Cresemba

BACKGROUND^1,2

Isavuconazonium sulfate (Cresemba), manufactured by Astellas Pharma Inc, is a new antifungal medication indicated for the treatment of invasive forms of aspergillosis and mucormycosis in patients at least 18 years of age. After receiving priority review, Cresemba was approved in March 2015. It is designated as a qualified infectious disease product and received orphan drug status based on its ability to treat rare yet serious fungal infections.

PHARMACOLOGY/ PHARMACOKINETICS^1,3

As a prodrug, isavuconazonium sulfate is quickly hydrolyzed by esterases to its active form, isavuconazole. This azole antifungal inhibits fungal lanosterol 14-alphademethylase, a cytochrome P-450— dependent enzyme that converts lanosterol to ergosterol. Ergosterol is a main element of fungal cell membranes; the cell membrane weakens due to a lack of ergosterol and a buildup of methylated sterol precursors.

Isavuconazole has activity against Aspergillus species, Mucormycetes species, and Mucorales such as Rhizopus oryzae. Isavuconazole has an oral bioavailability of 98%, an intravenous (IV) volume of distribution of 450 L, a plasma half-life of 130 hours, and is 99% protein-bound. Isavuconazole is metabolized by cytochrome P-450 enzymes (CYP3A4 and CYP3A5) and uridine diphosphate-glucuronosyltransferases, and is excreted in the urine (45.5%) and feces (46.1%).

DOSING AND ADMINISTRATION^1,3

Isavuconazonium sulfate can be administered orally or intravenously. No dosing changes are necessary when switching between dosage forms due to isavuconazole’s high bioavailability. The loading dose is 372 mg isavuconazonium sulfate every 8 hours for a total of 6 doses. The maintenance dose of 372 mg given once daily should be administered 12 to 24 hours after the last loading dose. Each 372-mg dose contains 200 mg of the active moiety, isavuconazole. When administered intravenously, the vial should be reconstituted with 5 mL sterile water and added to 250 mL normal saline or 5% dextrose. The infusion set should have an inline filter with pore size of 0.2 to 1.2 microns, and the dose should be infused over at least 1 hour.

CLINICAL EFFICACY^1,4

Two phase III trials were the basis for FDA approval of isavuconazonium sulfate for the treatment of invasive aspergillosis and mucormycosis. Trial 1 assessed the safety and efficacy of isavuconazole relative to voriconazole in treating invasive fungal disease due to Aspergillus species or other filamentous fungi. This was a randomized, doubleblind, noninferiority trial consisting of 2 groups of 258 patients each with proven, probable, or possible invasive fungal infections. Patients received the recommended dose of isavuconazole or voriconazole for at least 7 days after resolution of symptoms or for a maximum of 84 days.

The primary outcome of all-cause mortality (ACM) through day 42 was 18.6% in the isavuconazole group and 20.2% in the voriconazole group (adjusted treatment difference: -1.0; 95% CI, -8.0 to 5.9). Based on a predefined margin of 10%, isavuconazole demonstrated noninferiority to voriconazole. Fewer patients in the isavuconazole group experienced treatmentemergent serious adverse reactions (52.1% vs 57.5%) as well as treatment- emergent adverse reactions that resulted in discontinuation of the study drug (14% vs 23%).

Trial 2 was an open-label, noncomparative trial including 37 patients with proven or probable mucormycosis. Twenty-one patients received isavuconazole as first-line antifungal therapy and 16 received isavuconazole as salvage treatment. Patients received oral or IV isavuconazole at the recommended dose for a median of 84 days (range of 2 to 882 days). The primary end point of ACM was 37.8% at day 42 and 43.2% at day 84. Although no placebo or control groups were used in this study, ACM was lower compared with known historical rates of untreated infection (95.5% to 100%).

MEDICATION SAFETY^1,4

The most common adverse events associated with Cresemba (>15% in clinical trials), such as nausea, vomiting, diarrhea, headache, and elevated liver enzymes, were similar to other azole antifungals. Cresemba was shown to exhibit dose-related shortening of the QT interval, and although the clinical significance of this finding is unclear, it is recommended to avoid use in patients with familial short QT syndrome. Some patients with serious underlying medical conditions reported severe hepatic adverse events. Liver function tests should be completed before and during therapy. Cresemba should not be used concurrently with CYP3A4 inhibitors (eg, ketoconazole, high-dose ritonavir) or inducers (eg, rifampin, carbamazepine, St. John’s Wort, longacting barbiturates). Cresemba is a Pregnancy Category C medication.

AVAILABILITY AND COST^1,3,5

Cresemba is available as a 186-mg capsule and as a 372-mg singledose vial of white to yellow lyophilized powder. The average wholesale price is $1176 for 14 capsules and $286 for a 372-mg vial. More information is available at www .cresemba.com.

Jennifer L. Cruz, PharmD, BCPS, is an assistant professor of clinical education at UNC Eshelman School of Pharmacy. Katherine Summers is a PharmD candidate at UNC Eshelman School of Pharmacy.

References

• Cresemba [package insert]. Northbrook, IL: Astellas Pharma US, Inc; revised 2015.
• FDA approves new antifungal drug Cresemba [news release]. Silver Spring, MD: US Food and Drug Administration; March 5, 2015. www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm437106.htm. Accessed June 26, 2015.
• Cresemba. In: Facts & Comparisons eAnswers [online database]. St. Louis, MO: Wolters Kluwer Health, Inc. Updated April 2015. http://online.factsandcomparisons.com. Accessed June 17, 2015.
• FDA briefing document: anti-infective drugs advisory committee meeting. US Food and Drug Administration website. www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/Anti-InfectiveDrugsAdvisoryCommittee/UCM430747.pdf. Published January 22, 2015. Accessed June 19, 2015.
• Pricing obtained from AmerisourceBergen wholesaler.