Posaconazole

Posaconazole is a broad-spectrum triazole used for prophylaxis in profoundly immunosuppressed patients and for treatment of invasive aspergillosis and mucormycosis. Delayed-release tablets give reliable absorption; the older suspension does not. It is a strong CYP3A4 inhibitor, prolongs the QT interval and causes hepatotoxicity.

Class. Triazole antifungal.

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

Pharmacokinetics. Delayed-release tablets are absorbed in the intestine and are taken with food; the suspension needs a fatty meal and acid. Highly protein bound, half life 26 to 31 hours, glucuronidation with faecal elimination. Poor cerebrospinal fluid penetration.

Prophylaxis (neutropenia from acute myeloid leukaemia or myelodysplasia, graft-versus-host disease). - Delayed-release tablets: 300 mg twice daily on day 1, then 300 mg once daily. - Duration: until recovery from neutropenia or immunosuppression.

Treatment of invasive aspergillosis (alternative to voriconazole or isavuconazole) and mucormycosis (step-down or salvage after amphotericin B). - Intravenous or delayed-release tablets: 300 mg every 12 hours on day 1, then 300 mg once daily. - Duration: at least 6 to 12 weeks and through immunosuppression. - Maximum: 300 mg daily in routine practice.

Oral suspension (when tablets cannot be used). 200 mg three times daily for prophylaxis; 200 mg four times daily or 400 mg twice daily for treatment, with food.

Children. Weight-based dosing exists from 2 years; delayed-release tablets are used at 40 kg or more.

Therapeutic drug monitoring. Trough over 0.7 mg/L for prophylaxis; over 1.0 mg/L for treatment.

Contraindications. Hypersensitivity to azoles, and co-prescription of simvastatin, lovastatin, ergot alkaloids, pimozide, quinidine, and sirolimus (dose reduction instead where specialist-led).

Serious adverse effects. Hepatotoxicity, QT prolongation and torsades de pointes, hypokalaemia, hypertension, oedema and pseudohyperaldosteronism, and severe skin reactions.

Common adverse effects. Nausea, diarrhoea, headache, rash and raised transaminases.

Interactions. Rifampicin, rifabutin, phenytoin, efavirenz and cimetidine lower levels; reduce tacrolimus to one third and ciclosporin by one quarter; dose-reduce venetoclax; additive QT effect with macrolides, ondansetron and antipsychotics.

Common prescribing errors. Using suspension without a fatty meal, no loading dose, no trough check, and overlooking interactions.

Special groups. - Pregnancy: avoid; animal teratogenicity. - Breastfeeding: avoid. - Children: weight-based dosing with levels. - Older adults: usual dose; monitor ECG and electrolytes. - Kidney impairment: tablets unchanged; avoid intravenous use at CrCl under 50 mL/min unless benefit outweighs risk. - Liver impairment: use with caution; monitor liver tests and levels.

Formulations. Delayed-release tablets 100 mg; oral suspension 40 mg/mL; intravenous solution 18 mg/mL.

Administration. Tablets swallowed whole with food. Intravenous dose via central line over about 90 minutes.

Baseline. Liver tests, potassium, magnesium, calcium, ECG, pregnancy test.

Monitoring. Trough at day 5 to 7; liver tests weekly for the first month, then monthly; electrolytes and ECG on QT-prolonging therapy.

Stopping thresholds. Stop for QTcF over 500 ms, severe skin reaction or hepatic failure; review for ALT over five times the upper limit of normal.

Referral and escalation. Specialist review for invasive mycoses, treatment failure or subtherapeutic levels.