Injection-Site Nodules Associated With the Use of Exenatide Extended-Release Reported to the U.S. Food and Drug Administration Adverse Event Reporting System
نویسندگان
چکیده
G lucagon-like peptide-1 (GLP-1) receptor agonists are safe and effective U.S. Food and Drug Administration (FDA)-approved drug products for use in the treatment of type 2 diabetes. To date, the FDA has approved five GLP-1 receptor agonist parenteral formulations: exenatide, liraglutide, exenatide extended-release , and, most recently, albiglutide and dulaglutide. All of these formulations are administered subcutaneous-ly. Exenatide and liraglutide are administered twice daily and once daily, respectively. Until recent approvals of albiglutide and dulaglutide, exenatide extended-release was the only formulation approved for once-weekly use. Relative to other antidiabetic phar-macotherapies, such as metformin or sulfonylureas, GLP-1 receptor agonists are not widely used drugs. A recent study of the usage patterns of antidiabetic drugs estimate that, of 16,316,580 patients prescribed a noninsulin antidiabetic drug in 2012, GLP-1 receptor agonists were dispensed to 673,367 (4.1%) (1). Exenatide extended-release is formulated to encapsulate exenatide in poly-(D,L-lactide-co-glycolide) (also known as PLG matrix) microspheres, which release the active drug over a sustained time interval (2). PLG is a biodegradable and biocompatible medical polymer with an established safety profile used as a controlled release excipient in a variety of drug products (3). PLG undergoes hydro-lysis into lactic and glycolic acids, which are eventually eliminated as carbon dioxide and water. In 2012, the introduction of exenatide extended-release into the U.S. market offered GLP-1 receptor agonist users the advantage of fewer injections per week. At the time of approval, the FDA was aware of small, largely asymptomatic injection-site nodules that were associated with exenatide extended-release use. Based on the microsphere excipient, injection-site nodules could be expected with exen-atide extended-release administration. However, these reactions were considered nonserious and believed to resolve quickly. Based on controlled data provided in the U.S. approved prescribing information, injection-site reactions were observed more frequently in exenatide extended-release users (17.1%) than in those using exenatide (12.7%) or insulin glargine (1.8%). Patient withdrawal because of injection-site nodules was also higher in exenatide extended-release users (0.5%) relative to users of exenatide (0%) or other comparators (0%) (4). We recently became aware of two publications (5,6) that reported granulomas at the injection sites of exenatide extended-release users. Subsequent to these publications, we reviewed exenatide extended -release–associated injection-site reactions reported to the FDA via the FDA Adverse Event Reporting System (FAERS). The objective of our work was to review and characterize spontaneous (MedWatch) ©2015 by the American Diabetes Association. Readers may use this article as long as the work …
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