Terbinafine 250mg Tablets

Summary of Product Characteristics Updated 21-Apr-2016 | Kent Pharmaceuticals Ltd

1. Name of the medicinal product

Terbinafine 250mg Tablets

2. Qualitative and quantitative composition

Each tablet contains 250 mg terbinafine, as terbinafine hydrochloride. For excipients, see section 6.1.

3. Pharmaceutical form

Tablet

White, round, flat, 11 mm tablets, scored on both sides with side scores, marked 'T' above and '1' below the score on one side.

4. Clinical particulars
4.1 Therapeutic indications

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. Treatment of terbinafine sensitive fungal infections such as Tinea corporis, Tinea cruris and Tinea pedis (caused by Dermatophytes see Section 5.1) is considered appropriate due to the site, severity or extent of the infection.

2. The treatment of onychomycosis (terbinafine-sensitive fungal infection of the nails) caused by dermatophytes.

N.B. Orally administered terbinafine tablets are not effective against Pityriasis versicolor.

The official local guidelines should be borne in mind, for example, national recommendations relating to the correct use and prescription of antimicrobial drugs.

4.2 Posology and method of administration

Posology

Adults:

250mg once daily

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

Renal impairment

The 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).

Skin infections

The likely durations of treatment are as follows

Tinea pedis (interdigital, plantar/moccasin-type):

Tinea corporis

Tinea cruris

2 to 6 weeks

4 weeks

2 – 4 weeks.

Complete disappearance of the symptoms of the infection may not occur until several weeks after mycological cure.

Onychomycosis

In most patients the duration of successful treatment is 6-12 weeks.

Fingernail onychomycosis: In most cases 6 weeks' treatment is sufficient in fingernail onychomycosis. 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.

Toenail onychomycosis: In most cases 12 weeks' treatment is sufficient in toenail onychomycosis although a few patients may require treatment up to 6 months. 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 and is only seen several months after stopping treatment, which is the time for growth of a healthy nail.

Liver impairment

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

Children:

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 still limited its use is not recommended.

Elderly

There is no evidence to suggest that elderly patients (aged 65 years or above) 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 section 4.4).

Method of administration:

Oral use

They should preferably be taken at the same time each day and can be taken on an empty stomach or after a meal.

The duration of treatment is dependent on the indication and the degree of severity of the infection.

4.3 Contraindications

Known hypersensitivity to terbinafine or to any of the excipients. Severe renal impairment.

Severe hepatic impairment.

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 and a causal association with the intake of Terbinafine tablets was uncertain (see section 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, or jaundice, vomiting, fatigue, right upper 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. (See 4.8 Undesirable effects).

Single dose pharmacokinetic studies in patients with pre-existing liver disease have shown that the clearance of terbinafine can be reduced by 50% (see section 5.2). Therapeutic use of terbinafine in patients with chronic or active liver disease has not been studied in prospective clinical trials, and therefore cannot be recommended.

Haematological effects

Patients on terbinafine who develop a high fever or sore throat should be examined concerning possible haematological reactions (neutropenia, agranulocytosis, thrombocytopenia, and pancytopenia). Very rare cases of blood dyscrasias have been reported in patients treated with Terbinafine tablets. Aetiology of any blood dyscrasia that occurs in patients taking terbinafine should be carefully assessed and consideration should be given for a possible change in medication regimen, including stopping terbinafine.

Renal function

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

Dermatological effects

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

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 oral terbinafine. If progressive skin rash occurs treatment with terbinafine should be discontinued.

Other

Patients with autoimmune conditions are at increased risk of adverse reactions. Terbinafine 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 (such as rifampicin - Rifampicin increased the clearance of terbinafine by100%.) and may be inhibited by drugs, which inhibit cytochrome P450 (such as cimetidine - Cimetidine decreased the clearance of terbinafine by 30%.). Where co- administration of such drugs is required, it may be necessary to adjust the dose of terbinafine accordingly.

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.

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. For this reason, it is important to monitor patients who are treated simultaneously with drugs that are mainly metabolised by this enzyme, e.g. certain members of the following drug classes,tricyclic antidepressants (TCA's), β-blockers, selective serotonin re-uptake inhibitors (SSRIs),, antiarrhythmics (including class 1A, 1B and 1C) and monoamine oxidase inhibitors (MAO-Is) type B, especially if they have a narrow therapeutic window (see section 4.4)

In particular terbinafine decreases 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 status (phenotype).

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

Other in vitro and clinical studies (including studies undertaken 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).

There have been some cases reported of menstrual disturbances such as breakthrough bleeding and irregular cycle in patients taking terbinafine concomitantly with oral contraceptives (with both combined oestrogen and progestogen and progestogen only), although the incidence of these disorders remains within the background incidence of patients taking oral contraceptives alone.

Terbinafine does not interfere with 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.

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

Terbinafine increases the clearance of ciclosporin by 15%.

There are rare reports of changes in INR and/or prothrombin time when terbinafine is given 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 should not be administered during pregnancy unless the clinical condition of the mother requires treatment with oral terbinafine and the potential benefits outweigh any potential risks for the foetus.

Lactation:

Terbinafine is excreted in breast milk and therefore mothers should not receive terbinafine 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 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.

Blood and lymphatic system disorders

Very rare: Haematological disorders such as neutropenia, thrombocytopenia, agranulocytosis

Not known: Pancytopenia, anaemia

Immune system disorders

Very rare:

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

Not known: anaphylactic reaction, serum sickness-like reaction.

Psychiatric disorders

Very rare: Anxiety and depression symptoms secondary to taste disturbance

Nervous system disorders

Common:

Headache.

Uncommon:

Taste loss and taste disturbances have been reported in approximately 0.6% of patients treated with terbinafine. This usually resolves within several weeks on drug discontinuation, although isolated cases of prolonged taste disturbance leading to decreased food intake and weight loss has been reported.

Rare:

Paraesthesia, hypoaesthesia and dizziness

Not known:

Anosmia including permanent anosmia, hyposmia

Ear and labyrinth disorders:

Very rare: Vertigo

Not known:

Hypoacusis, impaired hearing, tinnitus

Vascular disorders:

Not known: vasculitis

Gastrointestinal disorders

Very common:

Gastrointestinal symptoms (Dyspepsia, feeling of fullness, loss of appetite, nausea, mild abdominal pain, diarrhea, abdominal distension,)

Very rare: Parotid

Swelling

Not known:

Pancreatitis

Metabolism and nutrition disorders:

Very common:

Decreasedappetite

Hepatobiliary disorders

Rare:

Serious hepatic dysfunction, including hepatic failure, hepatic enzymes increased, jaundice, cholestasis, liver decompensation and hepatitis. If hepatic dysfunction develops, treatment with terbinafine tablets 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 was uncertain.

Skin-and subcutaneous tissue disorders

Very common:

Non-serious forms of skin reactions (rash, urticaria)

Very Rare:

Serious skin reactions (e.g. Erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis)

Photosensitivity (e.g. Photodermatosis, photosensitivity allergic reaction and polymorphic light eruption)

Alopecia

If the skin rash is progressive then treatment with terbinafine should be discontinued.

Not known:

Psoriasiform eruptions or exacerbation of psoriasis, serious skin reactions e.g. acute generalised exanthematous pustulosis (AGEP).

Musculoskeletal and connective tissue disorders

Very common:

Arthralgia and myalgia. These may occur as part of a hypersensitivity reaction in association with allergic skin reactions.

Not known: Rhabdomyolysis

General disorders

Rare: Malaise

Not known: fatigue, influenza-like illness, pyrexia

Investigations:

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

Few cases of overdose (up to 5g) have been reported, giving rise to headache, nausea, upper abdominal pain and dizziness. Recommended treatment for overdose consists of eliminating the active substance, primarily by the administration of activated charcoal, and giving symptomatic supportive therapy if required.

5. Pharmacological properties
5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Dermatologicals; 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 selectively with fungal sterol biosynthesis at an early stage through inhibition of the enzyme squalene epoxidase. This leads to a deficiency in ergosterol and to an intracellular accumulation of squalene. Both the deficiency in ergosterol and the accumulation of squalene are responsible for fungal cell death. The enzyme squalene epoxidase is not linked to the cytochrome P450 system.

When given orally, the active substance concentrates in skin, hair and nails at levels associated with fungicidal activity. Measurable concentrations of the active substance are still evident 15 – 20 days after cessation of treatment.

Terbinafine is used for the treatment of fungal infections of the skin and nails, which is caused by Trichophyton (e.g.T. rubrum, T.mentagrophytes, T. verrucosum, T. violaceum), Microsporum canis and Epidermophyton floccosum. The following table outlines the range of minimum inhibitory concentrations (MIC) against the dermatophytes.

Organism

MIC rang (μg/ml)

Trichophyton rubrum

0.001 – 0.15

Trichophyton mentagrophytes

0.0001 – 0.05

Trichophyton verrucosum

0.001 – 0.006

Trichophyton violaceum

0.001 – 0.1

Microsporum canis

0.0001 – 0.1

Epidermophyton floccosum

0.001 – 0.05

Terbinafine exhibits poor efficacy against many yeasts of the Candida species.

Terbinafine tablets in contrast to locally administered terbinafine treatment, has no effect in the treatment of Pityriasis (Tinea) versicolor.

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 results in mean peak plasma concentrations of 1.30μg/ml within 1.5 hours after administration. The absorption half-life is 0.8 hours and the distribution half-life is 4.6 hours. Plasma concentrations decline in a triphasic manor, 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.

Terbinafine binds strongly to plasma proteins (99%).Terbinafine rapidly diffuses through the skin and concentrates in the lipophilic stratum corneum. Terbinafine is also secreted in sebum, thus achieving high concentrations in hair follicles, hair and parts of the skin rich in sebaceous glands. There is also evidence that terbinafine is distributed into the nail plate within a few weeks after commencing therapy.

Terbinafine is rapidly metabolised by the CYP-isoenzymes, mainly by CYP2C9, CYP1A2, CYP3A4, CYP2C8 and CYP2C19. 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 in the plasma.

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.

In patients with renal impairment (creatinine clearance <50 ml/min) and pre-existing mild to severe hepatic impairment, single dose pharmacokinetic studies have shown that the clearance of Terbinafine can be reduced by 50%.

The bioavailability of terbinafine is only slightly affected by food, and therefore a dose adjustment is not necessary.

5.3 Preclinical safety data

The approximate LD50 value of terbinafine is over 4 g/kg in both mice and rats.

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 69 mg/kg, at which systemic exposure was similar to clinical exposure. The mechanism of tumour development has not been established. The clinical relevance is unknown. 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 discontinuation of the active substance.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 undesirable effects on fertility or other reproduction parameters were observed in studies in rats or rabbits.

6. Pharmaceutical particulars
6.1 List of excipients

Magnesium stearate

Silica, colloidal anhydrous

Croscarmellose sodium

Hypromellose

Microcrystalline cellulose

6.2 Incompatibilities

Not applicable

6.3 Shelf life

36 months

6.4 Special precautions for storage

Keep the blister in the outer carton

6.5 Nature and contents of container

Al/PVC-PVdC blister. Pack Sizes: 14, 28 tablets.

Not all pack sizes may be marketed.

6.6 Special precautions for disposal and other handling

No special requirements

7. Marketing authorisation holder

Athlone Laboratories Ballymurray

Co. Roscommon

Ireland

8. Marketing authorisation number(s)

PL 06453/0060

9. Date of first authorisation/renewal of the authorisation

18th April 2005

10. Date of revision of the text

March 2016

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