Drug Interactions between amiodarone and infigratinib

GENERALLY AVOID: Grapefruit juice may significantly increase the plasma concentrations of orally administered amiodarone. The proposed mechanism is inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall by certain compounds present in grapefruits. In 11 nonsmoking, healthy volunteers, grapefruit juice (300 mL with drug administration, then 3 hours and 9 hours later) increased the mean peak plasma concentration (Cmax) and area under the concentration-time curve (AUC) of amiodarone (17 mg/kg single dose) by 84% and 50%, respectively, compared to water. Formation of the pharmacologically active metabolite, N-desethylamiodarone (N-DEA), was completely inhibited. Clinically, this interaction can lead to altered efficacy of amiodarone, since antiarrhythmic properties of amiodarone and N-DEA appear to differ. In the study, mean increases in PR and QTc intervals of 17.9% and 11.3%, respectively, were observed 6 hours postdose with water, while increases of 10.2% and 3.3%, respectively, were observed after administration with grapefruit juice.

ADJUST DOSING INTERVAL: Food increases the rate and extent of absorption of amiodarone. The mechanism appears to involve the effect of food-induced physiologic changes on drug release from its formulation. In 30 healthy volunteers, administration of a single 600 mg dose of amiodarone following a high-fat meal resulted in a Cmax and AUC that were 3.8 and 2.4 times the respective values under fasting conditions. The time to reach peak plasma concentration (Tmax) was decreased by 37%, indicating an increased rate of absorption. Mean Cmax and AUC for the active metabolite, N-DEA, also increased by 32% and 55%, respectively, but there was no change in the Tmax.

MANAGEMENT: Patients treated with oral amiodarone should avoid consumption of grapefruits and grapefruit juice. In addition, oral amiodarone should be administered consistently with regard to meals.

ADJUST DOSING INTERVAL: Food may increase the oral bioavailability of infigratinib. Coadministration with a high-fat, high-calorie meal (800 to 1,000 calories, with approximately 50% of total calories from fat) in healthy subjects increased mean infigratinib peak plasma concentration (Cmax) and total systemic exposure (AUC) by 60% to 80% and 80% to 120%, respectively, and increased the median time to Cmax from 4 hours to 6 hours. When coadministered with a low-fat, low-calorie meal (approximately 330 calories, with 20% of total calories from fat), mean infigratinib Cmax and AUC increased by 90% and 70%, respectively, while the median time to Cmax did not change.

GENERALLY AVOID: Grapefruit juice may increase the plasma concentrations of infigratinib and one of its active metabolites, BHS697, both of which are primarily metabolized by CYP450 3A4 in vitro. The proposed mechanism is inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall by certain compounds present in grapefruit. Inhibition of hepatic CYP450 3A4 may also contribute. The interaction has not been studied with grapefruit juice but has been reported for other CYP450 3A4 inhibitors. Coadministration of infigratinib with multiple doses of itraconazole, a potent CYP450 3A4 inhibitor, increased infigratinib peak plasma concentration (Cmax) and total systemic exposure (AUC) by 164% and 622%, respectively, and the AUC for the active metabolite, BHS697, by 174%. 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 infigratinib and BHS697 may increase the incidence and severity of serious adverse reactions such as infections, anemia, pyrexia, abdominal pain, hypercalcemia, hyperphosphatemia, ocular toxicity (e.g., retinal pigment epithelial detachment), sepsis, stomatitis, diarrhea, palmar-plantar erythrodysesthesia syndrome, increased blood creatinine, increased lipase, and onycholysis.

MANAGEMENT: Infigratinib should be administered on an empty stomach at least one hour before or two hours after food. Patients should avoid consumption of grapefruit, grapefruit juice, or supplements that contain grapefruit during treatment with infigratinib.