Drug Interactions between methotrimeprazine and pitolisant

ADJUST DOSE: Coadministration with strong inhibitors of CYP450 2D6 may increase plasma concentrations of pitolisant. The proposed mechanism is decreased clearance of pitolisant due to inhibition of its metabolism via this isoenzyme. Coadministration with the strong CYP450 2D6 inhibitor paroxetine was reported to increase the mean peak plasma concentration (Cmax) of pitolisant by approximately 47% and result in a 2-fold increase in its systemic exposure. Clinically, high plasma levels of pitolisant may increase the risk of QT interval prolongation, which has been associated with ventricular arrhythmias including torsade de pointes and sudden death.

MANAGEMENT: A dosage reduction is recommended for pitolisant during coadministration with strong inhibitors of CYP450 2D6. For patients receiving a strong CYP450 2D6 inhibitor, the dose of pitolisant should be initiated at 8.9 mg once daily and increased after 7 days to a maximum dosage of 17.8 mg once daily. For patients already receiving a stable dose of pitolisant, the dose of pitolisant should be reduced by half when initiating treatment with a strong CYP450 2D6 inhibitor. Patients should be monitored for clinical response and increased adverse effects such as headache, insomnia, nausea, anxiety, increased heart rate, QT prolongation, hallucinations, abdominal pain, upper respiratory tract infections, and musculoskeletal pain.