Fluconazole Tablets USP 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 USP 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 USP for AIDS patients with cryptococcal meningitis, please see CLINICAL STUDIES section. Studies comparing fluconazole to amphotericin B in non-HIV infected patients have not been conducted. Prophylaxis: Fluconazole Tablets USP 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.
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. Co-administration 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 .)
Warnings and precautions
(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 .)
Interactions
Drug Interactions (See CONTRAINDICATIONS .) Fluconazole is a moderate CYP2C9 and CYP3A4 inhibitor. Fluconazole is also a strong inhibitor of CYP2C19. Patients treated with fluconazole, who are also concomitantly treated with drugs with a narrow therapeutic window metabolized through CYP2C9 and CYP3A4, should be monitored for adverse reactions associated with the concomitantly administered drugs. In addition to the observed/documented interactions mentioned below, there is a risk of increased plasma concentration of other compounds metabolized by CYP2C9, CYP2C19, and CYP3A4 co-administered with fluconazole.
Therefore, caution should be exercised when using these combinations and the patients should be carefully monitored. The enzyme inhibiting effect of fluconazole persists 4 to 5 days after discontinuation of fluconazole treatment due to the long half-life of fluconazole. Clinically or potentially significant drug interactions between fluconazole and the following agents/classes have been observed and are described in greater detail below: Alfentanil: A study observed a reduction in clearance and distribution volume as well as prolongation of t ½ of alfentanil following concomitant treatment with fluconazole.
A possible mechanism of action is fluconazole's inhibition of CYP3A4. Dosage adjustment of alfentanil may be necessary. Amiodarone: Concomitant administration of fluconazole with amiodarone may increase QT prolongation. Caution must be exercised if the concomitant use of fluconazole and amiodarone is necessary, notably with high-dose fluconazole (800 mg). Amitriptyline, nortriptyline: Fluconazole increases the effect of amitriptyline and nortriptyline. 5-nortriptyline and/or S-amitriptyline may be measured at initiation of the combination therapy and after one week.
Dosage of amitriptyline/nortriptyline should be adjusted, if necessary. Amphotericin B: Concurrent administration of fluconazole and amphotericin B in infected normal and immunosuppressed mice showed the following results: a small additive antifungal effect in systemic infection with Candida albicans , no interaction in intracranial infection with Cryptococcus neoformans , and antagonism of the two drugs in systemic infection with A. fumigatus .
The clinical significance of results obtained in these studies is unknown. Azithromycin: An open-label, randomized, three-way crossover study in 18 healthy subjects assessed the effect of a single 1200 mg oral dose of azithromycin on the pharmacokinetics of a single 800 mg oral dose of fluconazole as well as the effects of fluconazole on the pharmacokinetics of azithromycin. There was no significant pharmacokinetic interaction between fluconazole and azithromycin.
Calcium channel blockers: Certain calcium channel antagonists (nifedipine, isradipine, amlodipine, verapamil, and felodipine) are metabolized by CYP3A4. Fluconazole has the potential to increase the systemic exposure of the calcium channel antagonists. Frequent monitoring for adverse events is recommended. Carbamazepine: Fluconazole inhibits the metabolism of carbamazepine and an increase in serum carbamazepine of 30% has been observed.
There is a risk of developing carbamazepine toxicity. Dosage adjustment of carbamazepine may be necessary depending on concentration measurements/effect. Celecoxib: During concomitant treatment with fluconazole (200 mg daily) and celecoxib (200 mg), the celecoxib C max and AUC increased by 68% and 134%, respectively. Half of the celecoxib dose may be necessary when combined with fluconazole. Coumarin-type anticoagulants: Prothrombin time may be increased in patients receiving concomitant fluconazole and coumarin-type anticoagulants.
In post-marketing experience, as with other azole antifungals, bleeding events (bruising, epistaxis, gastrointestinal bleeding, hematuria, and melena) have been reported in association with increases in prothrombin time in patients receiving fluconazole concurrently with warfarin. Careful monitoring of prothrombin time in patients receiving fluconazole and coumarin-type anticoagulants is recommended. Dose adjustment of warfarin may be necessary.
(See CLINICAL PHARMACOLOGY: Drug Interaction Studies .) Cyclophosphamide: Combination therapy with cyclophosphamide and fluconazole results in an increase in serum bilirubin and serum creatinine. The combination may be used while taking increased consideration to the risk of increased serum bilirubin and serum creatinine. Cyclosporine: Fluconazole significantly increases cyclosporine levels in renal transplant patients with or without renal impairment.
Careful monitoring of cyclosporine concentrations and serum creatinine is recommended in patients receiving fluconazole and cyclosporine. (See CLINICAL PHARMACOLOGY: Drug Interaction Studies .) This combination may be used by reducing the dosage of cyclosporine depending on cyclosporine concentration. Fentanyl: One fatal case of possible fentanyl-fluconazole interaction was reported. The author judged that the patient died from fentanyl intoxication.
Furthermore, in a randomized crossover study with 12 healthy volunteers, it was shown that fluconazole delayed the elimination of fentanyl significantly. Elevated fentanyl concentration may lead to respiratory depression. HMG-CoA reductase inhibitors: The risk of myopathy and rhabdomyolysis increases when fluconazole is co-administered with HMG-CoA reductase inhibitors metabolized through CYP3A4, such as atorvastatin and simvastatin, or through CYP2C9, such as fluvastatin.
If concomitant therapy is necessary, the patient should be observed for symptoms of myopathy and rhabdomyolysis and creatinine kinase should be monitored. HMG-CoA reductase inhibitors should be discontinued if a marked increase in creatinine kinase is observed or myopathy/rhabdomyolysis is diagnosed or suspected. Hydrochlorothiazide: In a pharmacokinetic interaction study, co-administration of multiple dose hydrochlorothiazide to healthy volunteers receiving fluconazole increased plasma concentrations of fluconazole by 40%.
An effect of this magnitude should not necessitate a change in the fluconazole dose regimen in subjects receiving concomitant diuretics. Ibrutinib: Moderate inhibitors of CYP3A4 such as fluconazole may increase plasma ibrutinib concentrations and increase risk of adverse reactions associated with ibrutinib. If ibrutinib and fluconazole are concomitantly administered, reduce the dose of ibrutinib as instructed in ibrutinib prescribing information and the patient should be frequently monitored for any adverse reactions associated with ibrutinib.
Lemborexant: Concomitant administration of fluconazole increased lemborexant C max and AUC by approximately 1.6- and 4.2-fold, respectively which is expected to increase risk of adverse reactions, such as somnolence. Avoid concomitant use of fluconazole with lemborexant. Losartan: Fluconazole inhibits the metabolism of losartan to its active metabolite (E-31 74) which is responsible for most of the angiotensin II-receptor antagonism which occurs during treatment with losartan.
Patients should have their blood pressure monitored continuously. Methadone: Fluconazole may enhance the serum concentration of methadone. Dosage adjustment of methadone may be necessary. Non-steroidal anti-inflammatory drugs: The C max and AUC of flurbiprofen were increased by 23% and 81%, respectively, when co-administered with fluconazole compared to administration of flurbiprofen alone. Similarly, the C max and AUC of the pharmacologically active isomer [S-(+)-ibuprofen] were increased by 15% and 82%, respectively, when fluconazole was co-administered with racemic ibuprofen (400 mg) compared to administration of racemic ibuprofen alone.
Although not specifically studied, fluconazole has the potential to increase the systemic exposure of other non-steroidal anti-inflammatory drugs (NSAIDs) that are metabolized by CYP2C9 (e.g., naproxen, lornoxicam, meloxicam, diclofenac). Frequent
Our copy of this section ends here. The full text is in the official label at the FDA. Open Drugs@FDA
Pregnancy and breastfeeding
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 Error! Hyperlink reference not valid. .) 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.
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 occurred during post-marketing experience. Immunologic: In rare cases, anaphylaxis (including angioedema, face edema and pruritus) has been reported. Body as a Whole: Asthenia, fatigue, fever, malaise. Cardiovascular: QT prolongation, torsade de pointes. (See PRECAUTIONS .) Central Nervous System: Seizures, dizziness. Hematopoietic and Lymphatic: Leukopenia, including neutropenia and agranulocytosis, thrombocytopenia.
Metabolic: Hypercholesterolemia, hypertriglyceridemia, hypokalemia. Gastrointestinal: Cholestasis, dry mouth, hepatocellular damage, dyspepsia, vomiting. Other Senses: Taste perversion. Musculoskeletal System: Myalgia. Nervous System: Insomnia, paresthesia, somnolence, tremor, vertigo. Skin and Appendages: Acute generalized exanthematous pustulosis, drug eruption including fixed drug eruption, increased sweating, exfoliative skin disorders including Stevens-Johnson syndrome and toxic epidermal necrolysis, drug reaction with eosinophilia and systemic symptoms (DRESS) (see WARNINGS ), alopecia.
Adverse Reactions in Children The pattern and incidence of adverse events and laboratory abnormalities recorded during pediatric clinical trials are comparable to those seen in adults. In Phase II/III clinical trials conducted in the United States and in Europe, 577 pediatric patients, ages 1 day to 17 years were treated with fluconazole at doses up to 15 mg/kg/day for up to 1,616 days. Thirteen percent of children experienced treatment- related adverse events.
The most commonly reported events were vomiting (5%), abdominal pain (3%), nausea (2%), and diarrhea (2%). Treatment was discontinued in 2.3% of patients due to adverse clinical events and in 1.4% of patients due to laboratory test abnormalities. The majority of treatment-related laboratory abnormalities were elevations of transaminases or alkaline phosphatase. Percentage of Patients with Treatment-Related Side Effects Fluconazole (N=577) Comparative Agents (N=451) With any side effect 13.0
9.3 Vomiting 5.4
5.1 Abdominal pain 2.8
1.6 Nausea 2.3
1.6 To report suspected ADVERSE REACTIONS, contact ANI Pharmaceuticals, Inc. at 1-800-308-6755 or the FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
Composition
Active ingredients
FLUCONAZOLE 150MG
Strengths and forms
The FDA lists each strength of a product separately; these pages share one label.
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