Fluconazole precautions

List of precautions
General Single dose Carcinogenesis Mutagenesis Impairment of fertility Pregnancy Nursing mothers Pediatric use Geriatric use Warnings
 * Hepatic injury
 * Anaphylaxis
 * Dermatologic

General
Some azoles, including Fluconazole, have been associated with prolongation of the QT interval on the electrocardiogram. During post-marketing surveillance, there have been rare cases of QT prolongation and torsade de pointes in patients taking Fluconazole. Most of these reports involved seriously ill patients with multiple confounding risk factors, such as structural heart disease, electrolyte abnormalities and concomitant medications that may have been contributory. Fluconazole should be administered with caution to patients with these potentially proarrhythmic conditions. Return to top

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. Return to top

Carcinogenesis
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 2–7× the recommended human dose). Male rats treated with 5 and 10 mg/kg/day had an increased incidence of hepatocellular adenomas. Return to top

Mutagenesis
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 µg/mL) showed no evidence of chromosomal mutations. Return to top

Impairment of fertility
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 5–15× 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. Return to top

Pregnancy
Pregnancy Category C Teratogenic effects: 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 20–60× 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. Fluconazole should be used in pregnancy only if the potential benefit justifies the possible risk to the fetus. Return to top

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

Pediatric use
An open-label, randomized, controlled trial has shown Fluconazole to be effective in the treatment of oropharyngeal candidiasis in children 6 months to 13 years of age. The use of Fluconazole in children with cryptococcal meningitis, Candida esophagitis, or systemic Candidainfections 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 have established a dose proportionality between children and adults. 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 1,616 days. Efficacy of Fluconazole has not been established in infants less than 6 months of age. A small number of patients (29) ranging in age from 1 day to 6 months have been treated safely with Fluconazole. Return to top

Geriatric use
In non-AIDS patients, side effects possibly related to Fluconazole treatment were reported in fewer patients aged 65 and older (9%, n =339) than for younger patients (14%, n=2240). However, there was no consistent difference between the older and younger patients with respect to individual side effects. Of the most frequently reported (>1%) side effects, rash, vomiting and diarrhea occurred in greater proportions of older patients. Similar proportions of older patients (2.4%) and younger patients (1.5%) discontinued Fluconazole therapy because of side effects. In post-marketing experience, spontaneous reports of anemia and acute renal failure were more frequent among patients 65 years of age or older than in those between 12 and 65 years of age. Because of the voluntary nature of the reports and the natural increase in the incidence of anemia and renal failure in the elderly, it is however not possible to establish a casual relationship to drug exposure. Controlled clinical trials of Fluconazole did not include sufficient numbers of patients aged 65 and older to evaluate whether they respond differently from younger patients in each indication. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. Fluconazole is primarily cleared by renal excretion as unchanged drug. Because elderly patients are more likely to have decreased renal function, care should be taken to adjust dose based on creatinine clearance. It may be useful to monitor renal function. Return to top

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. Return to top

Anaphylaxis
In rare cases, anaphylaxis has been reported. Return to top

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. Return to top