Pitolisant
Clinical data
Pronunciation/pɪˈtɒlɪsənt/
pi-TOL-i-sənt
Trade namesWakix, Ozawade
Other namesTiprolisant; Ciproxidine; BF2.649
AHFS/Drugs.comMonograph
MedlinePlusa619055
License data
Routes of
administration		By mouth
Drug classHistamine H3 receptor inverse agonists
ATC code
Legal status
Legal status
Identifiers
  • 1-[3-[3-(4-chlorophenyl)propoxy]propyl]piperidine
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard (EPA)
Chemical and physical data
FormulaC17H26ClNO
Molar mass295.85 g·mol−1
3D model (JSmol)
  • C1CCN(CC1)CCCOCCCC2=CC=C(C=C2)Cl
  • InChI=1S/C17H26ClNO/c18-17-9-7-16(8-10-17)6-4-14-20-15-5-13-19-11-2-1-3-12-19/h7-10H,1-6,11-15H2 checkY
  • Key:NNACHAUCXXVJSP-UHFFFAOYSA-N checkY
 ☒NcheckY (what is this?)  (verify)

Pitolisant, sold under the brand name Wakix among others, is a medication used for the treatment of excessive daytime sleepiness in adults with narcolepsy.[2] It is a histamine 3 (H3) receptor antagonist/inverse agonist.[2] It represents the first commercially available medication in its class, so that the US Food and Drug Administration (FDA) declares it a first-in-class medication.[6][7] Pitolisant enhances the activity of histaminergic neurons in the brain that function to improve a person's wakefulness.[8]

The most common side effects include difficulty sleeping, nausea, and feeling worried.[9]

Medical uses

Pitolisant is indicated in adults for the treatment of narcolepsy.[2][3] Narcolepsy is a chronic sleep disorder that causes overwhelming daytime drowsiness.[3] Pitolisant is also indicated to improve alertness and reduce excessive daytime sleepiness in adults with obstructive sleep apnea.[4]

Side effects

The most common side effects include insomnia, headache, nausea, anxiety, irritability, dizziness, depression, tremor, sleep disorders, tiredness, vomiting, vertigo, and dyspepsia (heartburn).[3] Rare but serious side effects are abnormal loss of weight and spontaneous abortion.[3]

Pharmacology

Pitolisant is an inverse agonist of the histamine 3 (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.[10] 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.[11]

History

Pitolisant is marketed in the European Union by Bioprojet Pharma.[3] It was approved for medical use in the European Union in March 2016.[3]

The US 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).[9] 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.[9] The trials were conducted in Europe and South America.[9]

The two primary trials enrolled adults with narcolepsy and excessive daytime sleepiness.[9] Participants received pitolisant, placebo, or an approved drug for narcolepsy for eight weeks.[9] 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.[9] Neither the participants nor the healthcare providers knew which treatment was being given during the trial.[9]

The benefit of pitolisant was evaluated by comparing changes in daytime sleepiness during the trial between pitolisant- and placebo-treated participants.[9] To measure the daytime sleepiness, the investigators used a scale called the Epworth Sleepiness Scale (ESS).[9] 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).[9] Participants rate each item from zero (would never doze) to three (high chance of dozing).[9]

Pitolisant was approved by the FDA in August 2019.[9] It was granted orphan drug designation for the treatment of narcolepsy,[12] 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.[13]

Society and culture

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,[14] has shown minimal abuse risk in studies.[14][15]

References

  1. ↑ "Summary Basis of Decision (SBD) for Wakix". Health Canada. 23 October 2014. Retrieved 29 May 2022.
  2. 1 2 3 4 "Wakix- pitolisant hydrochloride tablet, film coated". DailyMed. 6 November 2019. Retrieved 18 August 2020.
  3. 1 2 3 4 5 6 7 "Wakix EPAR". European Medicines Agency (EMA). 17 September 2018. Retrieved 18 August 2020. Text was copied from this source which is © European Medicines Agency. Reproduction is authorized provided the source is acknowledged.
  4. 1 2 "Ozawade EPAR". European Medicines Agency (EMA). 20 May 2021. Retrieved 15 October 2021.
  5. ↑ "Ozawade Product information". Union Register of medicinal products. Retrieved 3 March 2023.
  6. ↑ "New Drug Therapy Approvals 2019". U.S. Food and Drug Administration (FDA). 31 December 2019. Retrieved 15 September 2020.
  7. ↑ "FDA Approves Pitolisant for Daytime Sleepiness in Patients with Narcolepsy". Pharmacy Times. 16 August 2019. Retrieved 18 August 2020.
  8. ↑ Syed YY (September 2016). "Pitolisant: First Global Approval". Drugs. 76 (13): 1313–1318. doi:10.1007/s40265-016-0620-1. PMID 27438291. S2CID 42684839.
  9. 1 2 3 4 5 6 7 8 9 10 11 12 13 "Drug Trials Snapshots: Wakix". U.S. Food and Drug Administration (FDA). 14 August 2019. Retrieved 18 March 2020. Public Domain This article incorporates text from this source, which is in the public domain.
  10. ↑ West RE, Zweig A, Shih NY, Siegel MI, Egan RW, Clark MA (November 1990). "Identification of two H3-histamine receptor subtypes". Molecular Pharmacology. 38 (5): 610–613. PMID 2172771.
  11. ↑ Sarfraz N, Okuampa D, Hansen H, Alvarez M, Cornett EM, Kakazu J, et al. (30 May 2022). "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. doi:10.52965/001c.34222. PMC 9239364. PMID 35774905.
  12. ↑ "Pitolisant Orphan Drug Designations and Approvals". U.S. Food and Drug Administration (FDA). 17 May 2010. Retrieved 25 May 2021.
  13. ↑ "Harmony's pitolisant granted breakthrough and fast track designations". Pharma Business International. 22 May 2018. Archived from the original on 26 May 2021. Retrieved 25 May 2021.
  14. 1 2 Lamb YN (February 2020). "Pitolisant: A Review in Narcolepsy with or without Cataplexy". CNS Drugs. 34 (2): 207–218. doi:10.1007/s40263-020-00703-x. PMID 31997137. S2CID 210949049.
  15. ↑ de Biase S, Pellitteri G, Gigli GL, Valente M (February 2021). "Evaluating pitolisant as a narcolepsy treatment option". Expert Opinion on Pharmacotherapy. 22 (2): 155–162. doi:10.1080/14656566.2020.1817387. PMID 32941089. S2CID 221788777.
  • Clinical trial number NCT01067222 for "Efficacy and Safety Study of BF2.649 in the Treatment of Excessive Daytime Sleepiness in Narcolepsy (Harmony1)" at ClinicalTrials.gov
  • Clinical trial number NCT01638403 for "Effects of BF2.649 in the Treatment of Excessive Daytime Sleepiness in Narcolepsy." at ClinicalTrials.gov
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