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as well as clinical and laboratory monitoring may be appropriate for some drugs whenever lapatinib is added to or withdrawn from therapy.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: Alcohol may potentiate some of the pharmacologic effects of CNS-active agents. Use in combination may result in additive central nervous system depression and/or impairment of judgment, thinking, and psychomotor skills.

MANAGEMENT: Patients receiving CNS-active agents should be warned of this interaction and advised to avoid or limit consumption of alcohol. Ambulatory patients should be counseled to avoid hazardous activities requiring complete mental alertness and motor coordination until they know how these agents affect them, and to notify their physician if they experience excessive or prolonged CNS effects that interfere with their normal activities.

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.