Glaxo's Advair Combo Gets Broad Asthma Indication From FDA

Glaxo Wellcome's Advair Diskus will carry a broad indication for asthma patients requiring combination beta agonist/corticosteroid therapy.

The inhaled powder fluticasone/salmeterol combo product was approved Aug. 24 for "long-term, twice-daily, maintenance treatment of asthma in patients 12 years of age or older."

At the Nov. 23 review of Advair by FDA's Pulmonary And Allergy Drugs Advisory Committee, Pulmonary-Allergy Drug Products Division Director Robert Meyer, MD, characterized the proposed indication as "fairly vague," and asked the committee for input on how to "better define the population for whom the committee feels this drug is really indicated."

Advair was approved with a patient package insert, which cautions patients in capital letters not to use Advair to relieve sudden onset asthma symptoms. Instead, patients are directed to have their physician prescribe a short-acting bronchodilator such as albuterol for such symptoms.

Glaxo previously revised labeling and issued a "Dear Doctor" letter with similar warnings for Serevent in December 1995 in response to reports of patients reaching for the beta agonist during acute asthma exacerbations.

Advair patient labeling also warns patients not to take Advair more frequently than recommended because of the risk of taking too much salmeterol. At Advair's advisory committee review, committee members emphasized the importance of conveying these messages to patients.

The advisory committee voted unanimously in favor of approving Advair for use in patients already well controlled on inhaled corticosteroids and salmeterol, and for patients inadequately controlled on corticosteroids alone (¹ (Also see "Glaxo Wellcome Advair Compliance To Be Studied Following Approval" - Pink Sheet, 29 Nov, 1999.)).

However, the committee split on whether the product should be indicated for other populations of asthmatics.

Committee members expressed concern that if Advair were indicated for patients inadequately controlled on short and long acting beta agonists, that would suggest that the drug is appropriate for all asthmatics.

The committee voted unanimously in favor of the indication when it was narrowed to patients with "moderate to severe, persistent asthma." Only three members favored an indication for patients who have not yet tried inhaled corticosteroid monotherapy.

Labeling provides dosing recommendations "for patients who are not currently on an inhaled corticosteroid, whose disease severity warrants treatment with two maintenance therapies," (Advair 100/50 twice daily) and for patients on an inhaled corticosteroid (dose is dependent on the type and dose of corticosteroid therapy).

"For all patients it is desirable to titrate to the lowest effective strength after adequate asthma stability has been achieved," labeling emphasizes.

Each inhalation on the Diskus delivers 50 mcg of Glaxo's long-acting beta agonist Serevent (salmeterol) and either 100 mcg, 250 mcg or 500 mcg of Glaxo's inhaled corticosteroid Flovent (fluticasone).

In clinical trials, similar efficacy results were seen in patients on Advair versus those on concurrent therapy of Serevent and Flovent at corresponding doses from separate inhalers, labeling states.

"Improvements in most efficacy endpoints were greater with Advair than with the use of either fluticasone or salmeterol alone," labeling reports. Pivotal data was collected in three trials in 1,208 patients 12 years or older.

Glaxo will review potential gender differences in Flovent treatment in Phase IV. The company will review existing pharmacokinetic and pharmacodynamic data "in order to place in context the apparent gender effects that were observed in" one study, FDA said. If that data is inadequate, Glaxo will conduct a clinical pharmacology trial.

Most frequent adverse events listed in Advair labeling include upper respiratory tract infection (21%-27%), pharyngitis (10%-13%) and headache (12%-13%). Side effect rates appear similar to those experienced with fluticasone or salmeterol monotherapy.

The product had been "approvable" at FDA since Jan. 27. Glaxo has attributed the delay to agency concerns with the chemistry, manufacturing and controls section of its application (² (Also see "Glaxo Advair "Approvable" At FDA; Flovent Tops $1 Bil. In 1999" - Pink Sheet, 21 Feb, 2000.)).