Pitolisant

Overview

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. It is the first commercially available medication in its class; the U.S. Food and Drug Administration (FDA) designated it a first-in-class medication. Pitolisant enhances the activity of histaminergic neurons in the brain that function to improve a person's wakefulness. 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. The most common side effects include difficulty sleeping, nausea, and feeling worried.[1–6] WP

Drug class

Histamine H3 receptor inverse agonist WP

From the Wikipedia article's infobox.

Uses, dosage and effects

Medical uses

Pitolisant is indicated in adults for the treatment of narcolepsy. 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.[1][7][8][9] WP

Risks and side effects

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.[7] WP

Pharmacology

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. 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.[10][11] WP

Pitolisant is a drug that belongs to the class of central nervous system (CNS) stimulants. 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.[12–18] WP⚠ A table follows this text in the source and is not copied here. Open the source to see it.

Pitolisant has been demonstrated to exhibit high affinity for sigma-1 and sigma-2 receptors, as well as moderate affinity for 5-HT2A and D₃ receptors. There exist conflicting findings relating the intrinsic activity of pitolisant at the 5-HT2A receptor.[19] WP

Pharmacokinetics WP

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.[11] WP

History

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).[5][7] WP

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.[6] WP

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.[6] WP

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).[6] WP

Pitolisant was approved by the FDA in August 2019. It was granted orphan drug designation for the treatment of narcolepsy, 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.[5][6][20][21] WP

Legal status

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.[18][22] WP⚠ Wikipedia itself has flagged this text: failed verification.

Chemistry

Formula

C17H26ClNO PC

CAS number

362665-56-3 PC

Molar mass (g/mol)

295.8 PC

IUPAC name (computed by PubChem)

1-[3-[3-(4-chlorophenyl)propoxy]propyl]piperidine PC

SMILES

C1CCN(CC1)CCCOCCCC2=CC=C(C=C2)Cl PC

InChIKey

NNACHAUCXXVJSP-UHFFFAOYSA-N PC

PubChem CID

9948102

Harm reduction information

No harm reduction data is on file for this compound yet. That means no dose, timing or combination data from PsychonautWiki or TripSit. Please don't guess a dose from similar compounds. If you have taken it and feel unwell, contact emergency services or a poison control center.

User reports

Pop culture

No references added yet.

Sources

1. Journal / agency Wakix- pitolisant hydrochloride tablet, film coated. 6 November 2019
2. Journal / agency New Drug Therapy Approvals 2019. 31 December 2019
3. Other FDA Approves Pitolisant for Daytime Sleepiness in Patients with Narcolepsy. 16 August 2019
4. Journal / agency Syed YY. Pitolisant: First Global Approval. Drugs. September 2016. doi:10.1007/s40265-016-0620-1 · PMID 27438291
5. Journal / agency 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. March 2024. doi:10.7759/cureus.56561 · PMID 38646400 · PMC11028406
6. Journal / agency Drug Trials Snapshots: Wakix. 14 August 2019
7. Journal / agency Wakix EPAR. 17 September 2018
8. Journal / agency Ozawade EPAR. 20 May 2021
9. Journal / agency 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. August 2024. doi:10.1016/j.smrv.2024.101934 · PMID 38754208
10. Journal / agency West RE, Zweig A, Shih NY, Siegel MI, Egan RW, Clark MA. Identification of two H3-histamine receptor subtypes. Molecular Pharmacology. November 1990. doi:10.1016/S0026-895X(25)09479-9 · PMID 2172771
11. Journal / agency Sarfraz N, Okuampa D, Hansen H, Alvarez M, Cornett EM, Kakazu J, Kaye AM, Kaye AD. 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. 30 May 2022. doi:10.52965/001c.34222 · PMID 35774905 · PMC9239364
12. Journal / agency Pitolisant. 2012. PMID 34516055
13. Journal / agency LiverTox: Clinical and Research Information on Drug-Induced Liver Injury. 22 January 2012. PMID 31644012
14. Other Pitolisant Uses, Side Effects & Warnings
15. Other List of CNS stimulants + Uses & Side Effects
16. Journal / agency Pitolisant (Wakix) for Narcolepsy. JAMA. 21 September 2021. doi:10.1001/jama.2021.1349 · PMID 34546302
17. Journal / agency Kollb-Sielecka M, Demolis P, Emmerich J, Markey G, Salmonson T, Haas M. 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. Sleep Medicine. 1 May 2017. doi:10.1016/j.sleep.2017.01.002 · PMID 28449891
18. Journal / agency Lamb YN. Pitolisant: A Review in Narcolepsy with or without Cataplexy. CNS Drugs. February 2020. doi:10.1007/s40263-020-00703-x · PMID 31997137
19. Journal / agency Solages, Martine. Wakix (Pitolisant)
20. Journal / agency Pitolisant Orphan Drug Designations and Approvals. 17 May 2010
21. Other Harmony's pitolisant granted breakthrough and fast track designations. 22 May 2018
22. Journal / agency de Biase S, Pellitteri G, Gigli GL, Valente M. Evaluating pitolisant as a narcolepsy treatment option. Expert Opinion on Pharmacotherapy. February 2021. doi:10.1080/14656566.2020.1817387 · PMID 32941089

Text and values on this page are quoted from Wikipedia (CC BY-SA 4.0), PubChem (public domain). Each value links to the exact revision it came from.