Boxed Warning Pulled From Asthma Drugs That Combine LABAs and ICS

FDA announces that four studies showed no increased risk of death

The FDA is removing boxed warnings about asthma-related deaths from the labels of drugs that combine long-acting beta agonists (LABAs) with inhaled corticosteroids (ICS) after studies showed such combinations don’t cause more serious asthma-related side effects than ICS treatment alone.

However, using LABAs alone to treat asthma without an ICS to treat lung inflammation is associated with an increased risk of asthma-related death—so the agency said boxed warning to that effect will remain for all single-ingredient LABA medicines, which are approved to treat asthma, chronic obstructive pulmonary disease (COPD), and wheezing caused by exercise. The labels of medicines that contain both an ICS and LABA will retain a “warning and precaution” related to the increased risk of asthma-related death when LABAs are used without an ICS to treat asthma.

In 2011, the FDA required the drug companies that market LABAs to conduct trials to evaluate the safety of LABAs when used in combination with ICS, and the agency said it has reviewed the results of four large clinical safety trials completed recently. These trials showed that LABAs, when used with ICS, did not significantly increase the risk of asthma-related hospitalizations, the need to insert a breathing tube known as intubation, or asthma-related deaths, compared to ICS alone.

The trials involving 41,297 patients, three conducted in patients 12 years and older, and one in children 4 to 11 years. Patients in all the trials were treated for six months. The primary safety endpoint for all four trials was serious asthma-related events (hospitalizations, intubations, and deaths), which were adjudicated to determine relatedness to asthma. The three adult/adolescent trials were designed to rule out a risk margin of 2.0, and the pediatric trial was designed to rule out a risk margin of 2.7. Each trial met this objective.

Data from the three trials conducted in adults and adolescents were combined in a meta-analysis to provide greater precision of the risk of serious asthma-related events with ICS/LABA products. The results demonstrate that the use of ICS/LABA in fixed-dose combination does not result in a significant increase in the risk of serious asthma-related events compared to ICS alone, the FDA said.

The trials also showed that ICS/LABA combination medicines were more effective in decreasing asthma attacks (e.g., the need to use oral corticosteroids) compared to ICS alone. This additional information has also been added to the ICS/LABA labels.

Medicines that contain both an ICS and LABA are FDA-approved to treat both asthma and COPD. ICS medicines help decrease inflammation in the lungs. This inflammation can lead to breathing problems. LABAs help the muscles around the airways in the lungs stay relaxed to prevent symptoms such as wheezing, coughing, chest tightness, and shortness of breath.

ICS/LABA medicines are marketed under several brand names. They include fluticasone/salmeterol (Advair Diskus and Advair HFA, GlaxoSmithKline; and Airduo Respiclick, Teva); fluticasone/vilanterol (Breo Ellipta, GlaxoSmithKline); mometasone/formoterol (Dulera, Merck); and budesonide/formoterol (Symbicort, AstraZeneca).

Source: FDA; December 21, 2017.

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