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Fluconazole
Systematic (IUPAC) name
2-(2,4-difluorophenyl)- 1,3-bis(1H-1,2,4-triazol-1-yl)propan-2-ol
Identifiers
CAS number	86386-73-4
ATC code	D01AC15 J02AC01
PubChem	3365
DrugBank	APRD00327
Chemical data
Formula	C13H12F2N6O
Mol. mass	306.271 g/mol
Pharmacokinetic data
Bioavailability	>90%
Protein binding	11–12%
Metabolism	Hepatic 11%
Half life	30 hours (range 20-50 hours)
Excretion	Renal 61–88%
Therapeutic considerations
Pregnancy cat.	D (Au), C (U.S.)
Legal status	S3/S4 (Au), POM (UK), ℞-only (U.S.)
Routes	Oral, IV, topical

Fluconazole (INN) (pronounced^[help] /fluːˈkɒnəzoʊl/) is a triazole antifungal drug used in the treatment and prevention of superficial and systemic fungal infections. In a bulk powder form, it appears as a white crystalline powder, and it is very slightly soluble in water and soluble in alcohol.^[1] It is commonly marketed under the trade name Diflucan or Trican (Pfizer).

Contents 1 Pharmacology 1.1 Mode of action 1.2 Microbiology 2 Pharmacokinetics 3 Clinical use 3.1 Indications 3.2 Dosage 3.3 Contraindications 3.4 Precautions 3.5 Adverse effects 3.6 Drug interactions 4 References

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 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.

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.

Following oral dosing, fluconazole is almost completely absorbed within two hours. Bioavailability is not significantly affected by the absence of stomach acid. Concentrations measured in the urine, tears and skin are approximately 10 times the plasma concentration, while saliva, sputum and vaginal fluid concentrations are approximately equal to the plasma concentration, following a standard dose range of between 100 mg and 400 mg per day. The elimination half-life of fluconazole follows zero order kinetics and only 10% of elimination is due to metabolism, the remainder is excreted in urine and sweat. Patients with impaired renal function will be at risk of overdose as well as patients taking drugs such as warfarin.

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 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]

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).

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 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

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.

v • d • e Antifungals (D01 and J02)
Antibiotics	Griseofulvin • polyene antimycotics (Natamycin, Nystatin)
Topical azoles	imidazoles (Bifonazole, Clomidazole, Clotrimazole, Econazole, Fenticonazole, Ketoconazole, Isoconazole, Miconazole, Oxiconazole, Sertaconazole, Sulconazole, Tioconazole) • triazoles (Fluconazole) • benzimidazole (Thiabendazole)
Other topicals	Ciclopirox • Ethylparaben • Flucytosine • Salicylic acid • Selenium sulfide • Tolnaftate • Undecylenic acid • allylamines (Amorolfine, Butenafine, Naftifine, Terbinafine)
For systemic use	Griseofulvin • allylamine (Terbinafine) • polyene antimycotic (Amphotericin B) • triazoles (Itraconazole, Posaconazole, Voriconazole) • echinocandins (Anidulafungin, Caspofungin, Micafungin)
Other	Tea tree oil • citronella oil • lemon grass • orange oil • patchouli • lemon myrtle