Fluconazole

Fluconazole is a triazole antifungal with excellent oral bioavailability and wide tissue penetration, including cerebrospinal fluid. It is active against most Candida species and Cryptococcus. It is the main drug for mucosal candidiasis and for consolidation and maintenance in cryptococcal meningitis, and it has no activity against moulds such as Aspergillus.

Class. Triazole antifungal.

Mechanism. Inhibits fungal cytochrome P450 14-alpha-demethylase (CYP51), blocking ergosterol synthesis and damaging the cell membrane. Candida krusei is intrinsically resistant; Candida glabrata is often dose-dependently susceptible or resistant.

Pharmacokinetics. Bioavailability over 90% regardless of food, half life about 30 hours, low protein binding, penetration into cerebrospinal fluid about 80% of serum. About 80% excreted unchanged by the kidney. Moderate inhibitor of CYP2C9 and CYP3A4 and a strong inhibitor of CYP2C19.

Vaginal candidiasis. 150 mg orally as a single dose; recurrent: 150 mg every 72 hours for three doses, then 150 mg weekly for 6 months.

Oropharyngeal candidiasis. 200 mg on the first day, then 100 mg daily for 7 to 14 days.

Oesophageal candidiasis. 200 to 400 mg on the first day, then 100 to 200 mg daily for 14 to 21 days and until symptoms resolve (up to 400 mg daily).

Invasive candidiasis (candidaemia, when susceptible and stable). Load 800 mg (12 mg/kg), then 400 mg (6 mg/kg) daily, intravenous or oral; continue for 14 days after the first negative blood culture and resolution of symptoms. Echinocandin is preferred first for critically ill patients.

Cryptococcal infection.

• Induction (when amphotericin B and flucytosine are unavailable or as an adjunct): fluconazole 1200 mg daily (maximum) for 2 weeks, with flucytosine 100 mg/kg daily in four divided doses where available.
• Consolidation: 800 mg daily for 2 weeks, then 400 mg daily to complete 8 weeks.
• Maintenance (secondary prophylaxis): 200 mg daily for at least 6 months to 12 months, and until immune recovery (CD4 count over 100 cells/microlitre and suppressed HIV viral load).
• Antigen-positive without meningitis (pre-emptive): 800 mg daily for 2 weeks, then 400 mg daily for 8 weeks, then 200 mg daily.

Children. 3 to 6 mg/kg daily for mucosal infection, 6 to 12 mg/kg daily for invasive infection, maximum 400 mg daily (800 mg for cryptococcal consolidation); neonates every 72 hours.

Contraindications. Hypersensitivity to azoles, and co-prescription of drugs with serious interaction such as terfenadine, cisapride, dofetilide or high-dose simvastatin.

Serious adverse effects. Hepatotoxicity (rarely fulminant), QT prolongation and torsades de pointes, severe skin reactions, adrenal insufficiency and alopecia with prolonged high-dose use, teratogenicity at high dose.

Common adverse effects. Nausea, headache, abdominal pain, rash and raised transaminases.

Interactions. Raises warfarin, phenytoin, sulphonylureas, tacrolimus, ciclosporin, midazolam, zidovudine, methadone and statins. Raises omeprazole levels. Additive QT effect with macrolides, ondansetron and antipsychotics. Rifampicin lowers fluconazole levels by about 25 to 40%.

Common prescribing errors. Using monotherapy for cryptococcal induction where combination therapy is available, giving high doses in early pregnancy, forgetting renal dose reduction, and missing warfarin and phenytoin interactions.

Special groups.

• Pregnancy: avoid doses of 400 mg or more in the first trimester (skeletal and craniofacial defects); a single 150 mg dose carries lower risk; topical azoles preferred for vaginal infection.
• Breastfeeding: compatible at usual doses.
• Children: weight-based; monitor liver tests on prolonged courses.
• Older adults: adjust for kidney function.
• Kidney impairment: with CrCl 50 mL/min or less (not on dialysis), give 50% of the dose after the first full dose; on haemodialysis give the full dose after each session.
• Liver impairment: use with caution; monitor liver tests; no fixed dose reduction.

Regional points. In East Africa cryptococcal meningitis in advanced HIV is a major use; cryptococcal antigen screening with pre-emptive fluconazole, serial therapeutic lumbar puncture, and limited supplies of amphotericin B and flucytosine shape practice.

Formulations. Capsules 50 mg, 100 mg, 150 mg and 200 mg; oral suspension 50 mg/5 mL and 200 mg/5 mL; intravenous solution 2 mg/mL.

Administration. Oral with or without food. Intravenous infusion at no more than 200 mg an hour.

Baseline. Liver tests, creatinine, potassium, ECG if QT risk, pregnancy test, and drug review.

Monitoring. Liver tests at baseline and every 2 to 4 weeks on prolonged or high-dose courses; potassium and ECG with QT-prolonging drugs; creatinine for dose adjustment.

Stopping thresholds. Stop for ALT over five times the upper limit of normal, or over three times with symptoms; stop for QTcF over 500 ms or severe skin reactions.

Referral and escalation. Specialist review for cryptococcal meningitis, candidaemia, treatment failure, raised intracranial pressure or suspected azole resistance.