Drug Interaction Report

Coadministration with inhibitors of P-glycoprotein (P-gp) may increase the plasma concentrations of fidaxomicin and its main metabolite, OP-1118, both of which are substrates of the intestinal efflux transporter. When fidaxomicin 200 mg was administered in combination with cyclosporine 200 mg in 14 study subjects, fidaxomicin peak plasma concentration (Cmax) and systemic exposure (AUC) increased by an average of 4.2- and 1.9-fold, respectively, compared to when administered alone. The Cmax and AUC of OP-1118 was increased by 9.5- and 4.1-fold, respectively, with cyclosporine. Theoretically, concentrations of fidaxomicin and OP-1118 may also be decreased at the site of action (i.e., gastrointestinal tract) due to P-gp inhibition. However, concomitant use of a P-gp inhibitor had no attributable effect on safety or efficacy of fidaxomicin in controlled clinical trials. No dosage adjustment is recommended when fidaxomicin is coadministered with P-gp inhibitors.

ADJUST DOSING INTERVAL: Food may alter the oral bioavailability of cabozantinib. When healthy subjects were given a single 140 mg oral dose with a high-fat meal, cabozantinib peak plasma concentration (Cmax) and systemic exposure (AUC) increased by 41% and 57%, respectively, relative to administration under fasting conditions. In clinical studies, patients were administered cabozantinib without food.

GENERALLY AVOID: Coadministration with grapefruit juice is likely to increase the plasma concentrations of cabozantinib, which is primarily metabolized by CYP450 3A4. However, the interaction has not been studied. The proposed mechanism is inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall by certain compounds present in grapefruit.

MANAGEMENT: Cabozantinib should be administered at least one hour before or two hours after a meal. The consumption of grapefruit, grapefruit juice, and supplements that contain grapefruit extract should be avoided.