Drug Interaction Report

MONITOR: Coadministration with isavuconazonium sulfate (prodrug of isavuconazole) may increase the plasma concentrations of drugs that are substrates of CYP450 3A4 and/or P-glycoprotein (P-gp). The mechanism is decreased clearance due to inhibition of CYP450 3A4 activity and/or P-gp-mediated efflux of these drugs by isavuconazole. In pharmacokinetic studies, isavuconazole increased the systemic exposure (AUC) of sensitive CYP450 3A4 substrates midazolam, sirolimus, and tacrolimus by approximately 2-fold, thus it can be considered a moderate inhibitor of the isoenzyme.

MANAGEMENT: Caution is advised when isavuconazonium sulfate is used concomitantly with drugs that are substrates of the CYP450 3A4 isoenzyme or the P-gp transport protein, particularly those with a narrow therapeutic range. Dosage adjustments as well as clinical and laboratory monitoring may be appropriate for some drugs whenever isavuconazonium sulfate is added to or withdrawn from therapy.

GENERALLY AVOID: Alcohol may potentiate some of the pharmacologic effects of buspirone. Use in combination may result in additive central nervous system depression and/or impairment of judgment, thinking, and psychomotor skills.

ADJUST DOSING INTERVAL: In a small, randomized, crossover study, the consumption of large amounts of grapefruit juice (compared to water) was associated with significantly increased plasma buspirone concentrations, slightly prolonged elimination half-lives, and delayed times to reach peak drug concentration. The perceived pharmacodynamic effect of buspirone, as measured by subjective drowsiness and overall subjective drug effect, was also enhanced by grapefruit juice. These alterations may stem from the delay of gastric emptying as well as inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall induced by certain compounds present in grapefruits.

MANAGEMENT: Patients receiving buspirone should be advised to avoid consumption of alcohol. Patients also should preferably avoid the consumption of large amounts of grapefruits and grapefruit juice to prevent any undue fluctuations in plasma drug levels. If this is not possible, the buspirone dose should be taken at least 2 hours before or 8 hours after grapefruit or grapefruit juice. Monitoring for increased CNS depression is recommended.