NIH Asthma Guide Concurs With FDA In Supporting LABAs For Adjunctive Use

Sales of combination inhaled corticosteroid/long-acting beta2-agonists may receive a boost from NIH guidelines endorsing their use as adjunctive therapy in certain asthma patients.

The guidelines, released Aug. 29 by the National Asthma Education and Prevention Program, state that while LABAs should not be used as monotherapy for long-term treatment of asthma, they should now be considered for use as adjunctive therapy in patients five years of age and older who have asthma requiring more than low-dose inhaled corticosteroids.

The NIH guideline echoes FDA policy. The latter agency last year revised LABA labeling to include a "black box" warning that use of the drugs may increase the risk of asthma-related death, and therefore they should only be used as adjunctive therapy in patients not adequately controlled on other medications such as inhaled corticosteroids.

Combination therapies that could benefit from the NIH guidelines are GlaxoSmithKline's Advair (salmeterol/fluticasone) brand and AstraZeneca's asthma therapy Symbicort (budesonide/formoterol).

The safety of the LABAs came under scrutiny in light of data from the Salmeterol Multi-center Asthma Research Trial (SMART) that showed that salmeterol may be associated with rare, serious asthma episodes or asthma-related death.

In November 2005, FDA relegated Advair and GSK's Serevent (salmeterol), as well as Novartis/Schering-Plough's Foradil (formoterol), to second-line use for asthma (¹ (Also see "No Breathing Room For Advair: GSK Combo Part Of Asthma Drug Restrictions" - Pink Sheet, 28 Nov, 2005.), p. 8).

The NIH recommendations follow an expert panel's extensive review of literature involving LABAs. The review was undertaken as part of a broader look at the national asthma guidelines issued by NAEPP in 1991 and 1997, as well as an update on selected topics released in 2002.

According to the panel, the "established, beneficial effects of LABA for the great majority of patients whose asthma is not well controlled with ICS alone should be weighed against the increased risk for severe exacerbations, although uncommon, associated with the daily use of LABAs."

Based on that finding, the expert panel modified its 2002 recommendation "and has now concluded that, for patients who have asthma not sufficiently controlled with ICS alone, the option to increase the ICS dose should be given equal weight to the option of the addition of a LABA to ICS."

In addition, the guidelines recommend that daily use of LABA generally should not exceed 100 mcg salmeterol or 24 mcg formoterol, reflecting the dosing recommended in the products' respective labeling.

LABAs are not recommended to treat acute symptoms or exacerbations of asthma, although the expert reviewers note that there are studies under way examining the potential use of formoterol in acute exacerbations and in adjustable-dose therapy in combination with ICS.

In line with past recommendations, the panel advised that for long-term control of asthma, patients take medication including ICSs, inhaled long-acting bronchodilators, leukotriene modifiers, cromolyn, theophylline and immunomodulators.

ICSs are "the most potent and consistently effective long-term control medication for asthma," according to the guidelines. Clinical effects of ICSs include reduction in severity of symptoms, improvement in asthma control and quality of life, prevention of exacerbations and reductions of hospitalizations and deaths due to asthma, the report states.

While LABAs as adjunctive therapy need to be carefully weighed in terms of risks versus benefits, ICSs' "small risk of adverse events from the use of ICS treatment is well balanced by their efficacy," the report concludes.

Regarding short acting beta2-agonists, the guidelines note they are the most effective medication for relieving acute bronchoconstriction. In addition, SABAs, which include albuterol, levalbuterol and pirbuterol, are identified as "the drug of choice for treating acute asthma symptoms and exacerbations and for preventing exercise-induced bronchospasm."

However, the panel does not recommend daily, long-term use of SABAs, and notes that certain agents, such as isoprenaline and fenoterol, have in the past been associated with severe or fatal asthma attacks.

- Brooke McManus ([email protected])