Cardiac Safety Profile of Pitolisant in Patients With Narcolepsy
William Winter1, Stephen Wanaski2, Albena Patroneva 3, Jeffrey Dayno3
1Charlottesville Neurology and Sleep Medicine, 2Paragon Biosciences, 3Harmony Biosciences
Objective:
To further characterize the cardiac safety of pitolisant in adults with narcolepsy.
Background:

Cardiovascular diseases are comorbid in patients with narcolepsy. Cardiovascular adverse effects are of concern with narcolepsy medications because of this comorbidity and most patients require lifelong pharmacotherapy. Pitolisant, a selective histamine 3 (H3)-receptor antagonist/inverse agonist, increases histamine transmission in the brain. In a QT study of healthy volunteers, pitolisant (35.6mg/day) led to a mean increase of 4.2msec in QTc interval. This analysis further characterized the cardiac safety of pitolisant (maximum dose, 35.6mg/day) in adults with narcolepsy.

Design/Methods:
Data were obtained from a pooled analysis of 2 randomized, placebo-controlled, 7- or 8-week studies and from a 12-month, open-label study.
Results:

Pooled analysis included 166 patients (pitolisant, n=85; placebo, n=81). Mean change in heart rate from baseline to end-of-treatment was -0.5 beats/min with pitolisant and -0.2 beats/min with placebo (LS mean difference, -0.4; P=0.744). Mean change was also similar for pitolisant versus placebo in systolic (LS mean difference, 0.0; P=0.983) and diastolic (LS mean difference, -0.6; P=0.552) blood pressure, as was mean change in QTc interval (LS mean difference, 0.4; P=0.911). Cardiac adverse events with pitolisant included heart rate increase (n=4), right bundle branch block (n=1), sinus tachycardia (n=1), and palpitations (n=1), and with placebo included blood pressure increase (n=1). In the long-term study, mean change from baseline in QTc interval was 3.1msec at Month 6 (n=70) and 6.1 msec at Month 12 (n=67); 3 patients had a postbaseline increase >60msec but none had QTc >500msec.

Conclusions:
In this analysis, no cardiac safety signals were observed during treatment with pitolisant administered up to the maximum recommended dose. Because concomitant use of pitolisant with other drugs known to increase the QT interval may add to the QT effects of pitolisant, avoid use of pitolisant in combination with these medications.