Fluconazole

Fluconazole (Pfizer).

Pharmacology

Mode of action

Like other lanosterol to ergosterol, an essential component of the fungal cytoplasmic membrane, and subsequent accumulation of 14α-methyl sterols.^[2] Fluconazole is primarily fungistatic, however may be fungicidal against certain organisms in a dose-dependent manner.

Microbiology

Fluconazole is active against the following microorganisms:^[3]

• Blastomyces dermatitidis
• Candida spp. (except C. krusei and C. glabrata)
• Coccidioides immitis
• Cryptococcus neoformans
• Epidermophyton spp.
• Histoplasma capsulatum
• Microsporum spp.
• Trichophyton spp.

Pharmacokinetics

Following oral dosing, fluconazole is almost completely absorbed within two hours. warfarin.

Clinical use

Indications

Fluconazole is indicated for the treatment and prophylaxis of fungal infections where other antifungals have failed or are not tolerated (e.g. due to adverse effects), including:^[4]

• Candidiasis caused by susceptible strains of Candida
• Tinea corporis, tinea cruris or tinea pedis
• Onychomycosis
• Cryptococcal meningitis

Fluconazole can be used first-line for the following indications:^[4]

• Coccidioidomycosis
• Cryptococcosis
• Histoplasmosis
• Prophylaxis of candidiasis in immunocompromised people

Dosage

Dosage varies with indication and between patient groups, ranging from: a two week course of 150 mg/day for vulvovaginal candidiasis, to 150–300 mg once weekly for resistant skin infections or some prophylactic indications. 50–600 mg/day may be used for systemic or severe infections, and in urgent infections such as meningitis caused by yeast 800 mg/day have been used. Pediatric doses are measured at 6-12 mg/kg/d . A loading dose will be indicated when entering a daily dosage schedule, for example a loading dose of 200 mg on the first day is commonly used with 150 mg/day following that.^[4]

Contraindications

Fluconazole is contraindicated in patients with:^[4]

• Known hypersensitivity to fluconazole or other azole antifungals
• Concomitant use of cisapride, due to risk of serious cardiac arrhythmias (relative contraindication).

Precautions

Fluconazole therapy has been associated with QT interval prolongation, which may lead to serious cardiac arrhythmias. Thus it is used with caution in patients with risk factors for prolonged QT interval such as electrolyte imbalance or use of other drugs which may prolong the QT interval (particularly cisapride).

Fluconazole has also rarely been associated with severe or lethal hepatotoxicity and liver function tests are usually performed regularly during prolonged fluconazole therapy. Additionally, it is used with caution in patients with pre-existing liver disease.^[2]

High concentrations of fluconazole have been detected in human breast milk from patients receiving fluconazole therapy, thus its use is not recommended in breastfeeding mothers.^[2]

Adverse effects

Adverse drug reactions associated with fluconazole therapy include:^[4]

• Common (≥1% of patients): rash, headache, dizziness, nausea, vomiting, abdominal pain, diarrhea, and/or elevated liver enzymes
• Infrequent (0.1–1% of patients): anorexia, fatigue, constipation
• Rare (<0.1% of patients): oliguria, hypokalaemia, paraesthesia, seizures, alopecia, Stevens-Johnson syndrome, thrombocytopenia, other blood dyscrasias, serious hepatotoxicity including hepatic failure, anaphylactic/anaphylactoid reactions
• Very rare: prolonged QT interval, torsades de pointes

Drug interactions

Fluconazole is an inhibitor of the human CYP3A4. In theory, therefore, fluconazole decreases the metabolism and increases the concentration of any drug metabolised by these enzymes. Additionally, its potential effect on QT interval increases the risk of cardiac arrhythmia if used concurrently with other drugs that prolong the QT interval.

References