Drug Interactions between belzutifan and fluoxetine / olanzapine

MONITOR CLOSELY: Coadministration of belzutifan with inhibitors of uridine diphosphate glucuronosyltransferase 2B17 (UGT2B17) and/or CYP450 2C19 may increase the plasma concentrations and the risk and severity of adverse effects, including anemia and hypoxia, of belzutifan. The proposed mechanism is inhibition of UGT 2B17 and/or CYP450 2C19, the isoenzymes responsible for the metabolic clearance of belzutifan. Patients who are dual UGT 2B17 and CYP450 2C19 poor metabolizers are at a greater risk of adverse reactions.

MANAGEMENT: Close monitoring is recommended whenever belzutifan is used concomitantly with a UGT 2B17 and/or CYP450 2C19 inhibitor. Clinical and laboratory monitoring should be considered whenever a UGT 2B17 and/or CYP450 2C19 inhibitor is added to or withdrawn from therapy with belzutifan, and the dosage adjusted as necessary. Consult the manufacturer's product labeling for specific dose adjustment recommendations. Patients should be monitored for development of anemia and hypoxia.

MONITOR: It is uncertain whether olanzapine causes clinically significant prolongation of the QT interval. In pooled studies of adults as well as pooled studies of adolescents, there were no significant differences between olanzapine and placebo in the proportion of patients experiencing potentially important changes in ECG parameters, including QT, QTcF (Fridericia-corrected), and PR intervals. In clinical trials, clinically meaningful QTc prolongations (QTcF >=500 msec at any time post-baseline in patients with baseline QTcF <500 msec) occurred in 0.1% to 1% of patients treated with olanzapine, with no significant differences in associated cardiac events compared to placebo. Published studies have generally reported no significant effect of olanzapine on QTc interval, although both QTc prolongation and QTc shortening have also been reported. There have been a few isolated case reports of QT prolongation in patients receiving olanzapine. However, causality is difficult to establish due to confounding factors such as concomitant use of drugs that cause QT prolongation and underlying conditions that may predispose to QT prolongation (e.g., hypokalemia, congenital long QT syndrome, preexisting conduction abnormalities).

MANAGEMENT: Some authorities recommend caution when olanzapine is used with drugs that are known to cause QT prolongation. ECG monitoring may be advisable in some cases, such as in patients with a history of cardiac arrhythmias or congenital or family history of long QT syndrome. Patients should be advised to seek prompt medical attention if they experience symptoms that could indicate the occurrence of torsade de pointes such as dizziness, lightheadedness, fainting, palpitation, irregular heart rhythm, shortness of breath, or syncope.