Drug Interaction Report

MONITOR: Coadministration with tovorafenib may decrease the plasma concentrations of drugs that are substrates of CYP450 3A4. The proposed mechanism is increased clearance due to tovorafenib-mediated induction of CYP450 3A4 metabolism. According to the manufacturer, tovorafenib is predicted to decrease the peak plasma concentration (Cmax) and systemic exposure (AUC) of sensitive 3A4 substrate midazolam by at least 20%. However, data from formal clinical drug interaction studies are not available.

MANAGEMENT: Caution is recommended with the concomitant use of tovorafenib and CYP450 3A4 substrates. In particular, the manufacturer of tovorafenib advises that concomitant use with sensitive CYP450 3A4 substrates with narrow therapeutic ranges should generally be avoided. If coadministration is required, patients should be monitored carefully for potential loss of therapeutic effects.

Although they are often combined in clinical practice, the concomitant use of beta-2 adrenergic agonists and corticosteroids may result in additive hypokalemic effects. Since beta-2 agonists can sometimes cause QT interval prolongation, the development of hypokalemia may potentiate the risk of ventricular arrhythmias including torsade de pointes. However, clinical data are limited, and the potential significance is unknown. Patients who are receiving systemic or nebulized formulations of beta-2 agonists, high dosages of inhaled beta-2 agonists, or systemic corticosteroid therapy may be at a greater risk of developing hypokalemia.