Drug Interaction Report

MONITOR: Coadministration of alpelisib with inducers of CYP450 3A4 may reduce the plasma concentrations of alpelisib. The proposed mechanism, based on in vitro data, is increased clearance due to induction of CYP450 3A4, which is one of the routes of metabolism of alpelisib. According to the manufacturer, therapeutic efficacy of alpelisib may be reduced in the presence of potent CYP450 3A4 inducers; however, clinical data are lacking. Data are not available for mild to moderate CYP450 3A4 inducers.

MANAGEMENT: Caution is recommended when alpelisib is used with CYP450 3A4 inducers. Pharmacologic effects of alpelisib should be monitored more closely whenever the inducer is added to or withdrawn from therapy.

GENERALLY AVOID: Concurrent acute use of barbiturates and ethanol may result in additive CNS effects, including impaired coordination, sedation, and death. Tolerance of these agents may occur with chronic use. The mechanism is related to inhibition of microsomal enzymes acutely and induction of hepatic microsomal enzymes chronically.

MANAGEMENT: The combination of ethanol and barbiturates should be avoided.

ADJUST DOSING INTERVAL: Food significantly enhances the oral absorption and bioavailability of alpelisib. When administered with a high-fat high-calorie meal (985 calories with 58.1 g of fat) or a low-fat low-calorie meal (334 calories with 8.7 g of fat) the AUC and Cmax of a single dose of alpelisib was increased by 73% and 84% and 77% and 145%, respectively. There were no clinically significant differences in alpelisib AUC between the two types of meals. In addition, food appears to have a more pronounced effect on the solubility of alpelisib than gastric pH. When coadministered with a single 300 mg dose of alpelisib, ranitidine decreased the absorption and overall exposure of alpelisib. Following administration of ranitidine with a low-fat low-calorie meal, the mean AUC and Cmax of alpelisib was decreased by 21% and 36%, respectively. Administration of ranitidine under fasting conditions reduced the mean AUC and Cmax of alpelisib by 30% and 51%, respectively.

MANAGEMENT: To ensure maximal oral absorption, alpelisib should be administered with a meal.