Drug Interactions between atazanavir / cobicistat and pitolisant

MONITOR: Coadministration with pitolisant may decrease the plasma concentrations of drugs that are primarily metabolized by CYP450 3A4. Pitolisant is a borderline/weak inducer of CYP450 3A4. When studied with midazolam, a probe substrate for CYP450 3A4, pitolisant was found to reduce midazolam peak plasma concentration (Cmax) and systemic exposure (AUC) by less than 25%.

MANAGEMENT: Caution is advised when pitolisant is used in combination with sensitive CYP450 3A4 substrates. Clinical and laboratory monitoring may be appropriate whenever pitolisant is added to or withdrawn from therapy, and dosage adjustments made if necessary. It may be advisable to avoid concomitant use of pitolisant and CYP450 3A4 substrates with a narrow therapeutic index, if possible.

MONITOR: Coadministration with 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. No data are available for other, less potent CYP450 2D6 inhibitors. 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: Caution and clinical monitoring are recommended if pitolisant is used in combination with CYP450 2D6 inhibitors. 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, and the dosage of pitolisant adjusted as necessary in accordance with the product labeling. A prolonged duration of monitoring for adverse effects may be required depending on the elimination half-life of the concomitant drug. For example, it should be noted that rolapitant can increase plasma concentrations and the risk of adverse effects of pitolisant for at least 28 days after administration of rolapitant.