Drug Interaction Report

MONITOR: Coadministration with echinacea may alter the plasma concentrations and therapeutic effects of drugs that are substrates of CYP450 3A4. Echinacea appears to inhibit intestinal CYP450 3A4, which would lead to an increase in oral midazolam (a sensitive 3A4 substrate) bioavailability; however, plasma levels of midazolam following oral administration do not appear to be affected by echinacea. In contrast, it appears that echinacea may also induce hepatic CYP450 3A4; thereby increasing the hepatic clearance of drugs that are substrates of CYP450 3A4. According to reports, echinacea may increase the hepatic clearance of intravenous (IV) midazolam by 34% and decrease the area under the concentration-time curve (AUC) and half-life of IV midazolam by 20% and 42%, respectively.

MANAGEMENT: In general, patients should be advised to consult their healthcare provider before using any herbal or alternative medicines. If echinacea is prescribed with a drug that is a CYP450 3A4 substrate, the possibility of an altered (increased or decreased) therapeutic response should be considered. Patients should be monitored more closely following the addition or withdrawal of echinacea and the dosage of the CYP450 3A4 substrate adjusted as necessary.

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.