DO NOT USE! Strong New Safety Warning Added For The Asthma Inhaler Salmeterol (SEREVENT)

In the March 2003 Worst Pills, Best Pills News we listed the asthma drug salmeterol (SEREVENT) as a DO NOT USE drug after the Food and Drug Administration (FDA) announced on January 23, 2003 that a large safety study involving the drug 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 belongs to a family of asthma medications known as long-acting beta2-receptor agonists, or just beta agonists. Salmeterol is a long-acting beta agonist, in contrast to others in this family, such as albuterol (PROVENTIL, VENTOLIN), metaproterenol (ALUPENT) and pirbuterol (MAXAIR), which are short-acting.

Salmeterol is produced by GlaxoSmithKline of Research Triangle, NC.

On August 14, 2003, the FDA announced that a box warning is now required on the professional product labeling or package inserts for drug products containing salmeterol. This requirement applies to both SEREVENT and the combination of salmeterol with the steroid fluticasone sold as ADVAIR. The FDA has the regulatory authority to require 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 box warning is the strongest type of safety warning that the FDA can mandate in a drug’s professional product labeling.

The text of the new warning reads:

The terminated safety study was called 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 after reports of death had been submitted to the FDA.

Unfortunately, information about the SMART study is only fragmentary. GlaxoSmithKline has not published a full description of the study and its outcomes in a medical journal. The Health Research Group has filed a Freedom of Information Act request with FDA to obtain more information, but it may be months before this request is granted because of the FDA’s demonstrated lack of interest in making important information available to the public in a timely manner.

What is known about the SMART study is contained in the FDA’s January 23, 2003 announcement and the new additions to salmeterol’s professional product labeling. A very troubling aspect of the FDA’s announcement was the number of patients in the trial 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 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 only 47 percent according to the FDA announcement. Only 50 percent of Caucasian patients were receiving treatment with an inhaled steroid and an even fewer — 38 percent — of African-American patients were using them 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.

The “Clinical Trials” section of salmeterol’s professional labeling now has new information about the SMART study. The patients that were enrolled in the study were asthma patients that had never before used a long-acting beta2-agonist such as salmeterol. The average age of the patients was 39 years; 71 percent were Caucasian, 18 percent African-American, and 8 percent were Hispanic. There was a higher number of asthma-related deaths or life-threatening experiences (36 versus 23), and a higher number of asthma-related deaths (13 versus 4) occurred in the patients treated with salmeterol than in the placebo group.

An analysis of Caucasian patients showed no significant increase in respiratory- or asthma-related episodes, including deaths. However, in African-Americans the study showed a statistically significant greater number of respiratory-related deaths or respiratory-related life-threatening experiences (20 versus 7), asthma-related deaths or life-threatening experiences (19 versus 4), and asthma-related deaths (8 versus 1) in patients taking salmeterol compared to those taking placebo. A possible partial explanation offered by Glaxo is that fewer African-American patients were using steroids, but the data provided by the company are too meager to evaluate this claim.

The SMART study was designed to treat patients for only 28 weeks, a very short period for assessing a drug for a chronic disease such as asthma, yet serious adverse reactions were seen.

Salmeterol accounted for more than 4.5 million prescriptions in 2002. A large number of patients are taking this drug to treat their asthma and GlaxoSmithKline and the FDA must do much more in disclosing a complete accounting and disseminating the results of the SMART study. This is an important safety issue.

Until much more is known about the SMART study our recommendations remain.

What You Can Do

• You should be reluctant to newly start salmeterol.

• 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.