Long-acting beta-adrenoceptor agonist

Medical uses

When combined with inhaled steroids, β adrenoceptor agonists can improve symptoms. 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. 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. 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. At least with formoterol, an increased risk appears to be present even when steroids are used and this risk has not been ruled out for salmeterol.

Agents

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)
• bambuterol: Bambec, Oxeol
• clenbuterol: Dilaterol, Spiropent
• formoterol: Foradil, Oxis, Perforomist
• salmeterol: Serevent
• protokylol: Ventaire

Ultra-LABAs

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) and are now approved.

• indacaterol: approved by the European Medicines Agency (EMA) on November 30, 2009, 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)
• 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
• 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. This combination was approved by the FDA on December 18, 2013 for the long-term maintenance treatment of COPD. On March 28, 2014, it was approved in European countries and in Russia under the same trade name.

Under development

• abediterol (codenamed LAS100977)
• salmefamol (salbutamol and para-methoxyamphetamine (PMA) hybrid)

Failed agents

• carmoterol (formerly TA-2005): development terminated
• PF-610355: development terminated

Concerns

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). The proposed mechanism is that while LABAs relieve asthma symptoms, they can also promote bronchial inflammation and sensitivity without warning. On February 18, 2011, the FDA issued a safety alert for long-acting β agonists. 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.

References

References

1. Higashi, AS. (2011). "National trends in outpatient asthma treatment, 1997-2009.". Journal of General Internal Medicine.
2. (12 May 2010). "Addition of long-acting beta2-agonists to inhaled corticosteroids versus same dose inhaled corticosteroids for chronic asthma in adults and children". The Cochrane Database of Systematic Reviews.
3. Fanta CH. (March 2009). "Asthma". New England Journal of Medicine.
4. (3 December 2018). "Inhaled steroids with and without regular salmeterol for asthma: serious adverse events". The Cochrane Database of Systematic Reviews.
5. Cates CJ, Cates MJ. (2008). "Regular treatment with salmeterol for chronic asthma: serious adverse events". Cochrane Database Syst Rev.
6. (Feb 2010). "FDA Drug Safety Communication: New safety requirements for long-acting inhaled asthma medications called Long-Acting Beta-Agonists (LABAs)". U.S. [[Food and Drug Administration]] (FDA).
7. Cates, CJ. (Apr 18, 2012). "Regular treatment with formoterol for chronic asthma: serious adverse events". Cochrane Database of Systematic Reviews.
8. Cates, CJ. (Jul 16, 2008). "Regular treatment with salmeterol for chronic asthma: serious adverse events". Cochrane Database of Systematic Reviews.
9. (2007). "Ultra-Long-Acting β₂-Adrenoceptor Agonists: An Emerging Therapeutic Option for Asthma and COPD?". Drugs.
10. (July 2005). "Ultra long-acting beta 2-agonists in development for asthma and chronic obstructive pulmonary disease". Expert Opin Investig Drugs.
11. [http://www.ema.europa.eu/humandocs/Humans/EPAR/onbrez_breezhaler/onbrez_breezhaler.htm European Public Assessment Report for Onbrez Breezhaler] {{webarchive. link. (2010-01-16)
12. (2011-07-01). "FDA approves Arcapta Neohaler to treat chronic obstructive pulmonary disease". U.S. [[Food and Drug Administration]] (FDA).
13. (18 October 2013). "New once-daily Striverdi (olodaterol) Respimat gains approval in first EU countries". Boehringer-Ingelheim.
14. "Incruse Ellipta (umeclidinium inhalation powder) for Oral Inhalation Use. Full Prescribing Information". GlaxoSmithKline, Research Triangle Park, NC 27709.
15. "FDA approves Anoro Ellipta to treat chronic obstructive pulmonary disease". U.S. [[Food and Drug Administration]] (FDA).
16. "Assessment report: Anoro. INN: umeclidinium bromide/vilanterol".
17. "State Register of Nedicines: Anoro Ellipta (vilanterol + umeclidinium bromide)".
18. (October 2014). "Abediterol (LAS100977), a novel long-acting β₂-agonist: Efficacy, safety and tolerability in persistent asthma". Respiratory Medicine.
19. Cazzola, Mario. (May 2011). "β2-adrenoceptor agonists: current and future direction". Br J Pharmacol.
20. "Chiesi: Annual Report 2010". Chiesi Farmaceutici S.p.A..
21. "AdisInsight: PF 610355". Springer International Publishing AG.
22. (2006). "Meta-analysis: effect of long-acting beta-agonists on severe asthma exacerbations and asthma-related deaths". Ann Intern Med.
23. Krishna Ramanujan. (June 9, 2006). "Common asthma inhalers cause up to 80 percent of asthma-related deaths, Cornell and Stanford researchers assert". ChronicalOnline - Cornell University.
24. "Safety Alerts for Human Medical Products > Long-Acting Beta-Agonists (LABAs): New Safe Use Requirements". U.S. [[Food and Drug Administration]] (FDA).
25. (9 February 2019). "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)". U.S. [[Food and Drug Administration]] (FDA).