Users who use Advair Diskus, Advair HFA, Foradil Aerolizer, Serevent Diskus, and Symbicort for their asthma must decide if it makes sense to continue with these drugs despite the risks.

If you rely on one of the popular long-acting asthma medications -- Advair Diskus, Advair HFA, Foradil Aerolizer, or Serevent Diskus -- it must have been a jolt to read the medical advisory that you suddenly began to find in the package along with your asthma prescription. An increased risk of wheezing and even death seems a high price to pay for the fact that these medications decrease the number of wheezing episodes and remain effective for hours longer than other bronchodilators.

The U.S. Food and Drug Administration (FDA) agreed with that assessment, decreeing that these asthma drugs must now carry the most extreme class of medication warning label: the so-called black box warning.

All of these asthma products belong to the class of bronchodilators known as long-acting beta2-adrenergic agonists (LABAs), which reduce bronchospasm (wheezing) by relaxing the muscles around the airways. They take effect relatively slowly and act, as the name says, for a long period, a matter of hours. A new asthma drug, Symbicort, also carries the warning.

Why the Concern? The black box warnings came about because of findings from a large U.S. study, the Salmeterol Multi-center Asthma Research Trial, or SMART, that compared the safety of the LABA drug salmeterol (the active ingredient in Serevent and Advair) with placebo, when added to patients’ usual asthma treatment. The study showed an increase in asthma-related deaths among people who took salmeterol (13 deaths among 13,176 patients on salmeterol for 28 weeks versus only three among 13,179 patients on placebo).

The problems with these drugs weren’t apparent immediately because the data from the SMART study originally submitted to the FDA included a six-month follow-up period after the study had been completed. Apparently the risk of death declines when the drugs are no longer in use. This emerged from the statistics only after the FDA had removed the follow-up period from the analysis.

Even more disturbing news came in June 2006, when the Annals of Internal Medicine published an analysis of 19 studies on asthma medicines, reporting that, compared with placebo, the long-acting bronchodilators pose a substantially increased risk of hospitalization, life-threatening exacerbations, and death. The authors concluded that salmeterol (the active ingredient in these drugs) may be responsible for some 4,000 of the 5,000 asthma-related deaths that occur each year in the United States. They also suggest that the data could be used to reassess whether these asthma drugs should be taken off the market.

The Conundrum: Big Risk, Small Numbers -- Not surprisingly, the black box warning prompted a lot of people to stop taking Serevent, Advair, and Foradil. But it’s important to take into account the fact that, while the risk of death revealed in the study was statistically significant, it was not dramatic in terms of the magnitude of the increased risk of death (13 deaths versus three, out of two treatment groups that numbered more than 13,000 each). The FDA acted prudently as a government agency, but a wise decision for an individual involves a different set of issues.

Obviously it’s important to discuss with your physician whether you should reconsider using these asthma drugs, which do have advantages. Inevitably, this is a highly individualized decision, based on many factors. There are individuals whose asthma is severe, who have trouble breathing when they use a variety of other medications, and who do very well using a drug like Serevent. After conversations with their physicians, these people may decide that it is justified to continue using the LABA drug despite the risks.

When you talk to your doctor about your asthma medicine, keep in mind these recommendations from the FDA:

• LABAs should not be the first-choice medicine to treat your asthma. These drugs should be added to your treatment plan only if other medicines, such as low- or medium-dose inhaled corticosteroids, do not control your symptoms.

• Do not stop using your LABA or other prescription asthma medicines without consulting your doctor.

• Do not use your LABA to treat wheezing that is getting worse. If this happens, contact the doctor immediately. Because they are long acting, LABAs do not relieve sudden wheezing. You should keep a short-acting bronchodilator medicine close at hand so that you are always ready to treat wheezing that begins suddenly.

What If You’re Taking a LABA for Another Reason? The new warnings concern the use of LABAs for asthma. But people with asthma aren’t the only ones who use this class of medications. In addition to long-term control and prevention of asthma symptoms, LABAs are prescribed to prevent wheezing caused by exercise in adults and children (exercise-induced asthma) and for long-term control of wheezing in adults with chronic obstructive pulmonary disease (COPD).

Brovana, a LABA approved for COPD but not asthma has also received the black box warning. Although the active ingredient in Brovana is arformeterol, the FDA warns that the findings regarding salmeterol may apply to this drug as well.