Source: Health Products Regulatory Authority (IE) Revision Year: 2018 Publisher: Bayer Limited, The Atrium, Blackthorn Road, Dublin 18, Ireland
Pharmacotherapeutic group: Antifungals for topical use – imidazole and triazole derivatives
ATC code: D01AC10
Bifonazole is an imidazole derivative which is active against fungi such as dermatophytes.
Bifonazole exerts its anti-fungal action by inhibiting the biosynthesis of ergosterol on two different levels, thereby distinguishing bifonazole both from other azole derivatives and from other anti-fungals which act only on a single level. Inhibition of ergosterol synthesis leads to structural and functional impairment of the cytoplasmic membrane.
The resistance situation for bifonazole is favourable. Primary resistant variants of sensitive fungal species are very rare. Investigations so far did not provide any evidence of a development of secondary resistance in primarily sensitive strains.
Bifonazole penetrates well into infected skin layers. 6 hours after administration concentrations in the various skin layers reach from 1000 µg/cm3 in the top layer of the epidermis (stratum corneum) to 5 µg/cm in the stratum papillare.
Pharmacokinetic investigations after topical application to intact human skin have shown that only a small amount of bifonazole is absorbed (0.6-0.8% of the dose); the resulting serum concentrations were usually below the detection limit (i.e. <1 ng/mL). Higher absorption was observed after application to inflamed skin (2-4% of the respective dose).
Preclinical data reveal no special hazards for humans based on conventional studies of single dose toxicity and genotoxicity. Effects on the liver (enzyme induction, fatty degeneration) were observed in repeated dose toxicity studies with oral administration but only at exposures in excess of the maximum human exposure indicating little relevance to clinical use. No carcinogenicity studies were performed with bifonazole. Both in vitro and in vivo tests for detection of gene mutation did not demonstrate genotoxic activity.
In reproduction toxicology studies in rabbits, oral doses of 30 mg/kg body weight resulted in embryotoxicity including lethality. In the rats, bifonazole at oral doses up to 100 mg/kg body weight was not embryotoxic, but a retarded skeletal development in the fetuses was observed at the dose of 100 mg/kg. This fetal effect on the skeletal development can be considered as a secondary effects resulting from the maternal toxicity (a reduction in body weight). Given the low absorption of the active ingredient via the skin, the relevance of these findings to clinical use is unknown. No impairment of male or female fertility was observed in rats at oral doses up to 40 mg/kg body weight.
Bifonazole passes through the placental barrier in rats. A study with lactating rats administered bifonazole intravenously showed that the drug was secreted into milk.
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