Drug Interaction Report

GENERALLY AVOID: Coadministration with potent inducers of CYP450 3A4, such as enzalutamide, may significantly decrease the plasma concentrations of lapatinib, which is primarily metabolized by the isoenzyme. In healthy subjects, administration of lapatinib in combination with the CYP450 3A4 inducer carbamazepine (100 mg twice daily for 3 days, then 200 mg twice daily for 14 days) resulted in a 72% reduction of lapatinib systemic exposure (AUC) compared to control. In addition, coadministration with inhibitors of CYP450 2C8 and/or 3A4 such as lapatinib may increase the plasma concentrations of enzalutamide, which is primarily metabolized by CYP450 2C8 to its pharmacologically active metabolite, N-desmethyl enzalutamide, and to a lesser extent by CYP450 3A4. In healthy volunteers, administration of a single 160 mg oral dose of enzalutamide following multiple oral doses of the potent CYP450 2C8 inhibitor gemfibrozil resulted in a 2.2-fold increase in the composite systemic exposure (AUC) of enzalutamide plus N-desmethyl enzalutamide, with minimal effect on the peak plasma concentration (Cmax). Administration following multiple oral doses of the potent CYP450 3A4 inhibitor itraconazole resulted in a 1.3-fold increase in the composite AUC of enzalutamide plus N-desmethyl enzalutamide, with no effect on the Cmax.

MANAGEMENT: The use of lapatinib in combination with a potent CYP450 3A4 inducer, such as enzalutamide, should generally be avoided. If concomitant use is unavoidable, some authorities recommend titrating the lapatinib dosage gradually from 1250 mg/day up to 4500 mg/day or 1500 mg/day up to 5500 mg/day depending on the indication and patient tolerability. Based on pharmacokinetic studies, this dosage is predicted to adjust the lapatinib systemic exposure (AUC) to the range observed without inducers (UK, US). However, clinical data are lacking. The dosage of lapatinib should be reduced over approximately 2 weeks to the indicated dosage following discontinuation of the potent CYP450 3A4 inducer. In addition, the pharmacologic response to enzalutamide should be monitored more closely whenever a CYP450 2C8 and/or 3A4 inhibitor, such as lapatinib, is added to or withdrawn from therapy, and the dosage adjusted as necessary. Patients should be advised to contact their physician if they experience increased side effects such as seizure, asthenia, fatigue, diarrhea, arthralgia, musculoskeletal pain, paresthesia, hot flushes, peripheral edema, headache, dizziness, insomnia, hematuria, anxiety, and hypertension.

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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.

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