Diflucan Warnings & Precautions

Drug Library
Diflucan - Warnings & Precautions [Fluconazole]

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.

The disturbances in parturition were reflected by a slight increase in the number of still-born pups and decrease of neonatal survival at these dose levels. The effects on parturition in rats are consistent with the species specific estrogen-lowering property produced by high doses of fluconazole. Such a hormone change has not been observed in women treated with fluconazole. (See CLINICAL PHARMACOLOGY.)

Pregnancy Teratogenic Effects.

Pregnancy Category C:

Fluconazole was administered orally to pregnant rabbits during organogenesis in two studies, at 5, 10 and 20 mg/ kg and at 5, 25, and 75 mg/ kg, respectively. Maternal weight gain was impaired at all dose levels, and abortions occurred at 75 mg/ kg (approximately 20-60x the recommended human dose); no adverse fetal effects were detected. In several studies in which pregnant rats were treated orally with fluconazole during organogenesis, maternal weight gain was impaired and placental weights were increased at 25 mg/ kg. There were no fetal effects at 5 or 10 mg/ kg; increases in fetal anatomical variants (supernumerary ribs, renal pelvis dilation) and delays in ossification were observed at 25 and 50 mg/ kg and higher doses.