Drug Interaction Report

GENERALLY AVOID: Coadministration with potent inducers of CYP450 3A4 that also induce P-glycoprotein (P-gp) may significantly decrease the plasma concentrations of futibatinib, which is a substrate of both the isoenzyme and the efflux transporter. Drug interaction studies have shown single dose administration of futibatinib with multiple doses of rifampin, a combined P-gp and potent CYP450 3A4 inducer, decreased futibatinib peak plasma concentration (Cmax) and systemic exposure (AUC) by 53% and 64%, respectively, compared to futibatinib alone. Reduced efficacy of futibatinib may occur.

MANAGEMENT: Concomitant use of futibatinib with combined P-gp and potent CYP450 3A4 inducers should generally be avoided.

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: Concurrent use of rifampin in patients who ingest alcohol daily may result in an increased incidence of hepatotoxicity. The increase in hepatotoxicity may be due to an additive risk as both alcohol and rifampin are individually associated with this adverse reaction. However, the exact mechanism has not been established.

ADJUST DOSING INTERVAL: Administration with food may reduce oral rifampin absorption, increasing the risk of therapeutic failure or resistance. In a randomized, four-period crossover phase I study of 14 healthy male and female volunteers, the pharmacokinetics of single dose rifampin 600 mg were evaluated under fasting conditions and with a high-fat meal. Researchers observed that administration of rifampin with a high-fat meal reduced rifampin peak plasma concentration (Cmax) by 36%, nearly doubled the time to reach peak plasma concentration (Tmax) but reduced overall exposure (AUC) by only 6%.

MANAGEMENT: The manufacturer of oral forms of rifampin recommends administration on an empty stomach, 30 minutes before or 2 hours after meals. Patients should be encouraged to avoid alcohol or strictly limit their intake. Patients who use alcohol and rifampin concurrently or have a history of alcohol use disorder may require additional monitoring of their liver function during treatment with rifampin.