Source: Medicines and Medical Devices Safety Authority (NZ) Revision Year: 2022 Publisher: Multichem NZ Ltd, Private Bag 93527, Takapuna, AUCKLAND 0740 Telephone: (09) 478 3841
ATC Code: G01AF02, antifungals for vaginal use – imidazole and triazole derivatives
Azoles (e.g. clotrimazole) are usually recommended for the local treatment of vulvovaginal candidosis that is characterised by vulvovaginal symptoms such as itching, burning, discharge, redness, swelling and soreness.
Clotrimazole acts against fungi by inhibiting ergosterol synthesis. Inhibition of ergosterol synthesis leads to structural and functional impairment of the fungal cytoplasmic membrane.
Clotrimazole has a broad antimycotic spectrum of action in vitro and in vivo, which includes dermatophytes, yeasts, moulds, etc.
Under appropriate test conditions, the MIC values for these types of fungi are in the region of less than 0.062 – 8.0 μg/mL substrate.
The mode of action of clotrimazole is primarily fungistatic or fungicidal depending on the concentration of clotrimazole at the site of infection. In vitro activity is limited to proliferating fungal elements; fungal spores are only slightly sensitive.
In addition to its antimycotic action, clotrimazole also acts on gram-positive micro-organisms (Streptococci / Staphylococci / Gardnerella vaginalis) and gram-negative micro-organisms (Bacteroides).
In vitro clotrimazole inhibits the multiplication of Corynebacteria and gram-positive cocci (with the exception of Enterococci) in concentrations of 0.5 – 10 μg/mL substrate.
Primarily resistant variants of sensitive fungal species are very rare; the development of secondary resistance by sensitive fungi has so far only been observed in very isolated cases under therapeutic conditions.
Pharmacokinetic investigations after vaginal application have shown that only a small amount of clotrimazole (3 – 10%) is absorbed. Due to the rapid hepatic metabolisation of absorbed clotrimazole into pharmacologically inactive metabolites the resulting peak plasma concentrations of clotrimazole after vaginal application of a 500 mg dose were less than 10 ng/mL, suggesting that clotrimazole applied intravaginally is unlikely to lead to measurable systemic effects or side effects.
Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential and toxicity to reproduction and development.
The local and systemic tolerance of clotrimazole in different dosage forms was assessed in intravaginal studies in dogs and monkeys and in subacute dermal studies in rabbits. There was no evidence of treatment-related local or systemic adverse effects in any of these studies.
The oral toxicity of clotrimazole has been well-studied.
Following a single oral administration, clotrimazole was slight-to-moderately toxic in experimental animals, with LD50 values of 761 to 923 mg/kg bw for mice, 95 to 114 mg/kg bw for new born rats and 114 to 718 mg/kg bw for adult rats, >1000 mg/kg bw for rabbits and >2000 mg/kg bw for dogs and cats.
In repeated dose oral studies conducted in rats and dogs, the liver was found to be the primary target organ for toxicity. This was evidenced by an increase in serum transaminase activities and the appearance of liver vacuolation and fatty deposits starting at 50 mg/kg in the chronic (78-week) rat study and at 100 mg/kg in the subchronic (13-week) dog study.
Clotrimazole has been extensively studied in in vitro and in vivo mutagencity assays, and no evidence of mutagenic potential was found. A 78-week oral dosing study of clotrimazole in rats did not show any carcinogenic effect.
In a rat fertility study, groups of FB30 rats received oral doses of clotrimazole up to 50 mg/kg bw for 10 weeks prior to mating and either throughout a 3-week mating period (for males only) or, for females, until day 13 of gestation or 4-week postpartum. Neonatal survival was reduced in the 50 mg/kg bw group. Clotrimazole at doses up to 25 mg/kg bw did not impair the development of the pups. Clotrimazole at all doses did not affect fertility.
No teratogenicity effects were demonstrated in studies in mice, rabbits and rats, given oral doses of up to 200, 180 and 100 mg/kg respectively.
A study with 3 lactating rats administered 30 mg/kg clotrimazole intravenously showed that the medicine was secreted into milk at levels higher than in plasma by a factor of 10 to 20 at 4 hours after administration, followed by a decline to a factor of 0.4 by 24 hours.
Given the limited absorption of clotrimazole after vaginal application (estimated to be 3% - 10%) no hazard is expected from the use of vaginal clotrimazole.
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