ROCKVILLE, MD. — The benefits of the single-ingredient, long-acting β-agonist products salmeterol (Serevent) and formoterol (Foradil) do not outweigh their risks when used for treating asthma in adults, adolescents, and children, according to a majority of the three Food and Drug Administration advisory panels who reviewed the safety of these drugs.
However, most of the panelists agreed that the benefits of Advair, which combines salmeterol with the inhaled corticosteroid (ICS) fluticasone, and Symbicort, which combines formoterol with the ICS budesonide, outweighed the risks when used to treat asthma in adults and adolescents, according to last month's joint meeting of the FDA's Pulmonary-Allergy Drugs Committee, Drug Safety and Risk Management Committee, and Pediatric Advisory Committee.
The panel members recommended that safety be further studied in randomized, controlled trials; that health care providers and patients be educated about the importance of using an ICS as the first-line treatment for asthma; and that a long-acting β-agonist (LABA) always be used in combination with an ICS.
Support for the use of Advair in children aged 4–11 years was mixed: The panels voted 13–11, with 3 abstentions, that Advair's benefits outweighed its risks for the maintenance treatment of asthma. Advair, marketed by GlaxoSmithKline, is approved for children aged 4 years and older. Symbicort is approved only for children aged 12 years and older, so the panels did not vote on the younger age group for this product.
The panelists' primary concern was that an LABA not be used as monotherapy for maintenance treatment in patients with asthma and that when an LABA is used, it always be combined with an ICS, reflecting current asthma treatment guidelines. Some panelists noted that the labeling for the single-ingredient products was not strong enough regarding the importance of combining them with an ICS for asthma. The panelists also agreed that more safety data were needed for children on Advair and Symbicort.
Panelist Dr. Fernando Martinez, director of the Arizona Respiratory Center at the University of Arizona, Tucson, said that “there's no doubt” that LABAs have improved the lives of children with asthma, and it would be “irresponsible” to withdraw them from the market. He said he has not prescribed monotherapy with an LABA alone for at least 5 years.
“I don't consider the benefits trivial at all,” said Dr. Jesse Joad, another pediatric pulmonologist on the panel, who described the advent of these drugs as a “revolution” in treating pediatric asthma. However, the single-ingredient products should not be used for asthma, said Dr. Joad, professor and vice chair of pediatrics at the University of California, Davis.
Serevent and Foradil also are approved for COPD, so they will remain on the market, but the warnings about not using them without an ICS in patients with asthma likely will be strengthened.
The three-panel meeting was held to review the risks and benefits of Serevent and Advair (marketed by GlaxoSmithKline), Foradil (marketed by Novartis), and Symbicort (marketed by AstraZeneca Pharmaceuticals LP). The companies presented their own analyses of data at the meeting.
The joint session took place nearly 6 years after the Salmeterol Multicenter Asthma Research Trial (SMART), a large, randomized, double-blind study comparing salmeterol inhalation aerosol with placebo in about 26,000 people with asthma over age 12 years (about 12% were 12–18 years old). SMART was stopped early, in January 2003, because of recruitment problems.
The study found a small but significant increase in asthma-related deaths after 28 weeks among those on salmeterol, compared with those on placebo (13 deaths vs. 3, a relative risk of 4.4); the risk appeared to be higher among blacks.
A paradoxical finding was that some severe events were increased while immediate symptoms were improved with treatment
At the most recent meeting, the FDA presented a new meta-analysis of data obtained from the manufacturers from 110 trials of Advair, Serevent (72% of subjects), Foradil, and Symbicort in about 61,000 people aged 4–100 years (median age 37). The median treatment time was about 6 months. About half of patients reported using an ICS at baseline.
Treatment with an LABA was associated with an increased risk of asthma-related events, compared with treatment that did not include an LABA (an ICS, short-acting β-agonist, or other non-LABA treatment), as measured by a composite end point of asthma-related deaths, asthma-related intubations, and asthma-related hospitalizations.
There were 20 asthma-related deaths: 16 in the LABA group (all in Serevent-treated patients) and 4 in the non-LABA group.
The increased risk associated with LABAs, as measured by the composite end point, was not seen with Advair.