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) such as emphysema, chronic bronchitis, and bronchiectasis.

While 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, in December of 2017, the black box warning was removed.

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 and even 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 issued in response to clinical studies conducted after the drug has already been released. If any serious concerns are raised in the post-market research, 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) reported that the drug 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).

The problem with the assessment is that LABAs have long been known to provide inadequate relief when used alone. Moreover, if used in this manner, LABAs can trigger the very asthma attacks reported in the study.

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

By adding an inhaled corticosteroid (ICS), the adverse effects of LABAs could 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 studies mandated by the FDA were released. Called the AUSTRI trial, the study evaluated the safety of salmeterol and fluticasone in 12,000 people with asthma, some of whom were as young as 12. The investigators further ensured that 15 percent of the participants were African American to better determine whether any adverse events may be related to ethnicity.

What the investigators found was the risk of asthma attacks or other adverse effect was no greater for persons taking salmeterol-fluticasone than those who took fluticasone alone.

What this 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 to decrease inflammation in the lungs. Medicines that contain both an ICS and LABA are FDA-approved for asthma and COPD.

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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.

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