Drug Interactions between pazopanib and pitolisant

GENERALLY AVOID: Limited data suggest that pitolisant may produce mild to moderate QT interval prolongation (10 to 13 milliseconds) at doses 3 to 6 times the standard therapeutic dose. Theoretically, concurrent use of two or more drugs that can cause QT interval prolongation may result in additive effects and increased risk of ventricular arrhythmias including torsade de pointes and sudden death. In general, the risk of an individual agent or a combination of these agents causing ventricular arrhythmia in association with QT prolongation is largely unpredictable but may be increased by certain underlying risk factors such as congenital long QT syndrome, cardiac disease, and electrolyte disturbances (e.g., hypokalemia, hypomagnesemia). In addition, the extent of drug-induced QT prolongation is dependent on the particular drug(s) involved and dosage(s) of the drugs.

MONITOR: Coadministration with pitolisant may decrease the plasma concentrations and therapeutic effects 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: Concomitant use of pitolisant with other agents associated with QT interval prolongation should generally be avoided. 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. In addition, it may be advisable to avoid concomitant use of pitolisant with sensitive CYP450 3A4 substrates or those that demonstrate a narrow therapeutic index, if possible (e.g., ergot alkaloids, alfentanil, cisapride, colchicine, cyclosporine, fentanyl, ivacaftor, macrolide immunosuppressants, oral midazolam, pimozide, quinidine, sufentanil, triazolam, vinca alkaloids). Caution is advised if pitolisant is used in combination with these drugs. Clinical and laboratory monitoring may be appropriate whenever pitolisant is added to or withdrawn from therapy, and dosage adjustments made if necessary.