Comment on call for worldwide withdrawal of BAC from nebulizer solutions

Abstract

The JACI recently published an editorial calling for the banning of benzalkonium chloride (BAC) from all nebulizer solutions, based on concerns about its potential to cause bronchospasm in patients with hyperreactive airways. This editorial deserves comment from a regulatory perspective, inasmuch as it included a call for regulatory agencies to show “increased responsibility” in dealing with these issues. As a background to the recommendations, the authors contend that BAC and BAC-containing products had not received safety evaluations in asthmatic patients. It is important to point out that for US Food and Drug Administration (FDA) approval, new drug products—including their excipients or inactive ingredients—must be studied clinically in patients with the target disease. Therefore, new drug applications for nebulizer solutions containing BAC as a preservative contained studies to establish both the safety and the efficacy of the products in patients with asthma. Such products would have been approved only if these evaluations showed that the clinical safety and efficacy of the entire formulation, including any BAC or other preservative or additives, were favorable. Although the authors issued a definitive call for a ban on BAC use in all nebulizer solutions, their recommendation is based on differing levels of evidence of a safety problem, depending on the specifics of the drug itself. For ipratropium products, the authors’ recommendation is based on the identified potential for BAC to cause bronchospasm in patients exposed to ipratropium products that contain this preservative. It must be emphasized that the FDA has recognized this concern and that all US ipratropium inhalation solutions are free of BAC. However, the authors’ call for a ban on the use of BAC in albuterol and other β-agonist inhalation solutions is based not on definitive safety data but on the “principle of prudent avoidance.” Although such a proposal is worthy of consideration, there are, from a regulatory viewpoint, other important considerations that must also be taken into account. First and foremost, there are not clear data to suggest that the use of BAC in β-agonist nebulizer solutions presents a general concern. This lack of clear data is acknowledged in the editorial itself. Furthermore, multidose nebulizer solutions containing albuterol and other short-acting β-agonists remain very popular in the US market and are usually less costly on a per-dose basis than the unit-dose products. Although the FDA does not generally consider economics in its drug-approval process, the economic impact of a proposed regulation (which would be needed to “ban” BAC use in all nebulizer products) would have to be justified. More importantly, because there is no clear safety concern with the β-agonist solutions formulated with BAC, there is no basis for requiring through regulations that these products be produced and sold only in preservative-free unit-dose vials. Given that both configurations are produced and sold in the US marketplace, health providers and patients have a choice as to which kind of β-agonist nebulizer solutions to use. If particular patients appear to be intolerant of solutions with BAC, there are BAC-free alternatives that they can use. There are good clinical reasons why unit-dose sterile inhalation solutions might be preferred over multidose preparations (which are generally the products requiring preservatives or other additives). The unit-dose products contained in low-density polyethylene vials are not as prone to errors in handling or to bacterial contamination, because multidose products require proper dilution before dosing; furthermore, even though the latter are manufactured sterilely in the United States, they can be become contaminated after opening if not properly handled. Despite these considerations, it must also be emphasized that all nebulizer solutions available in the US market are considered by the FDA to be safe and effective products. Practitioners and patients who wish to practice “prudent avoidance” of albuterol products containing BAC may do so. However, absent a safety signal or definitive data regarding untoward effects of BAC as a preservative in albuterol products, a regulatory ban on the use of BAC in such products or a general ban on multidose inhalation solutions is neither warranted nor defensible. 1/8/117466