FDA imposes new safety requirements to curb use of LABAs in asthma patients

On February 18, 2010, FDA recommended drastic changes in the way long-acting beta2-adrenergic agonists are used in the treatment of asthma in order to limit their utilization.

Key Points

On February 18, 2010, FDA recommended drastic changes in the way long-acting beta2-adrenergic agonists (LABAs) are used in the treatment of asthma in order to limit their utilization. This decision was based upon an analysis of data from a surveillance study (Salmeterol Nationwide Surveillance Study; SNS), a large, randomized trial (Salmeterol Multicenter Asthma Research Trial; SMART), and a meta-analysis of asthma patients.

Data from the above sources demonstrated that LABAs increase the risk of severe exacerbation of asthma symptoms, potentially leading to more hospitalizations or even death in both pediatric and adult patients receiving these drugs. The excess death rate due to LABAs was estimated by FDA to be 8 (95% CI, 3–13) per 10,000 asthma patients treated or about 3–fold higher than those not treated with a LABA.

Currently two LABAs have FDA marketing approval for the treatment of asthma-salmeterol (the active ingredient in Serevent Diskus, Glaxo Group Ltd.; Advair Diskus, GlaxoSmithKline; Advair HFA, GlaxoSmithKline) and formoterol (the active agent in Foradil, Novartis and Symbicort, AstraZeneca). The LABA arformoterol (Brovana, Sepracor) is also available in the United States; however, it is only indicated for the treatment of chronic obstructive pulmonary disease.

Specifically, FDA is warning healthcare providers that the use of LABAs is contraindicated without the use of an "asthma controller medication" such as an inhaled corticosteroid. To ensure compliance, the agency is suggesting a combination product such as Advair Diskus, Advair HFA, or Symbicort be used, particularly in pediatric and adolescent patients. These products contain both a LABA and an inhaled corticosteroid such as fluticasone or budesonide.

Furthermore, FDA recommends that LABAs should be used for the shortest duration of time required to achieve control of asthma symptoms and then discontinued, if possible, once asthma control is achieved. LABAs should only be used long-term in patients whose asthma cannot be adequately controlled on asthma controller medications.

REMS FOR LABAS

FDA is also requiring a Risk Evaluation and Mitigation Strategy (REMS) for LABAs used to treat asthma. The REMS for these drugs will include a revised medication guide for asthma patients, a plan to educate healthcare professionals about the appropriate use of LABAs, and a requirement of manufacturers to conduct additional clinical trials to further evaluate the safety of these drugs when used in combination with inhaled corticosteroids to treat asthma.

BENEFITS OUTWEIGH RISKS

"The benefits of long-acting beta2 agonists in improving asthma symptoms outweigh the potential risks when used appropriately with an asthma controller medication in patients who need the addition of long-acting beta2 agonists," FDA officials noted. "FDA believes the safety measures recommended above will improve the safe use of these drugs."

Of the medications affected by this recent FDA safety announcement, Advair Diskus is the most commonly used. Of all drugs marketed in the United States, it was ranked 4th in revenue and 20th in number of prescriptions dispensed in 2008.

SOURCES

Castle W, Fuller R, Hall J, Palmer J. Serevent nationwide surveillance study: comparison of salmeterol with salbutamol in asthmatic patients who require regular bronchodilator treatment. Br Med J. 1993;306:1034–1037.

Nelson HS, Weiss ST, Bleecker ER, Yancey SW, Dorinsky PM; SMART Study Group. The Salmeterol Multicenter Asthma Research Trial: a comparison of usual pharmacotherapy for asthma or usual pharmacotherapy plus salmeterol. Chest. 2006;(1):15–26.

FDA. FDA Drug Safety Communication: New safety requirements for long-acting inhaled asthma medications called Long-Acting Beta-Agonists (LABAs) [02-18-2010]. Available at: http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ucm200776.htm. Accessed February 19, 2010.