Drug Interaction Report

MONITOR: Coadministration with inhibitors of CYP450 3A4 that can also inhibit P-glycoprotein (P-gp) may increase the plasma concentrations of futibatinib. Futibatinib is a substrate of both the CYP450 3A4 isoenzyme and P-gp efflux transporter. Drug interaction studies have shown that single dose administration of futibatinib with multiple doses of itraconazole, a combined potent P-gp and CYP450 3A4 inhibitor, increased futibatinib peak plasma concentration (Cmax) and systemic exposure (AUC) by 51% and 41%, respectively, compared to futibatinib alone. Increased exposure to futibatinib may increase the risk and severity 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. The interaction has not been studied with other, less potent dual inhibitors of CYP450 3A4 and P-gp.

MANAGEMENT: Caution is advised when futibatinib is used with inhibitors of CYP450 3A4 that can also inhibit P-gp. Clinical and laboratory monitoring for the development of adverse effects is recommended and the futibatinib dosage adjusted as necessary.

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.

GENERALLY AVOID: Grapefruit juice may increase the plasma concentrations of ivacaftor. The proposed mechanism is inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall by certain compounds present in grapefruit. Elexacaftor and tezacaftor are also CYP450 3A4 substrates in vitro and may interact similarly with grapefruit juice, whereas lumacaftor is not expected to interact.

ADJUST DOSING INTERVAL: According to prescribing information, systemic exposure to ivacaftor increased approximately 2.5- to 4-fold, systemic exposure to elexacaftor increased approximately 1.9- to 2.5-fold, and systemic exposure to lumacaftor increased approximately 2-fold following administration with fat-containing foods relative to administration in a fasting state. Tezacaftor exposure is not significantly affected by administration of fat-containing foods.

MANAGEMENT: Patients treated with ivacaftor-containing medications should avoid consumption of grapefruit juice and any food that contains grapefruit or Seville oranges. All ivacaftor-containing medications should be administered with fat-containing foods such as eggs, avocados, nuts, meat, butter, peanut butter, cheese pizza, and whole-milk dairy products. A typical cystic fibrosis diet will satisfy this requirement.