamisil tablets. Aetiology of any blood dyscrasias that occur in patients treated with Lamisil tablets should be evaluated and consideration should be given for a possible change in medication regimen, including discontinuation of treatment with Lamisil tablets.

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

Lamisil should be used with caution in patients with psoriasis, as very rare cases of exacerbation of psoriasis have been reported.

Renal function

In patients with renal impairment (creatinine clearance less than 50 mL/min or serum creatinine of more than 300 micro mol/L) the use of Lamisil tablets has not been adequately studied, and therefore, is not recommended (see section 5.2 Pharmacokinetic properties).

Effect of other medicinal products on terbinafine

The plasma clearance of terbinafine may be accelerated by drugs which induce metabolism and may be inhibited by drugs which inhibit cytochrome P450. Where co-administration of such agents is necessary, the dosage of Lamisil may need to be adjusted accordingly.

The following medicinal products may increase the effect or plasma concentration of terbinafine:

Cimetidine decreased the clearance of terbinafine by 30%.

Fluconazole increased the Cmax and AUC of terbinafine by 52% and 69% respectively, due to inhibition of both CYP2C9 and CYP3A4 enzymes. Similar increase in exposure may occur when other drugs which inhibit both CYP2C9 and CYP3A4 such as ketoconazole and amiodarone are concomitantly administered with terbinafine.

The following medicinal products may decrease the effect or plasma concentration of terbinafine:

Rifampicin increased the clearance of terbinafine by 100%.

Effect of terbinafine on other medicinal products

Studies undertaken in vitro and in healthy volunteers suggest that terbinafine shows negligible potential to inhibit or induce the clearance of drugs that are metabolised via other cytochrome P450 enzymes (e.g. tolbutamine, terfenadine, triazolam, oral contraceptives) with exception of those metabolised through CYP2D6 (see below).

Terbinafine does not interfere with the clearance of antipyrine or digoxin.

There was no effect of terbinafine on the pharmacokinetics of fluconazole. Further there was no clinically relevant interaction between terbinafine and the potential comedications cotrimoxazole (trimethoprim and sulfamethoxazole), zidovudine or theophylline.

Some cases of menstrual disturbance (breakthrough bleeding and irregular cycle) have been reported in patients taking Lamisil concomitantly with oral contraceptives.

Terbinaine may increase the effect or plasma concentration of the following medicinal products:

Caffeine – Terbinafine decreased the clearance of caffeine administered intravenously by 21%.

Compounds predominantly metabolised by CYP2D6 – In vitro and in vivo studies have shown that terbinafine inhibits the CYP2D6-mediated metabolism. This finding may be of clinical relevance for patients receiving compounds predominantly metabolised by CYP2D6, e.g. certain members of the following drug classes, tricyclic antidepressants (TCA's), β-blockers, selective serotonin reuptake inhibitors (SSRIs), antiarrhythmics (including class 1A, 1B and 1C) and monoamine oxidase inhibitors (MAO-Is) Type B.

Terbinafine decreased the clearance of desipramine by 82%.

In studies in healthy subjects characterized as extensive metabolisers of dextromethorphan (antitussive drug and CYP2D6 probe substrate), terbinafine increased the dextromethorphan/dextrorphan metabolic ratio in urine by 16- to 97-fold on average. Thus, terbinafine may convert extensive CYP2D6 metabolisers to poor metaboliser status.

Terbinafine may decrease the effect or plasma concentration of the following medicinal products:

Terbinafine increased the clearance of ciclosporin by 15%.

Rare cases of changes in INR and/or prothrombin time have been reported in patients receiving terbinafine concomitantly with warfarin.

Foetal toxicity and fertility studies in animals suggest no adverse effects.

There is no clinical experience with Lamisil in pregnant women, therefore, unless the potential benefits outweigh any potential risks, Lamisil should not be administered during pregnancy.

Terbinafine is excreted in breast milk and therefore mothers should not receive Lamisil treatment whilst breast-feeding.

No studies on the effects of Lamisil tablets treatment on the ability to drive and use machines have been performed. Patients who experience dizziness as an undesirable effect should avoid driving vehicles or using machines.

Side effects are generally mild to moderate, and transient. The following adverse reactions have been observed in the clinical trials or during post-marketing experience.

Adverse reactions are ranked under headings of frequency, using the following convention:

Very common ( 1/10); Common ( 1/100, < 1/10); Uncommon ( 1/1,000, <1/100); Rare ( 1/10,000, < 1/1,000); Very rare (< 1/10,000), Not known (frequency cannot be estimated from available data) including isolated reports.

Other adverse drug reactions from post-marketing spontaneous reports

The following adverse drug reactions have been identified based on post marketing spontaneous reports and are organized by system organ classes. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency.

Blood and lymphatic system disorders: anaemia.

Immune system disorders: anaphylactic reaction, serum sickness-like reaction.

Ear and labyrinth disorders: hypoacusis, impaired hearing, tinnitus.

Nervous system disorders: anosmia including permanent anosmia, hyposmia.

Vascular disorders: vasculitis.

Gastrointestinal disorders: pancreatitis.

Musculoskeletal and connective tissue disorders: rhabdomyolysis.

General disorders and administration site conditions: influenza-like illness, pyrexia.

Investigations: blood creatine phosphokinase increased.

A few cases of overdose (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.

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

Terbinafine is an allylamine which has a broad spectrum of antifungal activity. At low concentrations terbinafine is fungicidal against dermatophytes, moulds and certain dimorphic fungi. The activity versus 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.

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

A single oral dose of 250mg terbinafine results in mean peak plasma concentrations of 0.97μg/ml within 2 hours after administration. The absorption half-life is 0.8 hours and the distribution half-life is 4.6 hours. Terbinafine binds strongly to plasma proteins. 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 skins. There is also evidence that terbinafine is distributed into the nail plate within the first few weeks of commencing therapy. Biotransformation results in metabolites with no antifungal activity, which are excreted predominantly in the urine. The 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.

The bioavailability of Lamisil is unaffected by food.

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 100mg/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 dosage level of 69mg/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, dogs or monkeys.

During high-dose studies in monkeys, refractile irregularities were observed in the retina at the higher doses (non-toxic effect level 50mg/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.

Magnesium stearate, colloidal anhydrous silica, hydroxy propyl methylcellulose, sodium carboxy methyl starch, microcrystalline cellulose.

None known.

5 years.

Protect from light. Store below 25°C

PVC blister pack containing 7, 14 or 28 tablets.

Not applicable.

NOVARTIS PHARMACEUTICALS UK LIMITED

Frimley Business Park

Frimley

Camberley

Surrey

GU16 7SR

PL 0101/0304

01 November 2001

16 March 2012

POM