SUMMARY OF PRODUCT CHARACTERISTICS

1    NAME OF THE MEDICINAL PRODUCT

Teva Terbinafine 250 mg Tablets

2.    QUALITATIVE AND QUANTITATIVE COMPOSITION

Each tablet contains 281.3 mg of terbinafine hydrochloride, equivalent to 250 mg of terbinafine.

For excipients, see 6.1.

3.    PHARMACEUTICAL FORM

Tablet

White to off - white, capsule shaped biconvex tablet. Scored on one side and debossed “T” on each side of the score. Plain on the other side of the tablet.

4. CLINICAL PARTICULARS

4.1. Therapeutic indications

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

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

2.    Terbinafine is indicated in the treatment of onychomycosis.

Consideration should be given to official local guidance, e.g. national recommendations on the appropriate use and prescription of antimicrobial agents.

4.2 Posology and method of administration

Adults 250 mg daily

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

Skin infections

Likely duration of treatment is as follows:

Tinea pedis/manuum (interdigital, plantar/moccasin type):	2 to 6 weeks
Tinea corporis:	2 to 4 weeks
Tinea cruris:	2 to 4 weeks

Onychomycosis

The duration of treatment (finger & toe nails) for most patients is between 6 weeks and 3 months. 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.

Liver impairment

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

Renal impairment

Use of terbinafine 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).

Elderly

There is no evidence to suggest that elderly patients require different dosages or experience different side effects than younger patients. When prescribing terbinafine tablets for patients in this age group, the possibility of pre-existing impairment of hepatic or kidney function should be considered (see section 4.4. Special warnings and precautions for use).

Paediatric population

A review of safety experience with oral terbinafine 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 has been noted. However, as data is limited its use is not recommended.

Method of administration Oral use

4.3 Contraindications

Known hypersensitivity to terbinafine or to any of the excipients of terbinafine tablets.

4.4 Special warnings and precautions for use

Liver function

Terbinafine tablets are not recommended for patients with chronic or active hepatic disease. Before prescribing terbinafine tablets, liver function test should be performed. Hepatotoxicity may occur in patients with and without pre-existing hepatic disease therefore periodic monitoring (after 4-6 weeks of treatment) of liver function test is recommended. Terbinafine should be immediately discontinued in case of elevation of liver function test. Very rare cases of serious hepatic failure (some with a fatal outcome, or requiring hepatic transplant) have been reported in patients treated with terbinafine tablets. In the majority of hepatic failure cases the patients had serious underlying systemic conditions and a causal association with the intake of terbinafine tablets was uncertain. (see section 4.8 Undesirable effects).

Patients prescribed terbinafine tablets should be warned to report immediately any signs and symptoms of unexplained persistent nausea, decreased appetite, fatigue, vomiting, right upper abdominal pain, or jaundice, dark urine or pale faeces.

Patients with these symptoms should discontinue taking oral terbinafine and the patient's hepatic 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 terbinafine tablets. If progressive skin rash occurs, terbinafine tablets treatment should be discontinued.

Haematological effects

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

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 terbinafine tablets has not been adequately studied, and therefore, is not recommended (see section 5.2 Pharmacokinetic properties).

Terbinafine should be used with caution in patients with pre-existing psoriasis or lupus erythematosus as very rare cases of lupus erythematosus have been reported.

4.5 Interaction with other medicinal products and other forms of interaction

Effect of other medicinal products on terbinafine

The plasma clearance of terbinafine may be accelerated by drugs which 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 terbinafine 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 33%.

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

According to the results from studies undertaken in vitro and in healthy volunteers, terbinafine shows negligible potential for inhibiting or enhancing the clearance of most drugs that are metabolised via the cytochrome P450 system (e.g. terfenadine, triazolam, tolbutamide or oral contraceptives) with exception of those metabolised through CYP2D6 (see below).

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

Some cases of irregular menstruation have been reported in patients taking terbinafine tablets concomitantly with oral contraceptives, although the incidence of these disorders remains within the background incidence of patients taking oral contraceptives alone.

Terbinafine may increase the effect or plasma concentration of the following medicinal products

Caffeine

Terbinafine decreased the clearance of caffeine administered intravenously by 19%. 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 compounds predominantly metabolised by CYP2D6, e.g. certain members of the following drug classes, tricyclic antidepressants (TCAs), beta-blockers, selective serotonine reuptake inhibitors (SSRIs), antiarrhythmics (including class 1A, 1B and 1C) and monoamine oxidase inhibitors (MAO-Is) Type B, especially if they also have a narrow therapeutic window (see 4.4. Special warnings and precautions for use).

Terbinafine decreased the clearance of desipramine by 82%.

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

Terbinafine increased the clearance of ciclosporin by 15%.

4.6 Fertility, pregnancy and lactation

Pregnancy

Foetal toxicity and fertility studies in animals suggest no adverse effects. Since clinical experience in pregnant women is very limited, terbinafine tablets should not be used during pregnancy unless clinical condition of the woman requires treatment with oral terbinafine and the potential benefits for the mother outweigh any potential risks for the foetus.

Lactation

Terbinafine is excreted in breast milk; mothers receiving oral treatment with terbinafine should therefore not breast-feed.

Fertility

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

4.7 Effects on ability to drive and use machines

No studies on the effects of terbinafine 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.

4.8 Undesirable effects

The following adverse reactions have been observed in the clinical trials or during post marketing experience.

Adverse reactions (Table 1) are ranked under heading of frequency, the most frequent first, 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 (cannot be estimated from the available data).

Table 1

Blood and lymphatic system disorders

Very rare:	Neutropenia, agranulocytosis, thrombocytopenia, pancytopenia
Not known:	Anaemia.
Immune system disorders
Very rare:	Anaphylactoid reaction, angioedema, cutaneous and systemic lupus erythematosus
Not known:	Anaphylactic reactions, serum sickness-like reaction
Metabolism and nutrition disorders
Very common:	Decreased appetite
Psychiatric disorders
Not known:	Anxiety, depression*
Nervous system disorders
Common: Uncommon: Very rare:	Headache Hypogeusia**, ageusia** Dizziness, paraesthesia and hypoaesthesia
Not known:	Anosmia
Ear and labyrinth disorders Not known:	Hypoacusis, hearing impaired, tinnitus
Vascular disorders Not known:	Vasculitis
Gastrointestinal disorders
Very common:	Abdominal distension, dyspepsia, nausea, abdominal pain, diarrhoea.
Not known:	Pancreatitis
Hepatobiliary disorders
Rare:	Hepatic failure, hepatic enzymes increased
Not known:	hepatitis, jaundice, cholestasis

Skin and subcutaneous tissue disorders

Very common: Very rare:	Rash, urticaria Erythema multiforme ,Stevens-Johnson syndrome, toxic epidermal necrolysis, acute generalized exanthematous pustulosis (AGEP)). Psoriasiform eruptions or exacerbation of psoriasis. Alopecia,..
Not known:	Photosensitivity reaction, photodermatosis, photosensitivity allergic reaction and polymorphic light eruption

Musculoskeletal and connective tissue disorders

Very common:    Arthralgia, myalgia

Not known    Rhabdomyolysis

General disorders and administration site conditions

Not known:	Influenza like illness, pyrexia
Investigations Not known:	Blood creatinine phosphokinase increased, weight decreased ***

* Anxiety and depressive symptoms secondary to dysgeusia.

** Hypogeusia, including ageusia, which usually recover within several weeks after discontinuation of the drug. Isolated cases of prolonged hypogeusia have been reported.

** *Weight decreased secondary to hypogeusia.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard.

4.9    Overdose

A few cases of overdose (up to 5g) have been reported, giving rise to headache, nausea, upper abdominal pain and dizziness. The recommended treatment of overdosage consists of eliminating the drug, primarily by the administration of activated charcoal, and giving symptomatic supportive therapy if needed.

5.    PHARMACOLOGICAL PROPERTIES

5.1. Pharmacodynamic properties

Pharmacotherapeutic group: Antifungals for systemic use 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. Terbinafine does not influence the metabolism of hormones or other drugs.

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

5.2. Pharmacokinetic properties

A single oral dose of 250mg terbinafine results in mean peak plasma concentrations of 0.97 pg/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 (99%) 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 terbinafine is not significantly affected by food.

5.3 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 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.

6.    PHARMACEUTICAL PARTICULARS

6.1. List of excipients

Microcrystalline cellulose Sodium starch glycollate (Type A)

Hypromellose Colloidal hydrated silica Magnesium stearate

6.2    Incompatibilities

Not applicable.

6.3.    Shelf life

3 years

6.4.    Special precautions for storage

No special precautions for storage

6.5.    Nature and contents of container

Transparent PVC/aluminium or white opaque PVC/PVdC/ aluminium blister packs containing 8, 14, 28, 30, 42, 50 (hospital packs) and 56 tablets^{1, 2}

¹    Not all pack sizes may be marketed

²    Calender packs available

6.6.    Instructions for use and handling

No special requirements

7.    MARKETING AUTHORISATION HOLDER

Teva UK Limited Brampton Road, Hampden Park Eastbourne, East Sussex BN22 9AG United Kingdom

8.    MARKETING AUTHORISATION NUMBER

PL 00289/0442

9    DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

29/11/2007

10    DATE OF REVISION OF THE TEXT

13/06/2014