Isavuconazoniuminteractions

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. 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. Lopinavir/ritonavir 400 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. Rifampin Contraindicate coadministration of all potent CYP3A4 inducers There is a 97% decrease in exposure of isavuconazole upon coadministration with rifampin. Table 5. The Effect of CRESEMBA on the Pharmacokinetics of Other Drugs Recommendation Comments Lopinavir/ritonavir 400 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. 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. Cyclosporine Use with Caution Concomitant administration of CRESEMBA and cyclosporine results in increase in cyclosporine exposure. Monitor drug concentrations of cyclosporine and adjust dose as needed. Sirolimus Use with Caution Concomitant administration of CRESEMBA and sirolimus results in increase in sirolimus exposure. Monitor drug concentrations of sirolimus and adjust dose as needed. Tacrolimus Use with Caution Concomitant administration of CRESEMBA and tacrolimus results in increase in tacrolimus exposure. Monitor drug concentrations of tacrolimus and adjust dose as needed. Midazolam Use with Caution Concomitant administration of CRESEMBA and midazolam results in increase in midazolam exposure. Consider dose reduction of midazolam when isavuconazole is coadministered. Bupropion Use with Caution Concomitant administration of CRESEMBA and bupropion results in decrease in bupropion exposure. Dose increase of bupropion may be necessary when coadministered with CRESEMBA, but should not exceed the maximum recommended dose. Mycophenolate Mofetil Use with Caution Concomitant administration of CRESEMBA and MMF results in increase in MMF exposure. Patients receiving CRESEMBA concurrently with MMF should be monitored for MPA-related toxicities. Digoxin Use with Caution Concomitant administration of CRESEMBA and digoxin results in increase in digoxin exposure. Serum digoxin concentrations should be monitored and used for titration when dosed concurrently with CRESEMBA. Vincristine Avoid Concomitant Use Avoid concomitant use with CRESEMBA in pediatric and adult patients. CRESEMBA is predicted to have a less than 2‑fold increase in vincristine exposure in pediatric and adult patients, which may increase the risk of vincristine-related adverse reactions.

CYP3A4 inhibitors or inducers may alter the plasma concentrations of isavuconazole.

Appropriate therapeutic drug monitoring and dose adjustment of immunosuppressants (i.e., tacrolimus, sirolimus, and cyclosporine) may be necessary when coadministered with CRESEMBA.

Drugs with a narrow therapeutic window that are P-gp substrates, such as digoxin, may require dose adjustment when administered concomitantly with CRESEMBA.