Class & Mechanism
- Triazole antifungal
- Inhibits fungal lanosterol 14-α-demethylase (CYP51A1) → prevents conversion of lanosterol to ergosterol → disrupts fungal cell membrane.
- Broad-spectrum: active against Candida, Aspergillus, Mucorales (Rhizopus, Mucor).
Indications in Oncology / HSCT
- Primary prophylaxis of invasive fungal infections in:
- Allogeneic HSCT recipients with GVHD on intensive immunosuppression.
- Patients with prolonged neutropenia from AML or MDS induction chemotherapy.
- Treatment (off-label): salvage therapy for invasive aspergillosis, mucormycosis.
Formulations
- Oral suspension (40 mg/mL) – variable absorption, requires high-fat meal or acidic beverage (orange juice, ginger ale).
- Delayed-release oral tablets (100 mg) – better bioavailability, not affected by gastric pH.
- IV formulation (18 mg/mL) – avoids absorption issues, but risk of infusion-related reactions.
Dosing (Adults)
Prophylaxis (preferred in HSCT):
- Tablet or IV: 300 mg PO/IV BID on day 1, then 300 mg PO/IV once daily.
- Suspension: 200 mg PO TID (less favored due to erratic absorption).
Treatment (off-label):
- Similar to prophylaxis dosing, sometimes higher exposure targets needed.
Pediatric Dosing
- ≥13 years: use adult dosing.
- <13 years: suspension used; limited PK data, monitor levels closely.
- Some centers use 12 mg/kg/day divided TID (max 800 mg/day).
- Metabolism: primarily glucuronidation (UGT1A4), minor CYP3A4.
- Half-life: ~35 hours.
- Highly protein bound (~98%).
- TDM (therapeutic drug monitoring):
- Trough goal: >0.7 µg/mL (prophylaxis); >1.0 µg/mL (treatment).
Adverse Effects
- Common: GI upset, headache, elevated LFTs.
- Serious: hepatotoxicity, QTc prolongation (torsades risk), rare pseudohyperaldosteronism (HTN, hypokalemia, hypomagnesemia).
- IV: risk of infusion-related reactions (due to cyclodextrin vehicle).
Drug Interactions
- Strong CYP3A4 inhibitor → ↑ levels of cyclosporine, tacrolimus, sirolimus, midazolam, statins, vincristine (risk of neurotoxicity).
- Avoid PPIs/H2RAs with suspension (↓ absorption).
- Monitor calcineurin inhibitor levels closely in allo-HSCT with GVHD prophylaxis.
Role in HSCT & Oncology
- Superior to fluconazole/itraconazole for preventing invasive fungal disease in allo-HSCT patients with GVHD (Cornely et al., NEJM 2007).
- Now preferred first-line antifungal prophylaxis in:
- Allogeneic HSCT with GVHD
- AML/MDS induction chemotherapy with prolonged neutropenia
Summary for oncology pharmacists: