Frequency and Associated Costs of Anaphylaxis- and Hypersensitivity-Related Adverse Events for Intravenous Iron Products in the USA: An Analysis Using the US Food and Drug Administration Adverse Event Reporting System

Abstract

Introduction and Objective Intravenous iron preparations rapidly correct iron deficiency anemia, with the notable drug class effect of rare, yet potentially life-threatening, administration-related hypersensitivity or anaphylactic reactions. The objective of this comparative study was to assess adverse events associated with four intravenous iron preparations and estimated medical costs, in the US Food and Drug Administration Adverse Event Reporting System (FAERS) database. Methods Cases of hypersensitivity reactions and anaphylaxis/anaphylactic shock associated with iron dextran, iron sucrose, ferumoxytol, and ferric carboxymaltose, spontaneously reported to FAERS (1 January, 2014 to 31 December, 2019), were extracted. The reporting odds ratio lower bound 90% confidence interval (ROR05) > 1 and cases ≥ 5 defined a likely signal for a drug-adverse event association. Adverse event-associated medical costs were estimated using Agency for Healthcare Research and Quality/Healthcare Cost and Utilization Project 2016 data. Results For hypersensitivity reactions, ferumoxytol and iron dextran had the highest ROR05 values (5.00 and 4.35, respectively) and greatest proportions of associated deaths (7.1% and 5.3%), followed by iron sucrose (ROR05 3.94, deaths 2.4%), and ferric carboxymaltose (ROR05 3.03, deaths 0.2%). For anaphylaxis/anaphylactic shock, ROR05 for cases/deaths were: 39.32/13.4%, ferumoxytol; 37.80/4.5%, iron dextran; 17.60/4.7%, iron sucrose; and 8.77/no deaths, ferric carboxymaltose. Downstream medical costs per adverse event were highest with iron dextran (US$8615) and ferumoxytol (US$8164), followed by iron sucrose (US$4212), and ferric carboxymaltose (US$1832). Conclusions Reporting rates of hypersensitivity and anaphylaxis with intravenous iron preparations were highest with ferumoxytol and lowest with ferric carboxymaltose in the US FAERS database. Adverse event-related medical costs were highest for iron dextran and ferumoxytol, and lowest for ferric carboxymaltose.

Comment on: Frequency and Associated Costs of Anaphylaxis- and Hypersensitivity-Related Adverse Events for Intravenous Iron Products in the USA: An Analysis Using the US Food and Drug Administration Adverse Event Reporting System

“…Considering the burgeoning use of intravenous iron in a litany of maladies in which oral iron is either ineffective or harmful, I believe the conclusions in Trumbo et al [1] are inaccurate, inconsistent with the overwhelming preponderance of prospective randomized published evidence, misrepresentative, and harmful to the field. Of concern is that the study was funded by the company with the most to gain from these authors' conclusions.…”

“…Having read the article by Trumbo et al [1], published in Drug Safety, I wish to express several serious concerns. While this article was interesting, the authors used a methodology specifically proscribed by the US FDA.…”

“…This methodology is also referenced in Wysowski et al [2], the authors of which are all from the FDA and concluded not only that "allergic reactions are possible with all four parenteral iron products" but also that the current system of spontaneous adverse event reporting, particularly in the absence of headto-head trials, does not allow the relative rates of serious adverse events (SAEs) to be determined. Given this strong conclusion, it is prudent to look at the available head-to-head trials and comment on one of the studies cited by Trumbo et al [1], that of Wang et al [3] published in JAMA.…”

“…The FIRM trial by Adkinson et al [4], also referenced in Trumbo et al [1], used a double-blind prospective paradigm and examined 1997 patients who received two doses of either ferumoxytol or ferric carboxymaltose (FCM) according to the FDA label. No differences in SAEs were found.…”

“…No differences in SAEs were found. Trumbo et al [1], funded by the manufacturer of FCM, failed to mention prospective comparisons of FCM and iron sucrose, ferumoxytol and iron sucrose, ferric derisomaltose (formerly iron isomaltoside) and iron sucrose, or ferric derisomaltose and FCM [5][6][7][8]. None of these studies reported any differences in adverse events.…”