CRESEMBA For Treatment Of Aspergillosis & Mucormycosis

CRESEMBA (isavuconazonium sulfate) is an azole antifungal indicated for use in the treatment of Aspergillosis & Mucor mycosis

Indication of CRESEMBA

• Invasive aspergillosis
• Invasive mucormycosis

Contraindications of CRESEMBA

• Hypersensitivity to CRESEMBA 
• Coadministration with strong CYP3A4 inhibitors, such as ketoconazole or high-dose ritonavir
• Coadministration with strong CYP3A4 inducers, such as rifampin, carbamazepine, St. John’s wort, or long acting barbiturates 
• Use in patients with familial short QT syndrome 

Warning & Precautions for Use of CRESEMBA

Hepatic Adverse Drug Reactions: Serious hepatic reactions have been reported. Evaluate liver-related laboratory tests at the start and during the course of CRESEMBA therapyInfusion-related reactions were reported during intravenous administration of CRESEMBA. Discontinue the infusion if these reactions occur

Hypersensitivity Reactions: Serious hypersensitivity and severe skin reactions, such as anaphylaxis or Stevens Johnson syndrome, have been reported during treatment with other azole antifungal agents. Discontinue CRESEMBA for exfoliative cutaneous reactions 

Embryo-Fetal Toxicity: Do not administer to pregnant women unless the benefit to the mother outweighs the risk to the fetus. Inform pregnant patients of the hazard 

Drug Interactions: Review patient’s concomitant medications. Several drugs may significantly alter isavuconazole concentrations. Isavuconazole may alter concentrations of several drugs 

Drug Particulates: Intravenous formulation may form insoluble particulates following reconstitution. Administer CRESEMBA through an in-line filter

Adverse Reaction associated with CRESEMBA

 Most frequent adverse reactions: nausea, vomiting, diarrhea, headache, elevated liver chemistry tests, hypokalemia, constipation, dyspnea, cough, peripheral edema, and back pain.

Drug Interaction with CRESEMBA

CYP3A4 inhibitors or inducers may alter the plasma concentrations of isavuconazole (7). • Appropriate therapeutic drug monitoring and dose adjustment of immunosuppressants (i.e., tacrolimus, sirolimus, and cyclosporine) may be necessary when co-administered with CRESEMBA (7). • Drugs with a narrow therapeutic window that are P-gp substrates, such as digoxin, may require dose adjustment when administered concomitantly with CRESEMBA (7)

Mechanism of Action of 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.

Pharmacokinetic/Pharmacodynamic Relationship

 In patients treated with CRESEMBA (isavuconazonium sulfate) for invasive aspergillosis in a controlled trial, there was no significant association between plasma AUC or plasma isavuconazonium sulfate concentration and efficacy. Cardiac Electrophysiology The effect on QTc interval of multiple doses of CRESEMBA capsules was evaluated. CRESEMBA was administered as 2 capsules (equivalent to 200 mg isavuconazole) three times daily on days 1 and 2 followed by either 2 capsules or 6 capsules (equivalent to 600 mg isavuconazole) once daily for 13 days in a randomized, placebo- and active-controlled (moxifloxacin 400 mg single dose), four-treatment-arm, parallel study in 160 healthy subjects. Isavuconazole resulted in dose-related shortening of the QTc interval. 

For the 2-capsule dosing regimen, the least squares mean (LSM) difference from placebo was -13.1 msec at 2 hours postdose [90% CI: -17.1, -9.1 msec]. Increasing the dose to 6 capsules resulted in an LSM difference from placebo of -24.6 msec at 2 hours postdose [90% CI: -28.7, -20.4]. CRESEMBA was not evaluated in combination with other drugs that reduce the QTc interval, so the additive effects are not known. 12.3 Pharmacokinetics General Pharmacokinetics In healthy subjects, the pharmacokinetics of isavuconazole following oral administration of CRESEMBA capsules at isavuconazole equivalent doses up to 600 mg per day (6 capsules) are dose proportional (Table 5). 

Based on a population pharmacokinetics analysis of healthy subjects and patients, the mean plasma half-life of isavuconazole was 130 hours and the mean volume of distribution (Vss) was approximately 450 L following intravenous administration.

Absorption 

In healthy volunteers, the oral administration of CRESEMBA, the active moiety, isavuconazole, generally reaches maximum plasma concentrations (Cmax) 2 hours to 3 hours after single and multiple dosing. The absolute bioavailability of isavuconazole following oral administration of CRESEMBA is 98%. No significant concentrations of the prodrug or inactive cleavage product were seen in plasma after oral administration. 

Following intravenous administration of CRESEMBA, maximal plasma concentrations of the prodrug and inactive cleavage product were detectable during infusion and declined rapidly following the end of administration. The drug was below the level of detection by 1.25 hours after the start of a 1 hour infusion. The total exposure of the prodrug based on AUC was less than 1% that of isavuconazole. The inactive cleavage product was quantifiable in some subjects up to 8 hours after the start of infusion. The total exposure of inactive cleavage product based on AUC was approximately 1.3% that of isavuconazole.