Drug Interactions between ruxolitinib topical and zanubrutinib

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.

MONITOR CLOSELY: Smoking during treatment with topical ruxolitinib may increase the risk of major adverse cardiovascular events (MACE) and the risk of developing malignancies, including lymphomas. During clinical trials, patients who were current or past smokers and received oral Janus Kinase (JAK) inhibitors to treat inflammatory conditions had an additional increased risk of overall malignancies. Additionally, oral JAK inhibitors reportedly increase patients' risk of MACE, including cardiovascular death, myocardial infarction, and stroke, particularly in patients who are current or past smokers or patients with other cardiovascular risk factors.

MANAGEMENT: The potential risks and benefits of topical ruxolitinib should be carefully weighed prior to initiating therapy, particularly in patients with cardiovascular risk factors, as well as those with a history of malignancy, those who develop a malignancy while on treatment, and/or patients who are current or past smokers. Patients should be informed about the symptoms of serious cardiovascular events and the steps to take if they occur. The manufacturer recommends discontinuing topical ruxolitinib in patients who have experienced a myocardial infarction or stroke.