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ACCP Member Publication in Pharmacotherapy Contributes to FDA Safety Warning

September 12, 2017

Recently, the U.S. Food and Drug Administration (FDA) required manufacturers of albuterol products containing the preservative benzalkonium chloride (BAC) to list the following warning in the product labeling1:

Albuterol sulfate inhalation solution contains the preservative benzalkonium chloride. Benzalkonium chloride has been associated with bronchospasm in a dose-dependent manner. In patients who receive high doses (e.g. continuous nebulization) of albuterol sulfate inhalation solution and bronchospasm does not resolve, consider a trial of short-acting bronchodilator that does not contain the preservative benzalkonium chloride (see DOSAGE AND ADMINISTRATION).

This action was a result of three publications: a review of the literature by Dr. Leslie Hendeles and colleagues on benzalkonium-induced bronchospasm published in the May issue of Pharmacotherapy2 and two case reports of children with acute asthma being treated in an intensive care unit with continuous nebulized albuterol.3,4 In both case reports, patients’ clinical conditions failed to improve while receiving albuterol-containing BAC but rapidly improved within 2 hours after the albuterol product was changed to a preservative-free product. In the United States, the only formulation containing BAC is the 20-mL 0.5% multidose dropper bottle, whereas all other albuterol products are sterile preservative-free unit dose vials.

The dropper bottle contains 50 mcg of BAC in every 2.5 mg dose of albuterol. When this product is used to prepare solutions for continuous nebulization, usually ordered as 10–20 mg/hour of albuterol, a patient will receive 800–1600 mcg of BAC in 4 hours, whereas the threshold dose for BAC-induced bronchospasm in otherwise healthy patients with stable asthma is about 300 mcg.5 Of note, continuous nebulized albuterol is widely used “off-label” in the hospital treatment of severe acute asthma; it is not FDA approved. In the FDA-approved use of the albuterol dropper bottle product (i.e., 2.5 mg administered intermittently three or four times daily), a patient will inhale only 50 mcg of BAC per dose, which does not functionally antagonize the bronchodilator response to albuterol.6 However, when the dose or frequency of administration is increased in research subjects with mild stable asthma, the frequency and severity of BAC-induced bronchospasm also increases.5,7 Clinicians will likely not recognize the BAC antagonism of albuterol’s bronchodilator effect because patients with severe asthma may respond slowly or their condition sometimes worsens, even when treated with preservative-free products.

Hendeles and the pediatric pulmonologists who cowrote the Pharmacotherapy article recommend that only preservative-free albuterol products be used for patients. Otherwise, the preservative may prolong the administration of continuous nebulized albuterol, which can increase the amount reaching the systemic circulation and thus increase the risk of elevated heart rate and other adverse effects.

Hendeles pointed out in an e-mail that “administering a bronchoconstrictor (i.e., BAC) to a patient with severe life-threatening bronchospasm is analogous to giving warfarin to a patient with an acute GI bleed.”

Access the full text of the Pharmacotherapy article titled “Benzalkonium Chloride: A Bronchoconstricting Preservative in Continuous Albuterol Nebulizer Solutions” here.


  1. Hi-Tech Pharmacal. Albuterol Sulfate Solution Label. Daily Med 7/18/17. Available at Accessed July 26, 2017.
  2. Prabhakaran S, Abu-Hasan M, Hendeles L. Benzalkonium chloride: a bronchoconstricting preservative in continuous albuterol nebulizer solutions. Pharmacotherapy 2017;37:607-10.
  3. George M, Joshi S, Concepcion E, et al. Paradoxical bronchospasm from benzalkonium chloride (BAC) preservative in albuterol nebulizer solution in a patient with acute severe asthma. A case report and literature review of airway effects of BAC. Respir Med Case Rep 2017;21:39-41.
  4. Currie M, Jordan C, Loughlin C. When the nebs aren’t helping: paradoxical bronchoconstriction due to preservative in continuous albuterol nebulizer solution [abstract]. Am Rev Respir Crit Care Med 2016;193:A5614.
  5. Zhang YG, Wright WJ, Tam WK, et al. Effect of inhaled preservatives on asthmatic subjects. II. Benzalkonium chloride. Am Rev Respir Dis 1990;141:1405-8.
  6. Kwong T, Flatt A, Crane J, et al. The effect of benzalkonium chloride on the bronchodilator response to salbutamol nebulizer solution. N Z Med J 1990;103:457.
  7. Asmus MJ, Barros MD, Liang J, et al. Pulmonary function response to EDTA, an additive in nebulized bronchodilators. J Allergy Clin Immunol 2001;107:68-72.