FDA Approves Pitolisant for Treatment of Cataplexy in Pediatric Narcolepsy

The FDA has approved the supplemental new drug application (sNDA) for pitolisant tablets (Wakix; Harmony Biosciences) for the treatment of cataplexy in pediatric patients 6 years and older with narcolepsy, according to a news release from Harmony Biosciences. The approval marks a significant expansion of the drug's labeled indications and establishes pitolisant as the first and only FDA-approved nonscheduled treatment for narcolepsy, with or without cataplexy, in pediatric and adult patient populations.¹

“[Pitolisant] is now the first-and-only FDA-approved treatment option for both pediatric and adult narcolepsy patients with or without cataplexy that is not scheduled as a controlled substance, an important distinction that supports its clinical utility,” Jeffrey M. Dayno, MD, president and CEO of Harmony Biosciences, said in the news release.¹

What Is Its Mechanism of Action?

Pitolisant is a first-in-class, selective histamine 3 (H₃) receptor antagonist/inverse agonist. Although the precise mechanism of action is not fully described, its therapeutic effects are thought to be mediated by a novel blockade of presynaptic H₃ receptors, which results in increased synthesis and release of histamine—a wake-promoting neurotransmitter in the brain—in the central nervous system. Unlike many narcolepsy agents, pitolisant is not a controlled substance, which may offer prescribing and adherence advantages in the pediatric setting.^1,2

Understanding Treatment Efficacy

In a double-blind, placebo-controlled clinical trial, patients with narcolepsy who experience cataplexy were randomly assigned to receive either pitolisant or placebo. Weekly cataplexy rate, measured as the average number of cataplexy attacks per week, decreased by 75% in patients receiving pitolisant and by 38% in patients receiving placebo.³

Although treatment-related adverse events were more commonly observed in patients who received pitolisant, no serious adverse events were reported.³

Approval History and Regulatory Pathway

Pitolisant received its initial FDA approval in August 2019 for the treatment of excessive daytime sleepiness (EDS) in adult patients with narcolepsy. The indication was subsequently expanded in October 2020 to include cataplexy in adults with narcolepsy. In June 2024, the FDA approved the drug for EDS in pediatric patients 6 years and older with narcolepsy. The current sNDA approval for pediatric cataplexy completes the drug's indication profile across both symptoms and both age groups. Pitolisant was granted breakthrough therapy designation for the treatment of cataplexy in 2018.^2,4-6

Safety and Dosing Considerations for Pharmacists

Pharmacists should be aware of several clinically important safety considerations when dispensing pitolisant in pediatric patients. The most common adverse reactions reported in the placebo-controlled pediatric clinical trial (rates of 5% or higher) were headache (19%) and insomnia (7%). The overall adverse reaction profile was consistent with that observed in adult trials.^1,7

Pitolisant carries a risk of QT interval prolongation. Pharmacists should screen for concomitant use of other QT-prolonging agents and counsel prescribers accordingly. The drug is contraindicated in patients with severe hepatic impairment and 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.^1,7

Key drug interactions to monitor include concomitant use of strong CYP2D6 inhibitors, which 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 (eg, first-generation antihistamines) may attenuate the drug's efficacy and should be avoided. Patients of childbearing potential should be counseled that pitolisant may reduce the effectiveness of hormonal contraceptives; alternative nonhormonal contraception is recommended during treatment and for at least 21 days after discontinuation.^1,7

Narcolepsy and Cataplexy

Narcolepsy is a rare, chronic neurological disorder of sleep-wake state instability affecting thousands of patients. The condition is primarily characterized by 2 hallmark symptoms: EDS and cataplexy, with additional manifestations including hypnagogic hallucinations and sleep paralysis. In most patients, narcolepsy is caused by the loss of hypocretin, a neuropeptide essential for maintaining sleep-wake stability. The disease affects men and women equally, with symptom onset typically occurring during adolescence or young adulthood, although diagnosis is often delayed by up to a decade.¹

Cataplexy, which causes episodes of sudden, transient muscle weakness triggered by strong emotions, can be particularly debilitating in pediatric patients with narcolepsy, affecting academic performance, social development, and quality of life. Until now, FDA-approved pharmacologic options for cataplexy in the pediatric population were limited, and many agents carried controlled substance designations.¹

REFERENCES

1. Harmony Biosciences receives U.S. Food and Drug Administration approval for Wakix (pitolisant) for the treatment of cataplexy in pediatric narcolepsy. News release. Harmony Biosciences. February 17, 2026. Accessed February 17, 2026. https://ir.harmonybiosciences.com/news-releases/news-release-details/harmony-biosciences-receives-us-food-and-drug-administration-1

2. Kuntz L. Approved sNDA: Wakix for treatment of excessive daytime sleepiness in youth with narcolepsy. Psychiatric Times. June 24, 2024. Accessed February 17, 2026. https://www.psychiatrictimes.com/view/approved-snda-wakix-for-treatment-of-excessive-daytime-sleepiness-in-youth-with-narcolepsy

3. Szakacs Z, Dauvilliers Y, Mikhaylov V, et al; HARMONY-CTP study group. Safety and efficacy of pitolisant on cataplexy in patients with narcolepsy: a randomised, double-blind, placebo-controlled trial. Lancet Neurol. 2017;16(3):200-207. doi:10.1016/S1474-4422(16)30333-7

4. Hoffman M. FDA grants breakthrough therapy, fast track designations to narcolepsy treatment. Pharmacy Times. May 21, 2018. Updated January 4, 2022. Accessed February 17, 2026. https://www.pharmacytimes.com/view/fda-grants-breakthrough-therapy-fast-track-designations-to-narcolepsy-treatment

5. FDA approves pitolisant for daytime sleepiness in patients with narcolepsy. Pharmacy Times. August 16, 2019. Updated March 5, 2021. Accessed February 17, 2026. https://www.pharmacytimes.com/view/fda-approves-pitolisant-for-daytime-sleepiness-in-patients-with-narcolepsy

6. FDA approves expanded use of Wakix for narcolepsy. American Academy of Sleep Medicine. October 17, 2020. Accessed February 17, 2026. https://aasm.org/fda-approves-expanded-use-of-wakix-for-narcolepsy/

7. Wakix (pitolisant) tablets. Prescribing information. Harmony Biosciences; 2026. Accessed February 17, 2026. https://wakix.com/pdf/wakix-tablets-pi.pdf