Drug Interaction Report

MONITOR: Coadministration with alpelisib may decrease the plasma concentrations and therapeutic effects of drugs that are substrates of CYP450 2C9, such as warfarin. The proposed mechanism, based on in vitro data, is increased clearance due to alpelisib-mediated induction of CYP450 2C9.

MANAGEMENT: Patient monitoring is recommended if alpelisib is used concomitantly with drugs that are substrates of CYP450 2C9, particularly those with a narrow therapeutic range. The potential for diminished therapeutic effects should be considered when alpelisib is prescribed in combination with drugs that are CYP450 2C9 substrates. Dosage adjustments as well as clinical and laboratory monitoring should be considered whenever alpelisib is added to or withdrawn from therapy with these drugs. An alternative agent with no or minimal CYP450 2C9-inducing activity may also be considered.

GENERALLY AVOID: Alcohol may potentiate some of the pharmacologic effects of ramelteon. Use in combination may result in additive central nervous system depression and/or impairment of judgment, thinking, and psychomotor skills.

ADJUST DOSING INTERVAL: Administration of ramelteon with or immediately after a high-fat/heavy meal may delay the onset of hypnotic effects. In study subjects, administration of a 16 mg dose of ramelteon with a high-fat meal decreased the peak plasma drug concentration (Cmax) by 22% and delayed the median time to reach peak plasma drug concentration (Tmax) by approximately 45 minutes compared to administration in a fasted state.

MANAGEMENT: Patients receiving ramelteon should be advised to avoid the consumption of alcohol. For faster sleep onset, ramelteon should not be administered with or immediately after a high-fat/heavy meal.

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.