long-acting beta-adrenoceptor agonist#Ultra-LABAs

When combined with inhaled steroids, β adrenoceptor agonists can improve symptoms.{{cite journal|last=Higashi|first=AS|author2=Zhu S |author3=Stafford RS |author4= Alexander GC |title=National trends in outpatient asthma treatment, 1997-2009.|journal=Journal of General Internal Medicine|volume=26|pages=1465–70|year=2011|pmid=21769507|doi=10.1007/s11606-011-1796-4|issue=12 |pmc=3235617}}{{cite journal|last1=Ducharme|first1=Francine M|last2=Ni Chroinin|first2=Muireann|last3=Greenstone|first3=Ilana|last4=Lasserson|first4=Toby J|title=Addition of long-acting beta2-agonists to inhaled corticosteroids versus same dose inhaled corticosteroids for chronic asthma in adults and children|journal=The Cochrane Database of Systematic Reviews|date=12 May 2010|issue=5|pages=CD005535|doi=10.1002/14651858.CD005535.pub2|pmid=20464739|pmc=4169792}} In children this benefit is uncertain and they may be potentially harmful. They should not be used without an accompanying steroid due to an increased risk of severe symptoms, including exacerbation in both children and adults.{{cite journal |author=Fanta CH |title=Asthma |journal=New England Journal of Medicine|volume=360|issue=10 |pages=1002–14 |date=March 2009 |pmid=19264689 |doi=10.1056/NEJMra0804579}} A 2018 meta-analysis was unable to determine whether an increase serious adverse events reported in the previous meta-analysis on regular salmeterol alone is abolished by the additional use of regular inhaled corticosteroid.{{Cite journal|last1=Cates|first1=Christopher J.|last2=Schmidt|first2=Stefanie|last3=Ferrer|first3=Montse|last4=Sayer|first4=Ben|last5=Waterson|first5=Samuel|date=3 December 2018|title=Inhaled steroids with and without regular salmeterol for asthma: serious adverse events|journal=The Cochrane Database of Systematic Reviews|volume=2018|issue=12 |pages=CD006922|doi=10.1002/14651858.CD006922.pub4|issn=1469-493X|pmc=6524619|pmid=30521673}} Large surveillance studies are ongoing to provide more information. There were no asthma-related deaths and few asthma-related serious adverse events when salmeterol is used with an inhaled steroid.{{cite journal |author=Cates CJ, Cates MJ|title=Regular treatment with salmeterol for chronic asthma: serious adverse events |journal=Cochrane Database Syst Rev |issue=3 |pages=CD006363 |year=2008 |pmid=18646149 |pmc=4015854 |doi=10.1002/14651858.CD006363.pub2|editor1-last=Cates |editor1-first=Christopher J }}{{cite web|title=FDA Drug Safety Communication: New safety requirements for long-acting inhaled asthma medications called Long-Acting Beta-Agonists (LABAs)|url=https://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ucm200776.htm|work=U.S. Food and Drug Administration (FDA)|date=Feb 2010|quote=Based on the available information, FDA concludes there is an increased risk for severe exacerbation of asthma symptoms, leading to hospitalizations in pediatric and adult patients as well as death in some patients using LABAs for the treatment of asthma. The agency is requiring the REMS and class-labeling changes to improve the safe use of these products.|access-date=2019-12-16|archive-url=https://web.archive.org/web/20171102213110/https://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ucm200776.htm|archive-date=2017-11-02|url-status=dead}} At least with formoterol, an increased risk appears to be present even when steroids are used{{cite journal|last=Cates|first=CJ|author2=Cates, MJ |title=Regular treatment with formoterol for chronic asthma: serious adverse events|journal=Cochrane Database of Systematic Reviews|date=Apr 18, 2012|volume=4|issue=4|pages=CD006923|pmid=22513944|pmc=4017186|doi=10.1002/14651858.CD006923.pub3}} and this risk has not been ruled out for salmeterol.{{cite journal|last=Cates|first=CJ|author2=Cates, MJ |title=Regular treatment with salmeterol for chronic asthma: serious adverse events|journal=Cochrane Database of Systematic Reviews|date=Jul 16, 2008|issue=3|pages=CD006363|pmid=18646149|pmc=4015854|doi=10.1002/14651858.CD006363.pub2}}

Some of the currently available long-acting β₂ adrenoceptor agonists include:

International nonproprietary name (INN): Trade (brand) name

• arformoterol: Brovana (some consider it to be an ultra-LABA){{cite journal|last1=Matera|first1=MG|last2=Cazzola|first2=M|title=Ultra-Long-Acting β₂-Adrenoceptor Agonists: An Emerging Therapeutic Option for Asthma and COPD?|journal=Drugs|date=2007|volume=67|issue=4|pages=503–15|doi=10.2165/00003495-200767040-00002|url=https://www.researchgate.net/publication/6453632|accessdate=7 March 2016|pmid=17352511|s2cid=46976912}}
• bambuterol: Bambec, Oxeol
• clenbuterol: Dilaterol, Spiropent
• formoterol: Foradil, Oxis, Perforomist
• salmeterol: Serevent
• protokylol: Ventaire

Several long-acting β adrenoreceptor agonists have a duration of action of 24 hours, allowing for once-daily dosing. They are considered to be ultra-long-acting β adrenoreceptor agonists (ultra-LABAs){{cite journal |vauthors=Cazzola M, Matera MG, Lötvall J |title=Ultra long-acting beta 2-agonists in development for asthma and chronic obstructive pulmonary disease |journal=Expert Opin Investig Drugs |volume=14 |issue=7 |pages=775–83 |date=July 2005 |pmid=16022567 |doi=10.1517/13543784.14.7.775 |s2cid=11930383 }} and are now approved.

• indacaterol: approved by the European Medicines Agency (EMA) on November 30, 2009,[http://www.ema.europa.eu/humandocs/Humans/EPAR/onbrez_breezhaler/onbrez_breezhaler.htm European Public Assessment Report for Onbrez Breezhaler] {{webarchive|url=https://web.archive.org/web/20100116122038/http://www.ema.europa.eu/humandocs/Humans/EPAR/onbrez_breezhaler/onbrez_breezhaler.htm |date=2010-01-16 }} and by Russian FDA-equivalent under the trade name Onbrez Breezhaler. In the United States. it was approved by the Food and Drug Administration (FDA) under the trade name Arcapta Neohaler on July 1, 2011){{cite press release |url=https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm261649.htm |title=FDA approves Arcapta Neohaler to treat chronic obstructive pulmonary disease |publisher=U.S. Food and Drug Administration (FDA) |date=2011-07-01 |accessdate=2011-07-02 |archive-url=https://web.archive.org/web/20110703185258/http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm261649.htm |archive-date=2011-07-03 |url-status=dead }}
• olodaterol: approved in some European countries and Russia, and by the U.S. Food and Drug Administration (FDA) on July 31, 2014, under Striverdi Respimat{{cite news|url=https://www.boehringer-ingelheim.com/news/news_releases/press_releases/2013/18_october_2013_olodaterol.html|title=New once-daily Striverdi (olodaterol) Respimat gains approval in first EU countries|publisher=Boehringer-Ingelheim|date=18 October 2013}}
• vilanterol is the ultra-LABA not available by itself but only as a component of combination drugs:
• with fluticasone furoate: Breo Ellipta (U.S.), Relvar Ellipta (EU, RU). This second medication in this combination is the synthetic inhaled corticosteroid fluticasone furoate. This product was approved by the FDA in May 2013 as once-daily inhaled therapy for the treatment of chronic obstructive pulmonary disease (COPD)
• with umeclidinium bromide: Anoro Ellipta. Umeclidinium bromide is a long-acting muscarinic antagonist.{{cite web|title=Incruse Ellipta (umeclidinium inhalation powder) for Oral Inhalation Use. Full Prescribing Information|url=https://www.gsksource.com/pharma/content/dam/GlaxoSmithKline/US/en/Prescribing_Information/Incruse_Ellipta/pdf/INCRUSE-ELLIPTA-PI-PIL.PDF|publisher=GlaxoSmithKline, Research Triangle Park, NC 27709|accessdate=22 February 2016|archive-date=10 July 2018|archive-url=https://web.archive.org/web/20180710050003/https://www.gsksource.com/pharma/content/dam/GlaxoSmithKline/US/en/Prescribing_Information/Incruse_Ellipta/pdf/INCRUSE-ELLIPTA-PI-PIL.PDF|url-status=dead}} This combination was approved by the FDA on December 18, 2013{{cite web|title=FDA approves Anoro Ellipta to treat chronic obstructive pulmonary disease|url=https://www.fda.gov/newsevents/newsroom/pressannouncements/ucm379057.htm|publisher=U.S. Food and Drug Administration (FDA)|accessdate=25 March 2016|archive-url=https://web.archive.org/web/20160324173044/http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm379057.htm|archive-date=24 March 2016|url-status=dead}} for the long-term maintenance treatment of COPD. On March 28, 2014, it was approved in European countries{{cite web|title=Assessment report: Anoro. INN: umeclidinium bromide/vilanterol|url=http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Public_assessment_report/human/002751/WC500168425.pdf|website=European Medicines Agency|accessdate=25 March 2016}} and in Russia{{cite web|title=State Register of Nedicines: Anoro Ellipta (vilanterol + umeclidinium bromide)|url=http://grls.rosminzdrav.ru/GRLS.aspx?RegNumber=&MnnR=&lf=&TradeNmR=Аноро+Эллипта&OwnerName=&MnfOrg=&MnfOrgCountry=&isfs=0&isND=-1®type=&order=RegDate&orderType=desc&pageNum=1|website=Russian State Register of Medicinal Products|accessdate=25 March 2016|language=ru}} under the same trade name.

{{Update section|date=February 2020}}

• abediterol (codenamed LAS100977){{cite journal |last1=Beier |first1=J |last2=Fuhr |first2=R |last3=Massana |first3=E |last4=Jiménez |first4=E |last5=Seoane|first5=B|last6=de Miquel|first6=G|last7=Ruiz|first7=S|title=Abediterol (LAS100977), a novel long-acting β₂-agonist: Efficacy, safety and tolerability in persistent asthma|journal=Respiratory Medicine|date=October 2014|volume=108|issue=10|pages=1424–1429|doi=10.1016/j.rmed.2014.08.005|pmid=25256258|url=http://www.resmedjournal.com/article/S0954-6111(14)00287-X/pdf|accessdate=25 March 2016|doi-access=free}}{{cite journal|last=Cazzola|first=Mario|author2=Luigino Calzetta |author3=Maria Gabriella Matera3 |title=β2-adrenoceptor agonists: current and future direction|journal=Br J Pharmacol|date=May 2011|volume=163|issue=1|pages=4–17|doi=10.1111/j.1476-5381.2011.01216.x|pmid=21232045|pmc=3085864}}
• salmefamol (salbutamol and para-methoxyamphetamine (PMA) hybrid){{citation needed|date=December 2019}}

• carmoterol (formerly TA-2005): development terminated{{cite web|title=Chiesi: Annual Report 2010|url=http://www.chiesi.es/Assets/docs/Annual_report_2010.pdf|publisher=Chiesi Farmaceutici S.p.A.|accessdate=27 March 2016|page=20}}
• PF-610355: development terminated{{cite web|title=AdisInsight: PF 610355|url=http://adisinsight.springer.com/drugs/800025582|publisher=Springer International Publishing AG|accessdate=25 March 2016}}

A meta-analysis study from 2006 (pooled results of 19 trials, 33,826 participants) raised concerns that Salmeterol may increase the risk of death in asthmatics, and that the additional risk was not reduced with the adjunctive use of inhaled steroids (e.g., as with the combination product fluticasone/salmeterol).{{cite journal |vauthors=Salpeter S, Buckley N, Ormiston T, Salpeter E | title = Meta-analysis: effect of long-acting beta-agonists on severe asthma exacerbations and asthma-related deaths | journal = Ann Intern Med | volume = 144 | issue = 12 | pages = 904–12 | year = 2006 | pmid=16754916 | doi=10.7326/0003-4819-144-12-200606200-00126| s2cid = 30648411 | doi-access = }}

The proposed mechanism is that while LABAs relieve asthma symptoms, they can also promote bronchial inflammation and sensitivity without warning.{{cite news | author=Krishna Ramanujan | title=Common asthma inhalers cause up to 80 percent of asthma-related deaths, Cornell and Stanford researchers assert | url=http://www.news.cornell.edu/stories/June06/AsthmaDeaths.kr.html | date=June 9, 2006 | publisher=ChronicalOnline - Cornell University}} On February 18, 2011, the FDA issued a safety alert for long-acting β agonists.{{cite web|title=Safety Alerts for Human Medical Products > Long-Acting Beta-Agonists (LABAs): New Safe Use Requirements|url=https://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm201003.htm|publisher=U.S. Food and Drug Administration (FDA)|accessdate=25 March 2016|archive-url=https://web.archive.org/web/20160322034848/http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm201003.htm|archive-date=22 March 2016|url-status=dead}}

Following new clinical safety trials, the FDA issued updated guidance on 20 December 2017, that there is no significant increased risk of serious asthma outcomes with LABAs when used together with inhaled corticosteroids.{{cite web|title=FDA Drug Safety Communication: FDA review finds no significant increase in risk of serious asthma outcomes with long-acting beta agonists (LABAs) used in combination with inhaled corticosteroids (ICS)|date=9 February 2019 |url=https://www.fda.gov/drugs/drug-safety-and-availability/fda-drug-safety-communication-fda-review-finds-no-significant-increase-risk-serious-asthma-outcomes|publisher=U.S. Food and Drug Administration (FDA)}}

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Category:Long-acting beta2-adrenergic agonists