Pharmacotherapeutic Group: Antiinfectives and antiseptics, excl. combination with corticosteroids, imidazole derivatives. ATC Code: G01A F05.
Pharmacology: Pharmacodynamics: Mechanism of action: Econazole nitrate acts by damaging fungal cell membranes, resulting in increased permeability. Sub-cellular membranes in the cytoplasm are damaged. The site of action is most probably the unsaturated fatty acid acyl moiety of membrane phospholipids.
Pharmacodynamic effects: Microbiology: A broad spectrum of antimycotic activity has been demonstrated against dermatophytes, yeasts and molds. A clinically relevant action against gram-positive bacteria has also been found.
Pharmacokinetics: Absorption: Systemic absorption of econazole is extremely low after vaginal application. Following vaginal application of econazole nitrate cream, about 5% to 7% of the dose was absorbed. Mean peak plasma/serum concentrations of econazole and/or its metabolites were observed 1 to 2 days after dose administration and were approximately 65 ng/mL for the 150 mg Ovule.
Distribution: Econazole and/or its metabolites in the systemic circulation are extensively bound (> 98%) to serum proteins.
Metabolism: Econazole that reaches the systemic circulation is extensively metabolized by oxidation of the imidazole ring, followed by O-dealkylation and glucuronidation.
Excretion: Econazole and metabolites are eliminated in urine and feces.
Toxicology: Non-Clinical Information: Preclinical effects were observed only at exposures considered sufficiently in excess of the maximum human exposure, indicating little relevance to clinical use.
Acute toxicity studies indicate a wide margin of safety with rodent oral LD50 values ranging from >160-463 mg/kg. In repeat dose toxicity studies, at high doses (50 mg/kg/day) the liver was identified as a target organ with minimal toxicity and full recovery.
Neither significant topical toxicity, phototoxicity, local dermal irritation, vaginal irritation nor sensitization was noted. Only mild ocular irritation was noted with a cream formulation.
Carcinogenicity and Mutagenicity: No studies on the carcinogenic potential have been conducted due to the short course of proposed clinical therapy and the absence of any significant potential of econazole to be genotoxic in a way that could lead to initiation or promotion of tumor formation.
In various test systems either no or some limited gene-toxicity effects (structural chromosomal deviations) have been shown. Based on an overall assessment of these data and the indicated route of administration including the resulting minimal systemic exposure to econazole, there is little relevance for clinical use.
Reproductive Toxicology: Results of econazole reproduction studies showed no effects on teratogenicity.
Fertility: Results of econazole reproduction studies showed no effects on fertility.
Pregnancy: Low neonatal survival and fetal toxicity was associated only with maternal toxicity. In animal studies, econazole nitrate has shown no teratogenic effects but was fetotoxic in rodents at maternal subcutaneous doses of 20 mg/kg/day and at maternal oral doses of 10 mg/kg/day. The significance of this in humans is unknown.