Drug Interactions between isavuconazonium and rufinamide

MONITOR: Coadministration with inducers of the CYP450 3A4 isoenzyme may decrease the plasma concentrations of isavuconazole, which is primarily metabolized by CYP450 3A4 and 3A5 and subsequently by uridine diphosphate glucuronosyltransferases (UGT). When multiple doses of isavuconazonium sulfate (prodrug of isavuconazole) were administered to healthy volunteers with multiple doses of the potent CYP450 3A4 inducer rifampin (600 mg), mean isavuconazole peak plasma concentration (Cmax) and systemic exposure (AUC) decreased by 75% and 97%, respectively. The extent to which other, less potent inducers of CYP450 3A4 may interact with isavuconazole is unknown. In addition, coadministration with medicines known to decrease the QT interval may increase the arrhythmogenic risk of isavuconazole. Isavuconazole has been shown to shorten the QTc interval. In a QT study in healthy subjects, isavuconazole shortened the QTc interval by a least squares mean of 13.1 milliseconds after a 200 mg dose, and 24.6 milliseconds after a 600 mg dose, measured 2 hours post-dose. However, data are limited on the clinical significance of drug-induced QT-interval shortening. Familial short QT syndrome has been reported to increase the risk for sudden death and ventricular arrhythmias, particularly ventricular fibrillation. Isavuconazole is contraindicated in patients with familial short QT syndrome.

MANAGEMENT: Caution is advised during concomitant use with CYP450 3A4 inducers; the potential for decreased efficacy of isavuconazonium sulfate should be considered. Caution and clinical monitoring should also be considered during concomitant use of isavuconazonium sulfate and medicines known to shorten the QT interval.