Drug Interaction Report

MONITOR: Coadministration with futibatinib may increase the plasma concentrations of drugs that are substrates of the P-glycoprotein (P-gp) and/or breast cancer resistance protein (BCRP) efflux transporters. The proposed mechanism, based on in vitro data, involves decreased clearance due to inhibition of P-gp and BCRP by futibatinib. The clinical relevance is unknown.

MANAGEMENT: Caution is advised with the concomitant use of futibatinib with drugs that are P-gp and/or BCRP substrates, particularly narrow therapeutic index drugs. More frequent monitoring for increased adverse reactions of these drugs and dose adjustments as per their product labeling should be considered.

GENERALLY AVOID: Grapefruit juice may increase the plasma concentrations of futibatinib. The proposed mechanism is inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall by certain compounds present in grapefruit. In general, the effect of grapefruit juice is concentration-, dose- and preparation-dependent, and can vary widely among brands. Certain preparations of grapefruit juice (e.g., high dose, double strength) have sometimes demonstrated potent inhibition of CYP450 3A4, while other preparations (e.g., low dose, single strength) have typically demonstrated moderate inhibition. Increased exposure to futibatinib may increase the risk of adverse effects such as retinal pigment epithelial detachment, dry eye/corneal keratitis, pyrexia, hyperphosphatemia and soft tissue mineralization, palmar-plantar erythrodysesthesia syndrome, fatigue, nail toxicity, urinary tract infection, constipation, diarrhea, dry mouth, increased liver function tests (ALT and AST), stomatitis, abdominal pain, ascites, bile duct obstruction, and musculoskeletal pain.

MANAGEMENT: Patients should be advised to avoid consumption of grapefruit or grapefruit juice during treatment with futibatinib.

Administration of digoxin with a high-fiber meal has been shown to decrease its bioavailability by almost 20%. Fiber can sequester up to 45% of the drug when given orally. Patients should be advised to maintain a regular diet without significant fluctuation in fiber intake while digoxin is being titrated.

Grapefruit juice may modestly increase the plasma concentrations of digoxin. The mechanism is increased absorption of digoxin due to mild inhibition of intestinal P-glycoprotein by certain compounds present in grapefruits. In 12 healthy volunteers, administration of grapefruit juice with and 30 minutes before, as well as 3.5, 7.5, and 11.5 hours after a single digoxin dose (0.5 mg) increased the mean area under the plasma concentration-time curve (AUC) of digoxin by just 9% compared to administration with water. Moreover, P-glycoprotein genetic polymorphism does not appear to influence the magnitude of the effects of grapefruit juice on digoxin. Thus, the interaction is unlikely to be of clinical significance.