CONTRAINDICATIONS
Fluconazole is contraindicated in patients who have shown hypersensitivity to fluconazole
or to any of its excipients. There is no information regarding cross hypersensitivity
between fluconazole and other azole antifungal agents. Caution should be used in
prescribing fluconazole to patients with hypersensitivity to other azoles.
WARNINGS
1. Hepatic Injury: Fluconazole has been associated with rare cases of serious
hepatic toxicity, including fatalities primarily in patients with serious underlying
medical conditions. In cases of fluconazole associated hepatotoxicity, no obvious
relationship to total daily dose, duration of therapy, sex or age of the patient has
been observed. Fluconazole hepatotoxicity has usually, but not always, been
reversible on discontinuation of therapy. Patients who develop abnormal liver
function tests during fluconazole therapy should be monitored for the development
of more severe hepatic injury. Fluconazole should be discontinued if clinical signs
and symptoms consistent with liver disease develop that may be attributable to
fluconazole.
2. Anaphylaxis: In rare cases, anaphylaxis has been reported.
3. Dermatologic: Patients have rarely developed exfoliative skin disorders during
treatment with fluconazole. In patients with serious underlying diseases
(predominantly AIDS and malignancy), these have rarely resulted in a fatal
outcome. Patients who develop rashes during treatment with fluconazole should be
monitored closely and the drug discontinued if lesions progress.
PRECAUTIONS
General
Single Dose: The convenience and efficacy of the single dose oral tablet of fluconazole
regimen for the treatment of vaginal yeast infections should be weighed against the
acceptability of a higher incidence of drug related adverse events with fluconazole (26%)
versus intravaginal agents (16%) in U.S. comparative clinical studies. (See ADVERSE
REACTIONS and CLINICAL STUDIES.)
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 mg/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 p.o. In an intravenous perinatal
study in rats at 5, 20, and 40 mg, dystocia and prolongation of parturition were observed
in a few dams at 20 mg/kg (approximately 5-15´ 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 20-60´ 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. Fluconazole
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 fluconazole 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 fluconazole 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 fluconazole 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 fluconazole 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 fluconazole 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 1616 days.
(See ADVERSE REACTIONS.)
Efficacy of fluconazole 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 fluconazole.