Drug Interaction Report

Coadministration with inhibitors of CYP450 3A4 and/or P-glycoprotein may increase the systemic exposure to indacaterol following oral inhalation, as it is a substrate of both the isoenzyme and efflux transporter. When a single 300 mcg dose of indacaterol inhalation powder was administered in combination with the potent dual CYP450 3A4/P-glycoprotein inhibitor, ketoconazole (200 mcg twice daily for 7 days), indacaterol peak plasma concentration (Cmax) and systemic exposure (AUC) increased by 1.3- and 1.9-fold, respectively. These changes probably reflect the impact of maximal combined inhibition. Similarly, verapamil 80 mg three times a day for 4 days increased indacaterol Cmax by 1.5-fold and AUC by 2-fold, while erythromycin 400 mg four times a day for 7 days increased indacaterol Cmax by 1.2-fold and AUC by 1.4-fold. Ritonavir 300 mg twice daily for 7.5 days had no effect on the Cmax of indacaterol, but increased its AUC by 1.7-fold. Indacaterol oral inhalation powder has been evaluated in clinical trials for up to one year at doses up to 600 mcg. No dosage adjustment is necessary at the 75 mcg dose when used with CYP450 3A4 and P-glycoprotein inhibitors.

GENERALLY AVOID: Grapefruit and/or grapefruit juice may increase the systemic exposure to palbociclib. The proposed mechanism is inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall by certain compounds present in grapefruit. Increased exposure to palbociclib may increase the risk of adverse effects such as infections, neutropenia, leukopenia, anemia, thrombocytopenia, anorexia, nausea, vomiting, diarrhea, stomatitis, alopecia, asthenia, peripheral neuropathy, and epistaxis.

ADJUST DOSING INTERVAL: Food may enhance the oral bioavailability of palbociclib capsules and reduce the intersubject variability of palbociclib exposure. According to the product labeling, absorption and exposure of palbociclib from its oral capsule formulation were very low in approximately 13% of the population when taken in the fasted state. Food intake increased the palbociclib exposure in this small subset of the population but did not alter exposure in the rest of the population to a clinically relevant extent. Compared to palbociclib capsules given under overnight fasted conditions, the population average palbociclib peak plasma concentration (Cmax) and systemic exposure (AUC) increased by 38% and 21%, respectively, when given with high-fat, high-calorie food (approximately 800 to 1000 calories; 150, 250, and 500 to 600 calories from protein, carbohydrate and fat, respectively); by 27% and 12%, respectively, when given with low-fat, low-calorie food (approximately 400 to 500 calories; 120, 250, and 28 to 35 calories from protein, carbohydrate and fat, respectively); and by 24% and 13%, respectively, when given with moderate-fat, standard calorie food (approximately 500 to 700 calories; 75 to 105, 250 to 350 and 175 to 245 calories from protein, carbohydrate and fat, respectively) one hour before and two hours after palbociclib capsule dosing.

MANAGEMENT: Patients should avoid consumption of grapefruit or grapefruit juice while on treatment with palbociclib. To avoid variability in drug absorption between doses, palbociclib capsules should be taken with food. Palbociclib tablet formulations may be taken with or without food.