Pitolisant Explained

Pitolisant, sold under the brand name Wakix among others, is a medication used for the treatment of excessive daytime sleepiness in adults with narcolepsy. It is an inverse agonist of the histamine H₃ receptor.^[4] It represents the first commercially available medication in its class, so that the U.S. Food and Drug Administration (FDA) declares it a first-in-class medication.^{[5] [6]} Pitolisant enhances the activity of histaminergic neurons in the brain that function to improve a person's wakefulness.^[7] It was approved by the European Medicines Agency (EMA) in March 2016 for narcolepsy with or without cataplexy, and for excessive daytime sleepiness by the FDA in August 2019.^[8] The most common side effects include difficulty sleeping, nausea, and feeling worried.

Medical uses

Pitolisant is indicated in adults for the treatment of narcolepsy.^[9] Narcolepsy is a chronic sleep disorder that causes overwhelming daytime drowsiness. Pitolisant is also indicated to improve alertness and reduce excessive daytime sleepiness in adults with obstructive sleep apnea.^{[10] [11]}

Side effects

The most common side effects include insomnia, headache, nausea, anxiety, irritability, dizziness, depression, tremor, sleep disorders, tiredness, vomiting, vertigo, dyspepsia, and heartburn. Rare but serious side effects are abnormal weight loss and spontaneous abortion.

Pharmacology

Pitolisant is an inverse agonist of the histamine H₃ autoreceptor. The H₃ autoreceptors regulate histaminergic activity in the central nervous system (and to a lesser extent, the peripheral nervous system) by inhibiting histamine synthesis and release upon binding to endogenous histamine.^[12] By preventing the binding of endogenous histamine at the H₃, as well as producing a response opposite to that of endogenous histamine at the receptor (inverse agonism), pitolisant enhances histaminergic activity in the brain.^[13]

Pitolisant is a drug that belongs to the class of central nervous system (CNS) stimulants.^{[14] [15] [16] [17]} Pitolisant is also considered a eugeroic, which means that it promotes wakefulness and alertness. Eugeroics are different from traditional CNS stimulants such as amphetamine in that they have fewer side effects and lower abuse potential. Pitolisant is the first eugeroic drug that acts by blocking the histamine H₃ autoreceptor, which increases the activity of histamine neurons in the brain. Pitolisant has been shown to be effective and well-tolerated for the treatment of narcolepsy with or without cataplexy.^{[18] [19]}

Binding affinities^[20] !Target!Ki!Activity

H3	150 nM	Inverse agonist
σ1	<10 nM	Agonist
σ2	52 nM	Antagonist
D3	382 nM	Antagonist
5-HT2A	544 nM	Antagonist

Pitolisant has been demonstrated to exhibit high affinity for sigma-1 and sigma-2 receptors, as well as moderate affinity for 5-HT_2A and D₃ receptors. There exist conflicting findings relating the intrinsic activity of pitolisant at the 5-HT_2A receptor.^[21]

Pharmacokinetics

Pitolisant is readily absorbed when taken by mouth and reaches peak blood concentrations approximately 3 hours after administration. The biological half-life of Pitolisant ranges from 10 to 12 hours.

History

Pitolisant is marketed in the European Union by Bioprojet Pharma. It was approved for medical use in the European Union in March 2016 by the European Medicines Agency (EMA).^[8]

The U.S. Food and Drug Administration (FDA) approved pitolisant for excessive daytime sleepiness in participants with narcolepsy based primarily on evidence from two trials (Trial 1/NCT01067222, Trial 2/NCT01638403). An additional trial (Trial 3/NCT01800045), in which participants with a different type of narcolepsy were exposed to the same dose of pitolisant, was used to add data for evaluation of side effects. The trials were conducted in Europe and South America.

The two primary trials enrolled adults with narcolepsy and excessive daytime sleepiness. Participants received pitolisant, placebo, or an approved drug for narcolepsy for eight weeks. For participants receiving pitolisant, the dose could be increased during the first three weeks but had to remain the same for the next five weeks. Neither the participants nor the healthcare providers knew which treatment was being given during the trial.

The benefit of pitolisant was evaluated by comparing changes in daytime sleepiness during the trial between pitolisant- and placebo-treated participants. To measure the daytime sleepiness, the investigators used a scale called the Epworth Sleepiness Scale (ESS). The ESS asks participants to rate the likelihood that they would fall asleep while doing eight daily activities (such as sitting and reading or watching television). Participants rate each item from zero (would never doze) to three (high chance of dozing).

Pitolisant was approved by the FDA in August 2019.^{[8] [22]} It was granted orphan drug designation for the treatment of narcolepsy,^[23] fast track designation for the treatment of excessive daytime sleepiness and cataplexy in people with narcolepsy, and breakthrough therapy designation for the treatment of cataplexy in people with narcolepsy.^[24]

Society and culture

Legal status

Pitolisant is approved in the European Union and the United States to treat narcolepsy, and is not a controlled substance in these countries. Still, long-term studies comparing the effectiveness and tolerability of pitolisant with modafinil or sodium oxybate are lacking. Pitolisant, the only non-controlled anti-narcoleptic drug in the US, has shown minimal abuse risk in studies.^{[25] [26]}

Notes and References

1. Web site: Summary Basis of Decision (SBD) for Wakix . Health Canada . 23 October 2014 . 29 May 2022 . 22 December 2022 . https://web.archive.org/web/20221222054315/https://hpr-rps.hres.ca/reg-content/summary-basis-decision-detailTwo.php?linkID=SBD00550&lang=en . live .
2. Web site: Health product highlights 2021: Annexes of products approved in 2021 . . 3 August 2022 . 25 March 2024 . 25 March 2024 . https://web.archive.org/web/20240325234307/https://www.canada.ca/en/health-canada/services/publications/drugs-health-products/health-product-highlights-2021/appendices.html . live .
3. Web site: Ozawade Product information . Union Register of medicinal products . 3 March 2023 . 5 March 2023 . https://web.archive.org/web/20230305042454/https://ec.europa.eu/health/documents/community-register/html/h1546.htm . live .
4. Web site: Wakix- pitolisant hydrochloride tablet, film coated . DailyMed . 6 November 2019 . 18 August 2020 . 11 August 2020 . https://web.archive.org/web/20200811194709/https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=8daa5562-824e-476c-9652-26ceef3d4b0e . live .
5. Web site: New Drug Therapy Approvals 2019 . U.S. Food and Drug Administration (FDA) . 31 December 2019 . 15 September 2020 . 16 September 2020 . https://web.archive.org/web/20200916144738/https://www.fda.gov/drugs/new-drugs-fda-cders-new-molecular-entities-and-new-therapeutic-biological-products/new-drug-therapy-approvals-2019 .
6. Web site: FDA Approves Pitolisant for Daytime Sleepiness in Patients with Narcolepsy . Pharmacy Times . 16 August 2019 . 18 August 2020 . 12 August 2020 . https://web.archive.org/web/20200812030141/https://www.pharmacytimes.com/news/fda-approves-pitolisant-for-daytime-sleepiness-in-patients-with-narcolepsy . live .
7. Syed YY . Pitolisant: First Global Approval . Drugs . 76 . 13 . 1313–1318 . September 2016 . 27438291 . 10.1007/s40265-016-0620-1 . 42684839 .
8. Giliberto S, Shishodia R, Nastruz M, Brar C, Bulathsinhala S, Terry J, Pemminati S, Shenoy SK . A Comprehensive Review of Novel FDA-Approved Psychiatric Medications (2018-2022) . Cureus . 16 . 3 . e56561 . March 2024 . 38646400 . 11028406 . 10.7759/cureus.56561 . free .
9. Web site: Wakix EPAR . European Medicines Agency (EMA) . 17 September 2018 . 18 August 2020 . 12 November 2020 . https://web.archive.org/web/20201112021537/https://www.ema.europa.eu/en/medicines/human/EPAR/wakix . live . Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged.
10. Web site: Ozawade EPAR . European Medicines Agency (EMA) . 20 May 2021 . 15 October 2021 . 15 October 2021 . https://web.archive.org/web/20211015225951/https://www.ema.europa.eu/en/medicines/human/EPAR/ozawade . live .
11. Neshat SS, Heidari A, Henriquez-Beltran M, Patel K, Colaco B, Arunthari V, Lee Mateus AY, Cheung J, Labarca G . Evaluating pharmacological treatments for excessive daytime sleepiness in obstructive sleep apnea: A comprehensive network meta-analysis and systematic review . Sleep Med Rev . 76 . 101934 . August 2024 . 38754208 . 10.1016/j.smrv.2024.101934 .
12. West RE, Zweig A, Shih NY, Siegel MI, Egan RW, Clark MA . Identification of two H3-histamine receptor subtypes . Molecular Pharmacology . 38 . 5 . 610–613 . November 1990 . 10.1016/S0026-895X(25)09479-9 . 2172771 . 10 April 2023 . 10 December 2023 . https://web.archive.org/web/20231210105713/https://molpharm.aspetjournals.org/content/38/5/610 . live . subscription .
13. Sarfraz N, Okuampa D, Hansen H, Alvarez M, Cornett EM, Kakazu J, Kaye AM, Kaye AD . 6 . pitolisant, a novel histamine-3 receptor competitive antagonist, and inverse agonist, in the treatment of excessive daytime sleepiness in adult patients with narcolepsy . Health Psychology Research . 10 . 3 . 34222 . 30 May 2022 . 35774905 . 9239364 . 10.52965/001c.34222 . 1 July 2025 .
14. Web site: Pitolisant . 34516055 . 2012 . National Institute of Diabetes and Digestive and Kidney Diseases . 22 January 2024 . 14 November 2023 . https://web.archive.org/web/20231114161839/https://www.ncbi.nlm.nih.gov/books/NBK573784/ . live .
15. Book: LiverTox: Clinical and Research Information on Drug-Induced Liver Injury. Central Nervous System (CNS) Stimulants. 22 January 2012. National Institute of Diabetes and Digestive and Kidney Diseases. PubMed. 31644012. 22 January 2024. 29 January 2023. https://web.archive.org/web/20230129141034/https://www.ncbi.nlm.nih.gov/books/NBK548702/. live.
16. Web site: Pitolisant Uses, Side Effects & Warnings. Drugs.com. 22 January 2024. 19 January 2024. https://web.archive.org/web/20240119024743/https://www.drugs.com/mtm/pitolisant.html. live.
17. Web site: List of CNS stimulants + Uses & Side Effects. Drugs.com. 22 January 2024. 6 January 2024. https://web.archive.org/web/20240106222450/https://www.drugs.com/drug-class/cns-stimulants.html. live.
18. Pitolisant (Wakix) for Narcolepsy. 21 September 2021. JAMA. 326. 11. 1060–1061. Silverchair. 10.1001/jama.2021.1349. 34546302. 237583921.
19. The European Medicines Agency review of pitolisant for treatment of narcolepsy: summary of the scientific assessment by the Committee for Medicinal Products for Human Use. Kollb-Sielecka M, Demolis P, Emmerich J, Markey G, Salmonson T, Haas M. 1 May 2017. Sleep Medicine. 33. 125–129. Europe PMC. 10.1016/j.sleep.2017.01.002. 28449891.
20. Web site: Shah . Dhara . July 12, 2019 . OPDP Labeling Comments for WAKIX® (pitolisant) tablets, for oral use . www.accessdata.fda.gov . 28 September 2024 . 30 September 2024 . https://web.archive.org/web/20240930002541/https://www.accessdata.fda.gov/drugsatfda_docs/nda/2019/211150Orig1s000OtherR.pdf . live .
21. Web site: Solages . Martine . Wakix (Pitolisant) . www.accessdata.fda.gov . 28 September 2024 . 28 September 2024 . https://web.archive.org/web/20240928233331/https://www.accessdata.fda.gov/drugsatfda_docs/nda/2019/211150Orig1s000MedR.pdf .
22. Web site: Drug Trials Snapshots: Wakix . U.S. Food and Drug Administration (FDA) . 14 August 2019 . 18 March 2020 . 22 December 2020 . https://web.archive.org/web/20201222061051/https://www.fda.gov/drugs/drug-approvals-and-databases/drug-trials-snapshots-wakix .
23. Web site: Pitolisant Orphan Drug Designations and Approvals . U.S. Food and Drug Administration (FDA) . 17 May 2010 . 25 May 2021 . 26 May 2021 . https://web.archive.org/web/20210526041813/https://www.accessdata.fda.gov/scripts/opdlisting/oopd/detailedIndex.cfm?cfgridkey=307210 .
24. Web site: Harmony's pitolisant granted breakthrough and fast track designations . Pharma Business International . 22 May 2018 . 25 May 2021 . 26 May 2021 . https://web.archive.org/web/20210526041822/https://www.pbiforum.net/mag/featured/harmonys-pitolisant-granted-breakthrough-and-fast-track-designations/ .
25. Lamb YN . Pitolisant: A Review in Narcolepsy with or without Cataplexy . CNS Drugs . 34 . 2 . 207–218 . February 2020 . 31997137 . 10.1007/s40263-020-00703-x . 210949049 .
26. de Biase S, Pellitteri G, Gigli GL, Valente M . Evaluating pitolisant as a narcolepsy treatment option . Expert Opinion on Pharmacotherapy . 22 . 2 . 155–162 . February 2021 . 32941089 . 10.1080/14656566.2020.1817387 . 221788777.