Drug Interaction Report

MONITOR: Coadministration with weak inhibitors of CYP450 3A4 may increase the plasma concentrations of eplerenone, which is primarily metabolized by the isoenzyme. In pharmacokinetic studies, administration of a single 100 mg dose of eplerenone in combination with the potent CYP450 3A4 inhibitor ketoconazole (200 mg twice a day) resulted in a 1.7-fold increase in eplerenone peak plasma concentration (Cmax) and a 5.4-fold increase in systemic exposure (AUC), while administration with moderate inhibitors (erythromycin 500 mg twice daily; verapamil 240 mg once daily; saquinavir 1200 mg three times daily; fluconazole 200 mg once daily) resulted in increases in eplerenone Cmax ranging from 1.4- to 1.6-fold and AUC from 2.0- to 2.9-fold. No data are available for other, less potent inhibitors.

MANAGEMENT: Caution and monitoring are recommended when eplerenone is used with weak CYP450 3A4 inhibitors. Some authorities recommend against the concomitant use of eplerenone with weak CYP450 3A4 inhibitors in patients with an eGFR of 30 to 49 mL/min/1.73m2, and not to exceed 25 mg daily if coadministration is required in patients with an eGFR higher than 50 mL/min /1.73m2.

GENERALLY AVOID: Coadministration with grapefruit juice may increase the plasma concentrations of eplerenone. The primary mechanism is inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall by certain compounds present in grapefruits. Inhibition of hepatic CYP450 3A4 may also contribute. In drug interaction studies, administration of a single 100 mg dose of eplerenone in combination with grapefruit juice resulted in a 25% increase in eplerenone systemic exposure (AUC). High blood levels of eplerenone can increase the risk of side effects including hyperkalemia. 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.

MANAGEMENT: It may be advisable for patients to avoid the consumption of grapefruit, grapefruit juice, or supplements that contain grapefruit during treatment with eplerenone.

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.