Fluconazole

INDICATIONS AND USAGE Fluconazole tablets are indicated for the treatment of: 1. Vaginal candidiasis (vaginal yeast infections due to Candida ). 2. Oropharyngeal and esophageal candidiasis. In open noncomparative studies of relatively small numbers of patients, fluconazole tablets were also effective for the treatment of Candida urinary tract infections, peritonitis, and systemic Candida infections including candidemia, disseminated candidiasis, and pneumonia. 3. Cryptococcal meningitis. Before prescribing fluconazole tablets for AIDS patients with cryptococcal meningitis, please see CLINICAL STUDIES section. Studies comparing fluconazole tablets to amphotericin B in non-HIV infected patients have not been conducted. Prophylaxis: Fluconazole tablets are also indicated to decrease the incidence of candidiasis in patients undergoing bone marrow transplantation who receive cytotoxic chemotherapy and/or radiation therapy. Specimens for fungal culture and other relevant laboratory studies (serology, histopathology) should be obtained prior to therapy to isolate and identify causative organisms. Therapy may be instituted before the results of the cultures and other laboratory studies are known; however, once these results become available, anti-infective therapy should be adjusted accordingly.

DOSAGE AND ADMINISTRATION Dosage and Administration in Adults: Single Dose Vaginal candidiasis: The recommended dosage of fluconazole for vaginal candidiasis is 150 mg as a single oral dose. Multiple Dose SINCE ORAL ABSORPTION IS RAPID AND ALMOST COMPLETE, THE DAILY DOSE OF FLUCONAZOLE IS THE SAME FOR ORAL TABLETS AND INTRAVENOUS ADMINISTRATION. In general, a loading dose of twice the daily dose is recommended on the first day of therapy to result in plasma concentrations close to steady-state by the second day of therapy. The daily dose of fluconazole for the treatment of infections other than vaginal candidiasis should be based on the infecting organism and the patient’s response to therapy. Treatment should be continued until clinical parameters or laboratory tests indicate that active fungal infection has subsided. An inadequate period of treatment may lead to recurrence of active infection. Patients with AIDS and cryptococcal meningitis or recurrent oropharyngeal candidiasis usually require maintenance therapy to prevent relapse. Oropharyngeal candidiasis: The recommended dosage of fluconazole for oropharyngeal candidiasis is 200 mg on the first day, followed by 100 mg once daily. Clinical evidence of oropharyngeal candidiasis generally resolves within several days, but treatment should be continued for at least 2 weeks to decrease the likelihood of relapse. Esophageal candidiasis: The recommended dosage of fluconazole for esophageal candidiasis is 200 mg on the first day, followed by 100 mg once daily. Doses up to 400 mg/day may be used, based on medical judgment of the patient’s response to therapy. Patients with esophageal candidiasis should be treated for a minimum of three weeks and for at least two weeks following resolution of symptoms. Systemic Candida infections: For systemic Candida infections including candidemia , disseminated candidiasis, and pneumonia, optimal therapeutic dosage and duration of therapy have not been established. In open, noncomparative studies of small numbers of patients, doses of up to 400 mg daily have been used. Urinary tract infections and peritonitis: For the treatment of Candida urinary tract infections and peritonitis, daily doses of 50 to 200 mg have been used in open, noncomparative studies of small numbers of patients. Cryptococcal meningitis: The recommended dosage for treatment of acute cryptococcal meningitis is 400 mg on the first day, followed by 200 mg once daily. A dosage of 400 mg once daily may be used, based on medical judgment of the patient’s response to therapy. The recommended duration of treatment for initial therapy of cryptococcal meningitis is 10 to 12 weeks after the cerebrospinal fluid becomes culture negative. The recommended dosage of fluconazole for suppression of relapse of cryptococcal meningitis in patients with AIDS is 200 mg once daily. Prophylaxis in patients undergoing bone marrow transplantation: The recommended fluconazole daily dosage for the prevention of candidiasis in patients undergoing bone marrow transplantation is 400 mg, once daily. Patients who are anticipated to have severe granulocytopenia (less than 500 neutrophils cells/mm 3 ) should start fluconazole prophylaxis several days before the anticipated onset of neutropenia, and continue for 7 days after the neutrophil count rises above 1000 cells/mm 3 . Dosage and Administration in Pediatric Patient: Oropharyngeal candidiasis: The recommended dosage of fluconazole for oropharyngeal candidiasis in pediatric patients 6 months and older is 6 mg/kg on the first day, followed by 3 mg/kg once daily. Treatment should be administered for at least 2 weeks to decrease the likelihood of relapse. Esophageal candidiasis: For the treatment of esophageal candidiasis, the recommended dosage of fluconazole in pediatric patients 6 months and older is 6 mg/kg on the first day, followed by 3 mg/kg once daily. Doses up to 12 mg/kg/day may be used, based on medical judgment of the patient’s response to therapy.…

WARNINGS (1) Hepatic injury: Fluconazole should be administered with caution to patients with liver dysfunction. 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: Exfoliative skin disorders during treatment with fluconazole have been reported. Fatal outcomes have been reported in patients with serious underlying diseases. Patients with deep seated fungal infections who develop rashes during treatment with fluconazole should be monitored closely and the drug discontinued if lesions progress. Fluconazole should be discontinued in patients treated for superficial fungal infection who develop a rash that may be attributed to fluconazole. (4) Potential for fetal harm: There are no adequate and well-controlled clinical trials of fluconazole in pregnant women. Case reports describe a pattern of distinct congenital anomalies in infants exposed in utero to high dose maternal fluconazole (400 to 800 mg/day) during most or all of the first trimester. These reported anomalies are similar to those seen in animal studies. If fluconazole is used during pregnancy or if the patient becomes pregnant while taking the drug, the patient should be informed of the potential hazard to the fetus. Effective contraceptive measures should be considered in women of child-bearing potential who are being treated with fluconazole 400 to 800 mg/day and should continue throughout the treatment period and for approximately 1 week (5 to 6 half-lives) after the final dose. Epidemiological studies suggest a potential risk of spontaneous abortion and congenital abnormalities in infants whose mothers were treated with 150 mg of fluconazole as a single or repeated dose in the first trimester, but these epidemiological studies have limitations and these findings have not been confirmed in controlled clinical trials (see PRECAUTIONS: Pregnancy ).

CONTRAINDICATIONS Fluconazole tablets are 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. Coadministration of other drugs known to prolong the QT interval and which are metabolized via the enzyme CYP3A4 such as erythromycin, pimozide, and quinidine are contraindicated in patients receiving fluconazole (see CLINICAL PHARMACOLOGY: Drug Interaction Studies and PRECAUTIONS ).

Pregnancy Teratogenic Effects. Potential for Fetal Harm: Use in pregnancy should be avoided except in patients with severe or potentially life-threatening fungal infections in whom fluconazole may be used if the anticipated benefit outweighs the possible risk to the fetus. A few published case reports describe a pattern of distinct congenital anomalies in infants exposed in utero to high dose maternal fluconazole (400 to 800 mg/day) during most or all of the first trimester. These reported anomalies are similar to those seen in animal studies. Effective contraceptive measures should be considered in women of child-bearing potential who are being treated with fluconazole 400 to 800 mg/day and should continue throughout the treatment period and for approximately 1 week (5 to 6 half-lives) after the final dose. If fluconazole is used during pregnancy, or if the patient becomes pregnant while taking the drug, the patient should be informed of the potential hazard to the fetus. Spontaneous abortions and congenital abnormalities have been suggested as potential risks associated with 150 mg of fluconazole as a single or repeated dose in the first trimester of pregnancy based on retrospective epidemiological studies. There are no adequate and well-controlled studies of fluconazole in pregnant women (see WARNINGS: Potential for Fetal Harm ). Human Data Case reports describe a distinctive and rare pattern of birth defects among infants whose mothers received high-dose (400 to 800 mg/day) fluconazole during most or all of the first trimester of pregnancy. The features seen in these infants include brachycephaly, abnormal facies, abnormal calvarial development, cleft palate, femoral bowing, thin ribs and long bones, arthrogryposis, and congenital heart disease. These effects are similar to those seen in animal studies. Epidemiological studies suggest a potential risk of spontaneous abortion and congenital abnormalities in infants whose mothers were treated with 150 mg of fluconazole as a single or repeated dose in the first trimester, but these epidemiological studies have limitations and these findings have not been confirmed in controlled clinical trials. Animal Data Fluconazole was administered orally to pregnant rabbits during organogenesis in two studies at doses of 5 mg/kg, 10 mg/kg, and 20 mg/kg and at 5 mg/kg, 25 mg/kg, and 75 mg/kg, respectively. Maternal weight gain was impaired at all dose levels (approximately 0.25 to 4 times the 400 mg clinical dose based on body surface area [BSA] comparison), and abortions occurred at 75 mg/kg (approximately 4 times the 400 mg clinical dose based on BSA); no adverse fetal effects were observed. In several studies in which pregnant rats received fluconazole orally during organogenesis, maternal weight gain was impaired and placental weights were increased at 25 mg/kg. There were no fetal effects at 5 mg/kg or 10 mg/kg; increases in fetal anatomical variants (supernumerary ribs, renal pelvis dilation) and delays in ossification were observed at 25 mg/kg and 50 mg/kg and higher doses. At doses ranging from 80 to 320 mg/kg (approximately 2 to 8 times the 400 mg clinical dose based on BSA), embryolethality in rats was increased and fetal abnormalities included wavy ribs, cleft palate, and abnormal craniofacial 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.

Nursing Mothers Fluconazole was present in low levels in breast milk following administration of a single 150 mg dose, based on data from a study in 10 breastfeeding women who temporarily or permanently discontinued breastfeeding 5 days to 19 months postpartum. The estimated daily infant dose of fluconazole from breast milk (assuming mean milk consumption of 150 mL/kg/day) based on the mean peak milk concentration (2.61 mcg/mL [range: 1.57 to 3.65 mcg/mL] at 5.2 hours post-dose) was 0.39 mg/kg/day, which is approximately 13% of the recommended pediatric dose for oropharyngeal candidiasis. (Labeled pediatric dose is 6 mg/kg/day on the first day followed by 3 mg/kg/day; estimated infant dose is 13% of 3 mg/kg/day maintenance dose). There are no data on fluconazole levels in milk after repeated use or after high-dose fluconazole. A published survey of 96 breastfeeding women who were treated with fluconazole 150 mg every other day (average of 7.3 capsules [range 1 to 29 capsules]) for lactation-associated candida of the breasts reported no serious adverse reactions in infants. Caution should be exercised when fluconazole is administered to a nursing woman.

ADVERSE REACTIONS Fluconazole is generally well tolerated. In some patients, particularly those with serious underlying diseases such as AIDS and cancer, changes in renal and hematological function test results and hepatic abnormalities have been observed during treatment with fluconazole and comparative agents, but the clinical significance and relationship to treatment is uncertain. In Patients Receiving a Single Dose for Vaginal Candidiasis: During comparative clinical studies conducted in the United States, 448 patients with vaginal candidiasis were treated with fluconazole, 150 mg single dose. The overall incidence of side effects possibly related to fluconazole was 26%. In 422 patients receiving active comparative agents, the incidence was 16%. The most common treatment-related adverse events reported in the patients who received 150 mg single dose fluconazole for vaginitis were headache (13%), nausea (7%), and abdominal pain (6%). Other side effects reported with an incidence equal to or greater than 1% included diarrhea (3%), dyspepsia (1%), dizziness (1%), and taste perversion (1%). Most of the reported side effects were mild to moderate in severity. Rarely, angioedema and anaphylactic reaction have been reported in marketing experience. In Patients Receiving Multiple Doses for Other Infections: Sixteen percent of over 4000 patients treated with fluconazole in clinical trials of 7 days or more experienced adverse events. Treatment was discontinued in 1.5% of patients due to adverse clinical events and in 1.3% of patients due to laboratory test abnormalities. Clinical adverse events were reported more frequently in HIV infected patients (21%) than in non-HIV infected patients (13%); however, the patterns in HIV infected and non-HIV infected patients were similar. The proportions of patients discontinuing therapy due to clinical adverse events were similar in the two groups (1.5%). The following treatment-related clinical adverse events occurred at an incidence of 1% or greater in 4048 patients receiving fluconazole for 7 or more days in clinical trials: nausea 3.7%, headache 1.9%, skin rash 1.8%, vomiting 1.7%, abdominal pain 1.7%, and diarrhea 1.5%. Hepato-biliary: In combined clinical trials and marketing experience, there have been rare cases of serious hepatic reactions during treatment with fluconazole (see WARNINGS ). The spectrum of these hepatic reactions has ranged from mild transient elevations in transaminases to clinical hepatitis, cholestasis and fulminant hepatic failure, including fatalities. Instances of fatal hepatic reactions were noted to occur primarily in patients with serious underlying medical conditions (predominantly AIDS or malignancy) and often while taking multiple concomitant medications. Transient hepatic reactions, including hepatitis and jaundice, have occurred among patients with no other identifiable risk factors. In each of these cases, liver function returned to baseline on discontinuation of fluconazole. In two comparative trials evaluating the efficacy of fluconazole for the suppression of relapse of cryptococcal meningitis, a statistically significant increase was observed in median AST (SGOT) levels from a baseline value of 30 IU/L to 41 IU/L in one trial and 34 IU/L to 66 IU/L in the other. The overall rate of serum transaminase elevations of more than 8 times the upper limit of normal was approximately 1% in fluconazole-treated patients in clinical trials. These elevations occurred in patients with severe underlying disease, predominantly AIDS or malignancies, most of whom were receiving multiple concomitant medications, including many known to be hepatotoxic. The incidence of abnormally elevated serum transaminases was greater in patients taking fluconazole concomitantly with one or more of the following medications: rifampin, phenytoin, isoniazid, valproic acid, or oral sulfonylurea hypoglycemic agents. Post-Marketing Experience In addition, the following adverse events have …