Drug Interaction Report

MONITOR: Coadministration with inhibitors of CYP450 2C8 may increase exposure to the active metabolite of selexipag. According to the prescribing information, selexipag is hydrolyzed to its active metabolite in the liver and intestine by carboxylesterases, and the active metabolite subsequently undergoes oxidative metabolism catalyzed primarily by CYP450 2C8 and to a lesser extent by CYP450 3A4. Coadministration of selexipag with the moderate to potent CYP450 2C8 inhibitor clopidogrel, given at 300 mg loading dose or 75 mg once daily maintenance dose, had no relevant effect on exposure to selexipag but increased exposure to the active metabolite by approximately 2.2- and 2.7-fold following the loading and maintenance doses, respectively. The interaction has not been studied with other, less potent CYP450 2C8 inhibitors.

MANAGEMENT: Caution is advised when selexipag is prescribed with CYP450 2C8 inhibitors. Dosage adjustments as well as clinical and laboratory monitoring of selexipag may be appropriate whenever a CYP450 2C8 inhibitor is added to or withdrawn from therapy. Patients should be monitored for potentially increased side effects such as diarrhea, nausea, vomiting, flushing, anemia, and decreased appetite.

ADJUST DOSING INTERVAL: Food may significantly increase the oral bioavailability of some formulations of abiraterone acetate. Compared to administration in the fasted state, abiraterone peak plasma concentration (Cmax) and systemic exposure (AUC) were approximately 7- and 5-fold higher, respectively, when a single dose of abiraterone acetate was administered with a low-fat meal (7% fat; 300 calories) and approximately 17- and 10-fold higher, respectively, when it was administered with a high-fat meal (57% fat; 825 calories). Given the normal variation in the content and composition of meals, taking abiraterone acetate with meals has the potential to result in increased and highly variable exposures. The safety of these increased exposures during multiple dosing has not been assessed. However, the abiraterone acetate 125 mg tablet, commonly marketed as Yonsa, was found to have an approximately 6.5-fold higher Cmax and 4.4-fold higher AUC when a single dose of 500 mg (4 tablets) was administered with a high-fat meal (56% - 60% fat, 900 - 1000 calories) compared to overnight fasting in healthy volunteers. These differences were not considered clinically significant for this formulation.

MANAGEMENT: Some formulations of abiraterone acetate must be taken on an empty stomach. No food should be consumed for at least two hours before and one hour after the abiraterone acetate dose. However, the abiraterone acetate 125 mg tablet, commonly marketed as Yonsa, can be taken with or without food. The manufacturer's product labeling should be consulted for specific guidance.

Food prolongs the gastrointestinal absorption of selexipag. When taken with food, the time to peak concentration (Tmax) was delayed and peak plasma concentration (Cmax) was approximately 30% lower. Selexipag systemic exposure (AUC) and that of its active metabolite did not significantly change, however. Selexipag may be taken with or without food. Tolerability may be improved when taken with food.