The Food and Drug Administration (FDA) has removed the black box warning from the labeling of combination long-acting [beta]-agonists (LABAs) and corticosteroids used in the treatment of asthma. The warning stated that these combination drugs may increase the risk of serious asthma-related events such as hospitalization, intubation, or death. LABAs are used to treat chronic asthma and chronic obstructive pulmonary disease. Although they work primarily on [beta]2-receptors to promote bronchial dilation, LABAs can also stimulate, to a more limited degree, [beta]1-receptors in the heart, increasing heart rate and force of contraction. Inhaled corticosteroids decrease inflammation in the lungs.
Black box warnings for LABAs originated in 2006-after the Salmeterol Multicenter Asthma Research Trial found they increased the risk of asthma-related death-and were placed on both single-ingredient and combination drugs. The decision to remove the warnings was based on a review of findings from four clinical trials. The FDA required drug manufacturers to conduct these trials in 2011 to obtain more safety information on the drug combinations.
The four clinical trials involved 41,297 patients. Three of the trials included patients ages 12 years and older, and one trial included exclusively pediatric patients ages four to 11 years. Different inhaled LABA-corticosteroid combination drugs were used in each trial. The FDA examined data from these trials in a meta-analysis, the results of which indicated that inhaled LABA-corticosteroid combination therapy does not significantly increase the risk of serious asthma events compared with inhaled corticosteroid monotherapy. The data also indicated that the LABA-corticosteroid combination is more effective than inhaled corticosteroid monotherapy.
The use of LABA monotherapy increases the risk of asthma-related deaths, and single-ingredient LABA medications will continue to receive the black box warning related to this risk.
Examples of combination LABAs and corticosteroids are salmeterol-fluticasone (Advair Diskus, Advair HFA, Airduo Respiclick), vilanterol-fluticasone (Breo Ellipta), formoterol-mometasone (Dulera), and formoterol-budesonide (Symbicort). Nurses and NPs should review the revised labels of these asthma drugs (go to http://www.accessdata.fda.gov/scripts/cder/daf/index.cfm) and discuss the revised warnings with patients. To read the FDA Drug Safety Communication regarding LABA-corticosteroid combination inhalers, see http://www.fda.gov/Drugs/DrugSafety/ucm589587.htm.