Fluconazole

Fluconazole is a synthetic triazole antifungal. FDA-approved products include Diflucan (fluconazole) tablets and powder for oral suspension and fluconazole in sodium chloride injection for intravenous use. Compounded oral preparations of fluconazole are used when a strength or excipient profile not available commercially is needed.

• FDA-labeled (Diflucan, oral and intravenous): vaginal candidiasis; oropharyngeal and esophageal candidiasis; Candida urinary tract infection, peritonitis and systemic Candida infections including candidemia, disseminated candidiasis and pneumonia; cryptococcal meningitis; and prophylaxis to decrease the incidence of candidiasis in bone marrow transplant patients receiving cytotoxic chemotherapy or radiation.
• Labeled adult oral doses range from a single 150 mg dose for vaginal candidiasis to 50 to 400 mg once daily for other indications, with weight-based dosing in children and dose reduction in renal impairment. Dose and duration are as prescribed.

Fluconazole inhibits fungal cytochrome P450 lanosterol 14-alpha-demethylase, blocking conversion of lanosterol to ergosterol. Ergosterol depletion and accumulation of methylated sterols disrupt fungal cell membrane function. Fluconazole is fungistatic against Candida species and is active against Cryptococcus neoformans. Candida krusei is intrinsically resistant, and Candida glabrata often shows reduced susceptibility.

Oral bioavailability exceeds 90% and is not affected by food. Peak plasma concentrations occur 1 to 2 hours after an oral dose. Protein binding is about 11 to 12%. Fluconazole distributes widely into body fluids, including cerebrospinal fluid, saliva, sputum, vaginal tissue and breast milk.

Elimination is mainly renal, with about 80% of a dose excreted unchanged in the urine. The plasma half-life is about 30 hours in adults with normal renal function, which supports once-daily dosing, and is prolonged in renal impairment. Hemodialysis removes fluconazole.

• Known hypersensitivity to fluconazole or any of its excipients. Cross-hypersensitivity with other azoles is not established; use caution in patients with hypersensitivity to other azoles.
• Coadministration with other drugs that prolong the QT interval and are metabolized by CYP3A4, such as erythromycin, pimozide and quinidine.

• Hepatic injury: rare serious hepatotoxicity, including fatalities, mainly in patients with serious underlying conditions. Discontinue if signs of liver disease develop.
• QT prolongation and torsades de pointes: use caution with proarrhythmic conditions, electrolyte disturbances such as hypokalemia, and other QT-prolonging drugs; correct potassium, magnesium and calcium before and during therapy.
• Anaphylaxis and serious skin reactions, including exfoliative dermatitis, Stevens-Johnson syndrome, toxic epidermal necrolysis and DRESS. Monitor patients who develop rash, especially those with serious fungal infections or immunosuppression.
• Adrenal insufficiency has been reported, and was reversible on discontinuation. Use caution in renal impairment, adjusting the dose for multiple-dose therapy.

• Fluconazole is a moderate CYP2C9 and CYP3A4 inhibitor and a strong CYP2C19 inhibitor; inhibition persists for several days after the last dose because of the long half-life.
• It can increase exposure to warfarin (monitor INR), phenytoin, sulfonylureas, cyclosporine, tacrolimus, sirolimus, atorvastatin, simvastatin, lovastatin and fluvastatin, midazolam and triazolam, methadone, fentanyl, alfentanil, calcium channel blockers, celecoxib and other NSAIDs, theophylline, zidovudine, tofacitinib and vinca alkaloids.
• Avoid voriconazole with fluconazole. Use amiodarone and other QT-prolonging drugs with caution. Rifampin decreases and hydrochlorothiazide increases fluconazole concentrations.

Common adverse effects include headache, nausea, vomiting, abdominal pain, diarrhea, dyspepsia, taste disturbance, dizziness, rash and transaminase elevation. Less common or rare effects include hepatitis and hepatic failure, QT prolongation, anaphylaxis, angioedema, serious skin reactions, alopecia, hypokalemia, hypertriglyceridemia, agranulocytosis and thrombocytopenia.

Case reports describe a distinct pattern of congenital anomalies (including brachycephaly, abnormal facies, cleft palate and skeletal and cardiac defects) in infants of mothers given 400 to 800 mg/day for most or all of the first trimester. In a 2016 Drug Safety Communication, FDA reviewed a study reporting a possible increase in miscarriage with oral fluconazole in pregnancy. Use in pregnancy is a prescriber decision; topical azoles are generally preferred for vaginal candidiasis in pregnancy.

Fluconazole is present in breast milk at concentrations similar to plasma. Consider the dose, duration and infant age when deciding on use during breastfeeding.

Monitor clinical and mycologic response; liver function tests at baseline and periodically during prolonged or high-dose therapy; renal function for dose adjustment; ECG and electrolytes in patients with QT risk factors; INR with warfarin and levels of narrow-therapeutic-index drugs such as phenytoin, cyclosporine and tacrolimus; and skin for rash.

• Diflucan (fluconazole) Prescribing Information, Pfizer.
• FDA Drug Safety Communication: FDA to review study examining use of oral fluconazole (Diflucan) in pregnancy, April 2016.