ICS/LABA safe and cut exacerbations: FDA explains why ‘black box’ removed


By Michael Woodhead

28 Jun 2018

Members of an FDA safety committee have explained why they took the unusual step of removing ‘black box’ safety warnings from combined inhaled corticosteroid-long acting beta agonist inhalers in December 2017.

The warnings were originally put in place in 2011 as a precautionary measure after some trials involving LABA-containing inhalers suggested an increased risk of asthma-related deaths. The FDA also mandated companies marketing ICS/LABA combination inhalers to conduct large clinical safety trials.

Data from four of these trials have now been published in a combined analysis in NEJM, showing that combination ICS-LABA therapy did not result in a significantly higher risk of asthma-related hospitalisations, intubations or asthma-deaths compared with treatment with an ICS alone (hazard ratio 1.09).

The analysis, based on data from more than 36,000 patients, also showed that combination ICS/LABA inhaler treatment was associated with a 17% lower relative risk of asthma exacerbations (9.8%) compared to  ICS monotherapy (11.7%).

The US authors of the study say the safety findings were consistent across all inhalers and subgroups of patients. They also note that the rate of asthma-related deaths in their combined analysis was much lower than in the earlier trials that prompted the safety concerns. Those trials did not verify ICS use and so the latest analysis reinforced the evidence that LABA were safe when used in combination with ICS, they said.

The researchers concluded that “the convenience and safety of a combination inhaler is a likely plus” while emphasising their findings did not detract from current step-based  asthma treatment guidelines that recommend the use of a low-dose corticosteroid first before moving on to a medium-dose steroid, plus a LABA.

In a linked commentary, members of the FDA Safety Committee said the ‘decisive’ evidence from the four trials was the reason why they had immediately lifted  the black box warning, which they described as “an uncommon event”.

“The individual trials all met the primary safety objective, and results were consistent among trials. In addition, the observed reduction in asthma exacerbations that required systemic corticosteroids demonstrates a benefit associated with combination products,” wrote the committee members, led by Dr Sally Seymour of the FDA’s Center for Drug Evaluation and Research.

“On the basis of this strong and consistent evidence, we opted to remove the boxed warning right away, without convening an FDA advisory-committee meeting.”

However in their commentary they noted the analysis did not  include data from the safety  trial of ICS-LABA treatment in children.

“These results were analysed separately to address specific concerns in this age group,” they said.

In Australia, the product information for ICS-LABA inhalers have been updated to include data from the FDA-mandated safety trials.

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