Drug Interaction Report

MONITOR: Coadministration with inhibitors of CYP450 3A4 may increase the plasma concentrations of isavuconazole, which is primarily metabolized by CYP450 3A4 and 3A5 and subsequently by uridine diphosphate glucuronosyltransferases (UGT). When a single dose of isavuconazonium sulfate (equivalent to 200 mg of isavuconazole) was administered to healthy volunteers following multiple dosing of the potent CYP450 3A4 inhibitor ketoconazole (200 mg twice daily for 24 days), isavuconazole peak plasma concentration (Cmax) increased by 9% and systemic exposure (AUC) increased by 422%. Lopinavir-ritonavir (400 mg-100 mg twice daily) increased the Cmax and AUC of isavuconazole by 74% and 96%, respectively.

MANAGEMENT: Caution is advised when isavuconazonium sulfate is prescribed with CYP450 3A4 inhibitors. Patients should be monitored for adverse effects such as nausea, vomiting, diarrhea, peripheral edema, hypokalemia, hypomagnesemia, and hepatotoxicity. In addition, many CYP450 3A4 inhibitors are also substrates of the isoenzyme, thus pharmacologic response to these agents should also be monitored, as isavuconazole itself is reportedly a moderate CYP450 3A4 inhibitor.

Concurrent use of cimetidine and ethanol may result in increased ethanol concentrations. The mechanism appears to be due to inhibition of gastric alcohol dehydrogenase by cimetidine, leading to increased bioavailability of the alcohol and inhibition of hepatic metabolism of alcohol. The clinical significance of this interaction is limited. More importantly, patients requiring cimetidine for gastrointestinal disease should be counseled to avoid alcohol to prevent worsening of their disease. The other H-2 receptor antagonists appear to have minimal effects on the concentrations of alcohol.

Caffeine effects may be increased in patients also taking cimetidine. The mechanism may be due to decreased caffeine metabolism induced by cimetidine. Although adequate clinical data are lacking, a reduction in dose or elimination of caffeine may be needed if excess CNS stimulation is observed.

H2 antagonists may reduce the clearance of nicotine. Cimetidine, 600 mg given twice a day for two days, reduced clearance of an intravenous nicotine dose by 30%. Ranitidine, 300 mg given twice a day for two days, reduced clearance by 10%. The clinical significance of this interaction is not known. Patients should be monitored for increased nicotine effects when using the patches or gum for smoking cessation and dosage adjustments should be made as appropriate.