Drug Interaction Report

MONITOR: Coadministration with lemborexant may decrease the plasma concentrations and pharmacologic effects of CYP450 2B6 substrates. The proposed mechanism is lemborexant-mediated induction of the CYP450 2B6 isoenzyme. When bupropion, a CYP450 2B6 substrate, was coadministered with lemborexant, S-bupropion peak plasma concentration (Cmax) and systemic exposure (AUC) decreased approximately 50% and 45%, respectively, while the Cmax and AUC of [S,S]-hydroxylated bupropion decreased approximately 13% and 25%, respectively.

MANAGEMENT: Caution is advised if lemborexant is used concomitantly with drugs that are substrates of CYP450 2B6. Dosage adjustments as well as clinical and laboratory monitoring may be appropriate for some drugs whenever lemborexant is added to or withdrawn from therapy.

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.

GENERALLY AVOID: The combined use of ethanol and isotretinoin may result in a disulfiram-like reaction. The mechanism has not been established.

MANAGEMENT: Alcohol consumption should be avoided during isotretinoin therapy.