Diflucan

[Fluconazole]

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.)

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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.

At doses ranging from 80 mg/ kg (approximately 20-60x the recommended human dose) to 320 mg/ kg embryolethality in rats was increased and fetal abnormalities included wavy ribs, cleft palate and abnormal cranio-facial ossification. These effects are consistent with the inhibition of estrogen synthesis in rats and may be a result of known effects of lowered estrogen on pregnancy, organogenesis and parturition.

There are no adequate and well controlled studies in pregnant women. There have been reports of multiple congenital abnormalities in infants whose mothers were being treated for 3 or more months with high dose (400-800 mg/ day) fluconazole therapy for coccidioidomycosis (an unindicated use). The relationship between fluconazole use and these events is unclear.

DIFLUCAN should be used in pregnancy only if the potential benefit justifies the possible risk to the fetus.

Nursing Mothers

Fluconazole is secreted in human milk at concentrations similar to plasma. Therefore, the use of DIFLUCAN in nursing mothers is not recommended.

Pediatric Use

An open-label, randomized, controlled trial has shown DIFLUCAN to be effective in the treatment of oropharyngeal candidiasis in children 6 months to 13 years of age. (See CLINICAL STUDIES.)

The use of DIFLUCAN in children with cryptococcal meningitis, Candida esophagitis, or systemic Candida infections is supported by the efficacy shown for these indications in adults and by the results from several small noncomparative pediatric clinical studies. In addition, pharmacokinetic studies in children (see CLINICAL PHARMACOLOGY) have established a dose proportionality between children and adults. (See DOSAGE AND ADMINISTRATION.)

In a noncomparative study of children with serious systemic fungal infections, most of which were candidemia, the effectiveness of DIFLUCAN was similar to that reported for the treatment of candidemia in adults. Of 17 subjects with culture-confirmed candidemia, 11 of 14 (79%) with baseline symptoms (3 were asymptomatic) had a clinical cure; 13/ 15 (87%) of evaluable patients had a mycologic cure at the end of treatment but two of these patients relapsed at 10 and 18 days, respectively, following cessation of therapy.

The efficacy of DIFLUCAN for the suppression of cryptococcal meningitis was successful in 4 of 5 children treated in a compassionate-use study of fluconazole for the treatment of life-threatening or serious mycosis. There is no information regarding the efficacy of fluconazole for primary treatment of cryptococcal meningitis in children.

The safety profile of DIFLUCAN in children has been studied in 577 children ages 1 day to 17 years who received doses ranging from 1 to 15 mg/ kg/ day for 1 to 1,616 days. (See ADVERSE REACTIONS.)

Efficacy of DIFLUCAN has not been established in infants less than 6 months of age. (See CLINICAL PHARMACOLOGY.) A small number of patients (29) ranging in age from 1 day to 6 months have been treated safely with DIFLUCAN.

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