Drug Interaction Report

MONITOR: Coadministration with sotorasib may increase the plasma concentrations of drugs that are substrates of the P-glycoprotein (P-gp) and/or breast cancer resistance protein (BCRP) membrane transporters. The proposed mechanism involves enhanced absorption and bioavailability of substrate drugs due to inhibition of intestinal P-gp- and BCRP-mediated efflux by sotorasib. Inhibition of P-gp and BCRP transport in other organs such as the liver and kidney may also contribute in some cases, especially for non-oral drugs. When digoxin, a sensitive P-gp substrate, was coadministered with sotorasib, digoxin peak plasma concentration (Cmax) and systemic exposure (AUC) increased by 91% and 21%, respectively. When rosuvastatin, a BCRP substrate, was coadministered with sotorasib, rosuvastatin Cmax and AUC increased by 70% and 34%, respectively.

MANAGEMENT: Caution is advised when sotorasib is used concurrently with drugs that are P-gp and/or BCRP substrates, particularly those with a narrow therapeutic range. The prescribing information recommends avoiding coadministration of sotorasib with P-gp and BCRP substrates for which minimal concentration changes may lead to serious toxicities. If coadministration is required, dosage adjustments as well as clinical and laboratory monitoring may be appropriate whenever sotorasib is added to or withdrawn from therapy. The prescribing information for concomitant medications should be consulted to assess the benefits versus risks of coadministration of a P-gp and BCRP inhibitor like sotorasib and for any dosage adjustments that may be required.

GENERALLY AVOID: Coadministration with large amounts of certain fruit juices, including grapefruit, orange and apple, may decrease the oral bioavailability of fexofenadine. The proposed mechanism is inhibition of drug efflux via intestinal organic anion transporting polypeptides (e.g., P-glycoprotein), of which fexofenadine is a substrate. In a five-way crossover study with 10 healthy volunteers, 1/4-strength grapefruit juice, grapefruit juice, orange juice and apple juice (300 mL with drug administration and 150 mL every 1/2 hour for up to 3 hours, total volume 1.2 L) reduced the mean area under the plasma concentration-time curve (AUC) of a 120 mg dose of fexofenadine by 23%, 67%, 72% and 77%, respectively, compared to water. Mean peak plasma concentration (Cmax) was similarly affected. The clinical significance of these changes is unknown. However, results from studies using histamine-induced skin wheals and flares found that the size of wheal and flare was significantly larger when fexofenadine was administered with either grapefruit or orange juices compared to water.

MANAGEMENT: To maximize plasma levels and therapeutic effects, fexofenadine should be taken with water. In addition, patients should refrain from consuming large amounts of grapefruit, orange, or apple juice.

Food does not appear to have a clinically significant effect on the oral bioavailability of sotorasib. When a 960 mg dose of sotorasib was administered to study patients with a high-fat, high-calorie meal (approximately 800 to 1000 calories; 150, 250, and 500 to 600 calories from protein, carbohydrate, and fat, respectively), sotorasib peak plasma concentration (Cmax) did not change while systemic exposure (AUC 0-24 hours) increased by 25% compared to administration under fasted conditions. Sotorasib can be administered with or without food at approximately the same time each day.