Fluticasone plus salmeterol safety data ‘reassuring’


A fixed dose combination of the LABA salmeterol plus the inhaled glucocorticoid fluticasone has no higher risk of asthma related death or hospital admission than fluticasone alone, a randomised study published in the NEJM concludes. 

However  the findings may not apply to patients with the most severe and unstable disease because they were excluded from the study, an accompanying editorial to the paper warns.

Previous studies had shown a higher risk of asthma-related death among patients receiving salmeterol than among those receiving placebo.

In light of this evidence the FDA mandated the inclusion of a black-box warning in the package insert for these products and required that the manufacturers of LABAs conduct randomized, double-blind, controlled clinical trials comparing the combination of these drugs with inhaled glucocorticoids in a single inhaler, as compared with inhaled glucocorticoids alone.

In the current study  11 679 adolescent and adult patients with persistent asthma were randomised to either fluticasone with salmeterol delivered in a single inhaler or to fluticasone alone for 26 weeks.

All of the patients had had a severe asthma exacerbation in the year before randomisation but not in the previous month. Patients were excluded from the study if they had a history of life threatening or unstable asthma.

Results showed a total of 36 serious asthma related events occurred in 34 patients given fluticasone plus salmeterol, compared with 38 events in 33 patients given fluticasone only (hazard ratio 1.03 (95% confidence interval 0.64 to 1.66); non-inferiority achieved P=0.003).

There were no asthma related deaths and two patients treated with fluticasone only required asthma related intubation. Overall the risk of a severe asthma exacerbation was 21% lower in the fluticasone-salmeterol group than in patients treated with fluticasone alone (0.79 (0.70 to 0.89)).

“It is clear that among patients with asthma who have not had life threatening episodes in the past and are highly adherent to their drug regimen, it is likely that the use of salmeterol together with fluticasone in a single inhaler is safe,” wrote Fernando Martinez, of the University of Arizona in Tucson, USA, in an accompanying editorial 

“For these patients and this combination, the black box warning should be lifted.”

“This is an important result, and it stresses once again that most patients with asthma, and especially those without serious episodes, can reach high levels of symptom control and avoid frequent exacerbations by simply using their inhalers every day,” he said.

However what remained unanswered was whether this conclusion applies to patients who have the most severe and unstable disease since these are the patients for whom all guidelines still recommend the use of LABAs combined with inhaled glucocorticoids as first-line treatment.

“For these patients, the safe clinical approach is to maintain the same precautions in using fluticasone-salmeterol that have been recommended until now for all patients with asthma,” he concluded. 

The study was supported by GlaxoSmithKline.

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