Drug Interactions between rilpivirine and suvorexant

GENERALLY AVOID: Coadministration with grapefruit or grapefruit juice may increase the plasma concentrations of rilpivirine. The proposed mechanism is inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall induced by certain compounds present in grapefruit. In 15 study subjects given rilpivirine (150 mg once daily) with the potent CYP450 3A4 inhibitor ketoconazole (400 mg once daily), mean rilpivirine peak plasma concentration (Cmax), systemic exposure (AUC) and trough plasma concentration (Cmin) were increased by 30%, 49% and 76%, respectively. In 16 study subjects given a single 500 mg dose of a less potent CYP450 3A4 inhibitor chlorzoxazone two hours after rilpivirine (150 mg once daily), mean rilpivirine Cmax, AUC, and Cmin were increased by 17%, 25%, and 18%, respectively. Because grapefruit juice inhibits primarily intestinal rather than hepatic CYP450 3A4, the magnitude of interaction is greatest for those drugs that undergo significant presystemic metabolism by CYP450 3A4 (i.e., drugs with low oral bioavailability). 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.

ADJUST DOSING INTERVAL: The administration of rilpivirine in a fasting state may decrease its oral absorption. Under fasted conditions, the systemic exposure to rilpivirine was 40% lower compared to normal or high-fat caloric meals (533 to 928 Kcal). The systemic exposure was 50% lower when rilpivirine was taken with a protein-rich nutritional beverage.

MANAGEMENT: Coadministration of grapefruit or grapefruit juice with rilpivirine should preferably be avoided. For optimal absorption, it is recommended to take rilpivirine on a regular schedule with a meal.

GENERALLY AVOID: Alcohol may potentiate some of the pharmacologic effects of suvorexant. Use in combination may result in additive central nervous system depression and/or impairment of judgment, thinking, and psychomotor skills. In addition, alcohol may increase the risk of cognitive and complex behavioral changes associated with the use of hypnotics including suvorexant, such as amnesia, anxiety, hallucinations, sleep-driving, and other neuropsychiatric symptoms.

ADJUST DOSE: Grapefruit juice may significantly increase the plasma concentrations of suvorexant. The proposed mechanism is inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall by certain compounds present in grapefruit.

ADJUST DOSING INTERVAL: Administration with or soon after a meal may delay the gastrointestinal absorption of suvorexant. According to the product labeling, administration of suvorexant with a high-fat meal resulted in no meaningful change in peak plasma concentration (Cmax) or systemic exposure (AUC), but a delay in Tmax of approximately 1.5 hours.

MANAGEMENT: Concomitant use of suvorexant with alcohol should be avoided. Patients should be advised not to use suvorexant if they had alcohol that evening or before bed. Grapefruit juice should preferably be avoided; otherwise, the recommended dose of suvorexant is 5 mg when used with grapefruit juice and should not exceed 10 mg. Suvorexant may be taken with or without food; however, for faster sleep onset, suvorexant should not be administered with or soon after a meal.