Source: Medicines & Healthcare Products Regulatory Agency (GB) Revision Year: 2018 Publisher: Accord-UK Ltd (Trading style: Accord), Whiddon Valley, Barnstaple, Devon, EX32 8NS
Pharmacotherapeutic group: Dermatologicals; antifungals for systemic use
ATC code: D01BA02
Terbinafine tablets is an allylamine which has a broad spectrum of antifungal activity. At low concentrations Terbinafine tablets is fungicidal against dermatophytes, moulds and certain dimorphic fungi. The activity versus yeasts is fungicidal or fungistatic depending on the species.
Terbinafine tablets interfere 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 in the fungal cell membrane. Both the deficiency in ergosterol and the accumulation of squalene are responsible for fungal cell death.
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 tablets are 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 rubrun | 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 |
| Edidermorphyton fluccosum | 0.001–0.05 |
Terbinafine tablets exhibits poor efficacy against many yeasts of the Candida species.
Terbinafine tablets in contrast to locally administered Terbinafine tablets treatment, has no effect in the treatment of Pityriasis (Tinea) versicolor.
A single oral dose of 250mg Terbinafine tablets results in mean peak plasma concentrations of 0.97 mcg/ml within 2 hours after administration. The absorption half-life is 0.8 hours and the distribution half-life is 4.6 hours.
Terbinafine tablets binds strongly to plasma proteins (99%).
Terbinafine tablets rapidly diffuses through the skin and concentrates in the lipophilic stratum corneum. Terbinafine tablets are 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 tablets is distributed into the nail plate within a few weeks after commencing therapy.
Terbinafine tablets are 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 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 tablets.
In patients with pre-existing mild to severe hepatic impairment, single dose pharmacokinetic studies have shown that the clearance of Terbinafine tablets can be reduced by 50%.
The bioavailability of Terbinafine tablets is only slightly affected by food, and therefore a dose adjustment is not necessary.
The approximate LD50 value of Terbinafine tablets 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 tablets 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.
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