Parker Waichman LLP Injury Alerts
Evidence of Significant Risks Mounts Against Long-Acting Beta2 Agonists (Serevent, Symbicort, Foradil, and Advair)Jan 1, 2008
On December 11, advisers to the FDA voted to recommend that two single-agent long-acting beta2 agonist inhalers be stripped of their asthma indications. In the advisers’ opinion, the drugs, salmeterol (Serevent) and formoterol (Foradil), carry too high a risk for asthma-related complications and death, and too small of an apparent health benefit when without a steroid. The panel was comprised of the Pulmonary-Allergy Drugs Advisory Committee, the Drug Safety and Risk Management Advisory Committee, and the Pediatric Advisory Committee.
The recommendation, if followed by the FDA, would continue to permit both drugs to retain their indication for chronic obstructive pulmonary disease (COPD), or approximately 50% of the drugs’ current users.
The vote was taken separately as to three main age groups: The panel voted 17 to 10 that the benefits of Serevent do not outweigh the risks for adults 18 and older; 21 to 6 for ages 12 to 17; and 27 to 0 for children ages 4 to 11. For Foradil, the vote was 18 to 9 that the benefits of the drug do not outweigh the risks for adults 18 and older; 21 to 6 for the adolescent age group; and 27 to zero for those four to 11.
A statement released by Novartis and Schering-Plough expressed strong disagreement with the panel’s recommendation as to the risks of Foradil in patients using it according to current product labeling for the maintenance treatment of asthma, adding that "access to single-agent long acting beta agonists provides physicians with the ability to develop customized treatment approaches that best meet the needs of their patients."
Previously, Glaxo-Smith-Kline, which markets the salmeterol-containing products Advair and Serevent, defended the safety of its asthma drugs in its own set of briefing documents. The manufacturer acknowledged a potential increased risk of serious asthma-related events with salmeterol but wrote that for "Serevent, the signal of potential increased risk of serious asthma-related outcomes was only apparent when Serevent is used without concurrent inhaled corticosteroids or in patients who are likely non-adherent with their prescribed inhaled corticosteroids."
The company said that it has already submitted a supplement asking the FDA to revise the product label to provide more information about "appropriate use" of the product.
While the same panel recommended that two other long-acting inhalers (salmeterol/fluticasone [Advair] and formoterol/budesonide [Symbicort]) retain their current indications, that vote was based on data and testimony that both drugs contain a corticosteroid, which appears to limit the risks posed by long-acting beta agonists. Although the single-agent drugs already carry black-box warnings stating that they should be used with a corticosteroid, data presented at the hearing showed that of the 11,912 patients taking long-acting beta agonists, 48% never take the medication with a corticosteroid.
This evidence convinced a majority of the advisers that even a black-box warning is apparently not enough to ensure that patients use the single-agent drugs with a corticosteroid. "The first paragraph [of the black-box warning] doesn't mention inhaled corticoid steroid and many people don't read beyond the first paragraph," said Avital Cnaan, Ph.D., M.S., of the the Center for Clinical and Community Research in Washington.
The panel’s recommendations were based in part on an FDA meta-analysis of 110 trials of the four asthma drugs that found a statistically significant increased risk for hospitalization and death among patients taking Serevent.
Although the panel unanimously supported the use of Advair for adults (27-0) and overwhelming supported its use in adolescents (23-3-1), the vote to maintain the drug's current indications in children ages 4 to 11 passed by only a 13-11-3 margin.
Symbicort, the remaining long-lasting beta agonist with a steroid is already not indicated for children 4 to 11. The panel voted 26-1 that the benefits of Symbicort outweigh its risks for use in adults, and 25-2 that the benefits outweigh the risks for use in patients 12 to 17.
Notwithstanding its marginal support for Advair's use in children, the panel agreed that physicians should rely on inhaled corticoid steroids and not Advair as a “first line of treatment for childhood asthma,” stated pediatrician Fernando Martinez, M.D., of the Arizona Respiratory Center at the University of Arizona in Phoenix.
While some FDA staffers also called for a ban on two of the four drugs for use in adolescents and a complete ban on the remaining two because of the high mortality risk with them, other FDA staffers viewed this as too extreme a measure and some clinicians told the panel that banning the drugs would, on balance, be harmful to patients.
David Graham, M.D., associate director for science and medicine in the FDA's Office of Surveillance and Epidemiology, and a frequent critic of FDA practices and drug approvals, said "single-entity long-acting beta agonists products [Serevent and Foradil] should be withdrawn from the market because the benefits are small compared with albuterol, especially in children." Ann McMahon, M.D., M.S., acting director of the Division of Pharmocovigilance in the same office, took a similar position.
The FDA's recent meta-analyses of 110 trials (60,000 patients) of the four inhalers found patients who took three of the long-acting inhalers had an increased risk of asthma-related death and hospitalization compared with those who took non-long-acting beta agonists. The risk was especially pronounced in children.
Sixteen patients died in the inhaler group of the meta-analyses, all of whom were given Serevent only. Four patients died in control groups. Some 73% (43,824) of all patients in the analysis were from trials testing Serevent.
There was an increased composite risk for hospitalization, intubation, and death in groups taking Foridil, Serevent, and Symbicort; however, only the Serevent group had a significant composite risk for hospitalization, intubation, and death The Advair group did not have any increased risk in adverse events.
According to Dr. Graham, there were likely 5,460 deaths that occurred between 1994 and 2004 because of Serevent, which is about 10% of all asthma-related deaths during that time.