Tasimelteon: Difference between revisions

{{Short description|Wakefulness medication}}

{{cs1 config|name-list-style=vanc}}

| Verifiedfields = changed

| Watchedfields = changed

| verifiedrevid = 448209779

| image = Tasimelteon 2.svg

| width = 250

| image2 = Tasimelteon ball-and-stick model.png

| tradename = Hetlioz, Hetlioz LQ

| Drugs.com = {{drugs.com|monograph|tasimelteon}}

| MedlinePlus = a615004

| licence_EU = yes

| DailyMedID = Tasimelteon

| pregnancy_US = C

| legal_US = Rx-only

| legal_EU = Rx-only

| routes_of_administration = [[Oral administration|By mouth]]

| ATC_prefix = N05

| ATC_suffix = CH03

| dependency_liability = Low<ref name="Yang2022">{{cite journal |last1=Kim |first1=HK |last2=Yang |first2=KI |title=Melatonin and melatonergic drugs in sleep disorders. |journal=Translational and Clinical Pharmacology |date=December 2022 |volume=30 |issue=4 |pages=163–171 |doi=10.12793/tcp.2022.30.e21 |pmid=36632077|doi-access=free |pmc=9810491 }}</ref>

| bioavailability = not determined in humans<ref>{{cite web

|title=Tasimelteon Advisory Committee Meeting Briefing Materials

|publisher=Vanda Pharmaceuticals Inc.

|date=November 2013

|url=https://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/PeripheralandCentralNervousSystemDrugsAdvisoryCommittee/UCM374388.pdf

}}</ref>

| protein_bound = 89–90%

| metabolism = extensive liver, primarily [[CYP1A2]] and [[CYP3A4]]-mediated

| elimination_half-life = 0.9–1.7 h / 0.8–5.9 h (terminal)

| excretion = 80% in urine, 4% in feces

| IUPHAR_ligand = 7393

| CAS_number_Ref = {{cascite|correct|??}}

| ChemSpiderID_Ref = {{chemspidercite|changed|chemspider}}

| ChemSpiderID = 8395995

| ChEBI_Ref = {{ebicite|changed|EBI}}

| ChEBI = 79042

| IUPAC_name = (1''R'', 2''R'')-''N''-[2-(2,3-dihydrobenzofuran-4-yl)cyclopropylmethyl]propanamide

| smiles = CCC(=O)NC[C@@H]1C[C@H]1c1cccc2c1CCO2

| StdInChI_Ref = {{stdinchicite|changed|chemspider}}

| StdInChI = 1S/C15H19NO2/c1-2-15(17)16-9-10-8-13(10)11-4-3-5-14-12(11)6-7-18-14/h3-5,10,13H,2,6-9H2,1H3,(H,16,17)/t10-,13+/m0/s1

| StdInChIKey_Ref = {{stdinchicite|changed|chemspider}}

| StdInChIKey = PTOIAAWZLUQTIO-GXFFZTMASA-N

'''Tasimelteon''', sold under the brand name '''Hetlioz''', is a medication approved by the U.S. [[Food and Drug Administration]] (FDA)<ref>{{cite web |title=FDA transcript approval minutes |publisher=FDA |date=November 14, 2013 |url=https://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/PeripheralandCentralNervousSystemDrugsAdvisoryCommittee/UCM386061.pdf }}</ref> in January 2014, for the treatment of [[non-24-hour sleep–wake disorder]] (also called non-24, N24 and N24HSWD).<ref name=approval>{{cite press release |title=FDA approves Hetlioz: first treatment for non-24 hour sleep-wake disorder |author=Food and Drug Administration |date=January 31, 2014 |publisher=FDA |url=https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm384092.htm |access-date=December 16, 2019 |archive-date=February 2, 2014 |archive-url=https://web.archive.org/web/20140202132845/https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm384092.htm |url-status=dead }}</ref> In June 2014, the [[European Medicines Agency]] (EMA) accepted an EU filing application for tasimelteon<ref>{{cite web

|access-date=August 6, 2014

|url=http://www.ukmi.nhs.uk/applications/ndo/record_view_open.asp?newDrugID=5145

|title=tasimelteon (Hetlioz) UKMi New Drugs Online Database

|archive-date=June 29, 2016

|archive-url=https://web.archive.org/web/20160629171230/http://www.ukmi.nhs.uk/applications/ndo/record_view_open.asp?newDrugID=5145

|url-status=dead

}}</ref> and in July 2015, the drug was approved in the European Union for the treatment of non-24-hour sleep-wake rhythm disorder in totally blind adults,<ref>{{cite web |title=Hetlioz Receives European Commission Approval for the Treatment of Non-24-Hour Sleep-Wake Disorder in the Totally Blind |url=http://www.marketwatch.com/story/hetlioz-receives-european-commission-approval-for-the-treatment-of-non-24-hour-sleep-wake-disorder-in-the-totally-blind-2015-07-07 |website=MarketWatch |via=PR Newswire |access-date=8 July 2015 |date=7 July 2015 |archive-date=9 July 2015 |archive-url=https://web.archive.org/web/20150709121608/http://www.marketwatch.com/story/hetlioz-receives-european-commission-approval-for-the-treatment-of-non-24-hour-sleep-wake-disorder-in-the-totally-blind-2015-07-07 |url-status=dead }}</ref> but not in the case of non-24 in sighted people.

The most common side effects include headache, [[somnolence]], nausea (feeling sick) and dizziness.<ref name="Hetlioz EPAR" />

== Medical uses ==

In the United States, tasimelteon capsules are [[Indication (medicine)|indicated]] for the treatment of [[non-24-hour sleep–wake disorder]] (Non-24) in adults and for the treatment of nighttime sleep disturbances in [[Smith-Magenis Syndrome]] (SMS) in people sixteen years of age and older.<ref name="Hetlioz FDA label" /> Tasimelteon oral suspension is indicated for the treatment of nighttime sleep disturbances in SMS in children from 3 to 15 years of age.<ref name="Hetlioz FDA label" />

In the European Union, tasimelteon capsules are indicated for the treatment of non-24-hour sleep–wake disorder (Non-24) in totally blind adults.<ref name="Hetlioz EPAR">{{cite web | title=Hetlioz EPAR | website=[[European Medicines Agency]] (EMA) | url=https://www.ema.europa.eu/en/medicines/human/EPAR/hetlioz | access-date=2 December 2020}}</ref>

The capsule and liquid suspension forms of tasimelteon are not interchangeable.<ref name="Hetlioz FDA label">{{cite web | title=Hetlioz- tasimelteon capsule | website=DailyMed | url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=ca4a9b63-708e-49e9-8f9b-010625443b90 }}</ref>

Tasimelteon is a [[selective agonist]] for the [[melatonin receptor]]s MT₁ and MT₂, similar to other members of the [[melatonin receptor agonist]] class of which [[ramelteon]] (2005), [[melatonin (medication)|melatonin]] (2007), and [[agomelatine]] (2009) were the first approved.<ref>{{cite journal | vauthors = Vachharajani NN, Yeleswaram K, Boulton DW | title = Preclinical pharmacokinetics and metabolism of BMS-214778, a novel melatonin receptor agonist | journal = Journal of Pharmaceutical Sciences | volume = 92 | issue = 4 | pages = 760–72 | date = April 2003 | pmid = 12661062 | doi = 10.1002/jps.10348 }}</ref> As a treatment for N24HSWD, as with melatonin or other melatonin derivatives, the patient may experience improved sleep timing while taking the drug. Reversion to baseline sleep performance occurs within a month of discontinuation.<ref>{{cite journal | vauthors = Sack RL, Brandes RW, Kendall AR, Lewy AJ | title = Entrainment of free-running circadian rhythms by melatonin in blind people | journal = The New England Journal of Medicine | volume = 343 | issue = 15 | pages = 1070–7 | date = October 2000 | pmid = 11027741 | doi = 10.1056/NEJM200010123431503 | doi-access = free }}</ref>

==Development==

Tasimelteon (previously known as BMS-214,778) was developed for the treatment of [[insomnia]] and other sleep disorders. A phase II trial on circadian rhythm sleep disorders was concluded in March 2005.<ref>{{ClinicalTrialsGov|NCT00490945|Safety and Efficacy of VEC-162 on Circadian Rhythm in Healthy Adult Volunteers}}</ref> A phase III insomnia trial was conducted in 2006.<ref>{{ClinicalTrialsGov|NCT00291187|VEC-162 Study in Healthy Adult Volunteers in a Model of Insomnia}}</ref> A second phase III trial on insomnia, this time concerning primary insomnia, was completed in June 2008.<ref>{{ClinicalTrialsGov|NCT00548340|VEC-162 Study in Adult Patients With Primary Insomnia}}</ref> In 2010, the FDA granted [[orphan drug|orphan drug status]] to tasimelteon, then regarded as an investigational medication, for use in totally blind adults with N24HSWD.<ref>{{cite web |url=http://www.matildaziegler.com/category/n24hswd/ |title=Improving Sleep and Alertness in the Blind (Part 5) | first = Lynne | last = Lamberg |publisher=[[Matilda Ziegler Magazine for the Blind]] |access-date=May 15, 2014 }}</ref> (Through mechanisms such as easing the approval process and extending exclusivity periods, orphan drug status encourages development of drugs for rare conditions that otherwise might lack sufficient commercial incentive.)

On completion of Phase III trials, interpretations of the clinical trials by the research team concluded that the drug may have therapeutic potential for transient insomnia in circadian rhythm sleep disorders.<ref>{{cite journal | vauthors = Rajaratnam SM, Polymeropoulos MH, Fisher DM, Roth T, Scott C, Birznieks G, Klerman EB | title = Melatonin agonist tasimelteon (VEC-162) for transient insomnia after sleep-time shift: two randomised controlled multicentre trials | journal = Lancet | volume = 373 | issue = 9662 | pages = 482–91 | date = February 2009 | pmid = 19054552 | doi = 10.1016/S0140-6736(08)61812-7 | s2cid = 36568291 }}</ref> A year-long (2011–2012) study at Harvard tested the use of tasimelteon in blind subjects with non-24-hour sleep-wake disorder. The drug has not been tested in children nor in any non-blind people.

==FDA approval==

In May 2013, Vanda Pharmaceuticals submitted a [[New Drug Application]] to the [[Food and Drug Administration]] for tasimelteon for the treatment of non-24-hour sleep–wake disorder in totally blind people. It was approved by the FDA on January 31, 2014, under the brand name Hetlioz.<ref name="approval" /> In the opinion of [[Public Citizen]], an [[advocacy group]], the FDA erroneously allowed it to be labelled without stating that it is only approved for use by totally blind people.<ref>{{cite web |last1=Carome| first1=Michael |title=Outrage of the Month: FDA Makes Major Blunder After Approving Drug for Rare Sleep Disorder|url=http://www.huffingtonpost.com/michael-carome-md/outrage-of-the-month-fda-_b_7706492.html|website=Huffington Post|access-date=8 July 2015|date=1 July 2015}}</ref> However, FDA updated its press release on Oct. 2, 2014 to clarify the approved use of Hetlioz, which includes both sighted and blind individuals. The update did not change the drug labeling (prescribing information).<ref>{{cite news|title=FDA NEWS RELEASE: FDA approves Hetlioz: first treatment for non-24 hour sleep–wake disorder in blind individuals |author=Food and Drug Administration| date=January 31, 2014|publisher=FDA |url=https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm384092.htm}}</ref>

In Dec 2020, tasimelteon is approved by FDA for the treatment of [[Smith-Magenis Syndrome]].<ref>{{cite web

|title = Search Orphan Drug Designations and Approvals |url = https://www.accessdata.fda.gov/scripts/opdlisting/oopd/detailedIndex.cfm?cfgridkey=301410 |website= [[FDA]] | access-date=28 March 2023 |date=1 December 2020}}</ref>

==Toxicity==

Experiments with rodents revealed fertility impairments, an increase in certain cancers, and serious adverse events during pregnancy at dosages in excess of what is considered the "human dose".<ref>{{cite web

|publisher=RxList

|title=Side Effects Drug Center: Hetlioz Clinical Pharmacology

|date=February 10, 2014 <!-- latest revision -->

|url=http://www.rxlist.com/hetlioz-drug/clinical-pharmacology.htm

}}</ref><ref>{{cite web

|publisher=RxList

|date=February 10, 2014 <!-- latest revision -->

|title=Side Effects Drug Center: Hetlioz Warnings and Precautions

|url=http://www.rxlist.com/hetlioz-drug/warnings-precautions.htm#USP

|quote=In animal studies, administration of tasimelteon during pregnancy resulted in developmental toxicity (embryofetal mortality, neurobehavioral impairment, and decreased growth and development in offspring) at doses of up to 200 times greater than those used clinically.

}}</ref>

* [[Discovery and development of melatonin receptor agonists]]

{{clear}}

== External links ==

* {{cite web | url = https://druginfo.nlm.nih.gov/drugportal/name/tasimelteon | publisher = U.S. National Library of Medicine | work = Drug Information Portal | title = Tasimelteon }}

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