Terbinafine 250mg Tablets
SUMMARY OF PRODUCT CHARACTERISTICS
1 NAME OF THE MEDICINAL PRODUCT
Terbinafine 250mg Tablets
2 QUALITATIVE AND QUANTITATIVE COMPOSITION
Each tablet contains 281.25mg terbinafine hydrochloride, equivalent to 250mg terbinafine
For excipients, see 6.1.
3 PHARMACEUTICAL FORM
Tablet
White, round, flat, 11mm 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
- The treatment of 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.
- 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.
- The treatment of onychomycosis.
4.2 Posology and method of administration
Method of administration:
Via the oral route
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:
Tinea pedis (interdigital, plantar/moccasin type): 2 to 6 weeks Tinea corporis: 4 weeks Tinea cruris: 2 to 4 weeks
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. For 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.
Children
The use of Terbinafine is not recommended in children.
Use in the elderly
There is no evidence to suggest that elderly patients require different dosages or experience side-effects different to those of younger patients. However consideration should be given to the possibility of impairment of liver or kidney function within this age group (see section 4.4 Special warning and precautions for use).
4.3 Contraindications
Hypersensitivity to Terbinafine or to any of the excipients
4.4 Special warnings and precautions for use
Rarely, cases of cholestasis and hepatitis have been reported, these usually occur within two months of starting treatment. If a patient presents with signs or symptoms suggestive of liver dysfunction such as pruritis, unexplained persistent nausea, anorexia or tiredness, or jaundice, vomiting, fatigue, abdominal pain or dark urine, or pale stools, hepatic origin should be verified and Terbinafine therapy should be discontinued (see 4.8 Undesirable effects).
Single dose pharmacokinetic studies in patients with pre-existing liver disease have shown that the clearance of Terbinafine may be reduced by about 50%. The therapeutic use of Terbinafine in patients with chronic or active liver disease has not been studied in prospective clinical trials, and therefore can not be recommended.
Terbinafine should be used with caution in patients with psoriasis, as very rare cases of exacerbation of psoriasis have been reported.
Patients with impaired renal function (creatinine clearance less than 50ml/minute or serum creatinine of more than 300mmol/l) should receive half the normal dose.
4.5 Interaction with other medicinal products and other forms of interaction
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 required, it may be necessary to adjust the dose of Terbinafine accordingly.
In vitro studies have shown, that terbinafine inhibits the CYP2D6-mediated metabolism. For patients taking compounds which are predominantly metabolised by this enzyme, such as tricyclic antidepressants (TCA's), B-blockers, selective serotonin reuptake inhibitors (SSRIs), and monoamine oxidase inhibitors (MAO-Is) Type B this may be of clinical relevance.
Other in vitro and clinical studies suggest that terbinafine shows negligible potential to inhibit or induce the clearance of drugs that are metabolised via other cytochrome P450 enzymes (e.g. ciclosporin, tolbutamine, terfenadine, triazolam, oral contraceptives). There has been some cases reported of menstrual disturbances such as breakthrough bleeding and irregular cycle in patients taking Terbinafine concomitantly with oral contraceptives.
4.6 Pregnancy and lactation
Foetal toxicity and fertility studies in animals suggest no adverse effects.
There is no clinical experience with terbinafine in pregnant women, therefore, terbinafine should not be administered during pregnancy.
Terbinafine is excreted in breast milk and therefore mothers should not receive terbinafine treatment whilst breast-feeding.
4.7 Effects on ability to drive and use machines
No effects on ability to drive and use machines have been observed.
4.8 Undesirable effects
Side effects are generally mild to moderate, and transient. The most common are gastrointestinal symptoms (dyspepsia, fullness, loss of appetite, nausea, mild abdominal pain, diarrhoea), allergic skin reactions (rash, urticaria) and headache. Paraesthesia, hypoaesthesia, dizziness, malaise and fatigue have also been reported rarely. Extremely rare cases of vertigo have been reported.
Musculo skeletal disorders including arthralgia and myalgia have been reported. These may occur as part of a hypersensitivity reaction in association with allergic skin reactions.
Rare cases of serious skin reactions (e.g. Stevens-Johnson syndrome, toxic epidermal necrolysis, photosensitivity and angioneurotic oedema) have been reported. If the skin rash is progressive then treatment with Terbinafine should be discontinued.
Taste loss and taste disturbance have been reported in approximately 0.6 % of patients treated with Terbinafine. This usually resolves slowly on drug discontinuation.
Rare cases of serious hepatic dysfunction, including jaundice, cholestasis and hepatitis have been reported. If hepatic dysfunction develops, treatment with Terbinafine should be discontinued (see section 4.4. Special warnings and precautions for use).
Haematological disorders such as neutropenia, thrombocytopenia and agranulocytosis have been reported very rarely.
Terbinafine has been reported to exacerbate psoriasis in rare cases (see section 4.4). Psychiatric disturbances such as depression and anxiety have been reported very rarely.
4.9 Overdose
Few cases of overdose (up to 5g) have been reported, giving rise to headache, nausea, epigastric pain and dizziness. Recommended treatment for overdosage consists of eliminating the drug, primarily by the administration of activated charcoal, and giving symptomatic supportive therapy if required.
5 PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
ATC code: D01B A 02
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 ergestrol and to an intracellular accumulation 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 0.97pg/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 terbinafine is unaffected 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
Magnesium stearate Colloidal silicon dioxide Croscarmellose sodium Hypromellose Microcrystalline cellulose
6.2 Incompatibilities
None known
6.3 Shelf life
18 months
6.4 Special precautions for storage
Do not store above 25 °C.
Store in original packaging
6.5 Nature and contents of container
Al/PVC-PVdC blister pack and HDPE container with LDPE cap
Pack sizes: 14, 28 tablets
6.6 Special precautions for disposal
No special requirements
7 MARKETING AUTHORISATION HOLDER
Consilient Health Limited 5th Floor, Beaux Lane House Mercer Street Lower Dublin 2 Ireland
8 MARKETING AUTHORISATION NUMBER(S)
PL 24837/0003
9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
11th October 2004
10 DATE OF REVISION OF THE TEXT
May 2005