Asthma Medicines That Can Cause Asthma Attacks: SEREVENT, ADVAIR and FORADIL

The Food and Drug Administration advisory committee has voted in favor of putting stronger warnings on three widely used asthma inhalers — salmeterol (SEREVENT), salmeterol with the steroid fluticasone (ADVAIR) and formoterol (FORADIL). These medicines are long-acting asthma inhalers, used to keep asthma under control over time, rather than helping to stop an acute asthma attack.

The FDA convened a meeting of its Pulmonary-Allergy Drugs Advisory Committee on July 13, 2005 to discuss the safety of these drugs. The advisory committee voted to keep these drugs on the market but recommend stronger safety warnings on the professional product labels for all three drugs.

These inhalers are in the family of asthma drugs known as long-acting beta-agonist bronchodilators. Note that this is a different family of medicines than the asthma drugs albuterol (PROVENTIL, VENTOLIN), metaproterenol (ALUPENT) and pirbuterol (MAXAIR). Those are short-acting beta-agonist bronchodilators, and are used to improve breathing during an asthma attack.

GlaxoSmithKline of Research Triangle Park, N.C., sells both of the salmeterol-containing products. Salmeterol by itself was dispensed over 2.1 million times in U.S. pharmacies in 2004 with sales exceeding $200 million. The combination product, Advair, is what Wall Street terms a “blockbuster.” More than 16.1 million Advair prescriptions were sold in the U.S. in 2004; sales topped $2.1 billion for the year.

Formoterol is produced by the Schering Corp. of Kenilworth, N.J. Formoterol is not a top seller and sales figures for 2004 are not available.

We listed salmeterol as a DO NOT USE drug in the March 2003 issue of Worst Pills, Best Pills News after the FDA announced on January 23, 2003 that a large safety study involving salmeterol had been halted prematurely. The study was halted because an interim analysis of outcomes suggested that the drug may be associated with an increased risk of life-threatening asthma episodes or asthma-related deaths.

The prematurely terminated study went by the name of the Salmeterol Multi-center Asthma Research Trial, or SMART for short. GlaxoSmithKline initiated the study in 1996. It was designed to assess the safety of salmeterol because of concerns regarding the safety of regular use of short- and long-acting beta agonists in the management of asthma. There were 25,858 patients recruited before the study was stopped.

At that time, Public Citizen’s attempts to obtain detailed information about the SMART study from the FDA were fruitless. Because the SMART study was conducted after salmeterol was approved and did not fulfill any regulatory requirement on the part of GlaxoSmithKline, details of the study could not be released under the FDA’s interpretation of the Freedom of Information Act. The agency considered this important safety information to be protected confidential commercial information that could not be released to the public.

On August 14, 2003, the FDA announced that a black box warning was added to the professional product labeling for drug products containing salmeterol. This warning applied to both salmeterol by itself and Advair. The FDA can ask for black box warnings for drugs that have been associated with the deaths of patients and may also require them if there is strong evidence from animal experiments. A black box warning is the strongest type of safety warning that the FDA can seek for a drug’s professional product labeling (see Worst Pills, Best Pills News November 2003).

In the first serious congressional hearings examining drug safety held in almost 14 years, Dr. David Graham, an FDA medical epidemiologist, testified before Senator Charles Grassley’s Senate Finance Committee in October 2004 that the safety of salmeterol was of concern to the FDA.

It was not until the day before the July 13, 2005 Pulmonary-Allergy Drugs Advisory Committee meeting, when the FDA posted its review on the Internet, that the public was able for the first time to view the details of the SMART study. This was an unacceptable 31 months after the SMART study was stopped prematurely. The FDA’s review of the SMART study is available at http://www.fda.gov/ohrms/dockets/ac/05/briefing/2005-4148B1_03_00-FDA-TOC.htm.

The main purpose of the SMART study was to measure the combined number of respiratory-related deaths or respiratory-related life-threatening experiences such as the need for intubation and mechanical ventilation in patients taking salmeterol. This is called the  primary endpoint. The study consisted of a single clinic visit for each participant during which the person’s eligibility status was evaluated.  To be eligible to participate, patients had to have a clinical diagnosis of asthma and currently take prescription asthma medications. During the single clinic visit, patients were randomly assigned to receive either two puffs daily of salmeterol or a placebo.

At the end of the 28-week study, 50 patients out of 13,176 given salmeterol either died or suffered a life-threatening event compared to 36 receiving the placebo. The difference in life-threatening respiratory events and asthma-related deaths between the groups was significant in the FDA analysis.

The following is the proposed revised black box warning for salmeterol.

The black box warning added to salmeterol’s labeling on August 14, 2003 suggested that the risk may be greater in African-American patients compared to Caucasians. The FDA has proposed deleting this information from the black box warning because the risk for asthma-related deaths in Caucasians and African Americans treated with salmeterol relative to being treated with placebo were quite similar.

Warnings for Formoterol

The advisory committee also voted that formoterol should carry stronger warnings. At this time, formoterol does not have a black box warning in its professional product labeling as do salmeterol and Advair. The evidence for problems with formoterol is not as strong as it is with salmeterol.

In the three studies submitted by formoterol’s manufacturer to the FDA before the drug was approved, two dosages were evaluated: 12 micrograms and 24 micrograms, each given twice daily. The drug’s approval was restricted to the lower dosage because serious worsening of asthma occurred with more frequency in both adult and pediatric patients who received the higher dose. This result was serious enough to warrant a commitment from the manufacturer to conduct a post-marketing safety study, known as a phase IV study, to further examine the relative safety of the different doses of formoterol. No deaths occurred in this study.

The FDA concluded that the formoterol phase IV study was too small to provide a strong answer similar to the SMART study for salmeterol, but the results were generally compatible with the decision not to approve the higher 24-microgram-twice-daily dose of the drug.

The long-acting beta agonist asthma drugs should not be used as a replacement for inhaled steroids. These drugs should not be started in patients whose asthma is significantly worsening or acutely deteriorating. This may be life threatening. The long-acting beta agonists should not be used to treat acute asthma symptoms.

The weight of the available scientific evidence points to the long-acting beta agonists as being less safe than their short-acting counterparts. There is no evidence that patient outcomes are better with the long-acting agents compared to the older short-acting drugs.

What You Can Do

Do not stop any asthma medication without first consulting your physician. Abruptly stopping a medication may result in acutely deteriorating asthma control.

You should not use salmeterol (SEREVENT), the combination of salmeterol with the steroid fluticasone (ADVAIR), or formoterol (FORADIL) for the treatment of your asthma.

You should report to your physician any increased need for a short-acting beta agonist. This is a sign of deteriorating asthma.