FDA Mandates New Safety Controls for Long-Acting Beta Agonists

Disclosures

February 18, 2010

February 18, 2010 ( UPDATED February 24, 2010 ) — The US Food and Drug Administration (FDA) announced today that manufacturers of long-acting beta agonists (LABAs) must now state on product labels that asthma patients must not take LABAs on a long-term basis unless their condition cannot be adequately controlled with other medications such as inhaled corticosteroids.

The labels also must state that the LABAs should never be used alone in the treatment of asthma in adults or children. Instead, they should be combined with an asthma "controller" medication.

Roughly 95% of asthma patients using an LABA receive it in combination with a corticosteroid in a single inhaled product such as Advair Diskus, Advair HFA, or Symbicort, according to the FDA.

Advair Diskus and Advair HFA both contain a LABA called salmeterol (Severent), and Symbicort contains the LABA formoterol (Foradil). These LABAs, along with arformoterol (Brovana), are also marketed as stand-alone medications.

Under the agency's new safety controls, LABA manufacturers must state on product labels that pediatric and adolescent patients who need a LABA in addition to a corticosteroid should be prescribed one of these combination products, as opposed to 2 separate drugs, to ensure medication compliance.

As a result of the new warning labels required by the agency, patients who gain control of their asthma through these combination corticosteroid products need to be switched to a corticosteroid alone or some other controller medication, with no LABA added.

Recent analyses of clinical trials show that LABAs are associated with a higher risk of severe worsening of asthma symptoms, resulting in hospitalization, intubation, and sometimes death for adults and children alike, according to the FDA.

"We think the greater public health benefit is to reduce the use of LABAs, but keep them available for patients who really need them," said John Jenkins, MD, director of the Office of New Drugs in the FDA's Center for Drug Evaluation and Research, at a news conference today. "There is still a benefit to these drugs for patients who aren't absolutely controlled on asthma-control medications."

Clinical Trials Leading to Decision

Implementation of the risk evaluation and mitigation strategy for LABAs was based in part on data from a 28-week Salmeterol Multi-center Asthma Research Trial (SMART) in 26,355 patients, showing that addition of salmeterol to usual asthma therapy was associated with an increased risk for fatal asthma events vs placebo (13 vs 3 deaths; 0.10% vs 0.02%; relative risk [RR], 4.37; 95% confidence interval, 1.25 - 15.34). These findings led to early discontinuation of the study.

Similarly, findings from the 16-week Salmeterol Nationwide Surveillance (SNS) study (n = 25,180) revealed that salmeterol was linked to an increased risk for respiratory and asthma-related deaths relative to albuterol (12 vs 2 deaths; 0.07% vs 0.02%; RR, 3.0; P = .105).

Also, results of an FDA meta-analysis of 110 studies (n = 60,954) suggested an increased risk for severe exacerbation of asthma symptoms (asthma-related death, intubation, and hospitalization) in patients using LABAs vs those not using LABAs. The largest risk difference per 1000 treated patients was observed in children aged 4 to 11 years (14.8 vs 2.80 overall). The FDA notes that the increase was primarily driven by asthma-related hospitalizations; other meta-analyses evaluating LABA safety have not corroborated the significantly increased risk for severe asthma exacerbations.

FDA Orders More Studies on Safety of LABAs Used With Corticosteroids

Although the FDA is now recommending that LABAs should only be prescribed together with inhaled corticosteroids and other controller medications, agency officials noted today that they do not have enough data to conclude that the popular LABA–corticosteroid combo reduces or eliminates the risk of asthma-related death and hospitalizations. Accordingly, the FDA is requiring LABA manufacturers to conduct more studies on this safety question.

The mandated studies are part of a risk evaluation and mitigation strategy program ordered for LABAs. Under the program, LABA manufacturers must also revise medication guides for patients and develop a plan to educate clinicians about the safe use of the drugs.

LABAs also are prescribed to treat patients with chronic obstructive pulmonary disease. The new safety controls announced by the FDA today do not apply to this indication.

More information is available on the FDA Web site.

Yael Waknine Weiss contributed to the news article.

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