FDA Approves Pitolisant for Cataplexy in Pediatric Narcolepsy Patients

The FDA has approved the supplemental new drug application for pitolisant tablets (Wakix; Harmony Biosciences) for the treatment of cataplexy in pediatric patients aged 6 and older with narcolepsy. This supplemental approval makes pitolisant the only non-scheduled therapy approved in the US for both pediatric and adult patients with narcolepsy with or without cataplexy.

"With this approval, clinicians now have the option to prescribe WAKIX to treat excessive daytime sleepiness, cataplexy, or both, in patients 6 years and older with narcolepsy," noted the Chief Medical and Scientific Officer of Harmony Biosciences.

Pitolisant was approved in August 2019 for excessive daytime sleepiness in adult patients with narcolepsy, and the indication was expanded in October 2020 to include cataplexy in adults. In June 2024, the agency approved pitolisant for excessive daytime sleepiness in pediatric patients aged 6 years and older. The current approval extends the pediatric indication to include cataplexy.

The supplemental new drug application for the pediatric approval in cataplexy was supported by findings from a double-blind, randomized, placebo-controlled, multisite study that recruited patients with narcolepsy with or without cataplexy from 11 sleep centers in 5 countries (Italy, France, Netherlands, Russia, and Finland). Between June 6, 2016, and April 3, 2021, 115 participants were screened and 110 were randomly assigned (mean age, 12.9 [SD, 3.0] years, 61 [55%] male, and 90 [82%] with cataplexy; pitolisant: n = 72; placebo: n = 38); 107 (pitolisant: n = 70; placebo: n = 37) completed the double-blind period.

At the conclusion of the double-blind period of the trial, the mean adjusted difference in Ullanlinna Narcolepsy Scale (UNS) total score, the primary outcome, was -6.3 (SE, 1.1) in patients treated with pitolisant and -2.6 (1.4) in patients treated with placebo (least squares mean difference, -3.7; 95% CI, -6.4 to -1.0, P = 0.007). During the last week of treatment, the pitolisant to placebo rate ratio was 0.4 (95% CI, 0.2 - 1.0, P = 0.05) for the least squares mean weekly rate of cataplexy. Weekly cataplexy rate decreased by 75% in patients who received pitolisant and 38% in patients who received placebo.

The Pediatric Daytime Sleepiness Scale adjusted mean difference showed a greater decrease in the pitolisant group than in the placebo group from baseline to the end of the double-blind period.

Twenty-two (31%) of 72 patients reported treatment-emergent adverse events treated with pitolisant versus 13 (34%) of 38 patients treated with placebo. The most frequently reported adverse events (affecting ≥5% of patients) were headache (pitolisant, n = 14 [19%]; placebo, n = 3 [8%]) and insomnia (pitolisant, n = 5 [7%]; placebo, n = 1 [3%]). No serious adverse events were reported. In placebo-controlled trials in patients with narcolepsy with or without cataplexy, the most common adverse reactions in adults were insomnia, nausea, and anxiety.

Pitolisant is a selective histamine 3 receptor antagonist and inverse agonist. Although the precise mechanism of action is not fully established, its efficacy is believed to be mediated through histamine 3 receptor activity, leading to increased synthesis and release of histamine, a wake-promoting neurotransmitter. The drug received orphan drug designation for narcolepsy in 2010 and breakthrough therapy designation for cataplexy in 2018.

Pitolisant is contraindicated in patients with known hypersensitivity to the drug or with severe hepatic impairment. The medication prolongs the QT interval and should be avoided in patients with known QT prolongation, a history of cardiac arrhythmias, or other risk factors for torsade de pointes. The drug is not recommended in those with end-stage renal disease. Dose reductions are required in patients with moderate hepatic impairment, moderate-to-severe renal impairment (estimated glomerular filtration rate of less than 60 mL/min/1.73 m²), and poor CYP2D6 metabolizers.

Strong CYP2D6 inhibitors can increase pitolisant exposure and necessitate a 50% dose reduction. Strong CYP3A4 inducers may reduce pitolisant exposure, potentially requiring dose adjustments. Centrally acting H₁ receptor antagonists (e.g., first-generation antihistamines) may attenuate the drug's efficacy and should be avoided. Pitolisant may reduce the effectiveness of hormonal contraceptives; alternative non-hormonal contraception is recommended during treatment and for at least 21 days after discontinuation.

Narcolepsy is a rare, chronic neurologic disorder characterized by sleep-wake instability. It affects approximately 170,000 people in the US and is defined by excessive daytime sleepiness and cataplexy, along with other manifestations of rapid eye movement sleep dysregulation, including hallucinations and sleep paralysis. In most patients, narcolepsy is associated with loss of hypocretin or orexin signaling in the brain.