Does Advair Still Have a FDA Black Box Warning?

A Child Using Advair

Verywell / Vincent Iannelli

Advair (fluticasone + salmeterol) is an inhaled medication used to treat asthma and chronic obstructive pulmonary diseases (COPD), including emphysema and/or chronic bronchitis.

Advair was given a black box warning in 2003 from the U.S. Food and Drug Administration (FDA) advising that salmeterol could potentially increase the risk of life-threatening asthma attacks. The black box warning was removed in December 2017. Find out why.

Understanding Black Box Warnings

A black box warning is a precautionary statement issued by the FDA to inform the public that a medication can cause serious or life-threatening harm. The "black box" refers literally to the boldly rendered box on the packaging information which contains the FDA advisory.

Black box warnings are usually issued due to results of clinical studies that may be conducted after the drug has already been approved and made available. If serious safety concerns emerge after a drug has already been approved, the FDA will order the immediate revision of the packaging information. Media releases will be also dispersed to warn the public about the concerns.

FDA Concerns About Advair

In 2003, a clinical study called the Salmeterol Multicenter Asthma Research Trial (SMART) found that salmeterol was linked to a small but significant increase in the risk of death and hospitalization in people with asthma, particularly African Americans. As a result of the findings, a black box warning was issued regarding any and all medications containing salmeterol, including Advair.

The study further reported a similar risk of death and hospitalization with formoterol, a medication belonging to the same class of drug known as long-acting beta agonists (LABAs).

When used alone, LABAs do not provide adequate relief of symptoms. Moreover, if used alone, LABAs can trigger asthma attacks.

It is for this reason that co-formulated drugs like Advair, which also contains an inhaled corticosteroid (ICS), were first created.

When used with an ICS, the adverse effects of LABAs can be largely mitigated.

When the study was later reviewed, it was revealed that individuals who used a LABA with an ICS had no more or less risk of death or hospitalization than those who used a corticosteroid alone. Most researchers today acknowledge that the SMART trial was poorly designed and excluded factors that could have otherwise explain the anomaly.

What the FDA Says Today

In 2016, the first in a new round of Advair studies mandated by the FDA were released.

The AUSTRI trial evaluated the safety of fluticasone alone vs combination salmeterol and fluticasone in 11,679 people with asthma, some of whom were as young as 12. The investigators ensured that 15% of the participants were African American to better determine whether any adverse events may be related to race.

The investigators found that the risk of asthma attacks or other adverse effects was no greater for participants taking salmeterol-fluticasone than it was for those who took fluticasone (a corticosteroid) alone.

The study confirmed was that Advair, by delivering a LABA and corticosteroid in a single product, posed none of the risks suggested in the FDA black box warning.

While the FDA retains a black box warning on products that use LABAs alone, medications containing both an ICS and LABAs contain a Warning and Precaution reminding users of the risks of using LABAs without an ICS. Medicines that contain both an ICS and LABA are FDA-approved for treating asthma and COPD.

1 Source
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  1. Food and Drug Administration. FDA Drug Safety Communication: FDA review finds no significant increase in risk of serious asthma outcomes with long-acting beta agonists (LABAs) used in combination with inhaled corticosteroids (ICS). December 20, 2017.

Additional Reading

By Daniel More, MD
Daniel More, MD, is a board-certified allergist and clinical immunologist. He is an assistant clinical professor at the University of California, San Francisco School of Medicine and currently practices at Central Coast Allergy and Asthma in Salinas, California.