Drug Profile

Do Not Use: This drug has been associated with an increased death rate, and safer alternatives are available.

Fluticasone and salmeterol inhalation powders (ADVAIR DISKUS) combine powders of a steroid called fluticasone (FLOVENT) with a long-acting beta2 agonist called salmeterol (SEREVENT). The diskus is used to inhale the powders by mouth. The combination of powders allows a lower dose of fluticasone to be used, reducing steroid exposure and its attendant dangers.[1]

Fluticasone and salmeterol inhalation powders are approved by the Food and Drug Administration (FDA) for the treatment of chronic obstructive pulmonary disease (COPD) associated with chronic bronchitis and for chronic asthma. However, the powders are not intended for treatment of acute episodes or rapidly deteriorating asthma.

The inhaled powders decrease the constriction of bronchial smooth muscle and inflammation of the airway, thus opening the airway and making it easier to breathe. This may reduce the need for rescue medications such as albuterol (PROVENTIL, VENTOLIN), reduce severity of shortness of breath, reduce mortality, improve lung function, improve ability to endure strenuous activity and increase the number of symptom-free days.[2],[3],[4]

Adverse effects

Although inhaled steroids are less likely to cause systemic effects than are steroids taken by mouth, the risks are not eliminated. Steroids can suppress the adrenal glands and potentially reduce bone mineral density.[5],[6],[7]

High-dose steroids used for longer than six months have a stronger association with adrenal crisis than do those taken at lower doses or for shorter periods.[8] Adrenal crisis refers to the suppression of the body’s normal production of steroids by the adrenal glands due to steroid use. When the drugs are stopped suddenly, the body’s production of cortisone does not return right away, and the body is in a “crisis” because of the lack of cortisone.

Suppression of adrenal glands can cause low blood sugar, unconsciousness, convulsions, coma or death. Onset in adults may start with drowsiness and nausea.

A detachment of the retina, called chorioretinopathy, has been associated with steroid inhalers, especially in women.[9]

Use of inhaled and intranasal corticosteroids can cause glaucoma and cataracts.[10]

Behavior alteration in children

The most frequently reported adverse effect associated with inhaled corticosteroid use in children with asthma is behavior alteration, according to researchers from the Netherlands. There have been reports of behavioral changes in children associated with fluticasone and salmeterol inhalation powders as well as inhaled fluticasone propionate (FLOVENT DISKUS). The use of intranasal corticosteroids appears to be associated with psychiatric disorders.[11]

Studies show...

In 2007, Prescrire International compared the use of fluticasone and salmeterol inhalation powders, fluticasone product, salmeterol product and placebo product in patients with COPD. According to the article, patients treated with fluticasone and salmeterol inhalation powders had an increased risk of pneumonia.[12]

There also have been 18 reports of skin bruising associated with the use of inhalation and intranasal fluticasone products.[13]

In May 2010, The Medical Letter on Drugs and Therapeutics published an article reviewing the safety of using a long-term corticosteroid inhaler in patients with COPD. Fluticasone and salmeterol inhalation powders are approved for use in COPD patients, and the article discussed the efficacy and adverse effects of using this combination treatment. The conclusion by the authors of The Medical Letter was that there is an increased risk of fractures and pneumonia in patients with COPD who are using a long-term inhaled corticosteroid.[14]

In May 2013, an article was published in the Journal of the American Medical Association on the new use of inhaled long-acting beta agonist or long-acting anticholinergic medications in patients 66 years and older with COPD and the risk of cardiovascular events. The study found that patients using these medications had a higher risk of cardiovascular events than patients who were not using either medication. The study also found that there was no significant difference in the risk of cardiovascular events between users of either of the two classes of medications.[15]

An observational study published in BMC Infectious Disease in 2020 found that combination fluticasone and salmeterol was associated with a higher risk of tuberculosis in patients with COPD than combination budesonide and formoterol.[16]

Regulatory actions surrounding fluticasone and salmeterol inhalation powders

2003: The FDA announced that a black-box warning (see top of page) would be required on the labels of drug products containing salmeterol. This requirement applied to both salmeterol alone and fluticasone and salmeterol together. In 2017, the FDA removed the requirement for the black-box warning in the label for ADVAIR DISKUS, but not for SEREVENT (see below).[17]

The black-box warning was the result of a study known as the Salmeterol Multicenter Asthma Research Trial (SMART). This study, which was terminated early, was initiated by GlaxoSmithKline in 1996. It was designed to assess the safety of salmeterol after reports of death submitted to the FDA sparked concerns regarding the safety of regular use of the combination of short- and long-acting beta-agonists to manage asthma.

2005: Data revealed by the FDA in July 2005 led Public Citizen to conclude that fluticasone and salmeterol inhalation powders should not be used because of the increased risk of asthma deaths with use of salmeterol.

The FDA told manufacturers of fluticasone and salmeterol inhalation powders to update the existing product label with a new warning and a Medication Guide for patients. The intention of the new warnings was to alert health care professionals and patients that this medicine may increase the chance of severe asthma episodes and death when those episodes occur. Even though fluticasone and salmeterol inhalation powders decrease the frequency of asthma episodes, the drug may make asthma episodes more severe when they do occur.[18]

This product is one of a limited number of drugs for which the FDA requires an FDA-approved Medication Guide to be dispensed when the prescription is filled.

2006: The FDA officially designated this drug a “last choice” option for the treatment and management of asthma. The regulatory agency released the following guidelines for the use of fluticasone and salmeterol inhalation powders:

Long-acting beta2-adrenergic agonists, such as salmeterol, one of the active ingredients in ADVAIR DISKUS, may increase the risk of asthma-related death. Therefore, when treating patients with asthma, physicians should only prescribe ADVAIR DISKUS for patients not adequately controlled on other asthma-controller medications (e.g., low- to medium-dose inhaled corticosteroids) or whose disease severity clearly warrants initiation of treatment with two maintenance therapies. ADVAIR DISKUS is not indicated in patients whose asthma can be successfully managed by inhaled corticosteroids along with occasional use of inhaled, short-acting beta2-agonists.[18]

2010: The FDA updated the safety information on long-acting beta2-adrenergic agonists (LABAs) such as salmeterol, one of the active ingredients in fluticasone and salmeterol inhalation powders. The FDA required a risk-management strategy to educate health care professionals on the appropriate uses of these drugs and a revised Medication Guide for patients. The FDA made these changes based on studies in pediatric and adult patients using these drugs for asthma. The studies showed that there was an increased risk of severe exacerbation of asthma symptoms leading to hospitalizations, as well as death, in some patients.[19]

2011: The FDA announced that it has asked the drug manufacturers of LABAs to conduct five randomized, double-blind, controlled clinical trials to evaluate the safety of these drugs in the treatment of asthma when used with an inhaled corticosteroid drug (combination therapy) versus when an inhaled corticosteroid drug is used alone (single therapy). The clinical trials began in 2011, and the FDA expects to receive results in 2017.

2017: The FDA approved the removal of the black-box warning from the label for Advair (but not Serevent) after reviewing four large clinical safety trials that had been requested by the FDA in 2011 and that showed that treating asthma with LABAs in combination with inhaled corticosteroids (ICS) does not result in significantly more serious asthma-related adverse effects than treatment with an ICS alone.[17] The same studies also showed that the ICS/LABA combination reduced asthma exacerbations compared with an ICS alone.