Drug Interaction Report

MONITOR: Coadministration with danicopan may increase the plasma concentrations of drugs that are substrates of the efflux transporters breast cancer resistance protein (BCRP) and/or P-glycoprotein (P-gp). The proposed mechanism involves decreased clearance due to inhibition of BCRP and P-gp by danicopan. In clinical drug interaction studies, when subjects were coadministered the BCRP substrate rosuvastatin (single 20 mg dose) with danicopan at steady state (200 mg three times daily for 4 days), the peak plasma concentration (Cmax) and systemic exposure (AUC) of rosuvastatin increased by 3.3-fold and 2.2-fold, respectively. In addition, when the P-gp substrate fexofenadine (single 180 mg dose) was coadministered with danicopan (150 mg three times daily for 4 days), the peak plasma concentration (Cmax) and systemic exposure (AUC) of fexofenadine increased by 1.4-fold and 1.6-fold, respectively. Similarly, when subjects were coadministered the P-gp substrate tacrolimus (single 2 mg dose) with danicopan (200 mg three times daily for 5 days), the Cmax and AUC of tacrolimus increased by 1.1-fold and 1.5-fold, respectively.

MANAGEMENT: Caution and clinical monitoring are recommended if danicopan is coadministered with drugs that are substrates of the transporters BCRP and/or P-gp, particularly sensitive substrates, or those with a narrow therapeutic range. Dosage adjustments as well as closer clinical and laboratory monitoring for the development of adverse effects may be appropriate for some drugs whenever danicopan is added to or withdrawn from therapy. Individual product labeling should be consulted for further guidance.

GENERALLY AVOID: Grapefruit juice may increase the plasma concentrations of lemborexant, 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. Inhibition of hepatic CYP450 3A4 may also contribute. The interaction has not been studied with grapefruit juice but has been reported for other CYP450 3A4 inhibitors. When coadministered with itraconazole, a potent CYP450 3A4 inhibitor, lemborexant peak plasma concentration (Cmax) and systemic exposure (AUC) increased approximately 1.4-fold and 3.8-fold, respectively. When coadministered with fluconazole, a moderate CYP450 3A4 inhibitor, lemborexant Cmax and AUC increased approximately 1.6-fold and 4.2-fold, respectively. 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. Increased exposure to lemborexant may increase the risk of adverse reactions such as central nervous system (CNS) depression, sleep paralysis, hallucinations, complex sleep behaviors, worsening of depression or suicidal ideation, nightmares, palpitations, or headache.

After administration of a high-fat, high-calorie meal (approximately 1000 calories with 500 to 600 calories from fat), lemborexant Cmax decreased by 23%, AUC increased by 18%, and the time to maximum concentration (Tmax) was delayed by 2 hours.

MANAGEMENT: The manufacturer makes no recommendation regarding administration with food; however, the time to sleep onset may be delayed if taken with or soon after a meal. Patients should avoid consumption of grapefruit, grapefruit juice, or supplements that contain grapefruit during treatment with lemborexant.