What is the recommended dosing regimen and contraindications for isavuconazonium (the prodrug of isavuconazole) in adults with invasive aspergillosis or mucormycosis?

Isavuconazonium Dosing and Contraindications

Isavuconazonium (the prodrug of isavuconazole) is administered as a loading dose of 372 mg IV or PO every 8 hours for 6 doses over 48 hours, followed by maintenance dosing of 372 mg once daily starting 12-24 hours after the last loading dose. 1

Recommended Adult Dosing Regimen

Loading Phase

• 372 mg of isavuconazonium sulfate (equivalent to 200 mg isavuconazole) every 8 hours for 6 doses (total 48 hours) 1
• Can be administered intravenously or orally (capsules) 1

Maintenance Phase

• 372 mg once daily starting 12-24 hours after the last loading dose 1
• IV formulation: One reconstituted vial (372 mg) intravenously once daily 1
• Oral formulation: Two 186 mg capsules OR five 74.5 mg capsules once daily 1
• Capsules can be taken with or without food 1

Administration Requirements for IV Formulation

• Must be administered through an in-line filter over a minimum of 1 hour 1
• This is critical because the intravenous formulation may form insoluble particulates following reconstitution 1

FDA-Approved Indications

Isavuconazonium is FDA-approved for two specific invasive fungal infections: 1

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

Absolute Contraindications

Four absolute contraindications exist for isavuconazonium: 1

1. Hypersensitivity to isavuconazole - including anaphylactic reactions which have been reported with fatal outcomes 1

2. Coadministration with strong CYP3A4 inhibitors (e.g., ketoconazole, high-dose ritonavir) - these significantly increase isavuconazole concentrations to potentially toxic levels 1

3. Coadministration with strong CYP3A4 inducers (e.g., rifampin, carbamazepine, St. John's wort, long-acting barbiturates) - these decrease isavuconazole concentrations below therapeutic levels 1

4. Familial short QT syndrome - isavuconazole can further shorten the QT interval 1

Critical Warnings and Monitoring

Hepatotoxicity

• Serious hepatic reactions have been reported 1
• Evaluate liver function tests at baseline and monitor throughout therapy 1
• The most frequent adverse reactions in adults include elevated liver chemistry tests 1

Infusion-Related Reactions

• Can occur during IV administration 1
• Discontinue the infusion immediately if reactions occur 1

Hypersensitivity and Skin Reactions

• Anaphylactic reactions with fatal outcomes have been reported 1
• Stevens-Johnson syndrome has been reported with other azole antifungals 1
• Discontinue isavuconazole if anaphylactic or serious skin reactions occur and initiate supportive treatment 1

Embryo-Fetal Toxicity

• May cause fetal harm when administered to pregnant women 1
• Advise females of reproductive potential to use effective contraception during treatment 1

Guideline-Based Positioning

Invasive Aspergillosis

Isavuconazole is recommended as an alternative primary therapy to voriconazole for invasive pulmonary aspergillosis. 2 The 2016 IDSA guidelines note that isavuconazole demonstrated noninferiority to voriconazole in the SECURE trial with fewer drug-related adverse effects 2. The 2023 Taiwan COVID-19 guidelines recommend single or sequential monotherapy with voriconazole, isavuconazole, posaconazole, or liposomal amphotericin B for COVID-19 associated pulmonary aspergillosis 2.

Invasive Mucormycosis

Isavuconazole is recommended as an alternative first-line therapy to liposomal amphotericin B, particularly in patients with pre-existing renal compromise. 2 The 2019 global mucormycosis guideline recommends isavuconazole 200 mg (3 doses on day 1-2, then once daily from day 3) as a moderately recommended option when amphotericin B formulations are contraindicated or not tolerated 2.

Treatment Duration

• Minimum 6-12 weeks for invasive aspergillosis, dependent on degree and duration of immunosuppression, site of disease, and evidence of disease improvement 2
• For mucormycosis, treatment duration extends longer, often requiring months of therapy 2
• Secondary prophylaxis should be initiated in patients with successfully treated invasive aspergillosis who require subsequent immunosuppression 2

Clinical Efficacy Data

The SECURE trial demonstrated that isavuconazole was noninferior to voriconazole for primary treatment of invasive mold disease, with all-cause mortality at day 42 of 19% versus 20% respectively 3. Importantly, isavuconazole had significantly fewer drug-related adverse events (42% vs 60%, p<0.001) and lower frequencies of hepatobiliary disorders, eye disorders, and skin disorders 3.

For mucormycosis, the VITAL study showed a day-42 crude all-cause mortality of 33% with isavuconazole, similar to 39% with amphotericin B in matched controls 4. The overall response rate was 75% in a recent Chinese multicenter case series 5.