Manufacturer: GlaxoSmithKline

Rationale for Labeling Revision: An interim analysis of a large safety study—the Salmeterol Multicenter Asthma Research Trial (SMART)—of the approved asthma drug sal-meterol xinafoate inhalation aerosol suggested that this drug might be associated with an increased risk of life-threatening asthma episodes or asthma-related deaths. The analysis did not show a statistically significant result for the primary end-point—a combination of respiratory-related deaths or intubations (or ventilation failure). There was a trend, however, toward an increased number of asthma deaths and serious asthma episodes when all patients in the study were considered, although this trend did not reach statistical significance.

On further analysis, the risk appeared to be greater in African-American patients. In white patients (71% of the study population), there were no significant differences between treatment groups for primary events and asthma-related events. In African-Americans (17% of the trial’s enrollees), the study showed a statistically significant greater number of primary events and asthma-related events, including deaths, in patients taking salmeterol than in those taking placebo; however, fewer than 1% of all African-Americans enrolled in the study experienced such events during the 28-week trial. In addition, patients who were not taking inhaled corticosteroids at the time of enrollment appeared to be at greater risk for serious adverse outcomes than those who were taking inhaled corticosteroids.

Indication: In 1994, salmeterol xinafoate inhalation aerosol was approved to treat asthma. This approval was later extended to treat chronic obstructive pulmonary disease (COPD), including emphysema and chronic bronchitis. The drug belongs to the class of asthma medications known as p2-receptor agonists (commonly called beta agonists).

Label Change

Warnings: None exist at this time. Further review of the SMART interim analysis data is ongoing, and the FDA is discussing these findings with GlaxoSmithKline. The manufacturer and the FDA are also reviewing potential changes to the labeling that will reinforce guidance on appropriate and safe prescribing.

Current Warning Label: Salmeterol xinafoate inhalation aerosol therapy should not be initiated in patients with significantly or acutely worsening asthma, a potentially life-threatening condition. Serious acute respiratory events, including fatalities, have been reported in both the U.S. and worldwide after initiation of aerosol therapy in this situation.

Although it is unclear whether salmeterol xinafoate inhalation aerosol therapy contributed to these adverse effects or simply was unable to relieve the worsening asthma, its use in this setting is inappropriate. Usage guidelines are as follows:
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  • Inform patients that the aerosol should not be used to treat acute symptoms. Instead, prescribe an inhaled, short-acting p2-agonist for this purpose, and warn patients that their need to increase the use of inhaled p2-agonists is a signal of worsening asthma.
  • Do not prescribe salmeterol xinafoate inhalation aerosol as a substitute for inhaled or oral corticosteroids. The corticosteroids should be continued at the same dose, not stopped or reduced, when treatment with the inhalation aerosol is initiated.
  • Do not introduce this aerosol as a therapy for acutely worsening asthma. This aerosol formulation is intended for the maintenance treatment of asthma. Prescribe an inhaled, short-acting p2-agonist to relieve acute asthma or COPD symptoms.
  • Watch for increasing use of inhaled, short-acting p2-agonists, a marker of worsening asthma. Do not use this aerosol as a substitute for oral or inhaled cortico-steroids.
  • Do not exceed the recommended dosage of this drug.

Salmeterol xinafoate inhalation aerosol therapy can produce paradoxical bronchospasm, immediate hypersensitivity reactions, and upper respiratory symptoms such as laryngeal spasm, irritation, and swelling.

Conclusion: The National Asthma Education and Prevention

Program (NAEPP) Guidelines recommend that patients who require more than as-needed, short-acting p2-agonists take regular and adequate doses of an inhaled anti-inflammatory asthma medication, such as inhaled corticosteroids, for optimal benefits in the management of their asthma.

Consistent with these guidelines and reinforced by trends seen in the interim analysis of the SMART data, the manufac­turer recommends that patients using salmeterol xinafoate inhalation aerosol therapy for asthma also receive regular and adequate doses of an effective asthma-control medication, such as inhaled corticosteroids. pharmacy united kingdom

GlaxoSmithKline and the FDA agree on the need to reiterate and reinforce advice for the management of patients, including African-Americans, as established in the label for salmeterol xinafoate inhalation aerosol and in the national asthma management guidelines. Given the similar basic mechanisms of action of all p2-agonists, the findings observed in the SMART study might be consistent with a class effect.