Drug Interaction Report

Consumer information for this interaction is not currently available.

MONITOR: Coadministration with treosulfan may increase the plasma concentrations of drugs that are substrates of CYP450 3A4, 2C19, and/or the efflux transporter P-glycoprotein (P-gp). The proposed mechanism is decreased clearance due to inhibition of these routes of elimination due to treosulfan. According to physiologically-based pharmacokinetic modeling, treosulfan is predicted to be a weak to moderate CYP450 3A4 inhibitor and weak inhibitor of CYP450 2C19, with negligible inhibitory effects on P-gp. However, according to the manufacturer, in vitro studies were unable to exclude potential drug-drug interactions with high plasma concentrations of treosulfan and CYP450 3A4, 2C19, and/or P-gp substrates.

MANAGEMENT: Caution is recommended if treosulfan is coadministered with substrates of CYP450 3A4, 2C19, and/or P-gp, particularly those with a narrow therapeutic range. Some authorities advise that if concomitant use is required, the dosage of these substrates should be administered either 2 hours before or 8 hours after administration of the treosulfan infusion. The prescribing information of the substrates may be consulted for potential dose reductions.

Consumer information for this interaction is not currently available.

GENERALLY AVOID: Coadministration with grapefruit juice may increase the plasma concentrations of macitentan, which is primarily metabolized by CYP450 3A4. The proposed mechanism is inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall by certain compounds present in grapefruit. The interaction has not been studied with grapefruit juice but has been reported for ketoconazole, a potent CYP450 3A4 inhibitor. In ten healthy subjects, coadministration of a single 10 mg oral dose of macitentan on day 5 of treatment with ketoconazole (400 mg daily for 24 days) resulted in an approximately 2-fold increase in macitentan systemic exposure compared to administration alone. However, the clinical significance of the interaction is unclear. In general, the effect of grapefruit juice is concentration-, dose- and preparation-dependent, and can vary widely among brands. Certain preparations of grapefruit juice (e.g., high dose, double strength) have sometimes demonstrated potent inhibition of CYP450 3A4, while other preparations (e.g., low dose, single strength) have typically demonstrated moderate inhibition. Pharmacokinetic interactions involving grapefruit juice are also subject to a high degree of interpatient variability, thus the extent to which a given patient may be affected is difficult to predict.

MANAGEMENT: Until further information is available, patients receiving macitentan therapy should avoid the consumption of grapefruit or grapefruit juice.