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FDA panel: keep two bronchodilators on market; Unanimous vote backs the continued availability of salmeterol and formoterol for patients with asthma.

GAITHERSBURG, MD. -- The two long-acting inhaled [[beta].sub.2]-agonist bronchodilators available in the United States, salmeterol and formoterol, should remain on the market for people with asthma, but certain safety-related warnings in their labels should be strengthened, a federal advisory panel agreed at a recent meeting.

The Food and Drug Administration's Pulmonary-Allergy Drugs Advisory Committee panel unanimously agreed (13-0) that both drugs, approved for maintenance therapy and prevention of bronchospasm in adults, adolescents, and children, are beneficial and should not be taken off the market.

In the case of salmeterol--which already has a black-box warning on its label about the small but significant increase in asthma-related deaths in treated patients in a large postmarketing trial--the panel recommended that the warning against the use of monotherapy with long-acting [[beta].sub.2]-agonists (LABAs) be strengthened. The current label says that salmeterol should not be used as a substitute for oral or inhaled corticosteroid (ICS) therapy and recommends "early consideration" of anti-inflammatory agents such as corticosteroids in patients.

Although the same risk has not been detected in smaller studies of patients on the approved dose of formoterol (12 mcg twice a day), the panel agreed that there may be a class effect and recommended, in a 12-0 vote with one abstention, that similar warnings be added to formoterol's label, making clear that these adverse effects have been found in another drug in the same class, but not with formoterol.

The FDA should consider a "much stronger sanction of long-acting [beta]-agonist use in combination with inhaled corticosteroids, and that monotherapy be highly discouraged," said panel chair Erik Swenson, M.D., professor of medicine in the division of pulmonary and critical care medicine at the University of Washington, Seattle.

Because a small subset of patients may be adversely affected by these drugs, a specific warning might be considered for patients with brittle asthma, who have very rapid onset asthma leading to respiratory arrest or need for intubation without warning. For such patients, "this class of drugs may be considered potentially adverse," Dr. Swenson noted.

Ongoing studies are addressing such questions as why African Americans in the postmarketing trial seemed to be at greater risk of severe asthma exacerbation and death than white patients on salmeterol. Another research topic is whether polymorphisms in the [B.sub.2] receptor gene may affect response to the drug.

An inhalation powder formulation of salmeterol is marketed by GlaxoSmith-Kline Inc. as Serevent Diskus and in combination with the corticosteroid fluticasone Advair Diskus for maintenance treatment of asthma in people aged 4 years and older. The black-box warning appears on the labels of both products. (The inhalational aerosol, approved in 1994, is no longer marketed because of the phaseout of chlorofluorocarbon-containing products.) Formoterol inhalation powder, approved in 2001, is marketed as Foradil Aerolizer by Novartis Inc. for people aged 5 and older. Both are intended to be used as maintenance medications, not for acute relief of bronchospasm. (They are also approved for treating COPD, but their safety in people with asthma was the focus of the meeting.)

Both salmeterol and formoterol are recommended in national asthma treatment guidelines in combination with ICS therapy as the preferred daily treatment for moderate to severe persistent asthma. But concerns that these drugs may be associated with rare, severe asthma exacerbations, including deaths, date back to the early 1990s when severe respiratory events, including fatalities, were reported within 6 months of salmeterol's approval and in a study published before the U.S. approval of salmeterol in 1994.

In preapproval, phase III trials of formoterol, a higher dose of formoterol (24 mcg every 12 hours) was associated with a higher rate of serious asthma exacerbations than the dose that was approved in 2001 (12 mcg every 12 hours). The higher dose was not approved, so the same warnings do not appear on the formoterol label.

The FDA panel was convened to discuss these concerns and reports. The FDA usually follows the recommendations of its advisory panels.

In response to the postmarketing reports, GSK launched the Salmeterol Multicenter Asthma Research Trial (SMART), a large, randomized, double-blind trial of patients (average age 39) with asthma in 1996. The trial was stopped early in January 2003, after about 30,000 patients had been enrolled, when an interim analysis suggested, based on 28 weeks' treatment, that the risk of severe asthma exacerbations, including fatalities, was increased among those who had salmeterol added to "usual" asthma therapy treatment, than those on a placebo: There were 13 asthma-related deaths among 13,716 on salmeterol vs. 3 of 13,179 on placebo. This resulted in the addition of the black-box warning to the label in August 2003.

The risk appeared to be greater among African American patients and among those not treated with an ICS, although concomitant ICS therapy did not appear to be protective in African Americans. GSK officials at the meeting said that the SMART study was not designed to evaluate the impact of ICS therapy on these outcomes and that the low number of events prevented making definitive conclusions about ICS therapy.

After approval of formoterol, Novartis conducted a 16-week randomized, blinded study comparing different doses to placebo in 2,307 adolescent and adult patients, aged 12 and over, with mild to moderate persistent asthma between February 2002 and March 2004, which was much smaller and designed differently from SMART. Nearly 60% of subjects were on an ICS. The results were considered inconclusive.

Like other panelists, I. Marc Moss, M.D., of the division of pulmonary and critical care at Emory University, Atlanta, found it difficult to draw conclusions from the formoterol study, because it was not a large study like SMART. This signal may not have been picked up in the SMART study if it had enrolled only about 2,000 people, he noted.

If Novartis finds that formoterol is not associated with these adverse events in a large enough study, or in a smaller translational study, the reference to a possible class effect could be dropped, Dr. Moss added. He agreed that it was important to stress the role of ICS therapy, but he did not think the failure to use an ICS was the whole explanation behind the severe asthma exacerbations and deaths. But if ICS therapy was used more widely with these drugs, the event rates may be more favorable, he said.

Among the ongoing studies GSK is conducting an epidemiologic study of black and white patients, using state Medicaid data from 1995-1999, looking at the association between asthma-related prescriptions and asthma morbidity and mortality in different racial subgroups. Another study is performing genetic evaluations of patients and evaluating response to salmeterol by [[beta].sub.2]-receptor genotype, in a 38-week study of 540 subjects.

Eugene Bleeker, M.D., professor of medicine at Wake Forest University, Winston-Salem, N.C., who was at the meeting for GSK as an expert consultant, said that one genotype was more prevalent in African Americans than in whites, but that it is difficult to say how this disparity might affect outcomes.


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Author:Mechcatie, Elizabeth
Publication:Internal Medicine News
Geographic Code:1USA
Date:Sep 15, 2005
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