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Do not consume grapefruit or grapefruit juice during treatment with entrectinib. Doing so can significantly increase the blood levels of entrectinib and increase the risk and/or severity of side effects such as dizziness; confusion; hallucinations; problems with concentration, attention, thinking, and memory; mood changes; insomnia; drowsiness; liver problems; increased uric acid levels in the blood (hyperuricemia); congestive heart failure; fluid retention and swelling; changes in electrical activity of the heart (a condition known as QT prolongation, which may lead to irregular heart rhythm that can be life-threatening); vision problems; and low red or white blood cell counts. Talk to your doctor if you have any questions or concerns. It is important to tell your doctor about all other medications you use, including vitamins and herbs. Do not stop using any medications without first talking to your doctor.

GENERALLY AVOID: Grapefruit juice may increase the plasma concentrations of entrectinib. The proposed mechanism is inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall by certain compounds present in grapefruit. Inhibition of hepatic CYP450 3A4 may also contribute. The interaction has not been studied with grapefruit juice, but pharmacokinetic data are available for the potent CYP450 3A4 inhibitor, itraconazole. When a single 100 mg dose of entrectinib was administered with itraconazole, entrectinib peak plasma concentration (Cmax) and systemic exposure (AUC) increased by 1.7- and 6-fold, respectively. Coadministration of entrectinib with a moderate CYP450 3A4 inhibitor is predicted to increase entrectinib Cmax and AUC by 2.9- and 3-fold, respectively. In general, the effect of grapefruit juice is concentration-, dose- and preparation-dependent, and can vary widely among brands. Certain preparations of grapefruit juice (e.g., high dose, double strength) have sometimes demonstrated potent inhibition of CYP450 3A4, while other preparations (e.g., low dose, single strength) have typically demonstrated moderate inhibition. Increased exposure to entrectinib may increase the risk and/or severity of adverse effects such as cognitive impairment, mood disorders, dizziness, sleep disturbances, liver enzyme elevations, hyperuricemia, congestive heart failure, edema, myocarditis, QT prolongation, vision problems, anemia, and neutropenia.

MANAGEMENT: Patients should avoid consumption of grapefruit and grapefruit juice during treatment with entrectinib.