Fluconazole 200 mg Tablet, 30-count — NDC 63187-878-30 (Billing 63187-0878-30)

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) Use in Pregnancy: There are no adequate and well-controlled studies of fluconazole in pregnant women.

Available human data do not suggest an increased risk of congenital anomalies following a single maternal dose of 150 mg. A few published case reports describe a rare pattern of distinct congenital anomalies in infants exposed in utero to high dose maternal fluconazole (400-800 mg/day) during most or all of the first trimester. These reported anomalies are similar to those seen in animal studies.

If this drug 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. (See PRECAUTIONS, Pregnancy )

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%. Hepatobiliary: 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… [Excerpted — this section continues on DailyMed.]

PRECAUTIONS 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. Concomitant use of fluconazole and erythromycin has the potential to increase the risk of cardiotoxicity (prolonged QT interval, torsade de pointes) and consequently sudden heart death. This combination should be avoided.

Fluconazole should be administered with caution to patients with renal dysfunction. Fluconazole is a potent CYP2C9 inhibitor and a moderate CYP3A4 inhibitor. Fluconazole treated patients who are concomitantly treated with drugs with a narrow therapeutic window metabolized through CYP2C9 and CYP3A4 should be monitored.

When driving vehicles or operating machines, it should be taken into account that occasionally dizziness or seizures may occur. 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 .) Drug Interactions: (See CLINICAL PHARMACOLOGY: Drug Interaction Studies and CONTRAINDICATIONS .) Fluconazole is a potent inhibitor of cytochrome P450 (CYP) isoenzyme 2C9 and 2C19, and a moderate inhibitor of CYP3A4.

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 coadministered 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 4-5 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. These are described in greater detail below: Oral hypoglycemics Coumarin-type anticoagulants Phenytoin Cyclosporine Rifampin Theophylline Terfenadine Cisapride Astemizole Rifabutin Voriconazole Tacrolimus Short-acting benzodiazepines Tofacitinib Triazolam Oral Contraceptives Pimozide Quinidine Hydrochlorothiazide Alfentanil Amitriptyline, nortriptyline Amphotericin B Azithromycin Carbamazepine Calcium Channel Blockers Celecoxib Cyclophosphamide Fentanyl Halofantrine HMG-CoA reductase inhibitors Losartan Methadone Non-steroidal anti-inflammatory drugs Prednisone Saquinavir Sirolimus Vinca Alkaloids Vitamin A Zidovudine Oral hypoglycemics: Clinically significant hypoglycemia may be precipitated by the use of fluconazole with oral hypoglycemic agents; one fatality has been reported from hypoglycemia in association with combined fluconazole and glyburide use.

Fluconazole reduces the metabolism of tolbutamide, glyburide, and glipizide and increases the plasma concentration of these agents. When fluconazole is used concomitantly with these or other sulfonylurea oral hypoglycemic agents, blood glucose concentrations should be carefully monitored and the dose of the sulfonylurea should be adjusted as necessary. (See CLINICAL PHARMACOLOGY:Drug Interaction Studies .) 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,… [Excerpted — this section continues on DailyMed.]