What is Cresemba (isavuconazole) and what are its indications, dosing regimen, and contraindications?

What is Cresemba (Isavuconazole)?

Cresemba (isavuconazole) is a broad-spectrum triazole antifungal agent approved for treating invasive aspergillosis and invasive mucormycosis in adults and pediatric patients. 1

Drug Formulation and Administration

Cresemba is administered as isavuconazonium sulfate, a water-soluble prodrug that converts to the active drug isavuconazole. It is available in two interchangeable formulations 1, 2:

• Intravenous formulation: 372 mg isavuconazonium sulfate per vial (equivalent to 200 mg isavuconazole)
• Oral capsules:
  • 186 mg capsules (equivalent to 100 mg isavuconazole)
  • 74.5 mg capsules (equivalent to 40 mg isavuconazole)

The oral formulation has excellent bioavailability with no food effect, allowing flexible administration 2, 3. A key advantage of the IV formulation is the absence of cyclodextrin, making it safe for patients with renal impairment 2, 3.

FDA-Approved Indications

Cresemba is indicated for 1:

1. Invasive aspergillosis (adults and pediatric patients ≥1 year for IV; ≥6 years and ≥16 kg for oral)
2. Invasive mucormycosis (same age/weight restrictions)

Standard Dosing Regimen

Adult Dosing 1:

Loading dose: 372 mg (two 186 mg capsules OR one vial IV) every 8 hours for 6 doses (48 hours total)

Maintenance dose: 372 mg once daily, starting 12-24 hours after the last loading dose

Pediatric Dosing 1:

Dosing is weight-based with a maximum individual dose of 372 mg:

• Ages 1 to <3 years (<18 kg): 15 mg/kg IV every 8 hours × 6 doses, then 15 mg/kg daily
• Ages 3 to <18 years (<37 kg): 10 mg/kg IV every 8 hours × 6 doses, then 10 mg/kg daily
• ≥37 kg: Adult dosing (372 mg)

For oral capsules (ages 6-18 years, ≥16 kg), dosing ranges from 149 mg to 372 mg based on weight bands.

Guideline-Recommended Uses

Beyond FDA indications, guidelines support isavuconazole for 4:

COVID-19 Associated Pulmonary Aspergillosis (CAPA):

• Recommended as monotherapy or sequential monotherapy alongside voriconazole, posaconazole, and liposomal amphotericin B (Strong recommendation, 1C) 4
• Dosing: 200 mg IV every 8 hours × 6 doses, then 200 mg daily
• Duration: 6-12 weeks 4

COVID-19 Associated Mucormycosis (CAM):

• Alternative therapy for primary treatment when amphotericin B is contraindicated or not tolerated (Strong recommendation, 1C) 4
• Preferred agent for maintenance therapy (Strong recommendation, 1C) 4
• Dosing: 200 mg three times daily × 2 days, then 200 mg daily
• Duration: 3-6 months until clinical resolution 4

The 2019 global mucormycosis guideline positions isavuconazole as a moderately recommended alternative to liposomal amphotericin B for primary therapy 5.

Contraindications

Cresemba is absolutely contraindicated in 1:

1. Known hypersensitivity to isavuconazole (anaphylaxis with fatal outcomes reported)
2. Coadministration with strong CYP3A4 inhibitors (ketoconazole, high-dose ritonavir ≥400 mg every 12 hours) - significantly increases isavuconazole levels
3. Coadministration with strong CYP3A4 inducers (rifampin, carbamazepine, St. John's wort, long-acting barbiturates) - significantly decreases isavuconazole levels
4. Familial short QT syndrome - isavuconazole shortens QTc interval in a concentration-dependent manner

Key Safety Considerations

Hepatotoxicity 1:

• Monitor liver function tests at baseline and throughout therapy
• Elevations in ALT, AST, alkaline phosphatase, and bilirubin reported
• Cases of hepatitis, cholestasis, and hepatic failure (including deaths) documented
• Discontinue if clinical liver disease develops attributable to isavuconazole

Infusion-Related Reactions 1:

• Hypotension, dyspnea, chills, dizziness, paresthesia reported with IV administration
• Discontinue infusion if reactions occur
• IV must be administered through 0.2-1.2 micron in-line filter over minimum 1 hour 1

Severe Hypersensitivity 1:

• Anaphylaxis (including fatal cases) and Stevens-Johnson syndrome reported
• Discontinue immediately and provide supportive care

Clinical Efficacy Evidence

The SECURE trial (phase III) demonstrated isavuconazole was non-inferior to voriconazole for invasive aspergillosis with fewer drug-related adverse events 2, 6, 3.

The VITAL trial (phase III single-arm) and matched case-control analysis showed isavuconazole efficacy for mucormycosis with day-42 mortality of 33% versus 39% for amphotericin B (not statistically different) 2, 7.

Practical Advantages

Isavuconazole offers several clinical benefits 2, 6, 3:

• Predictable pharmacokinetics with once-daily maintenance dosing
• No therapeutic drug monitoring required in standard practice (though emerging data suggest TDM may optimize dosing in ICU patients and elderly) 8, 9, 10
• Fewer drug interactions than voriconazole
• No visual disturbances (common with voriconazole) 11
• Cyclodextrin-free IV formulation safe in renal impairment 2, 3
• Broad spectrum including Candida, Aspergillus, Cryptococcus, and variable Mucorales activity 6, 3

Common Pitfalls

Underexposure is frequent - one multicenter study found 42.2% of patients were underexposed 10. Consider TDM in critically ill patients, those with renal impairment, low BMI, or treatment failure 8, 9, 10.

Cost and insurance coverage may limit access - isavuconazole was more frequently discontinued due to coverage denial than voriconazole in one analysis 11.