Key Data Regarding The Risk
FDA's decision to require a Risk Evaluation and Mitigation Strategy (REMS) and class-labeling changes to the drug labels for Long-Acting Beta Agonists (LABAs) is based on analyses from the Salmeterol Multicenter Asthma Research Trial (SMART), the Salmeterol Nationwide Surveillance study (SNS), and a meta-analysis conducted by FDA in 2008 and discussed at the joint Pulmonary Allergy Drugs, Drug Safety and Risk Management, and Pediatric Advisory Committees, held on December 10-11, 2008 (for complete safety reviews and background information discussed at this meeting see the following link: December 10-11 2008 AC meeting).
SMART was a large, randomized, 28-week, placebo-controlled trial that evaluated a total of 26,355 patients 12 years of age and older receiving standard asthma therapy and the addition of either salmeterol or placebo. Results showed that patients receiving salmeterol were at an increased risk for asthma-related death compared to patients receiving placebo (13/13,176 in patients treated with salmeterol vs. 3/13,179 in patients treated with placebo; RR 4.37, 95% CI 1.25, 15.34). Subgroup analyses were also performed and found that asthma-related death in Caucasians and African Americans occurred at a higher rate in patients using salmeterol compared to placebo. The SNS was a 16-week, double-blind study that compared the addition of salmeterol or albuterol to standard asthma therapy in 25,180 asthma patients who were 12 years of age and older. In this study, there was an increase in the number of respiratory and asthma-related deaths in the salmeterol group compared to the albuterol group (0.07% [12 out of 16,787 patients]) compared to the albuterol group (0.02% [2 out of 8393 patients] relative risk of 3.0, p=0.105]).
In preparation for the December 2008 Advisory Committee, FDA conducted a meta-analysis of 110 studies evaluating the use of LABAs in 60,954 patients with asthma. The meta-analysis used a composite endpoint to measure severe exacerbation of asthma symptoms (asthma-related death, intubation, and hospitalization). The results of the meta-analysis suggested an increased risk for severe exacerbation of asthma symptoms in patients using LABAs compared to those not using LABAs. The largest risk difference per 1000 treated patients was seen in children 4-11 years of age, see table 2 below. The results of the meta-analysis were primarily driven by asthma-related hospitalizations. Other meta-analyses evaluating the safety of LABAs in the treatment of asthma have not shown a significant increase in the risk for severe asthma exacerbations.
At this time, there are insufficient data to conclude whether using LABAs with an inhaled corticosteroid reduces or eliminates the risk of asthma-related death and hospitalizations. FDA is requiring the manufacturers of LABAs to conduct studies evaluating the safety of LABAs when used in conjunction with an inhaled corticosteroid.
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.
See February 2010 LABA Drug Safety Communication for more information.