|Long-acting beta-adrenoceptor agonist|
Long-acting β adrenoceptor agonists (LABAs, more specifically, long-acting β2 adrenergic receptor agonists) are usually prescribed for moderate-to-severe persistent asthma patients or patients with chronic obstructive pulmonary disease (COPD). They are designed to reduce the need for shorter-acting β2 agonists such as salbutamol (albuterol), as they have a duration of action of approximately 12 hours in comparison with the 4-to-6-hour duration of salbutamol, making them candidates for sparing high doses of corticosteroids or treating nocturnal asthma and providing symptomatic improvement in patients with COPD. With the exception of formoterol, long-acting β2 agonists are not recommended for the treatment of acute asthma exacerbations because of their slower onset of action compared to salbutamol. Their long duration of action is due to the addition of a long, lipophilic side-chain that binds to an exosite on adrenergic receptors. This allows the active portion of the molecule to continuously bind and unbind at β2 receptors in the smooth muscle in the lungs.
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.
Some of the currently available long-acting β2 adrenoceptor agonists include:
International nonproprietary name (INN): Trade (brand) name
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.
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 however, 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.
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.