Drug Interaction Report

MONITOR: Coadministration with inhibitors of CYP450 3A4 and/or P-glycoprotein (P-gp) may increase the plasma concentrations of cobimetinib, which is a substrate of both the isoenzyme and the efflux transporter. In 15 healthy volunteers given a single 10 mg dose of cobimetinib with the potent CYP450 3A4 and P-gp inhibitor itraconazole (200 mg once daily for 14 days), mean cobimetinib peak plasma concentration (Cmax) and systemic exposure (AUC) increased by 3.2- and 6.7-fold, respectively, compared to cobimetinib administered alone. Simulations using physiologically-based pharmacokinetic (PBPK) models suggest that steady-state concentrations of cobimetinib given at a reduced dose of 20 mg with short-term (less than 14 days) use of a moderate CYP450 3A4 inhibitor would be similar to steady-state concentrations observed following a 60 mg dose given alone.

MANAGEMENT: Caution is advised when cobimetinib is prescribed with CYP450 3A4 and/or P-gp inhibitors. Patients should be monitored for adverse effects such as diarrhea, nausea, vomiting, stomatitis, hemorrhage, cardiomyopathy, rash, photosensitivity, retinopathy, retinal vein occlusion, liver enzyme abnormalities and rhabdomyolysis, and the cobimetinib dosage adjusted accordingly or treatment discontinued as necessary.

MONITOR: Grapefruit juice may increase the plasma concentrations of orally administered drugs that are substrates of the CYP450 3A4 isoenzyme, such as cobimetinib. However, the interaction seems to affect primarily those drugs that undergo significant presystemic metabolism by CYP450 3A4 (i.e., drugs with low oral bioavailability), presumably due to the fact that grapefruit juice inhibits primarily intestinal rather than hepatic CYP450 3A4. Because pharmacokinetic interactions involving grapefruit juice are often subject to a high degree of interpatient variability, the extent to which a given patient may be affected is difficult to predict.

MANAGEMENT: Patients who regularly consume grapefruit or grapefruit juice should be monitored for adverse effects and altered plasma concentrations of cobimetinib. Grapefruit and grapefruit juice should be avoided if an interaction is suspected. Orange juice is not expected to interact with these drugs.

MONITOR: Smoking during treatment with abrocitinib may increase the risk of major adverse cardiovascular events (MACE) and the risk of developing malignancies. During abrocitinib clinical studies, current or past smokers had an additional increased risk of overall malignancies. Also, abrocitinib may increase patients' risk of MACE, including myocardial infarction, stroke, and cardiovascular death.

Administration of abrocitinib with high-fat, high-calorie food increased abrocitinib peak plasma concentration (Cmax) and systemic exposure (AUC) by 29% and 26%, respectively, and prolonged the time to reach Cmax by 2 hours. These changes are not considered clinically relevant.

MANAGEMENT: Caution is advised if abrocitinib is prescribed to 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 abrocitinib in patients that have experienced a myocardial infarction or stroke. Abrocitinib may be taken with or without food.