Reply to McCulley et al., reports to FDA of fatal anaphylaxis associated with intravenous iron products
Authors: Michael Auerbach, John Adamson
Journal: American Journal of Hematology (2016)

To the Editor: We read the correspondence of McCulley et al., with great interest 1. While we can agree with several of the points made, we take exception to what we consider to be an overestimation of intravenous iron's danger based on inferential evidence, as opposed to prospective studies and high quality meta-analyses. In a recent meta-analysis by Avni et al. 2 comprising 10,391 patients treated with intravenous iron, 4,044 oral iron, 1,329 no iron, and 3,335 placebo or no treatment, no safety signal with intravenous iron was reported. Minor infusion reactions were increased with intravenous iron but the adverse event profile was markedly greater with oral iron. The formulations of intravenous iron included in the meta-analysis were iron sucrose, ferric gluconate, low molecular weight iron dextran, ferumoxytol, and ferric carboxymaltose. None of the formulations was found to be more or less likely to cause a serious adverse event than any of the others. Consistent with these findings, FDA's own publication 3 concluded that absent head to head studies it is impossible to determine any relative rates of adverse events among available formulations using current reporting mechanisms. While we appreciate that “49 deaths temporally associated with the administration of intravenous iron were adjudicated and determined to be anaphylaxis,” we believe the surrogates for anaphylaxis used in the adjudication preclude credible conclusions as to etiology of the events. One of us (MA) reviewed all of the reports of adverse events with intravenous iron to the Serious Adverse Event Reporting System via Freedom of Information from January 2007 to November 2010. It was impossible to determine which adverse events were associated with which form of iron dextran, whether or not there was premedication or not and, most importantly, whether or not there was intervention for minor infusion reactions with diphenhydramine or vasopressors. These kinds of intervention can convert a minor, self-limited reaction which resolves without treatment into a serious adverse event, and the event will be mistakenly attributed to the intravenous iron. This concern is at least in part supported by the study of Barton et al. 4 which reported that the majority of perceived adverse events with the administration of intravenous iron were due to premedication with diphenhydramine. Nonetheless, as we share the authors' concern about the risk of fatal anaphylaxis, albeit extremely rare, we endorse the use of an algorithm 5 which incorporates our recommendations for the management of minor reactions (Fig. 1). Treatment of iron reactions. With permission: Rampton et al. Hypersensitivity reactions to intravenous iron: Guidance for risk management. Haematologica 2014;99:1671–1676 The reports of increased anaphylaxis and death with ferumoxytol are of concern. While we applaud the inclusion of their reference no. 6 5, which reports the limitations of spontaneous adverse events reporting, the authors fail to mention the Weber effect which is relevant to the data with ferumoxytol reported in their letter. The reference stated “it was expected that the study findings would show evidence of an initial surge in the use of ferumoxytol, as there tends to be with most newly marketed agents, and that this would be associated with increased adverse event reporting due to the Weber effect.” Consistent with this conclusion, the Freedom of Information review revealed 36 serious adverse events reports in the 31-day period from October 10 to November 10, 2010. Further supporting these conclusions, at that time the FDA approval for ferumoxytol allowed a 510 mg bolus to be administered in not less than 17 sec. We believe this rapid infusion was ill-considered, and the side effect profile as a result of the rapid administration appears to be consistent with elevated levels of labile free iron 7 and not anaphylaxis 8. One of us (MA) has administered more than 2,500 doses of ferumoxytol. The first 90 were administered in 17 sec. Three episodes of hypotension occurred. There were no deaths or hospitalizations. The remaining doses were administered over 90–180 sec. No clinically significant adverse events have been observed. Subsequently, FDAs new recommendation to administer ferumoxytol as a 15-min infusion should mitigate the overwhelming majority of labile-free iron reactions. Consistent with our observations, is an outcomes analysis in hemodialysis centers comparing ferumoxytol to other intravenous formulations comprising 17,958 patients during 6433 person years, which reported no difference in serious adverse events 9, and two prospective, randomized trials comparing ferumoxytol to iron sucrose comprising 767 patients which also reported no difference 10, 11. While it is possible that the “risk of anaphylaxis may differ among intravenous iron products” we strongly disagree that the “risk of anaphylaxis is significantly higher for iron dextran compared to iron sucrose” 12. All prospective and intra-institutional observational studies published to date show no difference in safety among the available formulations. In the reported analysis only Medicare codes were used. Dialysis patients were excluded, eliminating the lion's share of those who received iron sucrose in the US, as well as the majority of subjects who received low molecular weight iron dextran during the study period. Examples of excluded patients who often receive intravenous iron are those who are pregnant, with heavy uterine bleeding, inflammatory bowel disease, and bariatric surgery. However, more importantly, from the authors' own data in their supplemental material online, a significantly lower death rate was reported with iron dextran compared to the other formulations. Table 1 shows the significantly decreased rate of anaphylaxis on the day of administration. These data are statistically significant (P = 0.04) and, for all intents and purposes, contradict the conclusion that iron dextrans have higher rates of anaphylaxis than other formulations. Our interpretation is supported by a recent publication from a KDIGO iron management position paper, which reported that, if serious adverse events are not observed after several minutes following parenteral iron administration, such reactions are unlikely to occur 13. Lastly, as pointed out by the authors, there was an inability to distinguish between high and low molecular weight forms of iron dextran, the former known to be associated with a markedly higher risk of serious adverse events. Fortunately, high-molecular weight iron dextran is no longer available. Finally, we agree that convenience is not a justification for choosing intravenous iron over oral iron in the proper clinical setting. We agree that for patients with no comorbidities who tolerate oral iron and are adherent, oral iron may be effective and it is inexpensive and readily available. However published evidence suggests that up to 70% of those for whom oral iron is prescribed will report significant gastrointestinal adverse side effects 14. For those patients who are intolerant of, or unresponsive to, oral iron, or with medical conditions in which oral iron is ineffective or inappropriate (e.g., heavy uterine bleeding or hereditary hemorrhagic telangiectasia; inflammatory bowel disease, following gastric bypass procedures [Roux-en-Y or biliopancreatic diversion]), intravenous administration is preferred. Parenteral iron is not just superior in these settings, it is a necessity 15. Exaggerating the adverse side effects of parenteral iron on the basis of suspect data is not only counterproductive but potentially harmful to patients who otherwise might benefit greatly. Michael Auerbach1* and John Adamson2 1Georgetown University School of Medicine, Baltimore, Maryland;2University of California San Diego, La Jolla, California