Diflucan - Warnings & Precautions

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Fluconazole tablets coadministered with ethinyl estradiol-and levonorgestrel-containing oral contraceptives produced an overall mean increase in ethinyl estradiol and levonorgestrel levels; however, in some patients there were decreases up to 47% and 33% of ethinyl estradiol and levonorgestrel levels. (See CLINICAL PHARMACOLOGY: Drug Interaction Studies.)

The data presently available indicate that the decreases in some individual ethinyl estradiol and levonorgestrel AUC values with fluconazole treatment are likely the result of random variation. While there is evidence that fluconazole can inhibit the metabolism of ethinyl estradiol and levonorgestrel, there is no evidence that fluconazole is a net inducer of ethinyl estradiol or levonorgestrel metabolism. The clinical significance of these effects is presently unknown.

Physicians should be aware that interaction studies with medications other than those listed in the CLINICAL PHARMACOLOGY section have not been conducted, but such interactions may occur.

Carcinogenesis, Mutagenesis and Impairment of Fertility

Fluconazole showed no evidence of carcinogenic potential in mice and rats treated orally for 24 months at doses of 2.5, 5 or 10 mg/ kg/ day (approximately 2-7x the recommended human dose). Male rats treated with 5 and 10 mg/ kg/ day had an increased incidence of hepatocellular adenomas.

Fluconazole, with or without metabolic activation, was negative in tests for mutagenicity in 4 strains of S. typhimurium, and in the mouse lymphoma L5178Y system. Cytogenetic studies in vivo (murine bone marrow cells, following oral administration of fluconazole) and in vitro (human lymphocytes exposed to fluconazole at 1000 g/ mL) showed no evidence of chromosomal mutations.

Fluconazole did not affect the fertility of male or female rats treated orally with daily doses of 5, 10 or 20 mg/ kg or with parenteral doses of 5, 25 or 75 mg/ kg, although the onset of parturition was slightly delayed at 20 mg/ kg PO. In an intravenous perinatal study in rats at 5, 20 and 40 mg/ kg, dystocia and prolongation of parturition were observed in a few dams at 20 mg/ kg (approximately 5-15x the recommended human dose) and 40 mg/ kg, but not at 5 mg/ kg.