Reports to FDA of fatal anaphylaxis associated with intravenous iron products
Authors: Lynda McCulley, Kate Gelperin, Steven Bird, Sarah Harris, Cunlin Wang, Peter Waldron
Journal: American Journal of Hematology (2016)

To the Editor: In the January 2016 issue of AJH, Auerbach and Adamson 1 in their review of the diagnosis and treatment of iron deficiency anemia, state that intravenous (IV) iron is safe to use "in all clinical circumstances including pregnancy." We note, however, that all IV iron products can cause fatal hypersensitivity reactions including anaphylaxis. During the past five years, the FDA has received 49 reports of death temporally associated with administration of IV iron, 30 of which were adjudicated and determined to be anaphylaxis. The use of IV iron agents, ferumoxytol, iron dextran, iron gluconate, and iron sucrose, has increased dramatically in the non-dialysis dependent population between 2003 and 2013. The median increase in incident IV iron utilization among Medicare enrolled beneficiaries was 8.1% per year (interquartile range 4.9–15.4%), growing from 32,413 in 2003 to 86,623 in 2013. Figure 1A (Supporting Information) depicts the relative utilization of IV iron by calendar year among patients in the FDA's Sentinel database, consisting primarily of privately insured patients 20 to 65 years of age; Figure 1B depicts the relative utilization of IV iron by calendar year among patients enrolled in Medicare with supplemental Part D coverage. In both populations, iron dextran utilization decreased in favor of iron sucrose as the predominant IV iron formulation. Ferumoxytol utilization increased starting at market approval in 2009. The increased use of ferumoxytol in the non-dialysis dependent population may have been due in part to the convenience factors of its faster rate of administration (17 seconds at 2009 market approval) and higher amount (510 mg) of iron delivered per dose. In March 2015, FDA issued a Drug Safety Communication 2 after a search of the FDA Adverse Event Reporting System (FAERS) database identified 79 cases of anaphylactic reactions associated with ferumoxytol administration. Of the 79 cases, 18 were fatal, despite immediate medical intervention and emergency resuscitation attempts. Based on these data, FDA strengthened an existing warning that fatal and serious hypersensitivity reactions can occur, and approved a Boxed Warning, FDA's strongest type of warning, regarding these serious risks for ferumoxytol. A new Contraindication, against use in patients who have had an allergic reaction to any IV iron product, was also added. The FDA uses contraindications to communicate criteria which identify persons for whom the risk from use clearly outweighs any possible therapeutic benefit. At the same time the ferumoxytol Dosage and Administration section underwent a significant modification with the recommendation to dilute the drug, and administer it over at least 15 minutes, in contrast to the original recommendation to infuse undiluted over 17 seconds. The FDA has received reports of fatal anaphylaxis reactions with onset of symptoms during or shortly after administration for all of the currently marketed IV iron products. Table 1 summarizes 30 fatal reports in FAERS from December 2010 through December 2015. Since the Table 1 data are from spontaneous reports, they must be interpreted cautiously because of potential underreporting, differential product reporting between older versus recently approved IV iron products, and inconsistent quality of information. An additional consideration is that the interpretation of anaphylaxis as a cause of death has inter-observer variability among clinicians, and criteria for adjudicating adverse events of anaphylaxis have changed over time 3. The reported indication for IV iron use was off-label in 44% of these cases, but it is unknown whether indication for use affects risk for fatal reactions. Death occurred within 24 hr of IV iron exposure in 18 (60%) cases, and within an hour for two cases of ferumoxytol administration, despite interventions in almost all cases. Given the March 2015 labeling recommendation to infuse ferumoxytol over a minimum of 15 minutes, it is noteworthy that 18 of the 19 patients who received IV iron by push administration received ferumoxytol, but also that three deaths associated with ferumoxytol occurred following an infusion of at least 15 minutes. Since deaths occurred after the first, second, and third administrations of IV iron, the risk of fatality may exist at any dose. A recent retrospective cohort study conducted by FDA researchers using Medicare data 4 suggested the risk of anaphylaxis may differ among IV iron products, and the risk was significantly higher for iron dextran compared to iron sucrose. Published analyses of post-marketing spontaneous reports 5 have also identified potential differential risks among IV iron products, but the limitations of spontaneous reports cited above apply 6. Hypersensitivity reactions have been reported during clinical trials with IV iron products, but direct comparisons of incidence rates among all currently marketed products are hindered by lack of standardized nomenclature and ascertainment methods for hypersensitivity adverse events. The underlying mechanisms of the anaphylaxis reaction are not understood. The high proportion of reactions with the first IV iron infusion supports a mechanism other than IgE-mediated 7. We remain concerned about the risk of fatal anaphylaxis with IV iron products, which may differ among products. Although such reactions may be rare, they have the potential to affect the benefit-risk balance of these products, especially when such reactions do not occur with oral iron preparations. In addition to patients with chronic kidney disease, there are disorders with anatomic and functional barriers to oral iron absorption which make oral iron ineffective. In these situations the choice of IV iron is straightforward. The more difficult decisions present when a course of oral iron replacement is started, but a mild to moderate adverse event (typically gastrointestinal) occurs, which may be an adverse drug reaction. The decision to advocate perseverance with the oral route, or a switch to IV, is done one case at a time. From the safety perspective, the worst justification for choosing IV iron is convenience, although the line between convenience and compliance can be indistinct. All IV iron products carry the warning, "Only administer product when personnel and therapies are immediately available for the treatment of anaphylaxis and other hypersensitivity reactions." The practitioner must ensure, as part of their process for optimizing the benefit risk ratio, that infusing personnel are well educated and practiced in managing these challenging situations. Lynda McCulley, Kate Gelperin, Steven Bird, Sarah Harris, Cunlin Wang, and Peter Waldron* U.S. Food and Drug Administration (FDA) Center for Drug Evaluation and Research (CDER), Office of Pharmacovigilance and Epidemiology, Silver Spring, Maryland Additional Supporting Information may be found in the online version of this article. Supporting Information Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.