Drug Interaction Report

MONITOR: Nonclinical data indicate that the solubility of lapatinib is pH-dependent. Therefore, long-term suppression of gastric acid secretion by H2-receptor antagonists or proton pump inhibitors may reduce lapatinib systemic exposure. In study subjects, coadministration with the proton pump inhibitor esomeprazole (40 mg once daily for 7 days) decreased lapatinib exposure by an average of 27% (range 6% to 49%). This effect decreases with increasing age from approximately 40 to 60 years. The clinical significance is unknown.

MANAGEMENT: Caution may be advisable if lapatinib is used in combination with H2-receptor antagonists or proton pump inhibitors. Patients should be monitored for potentially reduced therapeutic response to lapatinib.

GENERALLY AVOID: Grapefruit juice may increase the plasma concentrations of lapatinib. The proposed mechanism is inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall by certain compounds present in grapefruits.

ADJUST DOSING INTERVAL: Food can significantly increase the oral bioavailability of lapatinib. According to the manufacturer, lapatinib peak plasma concentration (Cmax) was approximately 2.5- and 3-fold higher and systemic exposure (AUC) 3- and 4-fold higher when administered with a low fat meal (5% fat; 500 calories) or with a high-fat meal (50% fat; 1000 calories), respectively, compared to fasting. Dividing the daily dose also resulted in an approximately 2-fold higher systemic exposure at steady state compared to the same total dose administered once daily.

MANAGEMENT: Patients treated with lapatinib should preferably avoid the consumption of grapefruit or grapefruit juice. The manufacturer recommends that lapatinib be administered at least one hour before or one hour after a meal. The lapatinib dose is administered once daily and should not be divided.