Asthma and COPD inhalers delivering fixed-dose combinations of inhaled corticosteroid (ICS) and long-acting beta agonists (LABA) drugs will no longer be required to carry a boxed warning about the possibility of asthma-related death associated with their use, the FDA said late Wednesday.
The removal comes after an FDA review of four large clinical safety trials which showed no increase in serious asthma-related side effects with the ICS/LABA fixed-dose products than with ICS agents alone.
The trials also showed no significant increase in the risk for asthma-related hospitalizations, intubation, or asthma-related deaths associated with the combination treatment.
In 2010, the FDA identified an increased risk of death with single-agent LABA products, and labels for ICS/LABA inhalers were required to carry a warning. The following year, ICS/LABA manufacturers were ordered to conduct 6-month randomized controlled safety trials to further evaluate the risk in combination products. The four resulting trials reviewed by the FDA included a total of 41,297 patients.
In addition to showing no overall increase in risk associated with ICS/LABA use, subgroup analyses from the trials showed no increase in serious asthma-related events with ICS/LABA drugs compared to ICS alone associated with gender, adolescent age, and African American ethnicity.
The trials also assessed the fixed-dose, combination drugs’ efficacy, compared to ICS alone, with primary outcome measure of asthma exacerbations (defined as deterioration of asthma requiring the use of systemic corticosteroids for at least three days, or hospitalization or emergency department visit requiring systemic corticosteroids).
Results showed a reduction in asthma exacerbations associated with use of the ICS/LABA combination and new language reflecting this treatment advantage has been added to the “Clinical Studies” section of these products’ labels.
The FDA said these changes apply to the following brand-name products: Advair Diskus, Advair HFA, Airduo Respiclick, Breo Ellipta, Dulera, and Symbicort. The ICS components in these products include fluticasone, mometasone, and budesonide; LABA components include salmeterol, vilanterol, and formoterol.