Isavuconazonium Sulfate) — New Orphan Drug Approval

Cresemba® (isavuconazonium sulfate) — New Orphan Drug Approval

• On March 6, 2015, the FDA announced the approval of Astellas’ Cresemba (isavuconazonium sulfate) for patients 18 years of age and older for the treatment of invasive aspergillosis and invasive mucormycosis.

• Aspergillosis is a fungal infection caused by the Aspergillus species, and mucormycosis is caused by the Mucorales fungi.

— Both aspergillosis and mucormycosis are rare, life-threatening infections that occur predominantly in people with weakened immune systems.

• Cresemba contains isavuconazonium sulfate. Isavuconazonium sulfate is the prodrug form of isavuconazole, an azole antifungal agent that interferes with fungal cell membrane synthesis.

• The approval of Cresemba to treat invasive aspergillosis or other filamentous fungi was based on a clinical trial involving 516 patients randomized to receive either Cresemba or voriconazole.

— Cresemba demonstrated non-inferiority to voriconazole for the primary endpoint of all-cause mortality at day 42 (18.6% vs. 20.2%).

• The approval of Cresemba to treat invasive mucormycosis was based on an open-label, non- comparative trial involving 37 patients. The trial examined Cresemba in light of the natural disease progression of untreated mucormycosis.

— At day 42, the all-cause mortality rate was 38%. The success in overall response at the end of treatment was 31%, as assessed by an independent review committee.

— However, the efficacy of Cresemba for the treatment of invasive mucormycosis has not been evaluated in concurrent, controlled clinical trials.

• Contraindications of Cresemba include the following:

— Patients with known hypersensitivity to isavuconazole

— Coadministration with strong CYP 3A4 inhibitors (eg, ketoconazole, high-dose ritonavir)

— Coadministration with strong CYP 3A4 inducers (eg, rifampin, carbamazepine, St. John’s wort, long-acting barbiturates)

— Patients with familial short QT syndrome

• Warnings and precautions of Cresemba include hepatic adverse drug reactions, infusion-related reactions, hypersensitivity reactions, embryo-fetal toxicity, drug interactions, and drug particulates.

• The most common adverse events with Cresemba use were nausea, vomiting, diarrhea, headache, elevated liver chemistry tests, hypokalemia, constipation, dyspnea, cough, peripheral edema, and back pain.

Continued . . .

• The recommended dose of Cresemba is as follows:

Loading Dose Maintenance Dose Cresemba injection 372 mg intravenously (IV) every 372 mg IV once daily 8 hours for 6 doses (48 hours) Cresemba capsules 2 capsules (372 mg) orally every 2 capsules (372 mg) orally 8 hours for 6 doses (48 hours) once daily

— The intravenous formulation of Cresemba must be administered via an infusion set with an in- line filter (pore size 0.2 – 1.2 micron).

— Switching between the intravenous and oral formulations of Cresemba is acceptable as bioequivalence has been demonstrated. Loading dose is not required when switching between formulations.

• Astellas plans to launch Cresemba in the coming months. Cresemba will be available as 186 mg capsules and 372 mg single-dose vials for injection. The 186 mg and 372 mg doses of isavuconazonium sulfate are equivalent to 100 mg and 200 mg of isavuconazole, respectively.

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