Three FDA advisory committees recommended the withdrawal of asthma indications for two long-acting beta agonists - GlaxoSmithKline's Serevent (salmeterol) and Novartis's Foradil (formoterol) -during a Dec. 11 meeting.

The benefits of treating asthma with GSK's Advair (fluticasone/salmeterol) and AstraZeneca's Symbicort (budesonide/formoterol), which combine the LABAs with inhaled corticosteroids, continue to outweigh their risks, members of the Pulmonary-Allergy Drugs, Drug Safety and Risk Management, and Pediatric Advisory Committees concluded.

National guidelines for asthma care currently recommend that LABAs not be used as monotherapy and that they be utilized with an inhaled corticosteroid when an ICS alone does not control the disease.

A major concern of panel members was that the asthma indication for salmeterol and formoterol as single-entity drugs increases the likelihood of their being used without an ICS. Serevent and Foradil also are approved to treat chronic obstructive pulmonary disease and would remain on the market even if the asthma indication is removed.

FDA Ponders Changing Labels Or Creating REMS

Several members said that labeling with stronger warnings against monotherapy and directions on use of the LABAs for asthma could resolve their concerns, Office of New Drugs Director John Jenkins pointed out during a press briefing after the meeting.

The task now before FDA is to decide whether "to continue to manage the risk with single ingredient products by changing the labeling contraindicating monotherapy, or even putting in place some other restrictions through a risk evaluation and mitigation strategy," he said (see ¹ [A#00700500013] ).

One question is whether that effort is warranted just so doctors can retain a choice of LABAs and corticosteroids when designing treatment regimes for patients, he said, noting that most LABAs for asthma are prescribed as the combination drugs.

The meeting of the three committees was convened to review an FDA meta-analysis of clinical trials to evaluate adverse events associated with LABAs. The agency had undertaken the study following a November 2007 meeting of the pediatrics panel, whose members were concerned about the safety of the drugs for children (² Also see "FDA To Conduct Pediatric Safety Analysis for Serevent, Other LABAs" - Pink Sheet, 3 December, 2007., p. 3).

GSK Proposes Risk Mitigation Strategies

GSK already has proposed to FDA that Serevent labeling be changed to stress that salmeterol is to be used with an ICS and to add a warning about asthma-related hospitalizations.

Labeling for the LABAs currently includes a boxed warning about an increased risk of asthma-related death associated with the drugs (³ Also see "Long-Acting Beta Agonists Revised Labeling Warns Of Asthma Death Potential" - Pink Sheet, 3 March, 2006.).

In addition to adding information to labeling, the medication guide and packaging, GSK's C. Elaine Jones discussed a company proposal to update pharmacy computer systems to alert pharmacists when Serevent is prescribed for asthma without an accompanying ICS so they can warn the prescriber, and to change insurer algorithms to couple an ICS with Serevent for asthma.

Committee members recommended eliminating the LABAs asthma indication for all age groups. Serevent is approved to treat asthma in patients 4 years of age and older; Foradil is approved for ages 5 and up.

On the question of whether the benefits of salmeterol outweigh the risks, panel members voted 10-17 that they do not for adults; 6-21 for adolescents aged 12-17; and 0-27 for children 4 to 11 years old. For formoterol, the vote tally was 9-18 in adults; 6-21 for adolescents, and another unanimous 0-27 for ages 5 to 11 years old.

The votes in favor of continuing an asthma indication for Advair were 27-0 in adults, 23-3 with one abstention for adolescents, and 13-11 with three abstentions for children. For Symbicort, the numbers were 26-0 with one abstention for adults, and 20-5 with two abstentions for adolescents.

AstraZeneca submitted a supplemental application last summer to extend the indication for Symbicort to patients aged 6 to 11 with persistent asthma (⁴ Also see "AstraZeneca Submits Symbicort For Asthmatics As Young As Six" - Pink Sheet, 4 June, 2008.).

Two other LABAs - Sepracor's Brovana (arformoterol tartrate) and Dey's Perforomist (formoterol fumarate) - are approved in the U.S. only for COPD and were not discussed at the meeting.

- Cathy Dombrowski (c.dombrowski@elsevier.com)

FDA Panels Favor Advair, Symbicort Over Single-Entity LABAs For Asthma

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