Fluconazole (INN) (IPA: ) is a triazole antifungal drug used in the treatment and prevention of superficial and systemic fungal infections. It is commonly marketed under the trade name Diflucan (Pfizer).

Pharmacology

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Mode of action

Like other imidazole- and triazole-class antifungals, fluconazole inhibits the fungal cytochrome P450 enzyme 14α-demethylase. Mammalian demethylase activity is much less sensitive to fluconazole than fungal demethylase. This inhibition prevents the conversion of lanosterol to ergosterol, an essential component of the fungal cell wall, and subsequent accumulation of 14α-methyl sterols.Pfizer Australia Pty Ltd. Diflucan (Australian Approved Product Information). West Ryde (NSW): Pfizer Australia; 2004. Fluconazole is primarily fungistatic, however may be fungicidal against certain organisms in a dose-dependent manner.

Microbiology

Fluconazole is active against the following microorganisms:Sweetman S, editor. Martindale: The complete drug reference. 34th ed. London: Pharmaceutical Press; 2004. ISBN 0-8536955-0-4

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

Pharmacokinetics

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Following oral dosing, fluconazole is almost completely absorbed within two hours. Bioavailability is not significantly affected by concomitant intake of meals or the use of H₂-antagonists (e.g. ranitidine). Concentrations measured in urine, saliva, sputum and vaginal secrete are approximately equal to the plasma concentration measured following a wide dose range from 100–400 mg oral as a single dose. The elimination half-life of fluconazole is increased in patients with impaired renal function.

Clinical use

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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:Rossi S, editor. Australian Medicines Handbook 2006. Adelaide: Australian Medicines Handbook; 2006. ISBN 0-9757919-2-3

• 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:Rossi S, editor. Australian Medicines Handbook 2006. Adelaide: Australian Medicines Handbook; 2006. ISBN 0-9757919-2-3

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

Dosage

Dosage varies with indication and between patient groups, ranging from: a 150 mg single dose for vulvovaginal candidiasis, to 150–300 mg once weekly for resistant skin infections or some prophylactic indications, to 50–400 mg once daily for systemic or severe infections.Rossi S, editor. Australian Medicines Handbook 2006. Adelaide: Australian Medicines Handbook; 2006. ISBN 0-9757919-2-3

Contraindications

Fluconazole is contraindicated in patients with:Rossi S, editor. Australian Medicines Handbook 2006. Adelaide: Australian Medicines Handbook; 2006. ISBN 0-9757919-2-3

• Known hypersensitivity to fluconazole or other azole antifungals
• Concomitant use of cisapride, due to risk of serious cardiac arrhythmias

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 fluconazole therapy. Additionally, it is used with caution in patients with pre-existing liver disease.Pfizer Australia Pty Ltd. Diflucan (Australian Approved Product Information). West Ryde (NSW): Pfizer Australia; 2004.

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.Pfizer Australia Pty Ltd. Diflucan (Australian Approved Product Information). West Ryde (NSW): Pfizer Australia; 2004.

Adverse effects

Adverse drug reactions associated with fluconazole therapy include:Rossi S, editor. Australian Medicines Handbook 2006. Adelaide: Australian Medicines Handbook; 2006. ISBN 0-9757919-2-3

• Common (≥1% of patients): rash, headache, dizziness, nausea, vomiting, abdominal pain, diarrhoea, and/or elevated liver enzymes
• Infrequent (0.1–1% of patients): anorexia, fatigue, constipation
• Rare (<0.1% of patients): oliguria, hypokalaemia, dizziness, 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 cytochrome P450 system, particularly the isozymes CYP2C9 and 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

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Antifungals

Fluconazol | Флуконазол