Comparison of Rates of Reported Adverse Events Associated With I.V. Iron Products in the United States

George R. Bailie


Am J Health Syst Pharm. 2012;69(4):310-320. 

In This Article

Abstract and Introduction


Purpose An analysis of reported adverse events (AEs) among patients using i.v. iron products, including the newer agent ferumoxytol, is presented.
Methods All AE reports to the Food and Drug Administration (FDA) citing iron sucrose, ferric gluconate, high- and low-molecular-weight iron dextran products, or ferumoxytol from October 2009 through June 2010 were evaluated. The rates of various classifications of reported AEs were calculated on a per-unit-sold basis and, for comparison of products supplied in different unit sizes, also in terms of 100-mg dose equivalents (DEq) of iron.
Results A total of 197 reported AEs were identified (a cumulative rate of 14.1 AEs per million units sold). The rates of all AE classifications combined ranged from 5.25 to 746 per million units sold for iron sucrose and ferumoxytol, respectively; using the other method of calculation, the rates ranged from 5.24 per million DEq (iron sucrose) to 147 per million DEq (ferumoxytol). Relative to iron sucrose and sodium ferric gluconate, ferumoxytol was associated with significantly elevated risks of death (odds ratio [OR], 475 and 156, respectively; p < 0.0001), serious nonfatal AEs (OR, 263 and 121, respectively; p < 0.0001), and all evaluated AE classifications combined (OR, 142 and 109, respectively; p < 0.05).
Conclusion Analysis of reports submitted to FDA revealed large differences among i.v. iron products in reported deaths, serious AEs, other major AEs, and other AEs. Iron sucrose and sodium ferric gluconate were associated with much lower rates of AEs per million units sold than iron dextran or ferumoxytol, which were associated with the highest rates of all reported AE classifications.


The appropriate use of i.v. iron is increasingly recognized as fundamental to the optimal management of iron deficiency anemia, a frequently reported complication of pregnancy and conditions such as chronic kidney disease (CKD), cancer, chronic heart failure, inflammatory bowel disease, and heavy uterine bleeding, and the management of anemia that can occur during the postpartum period and after gastric bypass surgery.[1–9] Recent studies of anemia management in dialysis- dependent and nondialysis-dependent CKD caution against the overuse of erythropoietin-stimulating agents,[10–14] and the most contemporary versions of some clinical practice guidelines encourage the judicious use of i.v. iron.[15] Clearly, a critical balance exists among providing sufficient iron to maintain adequate iron stores, ensuring the adequate availability of iron for brisk erythropoiesis, and minimizing the potential for long-term toxicity associated with iron overload.[16]

Most spontaneous reports of adverse events (AEs) associated with i.v. iron relate to acute toxicities, especially hypersensitivity or allergic reactions, and other acute and transient events that may be associated with the rapid release of labile, or "free," iron after administration.[17–20] Previous studies have compared the relative risks of various serious AEs with different i.v. iron products using registries of spontaneous reports[17–20] despite the well-documented limitations of registry-based research. Those limitations include reporting biases, influences of regulatory authorities, changes in the clinical use of drugs over time or in different countries, "protopathic bias" due to the use of a medication to treat an early manifestation of a disease that has not yet been diagnosed,[21] and confounding by indication (e.g., patients who are more sick tend to be treated with some medication but are also more likely to die; thus, there is not a true relationship between use of that medication and mortality). Another limitation of such studies is the "Weber effect": the tendency toward higher AE reporting rates for a newly released agent relative to other agents in the same class that have been available for a longer period.[22,23]

Some studies of i.v. iron products have compared the types and rates of AEs reported in the United States to the Food and Drug Administration (FDA),[17–19] while other research has contrasted experiences in North America and Europe using data collated by the World Health Organization (WHO).[20] While these investigations have supplied important information about the relative risks of acute AEs by product and in different countries, all have been limited to experiences with iron sucrose, iron dextran, and sodium ferric gluconate, which have been available in global markets for many years. However, a new agent, ferumoxytol, became available on the U.S. market recently (June 30, 2009); to date there have been no published comparative data on toxicities with preparations that contain this agent.

The study described here was designed to examine the reported AEs associated with all i.v. iron products available in the United States, including an examination of data on ferumoxytol that have accrued since its introduction. 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 AE reporting due to the Weber effect.[23]


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