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FDA Drug Safety Communication: New safety requirements for long-acting inhaled asthma medications called Long-Acting Beta-Agonists (LABAs)

 

Safety Announcement

Additional Information for Patients

Additional Information for Healthcare Professionals

FDA Approved Medications Containing a Long-Acting Beta Agonist (LABA)

Data Summary

 

Safety Announcement

[02-18-2010] Due to safety concerns, the U.S. Food and Drug Administration (FDA) is requiring changes to how long-acting inhaled medications called Long-Acting Beta-Agonists (LABAs) are used in the treatment of asthma. These changes are based on FDA's analyses of studies showing an increased risk of 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 (see Data Summary below).

LABAs are approved as single-ingredient products (Serevent and Foradil) and as an ingredient in combination products containing inhaled corticosteroids (Advair and Symbicort) for the treatment of asthma and chronic obstructive pulmonary disease (COPD). They work by relaxing muscles in the airway and lungs. This helps patients breathe easier, and lessens symptoms such as wheezing and shortness of breath. The new recommendations only apply to the use of LABAs in the treatment of asthma.

To ensure the safe use of these products:

  • The use of LABAs is contraindicated without the use of an asthma controller medication such as an inhaled corticosteroid. Single-ingredient LABAs should only be used in combination with an asthma controller medication; they should not be used alone.
  • LABAs should only be used long-term in patients whose asthma cannot be adequately controlled on asthma controller medications.
  • LABAs should be used for the shortest duration of time required to achieve control of asthma symptoms and discontinued, if possible, once asthma control is achieved. Patients should then be maintained on an asthma controller medication.
  • Pediatric and adolescent patients who require the addition of a LABA to an inhaled corticosteroid should use a combination product containing both an inhaled corticosteroid and a LABA, to ensure compliance with both medications.

FDA is also requiring a risk management program called a Risk Evaluation and Mitigation Strategy (REMS) for these products. The REMS for LABAs will include a revised Medication Guide written specifically for patients, and a plan to educate healthcare professionals about the appropriate use of LABAs. In addition, FDA is requiring the manufacturers to conduct additional clinical trials to further evaluate the safety of LABAs when used in combination with inhaled corticosteroids. FDA will seek input on these studies at a public advisory committee meeting on March 10-11, 2010. 

FDA has determined that the benefits of LABAs in improving asthma symptoms outweigh the potential risks when used appropriately with an asthma controller medication in patients who need the addition of LABAs. FDA believes the safety measures recommended above will improve the safe use of these drugs.

Additional Information for Patients

  • Long-Acting Beta Agonists (LABAs) do not relieve sudden-onset asthma symptoms. Patients should always have a rescue inhaler, such as an albuterol inhaler, to treat sudden onset asthma symptoms.
  • LABAs must never be taken alone for the treatment of asthma.
  • Patients who need a LABA plus an asthma controller medication that is not available as a combination product should work with their healthcare professionals to ensure that each individual medication is taken correctly.
  • Patients should read the Medication Guide for LABAs.
  • Patients should talk with their healthcare professional to learn the warning signs of worsening asthma.
  • Patients should discuss any questions they have about the use of LABAs with their healthcare professional.

Additional Information for Healthcare Professionals

  • Long-Acting Beta Agonists (LABAs) should not be started in patients with acutely deteriorating asthma.
  • Discuss with patients and families the warning signs of worsening asthma and advise them to seek immediate medical attention should their condition deteriorate.
  • LABAs do not relieve sudden-onset asthma symptoms. A rescue inhaler, such as an albuterol inhaler, should be prescribed to treat sudden asthma symptoms.
  • Encourage patients, families, and caregivers to read the Medication Guide that accompanies LABA prescriptions.
  • When possible, prescribe a combination inhaled corticosteroid – LABA product to pediatric and adolescent patients who need the addition of a LABA for better control of their asthma. Using a combination product will help ensure compliance with both of these medications.

FDA Approved Medications Containing a Long-Acting Beta Agonist (LABA)

Brand Name LABA active ingredient Corticosteroid active ingredient FDA Approved Uses  
Serevent Diskus Salmeterol None Asthma, COPD,
exercise-induced bronchospasm
Foradil Aerolizer Formoterol None Asthma, COPD, exercise-induced bronchospasm
Foradil Certihaler* Formoterol None Asthma
Advair Diskus Salmeterol Fluticasone Asthma, COPD
Advair HFA Salmeterol Fluticasone Asthma
Symbicort Formoterol Budesonide Asthma, COPD
Brovana Arformoterol None COPD
Perforomist Formoterol None COPD

* not currently marketed in the U.S.

 

 Data Summary

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 Multi-center 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 patients 12 years of age and older receiving standard asthma therapy and the addition of either salmeterol or placebo. A total of 26,355 patients were evaluated in this study. Results showed that patients receiving salmeterol were at an increased risk for asthma-related death compared to patients receiving placebo. 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. See Table 1 below for results from SMART.

Table 1. SMART Results

SMART Patients Asthma-Related Deaths in Salmeterol Group
n (%*)
Asthma-Related
Deaths in
Placebo Group
n (%*)
Relative Risk of Asthma-Related Death
(95% Confidence Interval)
Excess Deaths Expressed per 10,000 Patients+
(95% Confidence Interval)
All Patients§
salmeterol: n = 13,176
placebo: n = 13,179
13 (0.10%) 3 (0.02%) 4.37 (1.25, 15.34) 8 (3, 13)
Caucasian Patients
Salmeterol: n = 9,281
Placebo: n = 9,361
6 (0.07%) 1 (0.01%) 5.82 (0.70, 48.37) 6 (1, 10)
African American Patients
Salmeterol: n = 2,366
Placebo: n = 2,319
7 (0.31%) 1 (0.04%) 7.26 (0.89, 58.94) 27 (8, 46)

* 28‑week estimate, adjusted according to actual lengths of exposure to study treatment to account for early withdrawal of patients from the study.

+ Estimate of the number of additional asthma‑related deaths in patients treated with salmeterol in SMART, assuming 10,000 patients received salmeterol for a 28‑week treatment period. Estimate calculated as the difference between the salmeterol and placebo groups in the rates of asthma-related death multiplied by 10,000.

§ The Total Population includes Caucasian, African American, Hispanic, Asian, and "Other" and "not reported". No asthma‑related deaths occurred in the Hispanic (salmeterol n = 996, placebo n = 999), Asian (salmeterol n = 173, placebo n = 149), or "Other" (salmeterol n = 230, placebo n = 224) subpopulations. One asthma‑related death occurred in the placebo group in the subpopulation whose ethnic origin was "not reported" (salmeterol n = 130, placebo n = 127).

 

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 the study, there was an increase in the number of respiratory and asthma-related deaths in the salmeterol group (0.07% [12 out of 16,787 patients]) compared to the albuterol group (0.02% [2 out of 8,393 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.

Table 2. Meta-Analysis Results: Number of Patients Experiencing an Event*

Patient Population LABA Patients experiencing an event Non-LABA Patients experiencing an event Risk Difference Estimate per 1000 treated patients 95% Confidence Interval

All Patients

n = 30,148 LABA patients

n = 30,806 non-LABA patients

  381   304   2.80   1.11 – 4.49

Patients ages 12 to 17 years

n = 3,103 LABA patients

n = 3,289 non-LABA patients

  48   30   5.57   0.21 – 10.92

Patients ages 4 to 11 years

n = 1,626 LABA patients

n = 1,789 non-LABA patients

  61   39   14.83   3.24 – 26.43

* Event defined as the composite endpoint (asthma-related death, intubation, and hospitalization)

 

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.

 

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