4.1. Therapeutic indications

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

Oral terbinafine is indicated in the treatment of ringworm tinea corporis, tinea cruris and tinea pedis, when oral therapy is considered appropriate due to the site, severity or extent of the infection.

Treatment of onychomycosis caused by terbinafine sensitive dermatophytes.

Consideration should be given to official guidance concerning the appropriate use and prescription of antifungals.

In contrast to topical terbinafine, oral terbinafine is not effective in Pityriasis versicolor

4.2. Posology and method of administration

Posology

Adults:

250 mg once daily however, the duration of treatment will vary according to the indication and the severity of the infection.

Skin Infections:

Duration of the treatment

The likely durations of treatments are as follows:

Tinea pedis (interdigital, plantar/moccasin type): 2 to 6 weeks

Tinea corporis: 2 to 4 weeks

Tinea cruris: 2 to 4 weeks

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

Onychomycosis

The duration of treatment is usually between 6 weeks and 3 months. Treatment of 6 weeks for onychomycosis of the finger nails is generally sufficient. Regarding onychomycosis of the toe nails, a 12 week treatment is usually sufficient, although a few patients with poor nail outgrow may require a longer treatment duration (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 months after cessation of the treatment. This corresponds to the time needed for a healthy nail growth.

Children and adolescents (below 18 years of age):

A review of safety experience with oral Terbinafine in children, which includes 314 patients involved in the UK Terbinafine 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 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).

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).

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).

Method of administration

The tablets are taken orally with water. They should preferably be taken at the same time each day and can be taken on an empty stomach or after a meal.

4.3. Contraindications

• Known hypersensitivity to the terbinafine or to any of the excipients listed in section 6.1.

• Severe renal impairment (creatinine clearance < 30 ml/min).

• Severe hepatic impairment.

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.

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

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 there have been post-marketing reports of occurrences or deterioration of psoriasis or cutaneous/systemic lupus erythematosus.

Excipients:

Sodium

Terbinafine Aurobindo film-coated tablet contains Sodium. This medicine contains less than 1 mmol sodium (23 mg) per tablet, that is to say essentially 'sodium-free'.

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 and may be inhibited by drugs, which inhibit cytochrome P450. Where co-administration of such agents is necessary, the dosage of terbinafine tablets 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

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.

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

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

• In studies in healthy subjects characterized as extensive metabolizers 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 (genotype) to poor metabolizer phenotype status.

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%.

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

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.

Breastfeeding

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

Fertility

No human data on fertility are available. Foetal toxicity and fertility studies in animal species 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

In general terbinafine tablets are well tolerated. Side effects are usually mild to moderate and transient. The following adverse reactions have been observed in the clinical trials or during post marketing experience.

Adverse drug reactions from clinical trials or post-marketing experience are listed by MedDRA system organ class. Within each system organ class, the adverse drug reactions are ranked by frequency, with the most frequent reactions first. Within each frequency grouping, adverse drug reactions are presented in order of decreasing seriousness.

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 to < 1/10); uncommon (≥ 1/1,000 to < 1/100); rare (≥ 1/10,000 to < 1/1,000); very rare (< 1/10,000); not known (cannot be estimated from the available data)

Blood and lymphatic system disorders

Not known:

Anaemia, pancytopenia

Very rare:

Neutropenia, agranulocytosis, thrombocytopenia,

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 and depressive symptoms

Nervous system disorders

Common:

Headache

Uncommon:

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

Rare:

paraesthesia and *hypoaesthesia, dizziness

Not known:

Anosmia including permanent anosmia, Hyposmia

Eye Disorders

Not known:

Vision blurred, visual acuity reduced, visual impairment

Ear and labyrinth disorders

Very rare:

Vertigo

Not known:

Hypoacusis, hearing impaired, Tinnitus

Vascular disorders

Not known:

Vasculitis

Gastrointestinal disorders

Very common:

Gastrointestinal symptoms (feeling of fullness abdominal distension, dyspepsia, nausea, abdominal pain, diarrhoea.

Not known:

Pancreatitis

Hepatobiliary disorders

Rare:

Cases of serious hepatic dysfunction, including Hepatic failure, hepatic enzymes increased hepatitis, jaundice, cholestasis, If hepatic dysfunction develops, treatment with terbinafine should be discontinued (see also Section 4.4).

Very rare cases of serious liver failure have been reported (some with a fatal outcome or requiring liver transplant). In the majority of liver failure cases the patients had serious underlying systemic conditions and a causal association with the intake of terbinafine uncertain.

Skin and subcutaneous tissue disorders

Very common:

Rash, urticaria

Very Rare:

Photosensitivity reaction, photodermatosis, photosensitivity allergic reaction and polymorphic light eruption

Erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis, toxic skin eruption, Dermatitis exfoliative, Dermatitis Bullous, Alopecia,

Not known:

Psoriasiform eruptions or exacerbation of psoriasis. Serious skin reactions (e.g. acute generalized exanthematous pustulosis (AGEP) Drug rash with Eosinophilia and systemic symptoms

Musculoskeletal and connective tissue disorders

Very common:

Musculoskeletal reactions (Arthralgia, myalgia)

Not known

Rhabdomyolysis

General disorders and administration site conditions

Rare:

Malaise

Not known:

Fatigue Influenza like illness, pyrexia

Investigations

Uncommon

weight decreased **

**weight decreased secondary to dysgeusia

Not known:

blood creatinine phosphokinase increased

* 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, dysgeusia.

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: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in Google play or Apple App store.

4.9. Overdose

A few cases of overdosage (up to 5 g) 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.