Diflucan®

Fluconazole · oral tablet

Antifungal

Approved uses

Vaginal candidiasis, oropharyngeal and esophageal candidiasis, cryptococcal meningitis, and prophylaxis of candidiasis in bone marrow transplantation

Vaginal candidiasis 150 mg once. Oropharyngeal or esophageal candidiasis 200 mg on day 1, then 100 mg once daily. Cryptococcal meningitis 400 mg on day 1, then 200 to 400 mg once daily. Bone marrow transplant prophylaxis 400 mg once daily.

OFF-LABELNot in the FDA label for this product

Candida chorioretinitis and endophthalmitis

Loading dose 800 mg (12 mg/kg), then 400 to 800 mg (6 to 12 mg/kg) once daily for at least 4 to 6 weeks, with final duration set by resolution of the lesions.

Guideline · low-quality data

The IDSA candidiasis guideline recommends this regimen for fluconazole-susceptible isolates in chorioretinitis with or without vitritis, and grades both as a strong recommendation on low-quality evidence. With vitritis the same systemic regimen is given plus intravitreal amphotericin B deoxycholate 5 to 10 mcg/0.1 mL sterile water or voriconazole, and vitrectomy is considered. The label's tissue penetration table lists no ocular compartment; the supporting ocular pharmacokinetics come from a rabbit study in which aqueous and vitreous concentrations were at least 70% of serum in non-inflamed eyes, not from human data.

Pappas PG, Kauffman CA, Andes DR, et al. Clinical Practice Guideline for the Management of Candidiasis: 2016 Update by the Infectious Diseases Society of America. Clin Infect Dis. 2016;62(4):e1-50 (practice guideline), recommendations 85, 89 and 90. PMID 26679628. Ocular penetration: Mian UK, Mayers M, Garg Y, et al. Comparison of fluconazole pharmacokinetics in serum, aqueous humor, vitreous humor, and cerebrospinal fluid following a single dose and at steady state. J Ocul Pharmacol Ther. 1998;14(5):459-71 (rabbit pharmacokinetic study). PMID 9811235.

Contraindications

Hypersensitivity to fluconazole or to any of its excipients.
Coadministration of other drugs that prolong the QT interval and are metabolized by CYP3A4, such as erythromycin, pimozide and quinidine.

Available Forms

Tablets 50 mg, 100 mg and 200 mg; the 150 mg tablet is supplied as a single-dose blister, which is the one-dose treatment; powder for oral suspension 350 mg and 1400 mg per bottle delivering 35 mL at 10 mg/mL and 40 mg/mL

Mechanism of Action

Triazole antifungal; highly selective inhibitor of the fungal cytochrome P450 enzyme lanosterol 14-alpha-demethylase, so lanosterol is not converted to ergosterol and 14-alpha-methyl sterols accumulate, which may account for the fungistatic effect. Labeled activity covers Candida albicans, C. parapsilosis, C. tropicalis, C. glabrata (many isolates only intermediately susceptible) and Cryptococcus neoformans; C. krusei should be considered resistant, and no filamentous fungus appears on the label's activity list.

Warnings & Precautions

Hepatic injury: Rare serious hepatotoxicity including fatalities, primarily in patients with serious underlying medical conditions, with no observed relationship to total daily dose, duration, sex or age; discontinue if signs and symptoms of liver disease attributable to the drug develop.
QT prolongation: Inhibition of the rectifier potassium current prolongs QT; hypokalemia and advanced cardiac failure raise the risk of life-threatening ventricular arrhythmia and torsade de pointes, and concomitant erythromycin should be avoided.
Exfoliative skin disorders: Fatal outcomes reported in patients with serious underlying disease; in deep seated fungal infection monitor any rash closely and stop the drug if lesions progress, and in superficial fungal infection stop it for any rash attributable to the drug.
Fetal harm: Case reports describe a distinct pattern of congenital anomalies after 400 to 800 mg daily through most or all of the first trimester; effective contraception should be considered on 400 to 800 mg daily, through treatment and for about 1 week after the final dose.
CYP inhibition: Moderate CYP2C9 and CYP3A4 inhibitor and strong CYP2C19 inhibitor, and the enzyme inhibiting effect persists 4 to 5 days after the last dose because of the long half-life.
Statin myopathy: Risk of myopathy and rhabdomyolysis rises with atorvastatin, simvastatin or fluvastatin; monitor creatine kinase and discontinue the statin if it rises markedly or myopathy is suspected.
Sulfonylurea hypoglycemia: Clinically significant hypoglycemia may be precipitated with tolbutamide, glyburide or glipizide, and one fatality has been reported in association with glyburide.
Anticoagulant bleeding: Prothrombin time may increase on coumarin-type anticoagulants, with postmarketing bruising, epistaxis, gastrointestinal bleeding, hematuria and melena; monitor prothrombin time and adjust the warfarin dose.
Non-albicans superinfection: Superinfection with Candida species that are often inherently not susceptible, for example C. krusei, may require an alternative antifungal.
Adrenal insufficiency: Reversible cases have been reported in patients receiving azoles, including fluconazole.
Renal dysfunction: Administer with caution; halve the daily multiple-dose regimen when creatinine clearance is 50 mL/min or less.
Azole cross-hypersensitivity: No data on cross-hypersensitivity with other azoles; prescribe with caution in patients hypersensitive to another azole.

Common Side Effects

Single 150 mg dose: Headache 13%, nausea 7%, abdominal pain 6%, diarrhea 3%, dyspepsia 1%, dizziness 1%, taste perversion 1% in vaginal candidiasis; overall treatment-related event rate 26% versus 16% on active comparators.
Multiple-dose therapy: Nausea 3.7%, headache 1.9%, skin rash 1.8%, vomiting 1.7%, abdominal pain 1.7%, diarrhea 1.5% among 4048 patients treated 7 days or longer.
Hepatobiliary: Rare serious hepatic reactions spanning mild transient transaminase elevation, clinical hepatitis, cholestasis and fatal fulminant hepatic failure; transaminases above 8 times the upper limit of normal in roughly 1% of treated patients in trials.
Cardiovascular: QT prolongation and torsade de pointes, postmarketing, mostly in seriously ill patients with structural heart disease, electrolyte abnormalities or contributory concomitant drugs.
Dermatologic: Exfoliative skin disorders including Stevens-Johnson syndrome and toxic epidermal necrolysis, DRESS, acute generalized exanthematous pustulosis, fixed drug eruption and alopecia; postmarketing.
Immunologic: Anaphylaxis including angioedema, face edema and pruritus; rare.
Hematologic: Leukopenia including neutropenia and agranulocytosis, and thrombocytopenia; postmarketing.
Nervous system: Seizures, dizziness, insomnia, paresthesia, somnolence, tremor and vertigo; postmarketing.
Pediatric: Vomiting 5.4%, abdominal pain 2.8%, nausea 2.3%, diarrhea 2.1% among 577 patients aged 1 day to 17 years, a pattern comparable to adults.

Pregnancy & Lactation

Pregnancy: Avoid except in severe or potentially life-threatening fungal infection where the anticipated benefit outweighs the fetal risk. Case reports describe a rare distinctive pattern of birth defects, brachycephaly, abnormal facies, abnormal calvarial development, cleft palate, femoral bowing, thin ribs and long bones, arthrogryposis and congenital heart disease, in infants exposed to 400 to 800 mg daily through most or all of the first trimester. Retrospective epidemiological studies suggest a potential risk of spontaneous abortion and congenital abnormality after single or repeated 150 mg first-trimester doses, unconfirmed in controlled trials.

Lactation: Present in milk at low levels. After a single 150 mg dose in 10 breastfeeding women the estimated daily infant dose was 0.39 mg/kg/day, about 13% of the labeled pediatric maintenance dose, and a published survey of 96 women taking 150 mg every other day reported no serious adverse reactions in infants. No data after repeated or high-dose use; exercise caution.

Pediatric Use

Shown effective for oropharyngeal candidiasis in patients 6 months to 13 years.