Drug Interaction Report

MONITOR CLOSELY: Coadministration of regorafenib and drugs that interfere with platelet function or coagulation may potentiate the risk of bleeding complications. Treatment with regorafenib is associated with a high frequency of hemorrhage and thrombocytopenia. In one study, the overall incidence of hemorrhage (grades 1 to 5) was 21% in regorafenib-treated patients compared to 8% in placebo-treated patients, and the incidence of thrombocytopenia was 41% versus 17%. Fatal hemorrhage occurred in 4 of 500 (0.8%) patients receiving regorafenib and involved the respiratory, gastrointestinal, or genitourinary tracts.

GENERALLY AVOID: Coadministration of regorafenib with strong UGT1A9 inhibitors such as mefenamic acid or diflunisal may theoretically increase systemic exposure to regorafenib.

MANAGEMENT: Concomitant use of other medications that interfere with platelet function or coagulation should be considered cautiously in patients treated with regorafenib. Close clinical and laboratory observation for bleeding complications is recommended during therapy. The INR should be monitored more frequently during coadministration of warfarin. Patients should be advised to promptly report any signs of bleeding to their physician, including pain, swelling, headache, dizziness, weakness, prolonged bleeding from cuts, increased menstrual flow, vaginal bleeding, nosebleeds, bleeding of gums from brushing, unusual bleeding or bruising, red or brown urine, or red or black stools. According to European labeling, concomitant use of regorafenib with mefenamic acid or diflunisal should be avoided.

GENERALLY AVOID: Grapefruit and/or grapefruit juice may increase the plasma concentrations of zanubrutinib. 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 has been reported for other CYP450 3A4 inhibitors. When zanubrutinib was administered with the potent CYP450 3A4 inhibitor itraconazole (200 mg once daily) in clinical study subjects, zanubrutinib peak plasma concentration (Cmax) and systemic exposure (AUC) increased by 157% and 278%, respectively. Data derived from pharmacokinetic modeling have also been reported for several additional CYP450 3A4 inhibitors. For example, the potent CYP450 3A4 inhibitor clarithromycin (250 mg twice daily) is predicted to increase zanubrutinib Cmax and AUC by 175% and 183%, respectively. The moderate CYP450 3A4 inhibitor diltiazem (60 mg three times daily) is predicted to increase zanubrutinib Cmax and AUC by 151% and 157%, respectively. Another moderate CYP450 3A4 inhibitor, erythromycin (500 mg four times daily), is predicted to increase zanubrutinib Cmax and AUC by 284% and 317%, respectively. Likewise, fluconazole 200 mg once daily is predicted to increase zanubrutinib Cmax and AUC by 179% and 177%, respectively; while fluconazole 400 mg once daily is predicted to increase zanubrutinib Cmax and AUC by 270% and 284%, respectively. In general, the effects of grapefruit products are concentration-, dose- and preparation-dependent, and can vary widely among brands. Certain preparations of grapefruit (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 zanubrutinib exposure may potentiate the risk of toxicities such as hemorrhage, infection, cytopenias, malignancies, and serious cardiac arrhythmias (primarily atrial fibrillation and atrial flutter).

Food does not affect the oral bioavailability of zanubrutinib. No clinically significant differences in zanubrutinib Cmax or AUC were observed following administration of a high-fat meal (approximately 1000 calories; 50% from fat) in healthy subjects.

MANAGEMENT: Zanubrutinib may be administered with or without food. Patients should avoid consumption of grapefruit, grapefruit juice, Seville oranges, and Seville orange juice during treatment with zanubrutinib.

ADJUST DOSING INTERVAL: Depending on the amount of fat, food may enhance the oral bioavailability of both regorafenib and its active metabolites, M-2 and M-5. In 24 healthy male subjects, administration of regorafenib with a high-fat meal (945 calories; 54.6 g fat) increased the mean systemic exposure (AUC) of regorafenib by 48% but decreased the mean AUC of M-2 and M-5 by 20% and 51%, respectively, compared to administration under the fasted state. In contrast, administration with a low-fat meal (319 calories; 8.2 g fat) increased the mean AUC of regorafenib, M-2 and M-5 by 36%, 40% and 23%, respectively, compared to administration during fasting.

GENERALLY AVOID: Coadministration with grapefruit juice may alter the pharmacokinetics of regorafenib and its active metabolites. The proposed mechanism is inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall by certain compounds present in grapefruit. The interaction has not been studied specifically with grapefruit juice, but has been reported with the potent CYP450 3A4 inhibitor, ketoconazole. In 18 healthy male study subjects, administration of a single 160 mg dose of regorafenib on day 5 of treatment with ketoconazole (400 mg daily for 18 days) resulted in a 33% increase in mean regorafenib systemic exposure (AUC) compared to administration of regorafenib alone. Additionally, there was a 93% decrease each in the mean AUC of the M-2 and M-5 metabolites. Both have been shown to have similar in vitro pharmacological activity and steady-state concentrations as regorafenib, thus the net clinical effect of these pharmacokinetic changes is unknown.

MANAGEMENT: To ensure optimal oral absorption, regorafenib should be administered with a low-fat breakfast that contains less than 30% fat. Examples of a low-fat breakfast include: 2 slices of white toast with 1 tablespoon of low-fat margarine and 1 tablespoon of jelly, plus 8 ounces of skim milk (319 calories; 8.2 g fat); or 1 cup of cereal, 8 ounces of skim milk, 1 slice of toast with jam, apple juice, and 1 cup of coffee or tea (520 calories; 2 g fat). Patients should be advised to avoid consuming grapefruit or grapefruit juice during treatment with regorafenib.