Advisory committee recommends continued marketing of beta 2-agonists, black box warning for formoterol

FDA's Pulmonary-Allergy Drugs Advisory Committee voted unanimously that the long-acting beta₂-agonists salmeterol (Serevent and Advair, GlaxoSmithKline) and formoterol (Foradil, Novartis) should remain on the market despite concern over reports of asthma-related deaths associated with the use of salmeterol. The committee also voted 12 to 0, with 1 abstention, that the labeling for formoterol should carry a black-box warning similar to that found in the labeling of salmeterol to indicate that the safety signals observed with the latter drug may be a class effect.

The labeling for the salmeterol products was revised to include a black-box warning in 2003 based on preliminary results from the Salmeterol Multicenter Asthma Research Trial (SMART). A complete analysis of the SMART data was completed by FDA in 2004. The agency found a statistically significant increase for salmeterol over placebo in the trial's 3 secondary end points: asthma-related deaths (4.37; 95% CI, 1.25–15.34), respiratory-related deaths (2.16; 95% CI, 1.01–2.89), and combined asthma-related deaths or life-threatening experiences (1.71; 95% CI, 1.01–2.89).

These results were the impetus for the Advisory Committee meeting, which took place in July, as well as the cause for labeling changes reporting data from SMART in addition to the original black-box warning. FDA's analysis did not find a statistically significant difference between salmeterol and placebo in the trial's primary end point, combined respiratory-related deaths or respiratory-related life-threatening experiences (RR 1.40; 95% CI, 0.91–2.14).

According to committee members, although clear risks exist for salmeterol, the benefit of the drug in asthma control justifies keeping it on the market. The committee concluded that data evaluating similar end points for formoterol were inclusive.

A phase 3 trial comparing formoterol 12 mcg twice-daily, formoterol 24 mg twice-daily, and placebo resulted in 4 serious asthma exacerbations in the 24-mcg formoterol group compared with 0 in the 12-mcg and placebo groups. Likewise, a post-marketing trial revealed 2 asthma exacerbations in the formoterol 24-mcg group, 5 in the 12-mcg group, and 1 in the placebo group. Although these rates were too small to draw any firm conclusions, the committee recommended including a black-box warning in the formoterol labeling based on a possible class effect demonstrated with salmeterol. The committee further recommended that the formoterol warning explicitly state that the risk has not been directly established for formoterol.