By William T. Elliott, MD, FACP, and James Chan, PharmD, PhD
Dr. Elliott is Chair, Formulary Committee, Northern California Kaiser Permanente; and Assistant Professor of Medicine, University of California, San Francisco. Dr. Chan is Pharmacy Quality and Outcomes Manager, Kaiser Permanente, Oakland, CA
Drs. Elliott and Chan report no financial relationships relevant to this field of study.
The FDA has approved a new antifungal agent for the treatment of serious fungal infections. Isavuconazonium sulfate is designated as a Qualified Infectious Disease Product (QDIP), a designation given to drugs to treat serious or life-threatening infections. Isavuconazonium is an azole antifungal and the prodrug of isavuconazole. It was also given an orphan status for rare fungal infections. It is marketed by Astellas Pharma US, Inc. as Cresemba.
INDICATIONS
Isavuconazole is indicated for the treatment of invasive aspergillosis and invasive mucormycosis.1
DOSAGE
The recommended dose is 372 mg intravenously or orally every 8 hours for 6 doses and once daily thereafter. Isavuconazonium sulfate is available as 372 mg (equivalent to 200 mg of isavuconazole) single dose vials or 186 mg of isavuconazonium sulfate (equivalent to 100 mg of isavuconazole) capsules.
POTENTIAL ADVANTAGES
Isavuconazole provides an alternative for the treatment of invasive aspergillosis and mucormycosis. The prodrug is water soluble and in contrast to voriconazole does not require the solubilizing agent sulfobutyl ether-ß-cyclodextrin (SBECD) — an excipient that accumulates in patients with moderate to severe renal insufficiency. The oral formulation is recommenced for this population.2
POTENTIAL DISADVANTAGES
Cases of severe liver adverse events (hepatitis, cholestasis or hepatic failure, including death) have been reported in patients with serious underlying medical conditions such as hematologic malignancy.1 Isavuconazole is a substrate for CYP3A4 as well as a moderate inhibitor of CYP3A4; therefore, its levels may be altered by CYP3A4 inhibitors and inducers. Infusion-related reactions have been reported.1 Common adverse events, including gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea), peripheral edema, and headache, were similar to that reported for voriconazole.1 Isavuconazole may be less active in vitro against Aspergillus spp. than voriconazole.3
COMMENTS
The approval of isavuconazole was based on two studies. Trial 1 was a randomized, double-blind, non-inferiority active controlled trial comparing isavuconazole to voriconazole in participants with proven, probable, or possible invasive aspergillosis. The second was an open-label noncomparative trial in participants with proven or probable invasive mucormycosis.1 In trial 1, participants generally had hematologic malignancies (84%) with a high percentage of neutropenia (65%). Participants (n = 516) were randomized to isavuconazole (200 mg IV every 8 hours for 48 hours, then 200 mg once IV or orally daily) or voriconazole (6 mg/kg IV every 12 hours for the first 24 hours, 4 mg/kg IV every 12 hours for the next 24 hours, then 200 mg orally every 12 hours). The maximum duration was 84 days (mean 47 days). The efficacy endpoint was all-cause mortality through day 42 and overall response success at end-of-treatment (EOT), last day of drug administration. Overall, success was assessed by a blinded committee based on predetermined clinical, mycological, and radiological responses. The rates for all-cause mortality were 18.6% for isavuconazole and 20.2% for voriconazole for a difference of -1.6% (95% confidence interval, -8.0 to 5.9). EOT rates were 35% compared to 38.9% for voriconazole. In the open-label trial in participants with invasive mucormycosis, all-cause mortality was 38% and EOT success was 31%.
CLINICAL IMPLICATIONS
Isavuconazole provides an alternative for the treatment of invasive aspergillosis and mucormycosis. Currently, voriconazole is the treatment of choice for invasive aspergillosis and liposomal amphotericin or amphotericin lipid complex is treatment of choice for mucormycosis.4,5 The wholesale cost for an oral one-week maintenance dose of isavuconazole is $1960.
REFERENCES
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Cresemba Prescribing Information. Astellas Pharma US. Inc. March 2015.
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Vfend Prescribing Information. Pfizer, Inc. February 2015.
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Pfaller MA et al. In vitro activities of isavuconazole and comparator antifungal agents tested against a global collection of opportunistic yeasts and molds. J Clin Microbiol 2013;51:2608-2616.
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Walsh TJ et al. Treatment of aspergillosis: Clinical practice guidelines of the Infectious Diseases Society of America. Clin Infect Dis 2008;46:327-360.
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Sklada A et al. Diagnosis and treatment of mucormycosis in patients with hematological malignancies: Guidelines from the 3rd European Conference on Infections in Leukemia (ECIL 3). Haematologica 2013;98:492-504.
