That's the question facing a three-way meeting of the FDA's advisory panels on asthma, drug safety, and pediatrics.
Analysis of data pulled from clinical trials shows that patients taking Serevent, Symbicort, or Foradil have a small increased risk of asthma-related hospitalization. This is especially true for kids 4 to 11.
The same analysis shows that patients taking Serevent have a small but significantly increased risk of asthma-related death.
A fourth related drug, Advair, was not linked to these risks in the FDA analysis. Advair is a combination of an inhaled corticosteroid and the long-acting beta-agonist (LABA) Serevent. Symbicort is a combination of a different inhaled corticosteroid and a different LABA, Foradil.
Nobody is suggesting the drugs don't help a lot of children and adults with asthma. But do the drugs benefits outweigh their risks? The drugs already carry the FDA's top-level "black box" warning -- but are more warnings or restrictions needed? That's what the panel must decide in their two-day joint meeting, scheduled for Dec. 10-11.
Inhaled asthma drugs include:
- Inhaled short-acting beta-agonists, often called rescue inhalers, which open the airways to fight the bronchial spasms that make it hard to breathe. These drugs are taken only as needed.
- Inhaled corticosteroids, which fight lung inflammation. These drugs are taken every day for long-term asthma control.
- Inhaled long-acting beta-agonists, LABAs, which open the airways to prevent bronchial spasms for long-term asthma control. These drugs are taken every day to prevent asthma attacks.
- Intal and Tilade, which are another class of inhaled anti-inflammatory drugs. They are not steroids. Intal and Tilade are not under safety review.
When Serevent was first introduced, doctors didn't fully appreciate how important it was to fight inflammation as well as bronchial spasms. In early trials of the drug, fewer than half of patients took a corticosteroid along with Serevent.
In the early 1990s, a U.K. trial suggested there might be too many deaths among patients taking Serevent. This didn't stop the FDA from approving the drug -- but after a series of nagging adverse-event reports, Serevent maker GSK agreed to conduct a large safety study.
That study, the SMART trial, was ended early when patients taking Serevent turned out to have a small but significant increase in asthma-related deaths compared to patients taking a placebo. This led to the black-box warning on all LABA-containing drugs.
In more recent years, doctors have stressed the use of either the combination inhalers or the concurrent use of both steroid and LABA inhalers. Use of LABA inhalers has gone way up, but the rate of serious asthma attacks requiring hospitalization and the rate of asthma-related deaths have both gone down.
So why sell Serevent alone? GSK says it should stay on the market because doctors may wish to used a different dose of steroid than the one in the Advair combination product, or patients may need a different steroid than the one used in Advair.
But troubling questions remain for the joint FDA panel to resolve:
- Why, if combination products are safer, does there still seem to be a significant increase in asthma-related problems with Symbicort?
- Do LABA drugs do something to make asthma worse in some patients, or is it just that people who have LABA problems aren't getting their inflammation under control with corticosteroids?
- Why do LABA-related adverse events seem to be more frequent in children under age 12?
- If single-agent LABA drugs remain on the market, what is the best way to ensure patient safety?
- Are there subgroups of patients for whom the risks of LABA drugs outweigh their benefits?
The joint panel's 27 voting members are scheduled to vote on Dec. 11, although the final questions they'll be deciding have not been announced.