Drug Interaction Report

MONITOR: Coadministration with berotralstat may increase the plasma concentrations and effects of drugs that are substrates of the efflux transporter P-glycoprotein (P-gp). The mechanism is decreased clearance due to inhibition of P-gp activity by berotralstat. The administration of a 300 mg dose of berotralstat (twice the recommended daily dose) increased the peak plasma concentration (Cmax) and systemic exposure (AUC) of the sensitive P-gp substrate digoxin, by approximately 1.6-fold and 1.5-fold, respectively. Clinical data are not available.

MANAGEMENT: Caution is advised when berotralstat is coadministered with drugs that are substrates of P-gp, particularly those with a narrow therapeutic index. This interaction has only been reported at twice the recommended daily dose of berotralstat. Clinical and laboratory monitoring should be considered following the initiation or discontinuation of berotralstat, and the individual dosage of the concomitant agents adjusted as needed.

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.

MONITOR: Coadministration of two or more sympathomimetic agents may increase the risk of adverse effects such as nervousness, irritability, and increased heart rate. Central nervous system (CNS) stimulants, particularly amphetamines, can potentiate the adrenergic response to vasopressors and other sympathomimetic agents. Additive increases in blood pressure and heart rate may occur due to enhanced peripheral sympathetic activity.

MANAGEMENT: Caution is advised if two or more sympathomimetic agents are coadministered. Pulse and blood pressure should be closely monitored.