Important Safety Alert! DO NOT USE — Asthma Inhaler Salmeterol (SEREVENT)

The Food and Drug Administration (FDA) announced on January 23, 2003 that a large safety study involving the asthma drug salmeterol (SEREVENT) had been halted prematurely 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.

Salmeterol is produced by GlaxoSmithKline of Research Triangle, NC. The FDA approved the drug in 1994 to treat asthma, and later approval was extended to treatment of chronic obstructive pulmonary disease (COPD). The drug belongs to a family of asthma medications known as beta2-receptor agonists, or just beta agonists, and salmeterol is a long-acting beta agonist. Others in this family, such as albuterol (PROVENTIL, VENTOLIN), metaproterenol (ALUPENT) and pirbuterol (MAXAIR) are short-acting beta agonists.

Salmeterol is also contained in the asthma drugs Serevent Diskus and Advair Diskus, also manufactured by GlaxoSmithKline.

The prematurely terminated study went by the name of the Salmeterol Multi-center Asthma Research Trial, or SMART for short. This study was initiated by GlaxoSmithKline in 1996 and 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.

The number of asthma-related life-threatening experiences, including deaths, that occurred in the patients treated with salmeterol was higher compared to those using a placebo, though the difference was not statistically significant. A result that shows statistical significance is not necessary to warn healthcare professionals about salmeterol. The important issue is that there was a higher rate of life-threatening adverse outcomes in the salmeterol-treated patients. It is possible that if the SMART study had run long enough to include the 60,000 patients that were originally planned for the study, the difference would have been statistically significant.

A troubling aspect of the announcement of the SMART study interim results was the number of patients not using an inhaled steroid as the foundation of their asthma treatment. The National Asthma Education and Prevention Program (NAEPP) guidelines published in 1997 recommend that patients requiring more medicine than as needed for simply treating an acute attack with short-acting beta agonists should be using regular and adequate doses of an inhaled steroid for optimal management of their asthma. There are a number of inhaled steroids on the market in the U.S., including beclomethasone (BECLOVENT, VANCERIL), budesonide (PULMICORT), flunisolide (AEROBID), fluticasone (FLOVENT) and triamcinolone (AZMACORT).

In contrast to the recommendations of the NAEPP, the number of patients using inhaled steroids in the SMART study was 47 percent. Only 50 percent of Caucasian patients were receiving treatment with an inhaled steroid and an even lower 38 percent of African-American patients were using inhaled steroids at the beginning of the study. In the total group of patients not receiving inhaled steroids, there was a statistically significant greater number of asthma-related deaths in all patients taking salmeterol compared to those taking placebo.

Historically, worldwide, there have been two beta agonist-induced epidemics of increased deaths in asthmatics. In the 1960s, an isoproterenol (ISUPREL) inhaler containing five times the usual concentration of the drug was marketed in the United Kingdom. Isoproterenol is a short-acting beta agonist. While this product was being prescribed in the U.K., there was a significant increase in asthma deaths. A parallel increase was not seen in other countries in which the high-concentration preparation was not available.

Fenoterol, a long-acting beta agonist that was never marketed in the U.S., was shown to be associated with an epidemic of asthma deaths in New Zealand starting in 1976. This epidemic ended abruptly after New Zealand authorities warned of the possible link between the drug and deaths.

These unfortunate experiences serve to strikingly illustrate the potential dangers of some inhaled beta agonists. GlaxoSmithKline has not released the details of the SMART study and until the company releases more data to the public, it is not possible to place salmeterol into the same category as high-potency isoproterenol or fenoterol as a cause of deaths among asthmatics.

What You Can Do

You should not use salmeterol as a replacement for inhaled steroids, which should be continued at the same dose and not stopped or reduced when treatment with salmeterol is started.

You should not begin treatment with salmeterol if your asthma is significantly worsening or acutely deteriorating. This may be life threatening.

You should not use salmeterol to treat acute asthma symptoms.

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