Drug Interactions between PC-CAP and pitolisant

MONITOR: Concomitant use of pitolisant with NSAIDs and/or corticosteroids may increase the risk of gastrointestinal adverse effects such as dyspepsia, abdominal pain or discomfort, and gastritis due to potential additive irritant effects on the gastrointestinal mucosa. Clinical studies with pitolisant reported gastric disorders caused by hyperacidity in 3.5% of patients. However, the effects were described as mostly mild to moderate in severity. Data are not available on the potential for serious gastrointestinal (GI) toxicity, including inflammation, bleeding, ulceration, and perforation.

MANAGEMENT: Caution is advised if pitolisant is used in combination with NSAIDs and/or corticosteroids, particularly in patients with a prior history of peptic ulcer disease or GI bleeding and in elderly or debilitated patients. If concomitant therapy is required, patients should be advised to report signs and symptoms of adverse GI effects, including abdominal pain or discomfort, dyspepsia, gastroesophageal reflux disease, gastritis, or the appearance of black, tarry stools.

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. In addition, coadministration with inhibitors of the CYP450 2D6 isoenzyme may increase plasma concentrations of pitolisant, which is a substrate of this isoenzyme. 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. 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). The extent of drug-induced QT prolongation is dependent on the particular drug(s) involved and dosage(s) of the drug(s). Coadministration with the 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. However, clinical data are not available.

MANAGEMENT: Concomitant use of pitolisant with other agents associated with QT interval prolongation and CYP450 2D6 inhibition should generally be avoided. Caution and clinical monitoring are recommended if concomitant use is required. Dosage adjustment of pitolisant may be considered. 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.

One study has reported that coadministration of caffeine and aspirin lead to a 25% increase in the rate of appearance and 17% increase in maximum concentration of salicylate in the plasma. A significantly higher area under the plasma concentration time curve of salicylate was also reported when both drugs were administered together. The exact mechanism of this interaction has not been specified. Physicians and patients should be aware that coadministration of aspirin and caffeine may lead to higher salicylate levels faster.