Isavuconazonium Sulfate (1 brand name, 2 dosage forms, 2 routes)
Available dosage forms: POWDER, CAPSULE.
Routes of administration: INTRAVENOUS, ORAL.
Brand Names
- CRESEMBA
Contraindications
•CRESEMBA is contraindicated in persons with known hypersensitivity to isavuconazole. •Coadministration of strong CYP3A4 inhibitors, such as ketoconazole or high-dose ritonavir (400 mg every 12 hours), with CRESEMBA is contraindicated because strong CYP3A4 inhibitors can significantly increase the plasma concentration of isavuconazole [see Drug Interactions (7) and Clinical Pharmacology ( 12.3 )]. •Coadministration of strong CYP3A4 inducers, such as rifampin, carbamazepine, St. John’s wort, or long acting barbiturates with CRESEMBA is contraindicated because strong CYP3A4 inducers can significantly decrease the plasma concentration of isavuconazole [see Drug Interactions (7) and Clinical Pharmacology ( 12.3 )]. •CRESEMBA shortened the QTc interval in a concentration-related manner. CRESEMBA is contraindicated in patients with familial short QT syndrome [see Clinical Pharmacology ( 12.2 )].
Adverse Reactions
The following are discussed in more detail in other sections of the labeling: •Hepatic Adverse Drug Reactions [see Warnings and Precautions (5.1)] •Infusion-Related Reactions [see Warnings and Precautions (5.2)] •Hypersensitivity Reactions [see Warnings and Precautions (5.3)] •Embryo-Fetal Toxicity [see Warnings and Precautions (5.4)]
Drug Interactions
Isavuconazole is a sensitive substrate of CYP3A4. CYP3A4 inhibitors or inducers may alter the plasma concentrations of isavuconazole. Isavuconazole is a moderate inhibitor of CYP3A4, and a mild inhibitor of P-glycoprotein (P-gp), and organic cation transporter 2 (OCT2). Drug interaction studies were conducted to investigate the effect of coadministered drugs on the pharmacokinetics of isavuconazole and the effect of isavuconazole on the pharmacokinetics of coadministered drugs [see Clinical Pharmacology (12.3)]. Table 4. Drug(s) Affecting Pharmacokinetics of CRESEMBA Recommendation Comments Ketoconazole Contraindicate coadministration of all potent CYP3A4 inhibitors There is more than a 5-fold increase in exposure of isavuconazole upon coadministration with ketoconazole [see Clinical Pharmacology (12.3)]. Lopinavir/ritonavir400 mg of lopinavir in combination with 100 mg of ritonavir. Caution is advised when CRESEMBA is coadministered with lopinavir/ritonavir There is a 96% increase in exposure of isavuconazole when coadministered with lopinavir/ritonavir [see Clinical Pharmacology (12.3)]. Rifampin Contraindicate coadministration of all potent CYP3A4 inducers There is a 97% decrease in exposure of isavuconazole upon coadministration with rifampin [see Clinical Pharmacology (12.3)]. Table 5. The Effect of CRESEMBA on the Pharmacokinetics of Other Drugs Recommendation Comments Lopinavir/ritonavir400 mg of lopinavir in combination with 100 mg of ritonavir. Use with Caution Concomitant administration of lopinavir/ritonavir and CRESEMBA resulted in decreased exposure of lopinavir and ritonavir that could possibly result in loss of antiviral efficacy [see Clinical Pharmacology (12.3)]. Atorvastatin Use with Caution Caution should be used when atorvastatin is used with CRESEMBA due to a potential increase in atorvastatin exposure. Monitor patients for adverse reactions that are typical of atorvastatin [see Clinical Pharmacology (12.3)]. Cyclosporine Use with Caution Concom
Mechanism of Action
Isavuconazonium sulfate is the prodrug of isavuconazole, an azole antifungal [see Microbiology (12.4)].
Overdosage
During clinical studies, total daily CRESEMBA doses higher than the recommended dose regimen were associated with an increased rate of adverse reactions. At supratherapeutic doses (three times the recommended maintenance dose) evaluated in a thorough QT study, there were proportionally more treatment-emergent adverse reactions than in the therapeutic dose group (maintenance dose) for the following: headache, dizziness, paresthesia, somnolence, disturbance in attention, dysgeusia, dry mouth, diarrhea, oral hypoesthesia, vomiting, hot flush, anxiety, restlessness, palpitations, tachycardia, photophobia and arthralgia. Adverse reactions leading to discontinuation of study drug occurred in 7 of 39 (17.9%) subjects in the supratherapeutic dose group. Isavuconazole is not removed by hemodialysis. There is no specific antidote for isavuconazole. Treatment should be supportive with appropriate monitoring.