Drug Interaction Report

MONITOR: Coadministration with lapatinib may increase the plasma concentrations of drugs that are substrates of the CYP450 2C8 isoenzyme, CYP450 3A4 isoenzyme, and/or P-glycoprotein (P-gp) efflux transporter. The mechanism is decreased clearance via these routes due to inhibition by lapatinib. In cancer patients treated with lapatinib and paclitaxel, a CYP450 2C8 and P-gp substrate, 24-hour systemic exposure (AUC) of paclitaxel was increased by 23%. This increase may have been underestimated from the in vivo evaluation due to study design limitations. Lapatinib also increased the 24-hour AUC of midazolam, a CYP450 3A4 probe substrate, by 45% when midazolam was administered orally and 22% when administered intravenously. Likewise, lapatinib increased the AUC of single-dose digoxin, a P-gp probe substrate, by approximately 2.8-fold.

MANAGEMENT: Caution is advised if lapatinib must be used concurrently with medications that are substrates of the CYP450 2C8 isoenzyme, CYP450 3A4 isoenzyme, and/or P-gp efflux transporter, particularly those with a narrow therapeutic range. Dosage adjustments as well as clinical and laboratory monitoring may be appropriate for some drugs whenever lapatinib is added to or withdrawn from therapy.

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.