Voriconazole

Voriconazole is a broad-spectrum triazole and a first-line drug for invasive aspergillosis. It is also active against Candida (including fluconazole-resistant C. krusei), Fusarium and Scedosporium. Its exposure varies widely with CYP2C19 genotype and drug interactions, so levels are measured. Visual disturbance, hepatotoxicity and skin phototoxicity are its characteristic effects.

Class. Triazole antifungal.

Mechanism. Inhibits fungal CYP51 (14-alpha-demethylase), blocking ergosterol synthesis.

Pharmacokinetics. Oral bioavailability over 90% on an empty stomach, non-linear kinetics, half life about 6 hours (dose-dependent). Metabolised by CYP2C19, CYP2C9 and CYP3A4; it also inhibits all three. CYP2C19 poor metabolisers have higher levels and ultra-rapid metabolisers lower levels; allele frequencies differ between populations.

Invasive aspergillosis (first line).

• Intravenous: loading 6 mg/kg every 12 hours for 2 doses, then 4 mg/kg every 12 hours.
• Oral (40 kg or more): loading 400 mg every 12 hours for 2 doses, then 200 mg every 12 hours; may increase to 300 mg every 12 hours if response or levels are inadequate.
• Oral (under 40 kg): loading 200 mg every 12 hours for 2 doses, then 100 mg every 12 hours; may increase to 150 mg.
• Duration: at least 6 to 12 weeks, continuing through immunosuppression.

Other uses.

• Candidaemia (step-down or when fluconazole-resistant): same maintenance dosing, 14 days after the first negative blood culture.
• Oesophageal candidiasis: 200 mg orally every 12 hours for 14 days after symptoms resolve.
• Fusariosis and scedosporiosis: same loading and maintenance, duration individualised.
• Chronic pulmonary aspergillosis: 200 mg every 12 hours for 6 months or longer.
• Maximum: 300 mg orally every 12 hours; 4 mg/kg every 12 hours intravenously, adjusted to levels.

Children (2 to under 12 years, or 12 to 14 years under 50 kg). Intravenous loading 9 mg/kg every 12 hours for 2 doses, then 8 mg/kg every 12 hours; oral 9 mg/kg every 12 hours (maximum 350 mg).

Therapeutic drug monitoring. Trough at day 4 to 7: aim for 1 to 5.5 mg/L (treatment usually over 1.5 mg/L; toxicity risk rises over 5.5 mg/L).

Contraindications. Hypersensitivity to azoles and co-prescription of rifampicin, rifabutin, carbamazepine, long-acting barbiturates, St John’s wort, ergot alkaloids, pimozide, quinidine, sirolimus, usual-dose efavirenz and high-dose ritonavir.

Serious adverse effects. Hepatotoxicity, QT prolongation and torsades de pointes, phototoxicity and skin cancer with prolonged use, periostitis (fluoride excess), visual hallucinations and encephalopathy, peripheral neuropathy and severe skin reactions.

Common adverse effects. Transient visual disturbance (blurring, photopsia, colour change) in about 30%, rash, nausea, headache and raised liver enzymes.

Interactions.

• Phenytoin lowers voriconazole (increase to 5 mg/kg intravenously or 400 mg orally every 12 hours); voriconazole raises phenytoin.
• Reduce tacrolimus to one third and ciclosporin to one half at the start; monitor levels.
• Raises warfarin effect; halve omeprazole when the dose exceeds 40 mg daily.

Common prescribing errors. No loading dose, not measuring troughs, missing interactions, giving it with food, and no sun protection counselling.

Special groups.

• Pregnancy: avoid unless life-threatening infection with no alternative.
• Breastfeeding: limited data; avoid.
• Children: higher weight-based dose; levels essential.
• Older adults: usual dose with level monitoring.
• Kidney impairment: oral dose unchanged; avoid intravenous use at CrCl under 50 mL/min unless benefit outweighs risk (cyclodextrin accumulation).
• Liver impairment: Child-Pugh A and B: usual loading dose, halve maintenance; Child-Pugh C: use only if benefit outweighs risk, with levels.

Formulations. Tablets 50 mg and 200 mg; oral suspension 40 mg/mL; intravenous powder 200 mg.

Administration. Oral doses at least 1 hour before or after a meal. Intravenous infusion over 1 to 3 hours at no more than 3 mg/kg an hour; never as a bolus.

Baseline. Liver tests, creatinine, potassium, magnesium, ECG, visual baseline, CYP2C19 status where available, pregnancy test.

Monitoring. Liver tests weekly for the first month and then monthly; trough at day 4 to 7 and after any dose or interacting-drug change; ECG when other QT drugs are used; skin check on long courses.

Stopping thresholds. Review dose and level for ALT over five times the upper limit of normal or rising bilirubin; stop for hepatic failure, QTcF over 500 ms or severe skin reaction.

Referral and escalation. Infectious diseases or mycology review for all invasive mycoses, subtherapeutic levels or toxicity.