General Information

Cresemba (isavuconazonium sulfate) is an azole antifungal.

Cresemba is specifically indicated for the treatment of invasive aspergillosis and invasive mucormycosis.

Cresemba for injection is approved for adults and now for pediatric patients 1 year of age and older.

Cresemba capsules are approved for adults and now for pediatric patients 6 years of age and older, who weigh 16 kilograms and greater.

Cresemba is supplied as a solution for intravenous infusion and as a capsule for oral administration. The recommended dose is as follows:

Cresemba injection:

Loading dose: 1 reconstituted vial (372 mga ) intravenously every 8 hours for 6 doses (48 hours) 

Maintenance dose: 1 reconstituted vial (372 mga ) intravenously once daily

Cresemba capsules:

Loading dose: 2 capsules (372 mga ) orally every 8 hours for 6 doses (48 hours) 

Maintenance dose: 2 capsules (372 mga ) orally once daily 

Mechanism of Action

Cresemba (isavuconazonium sulfate) is the prodrug of isavuconazole, an azole antifungal drug. Isavuconazole inhibits the synthesis of ergosterol, a key component of the fungal cell membrane, through the inhibition of cytochrome P-450 dependent enzyme lanosterol 14-alpha-demethylase. This enzyme is responsible for the conversion of lanosterol to ergosterol. An accumulation of methylated sterol precursors and a depletion of ergosterol within the fungal cell membrane weakens the membrane structure and function. Mammalian cell demethylation is less sensitive to isavuconazole inhibition. 

Side Effects

Adverse effects associated with the use of Cresemba may include, but are not limited to, the following:

• nausea
• vomiting
• diarrhea
• headache
• abnormal liver blood tests
• hypokalemia
• constipation
• dyspnea
• coughing
• peripheral edema

Cresemba may also cause serious side effects including liver problems, infusion reactions and severe allergic and skin reactions.

Clinical Trial Results

The FDA approval of Cresemba was based on the following trials:

Invasive Aspergillus

Trial 1 was a randomized, double-blind, non-inferiority active controlled trial which evaluated the safety and efficacy of Cresemba versus voriconazole for primary treatment of invasive fungal disease caused by Aspergillus species or other filamentous fungi. Patients randomized to receive Cresemba treatment were administered a loading dose intravenously of 372 mg of isavuconazonium sulfate (equivalent to 200 mg of isavuconzole) every 8 hours for the first 48 hours. Beginning on day 3, patients received intravenous or oral therapy of 372 mg of isavuconazonium sulfate (equivalent to 200 mg of isavuconazole) once daily. Patients randomized to receive voriconazole treatment were administered voriconazole intravenously with a loading dose of 6 mg/kg every 12 hours for the first 24 hours followed by 4 mg/kg intravenously every 12 hours for the following 24 hours. Therapy could then be switched to an oral formulation of voriconazole at a dose of 200 mg every 12 hours. In this trial, the protocol-defined maximum treatment duration was 84 days. Mean treatment duration was 47 days for both treatment groups, of which 8 to 9 days was by an intravenous route of administration. All-cause mortality through Day 42 in the overall population (ITT) was 18.6% in the Cresemba treatment group and 20.2% in the voriconazole treatment group for an adjusted treatment difference of -1.0% with 95% confidence interval of -8.0% to 5.9%. Similar results were seen in patients with proven or probable invasive aspergillosis confirmed by serology, culture or histology.

Invasive Mucormycosis

This open-label non-comparative trial evaluated the safety and efficacy of a subset of patients with invasive mucormycosis. Thirty-seven (37) patients had proven or probable mucormycosis. Patients were treated with Cresemba intravenously or via oral administration at the recommended doses. Median treatment duration was 102 days for patients classified as primary, 33 days for refractory, and 85 days for intolerant. The trial compared treatment with Cresemba with the natural disease progression associated with untreated mucormycosis. Cresemba was safe and effective. However, the efficacy of Cresemba for the treatment for invasive mucormycosis has not been evaluated in concurrent, controlled clinical trials.