Drug Interactions between capivasertib and ruxolitinib topical

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.

GENERALLY AVOID: Grapefruit juice may increase the plasma concentrations of capivasertib, which is primarily metabolized by CYP450 3A4. 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 studied with other CYP450 3A4 inhibitors. Based on clinical studies and model-informed approaches, concomitant use with the potent CYP450 3A4 inhibitor itraconazole is predicted to increase capivasertib systemic exposure (AUC) by up to 1.7-fold and peak plasma concentration (Cmax) by up to 1.4-fold. Coadministration with the moderate CYP450 3A4 inhibitors erythromycin and verapamil is predicted to increase the AUC and Cmax of capivasertib by up to 1.5-fold 1.3-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 capivasertib may increase the risk of adverse effects such as diarrhea, cutaneous adverse reactions, decreased lymphocytes, decreased hemoglobin, hyperglycemia, nausea, and fatigue.

MANAGEMENT: It may be advisable for patients to avoid the consumption of grapefruit, grapefruit juice, or supplements that contain grapefruit during treatment with capivasertib.