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 mcg/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 5-15x
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. 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.
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