This information is intended for use by health professionals

1. Name of the medicinal product

Terbinafine 250mg Tablets

2. Qualitative and quantitative composition

Terbinafine Hydrochloride equivalent to 250mg Terbinafine per tablet

For the full list of excipients, see 6.1.

3. Pharmaceutical form

Tablet

Round white to off-white flat bevelled edge tablets with score line and R250 on reverse

Diameter approx. 11 mm

The score line is only to facilitate breaking for ease of swallowing and not to divide into equal doses.

4. Clinical particulars
4.1 Therapeutic indications

Terbinafine tablets are for the treatment of fungal infections of the skin and nails caused by Trichopyton (T.rubrum, T.mentagrophytes, T.verrucosum, T.violaceum), Microsporum canis and Epidermophyton floccosum.

1. Terbinafine 250 mg Tablets are 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. Terbinafine 250 mg Tablets are indicated in the treatment of onychomycosis

4.2 Posology and method of administration

Adults: 250mg once daily

The duration of treatment varies according to the indication and severity

Skin Infections

Likely duration of treatment are as follows:

Tinea pedis (interdigital, plamtar/moccoasin type):

Tinea corporis:

Tinea cruris:

2 to 6 weeks

4 weeks

2 to 4 weeks

Onychomycosis

For most patients the duration of treatment is between 6 weeks and 3 months although treatment periods of less than 3 months can be anticipated in younger patients or those with fingernail infections or toenail infections other than the big toe. 3 months is usually sufficient in the treatment of toenail infections although some patients may require 6 months treatment or longer. Poor nail outgrowth during the first weeks of treatment may indicate those patients where longer therapy is required. The complete resolution of signs and symptoms of infection may not occur until several weeks after mycological cure.

Additional information on special population

Liver impairment

Terbinafine tablets are not recommended for patients with chronic or active liver disease (see section 4.3 Contraindications and 4.4. Special warnings and precautions for use).

Renal impairmentThe 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).

Children

Not recommended. A review of the safety experience with oral terbinafine in children, which includes 314 patients involved in the Terbinafine Post-Marketing Surveillance study, has shown 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 indicate the elderly (aged 65 years or above) require a different dose or experience different side effects to other patients, other than there is an increased risk of renal or hepatic impairment in this patient group (see section 4.4).

Method of administration

The scored 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

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

Chronic or active hepatic disease

4.4 Special warnings and precautions for use

Liver Function

Terbinafine Tablets are not recommended for patients with chronic or active liver disease. Before prescribing Terbinafine Tablets, a liver function test should be performed and any pre-existing liver disease should be assessed.

Hepatotoxicity may occur in patients with and without pre-existing liver disease therefore periodic monitoring (after 4-6 weeks of treatment) of liver function test is recommended. Terbinafine Tablets should be immediately discontinued in case of elevation of liver function test.

Very rare cases of serious liver failure (some with a fatal outcome, or requiring liver transplant) have been reported in patients treated with Terbinafine Tablets. In the majority of liver failure cases, the patients had serious underlying systemic conditions .(see section 4.3 Contraindications and 4.8 Undesirable effects).

Patients prescribed Terbinafine Tablets should be instructed to report immediately any signs or symptoms suggestive of liver dysfunction such as pruritus, unexplained persistent nausea, decreased appetite, anorexia, jaundice, vomiting, fatigue, right upper abdominal pain, 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, drug rash with eosinophilia and systemic symptoms) have been very rarely reported in patients taking Terbinafine Tablets. If progressive skin rash occurs, Terbinafine Tablets treatment should be discontinued.

Terbinafine Tablets 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 dyscrasias (neutropenia, agranulocytosis, thrombocytopenia, pancytopenia) have been reported in patients treated with terbinafine tablets. Aetiology of any blood dyscrasias 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).

Other

Terbinafine tablets should be used with caution in patients with 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 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

Terbinafine 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, especially if they also have a narrow therapeutic window (see section 4.4).

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 (genotype) to poor metaboliser (phenotype) status.

Information on other drug concomitantly used with Lamisil resulting in no or negligible interactions

Studies undertaken in vitro and in healthy volunteers suggest that terbinafine shows negligible potential to inhibit or induce the clearance of most 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 Terbinafine concomitantly with oral contraceptives, although the incidence of these disorders remains within the background incidence of patients taking oral contraceptives alone.

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 effect. Since clinical experience in pregnant women is very limited, Terbinafine Tablets should not be used during pregnancy unless clinical conditions of the woman requires treatment with oral terbinafine and the potential benefits for the mother outweigh any potential risks for the foetus.

Lactation

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

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

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:

Common:

Uncommon:

Rare:

Very rare:

Not known:

≥ 1/10

≥ 1/100 to < 1/ 10

≥ 1/ 1,000 to < 1/ 100

≥ 1/10,000 to < 1/ 1,000

< 1/10,000

frequency cannot be estimated from available data (including isolated reports)

Blood and lymphatic system disorders

Very rare

Neutropenia, agranulocytosis, thrombocytopenia.

Not known

Anaemia Pancytopenia

Immune system disorders

Very rare

Anaphylactoid reactions (including angioedema), cutaneous and systemic lupus erythematosus.

Not known

Anaphylactic reaction, 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* including ageusia*

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

Rare

Paraesthesia, hypoaesthesia, dizziness

Not known

Anosmia including permanent anosmia, hyposmia

Ear and labyrinth disorders

Very rare

Vertigo

Not known

Hypoacusis, impaired hearing, tinitus

Vascular disorders

Not known

Vasculitis

Gastrointestinal disorders

Very common

Gastrointestinal symptoms (feeling of fullness, loss of appetite, dyspepsia, nausea, abdominal pain, diarrhoea).

Not known

Pancreatitis

Hepatobiliary disorders

Rare

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

Very rare

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 casual association with the intake of Terbinafine Tablets was uncertain.

Skin and subcutaneous tissue disorders

Very common

Rash, urticaria.

Very rare

Stevens-Johnson syndrome, toxic epidermal necrolysis, erythema multiforme, toxic skin eruption, dermatitis exfoliative, dermatitis bullous.

Photosensitivity reactions

Alopecia

If progressive skin rash occurs, terbinafine treatment should be discontinued.

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

Rare

Malaise

Not known

Fatigue

Influenza-like illness, pyrexia

Investigations

Uncommon

Weight decreased**

**weight decreased secondary to dysgeusia

Not known

Blood creatine phosphokinase increased

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

Reports of overdose are rare but a few cases have been reported where up to 5g has been taken giving rise to headache, nausea, epigastric pain and dizziness.

Treatment: Activated charcoal to adsorb and eliminate the drug and symptomatic supportive therapy.

5. Pharmacological properties
5.1 Pharmacodynamic properties

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 yeast 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.

5.2 Pharmacokinetic properties

Following oral administration, terbinafine is well absorbed (>70%) and the absolute bioavailability of terbinafine from Terbinafine tablets as a result of first-pass metabolism is approximately 50%. A single oral dose of 250mg terbinafine resulted in mean peak plasma concentrations of 1.30μg/ml within 1.5 hours after administration. Plasma concentrations decline in a triphasic manner, with a terminal half-life of 16.5 days. At 28 days, when around 70% steady state levels have been achieved, peak concentrations of terbinafine was on average 25% higher and plasma AUC increased by a factor of 2.3 when compared to single dose administration. From the increase in plasma AUC an effective half-life of ~30 hours can be calculated. The bioavailability of terbinafine is moderately affected by food (increase in the AUC of less than 20%), but not sufficiently to require dose adjustments.

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.

Terbinafine is metabolised rapidly and extensively by at least seven CYP isoenzymes with major contributions from CYP2C9, CYP1A2, CYP3A4, CYP2C8 and CYP2C19. Biotransformation results in metabolites with no antifungal activity, which are excreted predominantly in the urine.

No clinically-relevant 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.

Single dose pharmacokinetic studies in patients with renal impairment (creatinine clearance <50 ml/min) or with pre-existing liver disease have shown that clearance of terbinafine may be reduced by about 50%.

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 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 attributed 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 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 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 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 reproductive parameters were observed in studies in rats or rabbits.

6. Pharmaceutical particulars
6.1 List of excipients

Microcrystalline Cellulose, Croscarmellose Sodium, Anhydrous Colloidal Silica, Hypromellose and Magnesium Stearate.

6.2 Incompatibilities

None known

6.3 Shelf life

3 years (36 months)

6.4 Special precautions for storage

Do not store above 25°C store in the original package

Keep blister in the outer carton

6.5 Nature and contents of container

Aluminium foil/PVC/PVdC blisters in cartons of 14 or 28 tablets

White HDPE bottles with CRC cap containing 60, 100 or 500 tablets

6.6 Special precautions for disposal and other handling

Not applicable

7. Marketing authorisation holder

Dr Reddy's Laboratories (UK) Ltd

6 Riverview Road

Beverley

HU17 0LD

8. Marketing authorisation number(s)

PL 08553/0213

9. Date of first authorisation/renewal of the authorisation

13/12/2005

10. Date of revision of the text

02/03/2017