Isavuconazole

Isavuconazole is a broad-spectrum triazole given as the prodrug isavuconazonium sulfate. It is used for invasive aspergillosis and mucormycosis, and in some regions for invasive candidiasis. It has predictable pharmacokinetics, a long half life and fewer visual and hepatic effects than voriconazole. It shortens the QT interval. Availability and cost limit use in many low-resource settings.

Class. Triazole antifungal.

Mechanism. Inhibits fungal CYP51, blocking ergosterol synthesis, including activity against Mucorales.

Pharmacokinetics. The prodrug is hydrolysed by plasma esterases to the active drug. Oral bioavailability about 98%, half life about 130 hours, highly protein bound. Moderate CYP3A4 inhibitor. Routine monitoring of levels is not required.

Invasive aspergillosis and mucormycosis (adults). Doses are expressed as isavuconazonium sulfate (372 mg equals 200 mg of isavuconazole). - Loading: 372 mg every 8 hours for 6 doses (48 hours), oral or intravenous. - Maintenance: 372 mg once daily, starting 12 to 24 hours after the last loading dose. - Duration: at least 6 to 12 weeks and through immunosuppression. - Maximum: 372 mg daily in maintenance.

Invasive candidiasis (where licensed). Same dosing.

Children. Weight-based dosing exists for ages 1 year and over where licensed; specialist use.

Main alternatives. Voriconazole or posaconazole for aspergillosis; liposomal amphotericin B first for mucormycosis.

Contraindications. Familial short QT syndrome, hypersensitivity, and co-prescription of strong CYP3A4 inducers (rifampicin, carbamazepine, phenytoin, St John’s wort) or strong inhibitors (high-dose ketoconazole, ritonavir at high dose).

Serious adverse effects. Hepatotoxicity, severe skin reactions, anaphylaxis, infusion reactions and QT shortening.

Common adverse effects. Nausea, vomiting, diarrhoea, hypokalaemia, raised liver enzymes, headache and rash.

Interactions. Raises tacrolimus, ciclosporin, sirolimus, digoxin, midazolam and bupropion; monitor levels and reduce doses.

Common prescribing errors. Dosing in milligrams of active drug rather than the prodrug, missing inducers, and omitting the loading phase.

Special groups. - Pregnancy: avoid; embryofoetal toxicity in animals. - Breastfeeding: avoid. - Children: licensed use is age-restricted; weight-based. - Older adults: no adjustment. - Kidney impairment: no adjustment; no cyclodextrin vehicle. - Liver impairment: mild to moderate: no adjustment; severe: use only if benefit outweighs risk, with monitoring.

Formulations. Capsules containing 186 mg of isavuconazonium sulfate (100 mg of isavuconazole); intravenous powder 372 mg.

Administration. Capsules swallowed whole, with or without food. Intravenous infusion over at least 1 hour through an in-line filter.

Baseline. Liver tests, potassium, ECG, pregnancy test, drug review.

Monitoring. Liver tests at baseline and weekly for the first month, then monthly; electrolytes; skin review.

Stopping thresholds. Stop for hepatic failure, severe skin reaction, anaphylaxis, or ALT over five times the upper limit of normal with symptoms.

Referral and escalation. Specialist review for invasive mycoses and treatment failure.