A class of asthma medications called long-acting beta agonists, linked three years ago to worsening asthma and even death, is back on the agenda at the Food and Drug Administration. There was a burst of coverage after the FDA issued a public health advisory in 2005 saying that these medications were tied to a possible heightened risk of worsening wheezing, but then the issue faded. The agency plans to call another meeting on the safety of LABAs this fall or winter.
The drugs—which include salmeterol xinafoate (Serevent Diskus), formoterol fumarate (Foradil), and formoterol fumarate (Perforomist Inhalation Solution)—do a good job of opening airways by relaxing surrounding smooth muscles. But because LABAs do not reduce airway inflammation, an inhaled corticosteroid is needed, in addition to LABA treatment, to address both key components of asthma. Otherwise, treatment "can cover up symptoms of asthma without treating the underlying problem," says Harold Nelson, a professor of medicine and an allergist at National Jewish Health in Denver. A couple of medications—fluticasone propionate/salmeterol xinafoate (Advair) and budesonide/formoterol fumarate dihydrate (Symbicort)—include a combination of both an LABA and an inhaled corticosteroid.
The renewed interest at the FDA grows out of a concern that the drugs are still being tried before other, possibly less risky treatments have been attempted and that they haven't been sufficiently studied in children. The data on safety and effectiveness "isn't there for children like it is for adults," says Robert F. Lemanske Jr., head of the Division of Pediatric Allergy, Immunology, and Rheumatology at the University of WisconsinMadison. In kids ages 5 to 11, in particular, more information is needed on whether LABAs cause a worsening of asthma. (Lemanske has served as a speaker and consultant to various drug manufacturers.)
Meanwhile, physicians who prescribe LABAs stress that the drugs are not intended to be used as a first-line therapy for asthmatics with persistent symptoms requiring daily medication. The National Heart, Lung, and Blood Institute recommends that inhaled corticosteroids be used first as the preferred long-term treatment for all age groups. Next, a combined approach of LABAs and inhaled corticosteroids is preferred for patients 5 and older. LABAs are not intended to be used as "rescue" medications in the case of an attack—for that, patients should carry a separate bronchodilator such as albuterol, a short-acting beta agonist that acts quickly to ease shortness of breath.
"Many experts in the field of asthma feel that there is no risk in using long-acting beta agonists as long as they're used in conjunction with an inhaled corticosteroid," says Nelson, who led the Salmeterol Multicenter Asthma Research Trial that prompted much of the concern about LABAs. And using a combination approach seems to help patients feel better, too. With medications like Advair—which combines the LABA salmeterol with the inhaled corticosteroid fluticasone propionate—"patients recognized right away that they felt better, so all of those things created clinician and physician preference for the combination therapy," says Stanley Szefler, head of pediatric clinical pharmacology at National Jewish Health, who has served as a consultant for various drug companies. Nelson's study, the results of which were published in 2006 in the journal Chest, found a small but statistically significant increase in deaths and life-threatening experiences among those who received the LABA salmeterol by itself. That risk seemed greater among African-Americans, but it was not clear if the results were attributable to genetic factors, patient behaviors, or other issues that may have led to poorer outcomes in certain patients.
The problem remains that, because some drugs are heavily marketed, patients ask their doctors to prescribe LABAs before they've ever tried taking an inhaled corticosteroid alone—or they get an LABA first because samples are readily available. "There is evidence that LABAs are still used as first-line therapy, even though the guidelines say they should only be used when other agents have failed," says Shelley Salpeter, a Stanford University School of Medicine clinical professor of medicine and lead author of a 2006 meta analysis published in the Annals of Internal Medicine that suggested that LABAs shouldn't be used in asthma treatment. Salpeter, who reports no ties to drug manufacturers, says she does not believe that "the benefits of LABAs are worth the risks, and I do not use them in my practice at all."