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A rare removal of a box warning after large-scale clinical trials.
The FDA is removing the boxed warning from labeling for drugs containing both long-acting beta agonists (LABAs) and inhaled corticosteroids (ICS). Boxed warnings are the most prominent warning that the FDA requires, but they are added to a drug’s labeling far more often than they are removed.
The warning had been about an increased risk of asthma-related deaths associated with the use of LABAs and ICS. But a review of four large clinical safety trials found that treating asthma LABAs in combination with ICS does not result in significantly more serious asthma-related side effects than treatment with ICS alone. The four trials showed that using the two types of drugs together did not significantly increase the risk of asthma-related hospitalizations, the need for intubation, or asthma-related deaths, compared to ICS alone.
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The FDA required three companies that made products containing a LABA and an ICS-GlaxoSmithKline, Merck, and AstraZeneca-to conduct several large clinical trials to evaluate the risk of serious adverse effects in asthma patients and the efficacy of the drugs. The trials involved nearly 41,300 patients. There was no significant increase in the risk of serious asthma-related events compared to ICS alone and the combination of ICS and LABA reduced asthma exacerbations compared to ICS alone.
Boxed warnings are removed occasionally, according to Michael R. Cohen, RPh, MS, FASHP, President of the Institute for Safe Medication Practices. The last one that he could remember was about a year ago, he told Drug Topics.
In a response to a query from Drug Topics, the FDA stated: "The FDA does not routinely track the number of times that a Boxed Warning was removed from the prescribing information (PI) for human prescription drug and biological products." The agency notes that recent instances of removal of a boxed warning included such drugs as Chantix, Zyban, Avandial, Vivtrol, and Letairis.
In 2016, researchers from Brigham and Women's Hospital and Harvard Medical School called for the FDA to create guidelines for its decision making on when to remove a boxed warning. “To promote safe use of approved prescription drugs, the FDA should adopt a uniform and transparent process governing decisions to impose or remove boxed warnings,” they wrote in an article in the journal Drug Safety.