Drug Interactions between ivosidenib and suvorexant

GENERALLY AVOID: Grapefruit juice may increase the plasma concentrations of ivosidenib. 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. Pharmacokinetic data are available for the potent CYP450 3A4 inhibitor, itraconazole, and the moderate inhibitor, fluconazole. When a single 250 mg dose of ivosidenib was administered with itraconazole 200 mg once daily for 18 days, ivosidenib systemic exposure (AUC) increased to 269% of control, with no change in peak plasma concentration (Cmax). Based on physiologically-based pharmacokinetic modeling, coadministration of a 500 mg dose of ivosidenib with fluconazole (dosed to steady-state) is predicted to increase ivosidenib single-dose AUC to 173% of control, while multiple-dosing of both is predicted to increase ivosidenib steady-state Cmax and AUC to 152% and 190% of control, 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 ivosidenib may increase the risk of QT interval prolongation, which has been associated with ventricular arrhythmias including torsade de pointes and sudden death.

GENERALLY AVOID: Coadministration with a high-fat meal may increase the plasma concentrations of ivosidenib. According to the product labeling, administration of a single dose with a high-fat meal (approximately 900 to 1000 calories; 500 to 600 calories in fat, 250 calories in carbohydrate, 150 calories in protein) increased ivosidenib Cmax and AUC by 98% and 25%, respectively, in healthy study subjects.

MANAGEMENT: Ivosidenib may be administered with or without food, but should not be administered with a high-fat meal. Patients should avoid consumption of grapefruit and grapefruit juice during treatment with ivosidenib.

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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.

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