Focused Update: On the Relative Safety of Intravenous Iron Formulations

Michael Auerbach, MD, FACP
Hematology and Oncology
Clinical Professor of Medicine
Georgetown University
Washington, DC, USA


Seven intravenous (IV) iron products are available in the United States (USA) and Europe (Table 1). An eighth product, iron polymaltose, is used in Australia and will not be discussed in this focused update.

A publication in the American Journal of Hematology by Wysowski et al., principals of the FDA, using data from monitoring systems, emergency room visits and death certificates, concluded that, in the absence of head-to-head trials, which are unlikely to be performed, it is impossible to tell the relative rates of adverse events among the existing products [1]. This conclusion was supported by a review of all adverse events on the use of all of the available IV iron formulations in the USA, including any untoward event, reported to the FDA through MedWatch from January 1, 2007 through December 31, 2009. The data were obtained through Freedom of Information. A total of 704 adverse events were reported. Of the two iron dextran products available in the USA, the majority of events reported for the products were either unidentifiable by brand. If reported deaths were calculated, there were more associated with, but no necessarily due to, iron sucrose than with the other four combined but there were nearly fives times as many doses of iron sucrose sold over the time period than the other four combined. Only two small prospective head-to-head studies [2, 3] have ever been performed among existing products (low-molecular-weight iron dextran and iron sucrose), which showed no difference in safety or efficacy. Further, the FDA mandated that manufacturers cease claims that one IV iron product is safer than another and that all advertisements containing such claims be withdrawn.

 Intravenous Iron Preparations

Complete replacement dosing in a single setting was until recently not available with the exception of iron dextran. When doses higher than 250 mg with ferric gluconate or 300 mg with iron sucrose are administered, infusion reactions occur, probably due to free iron release from the less tightly bound carbohydrate carriers. In the past two years, three new products, which promise to allow for the administration of higher doses of iron in 15-60 minutes, have been released for use. One in the USA and Europe, ferumoxytol (Feraheme®/Rienso®, AMAG Pharmaceuticals, Inc, Lexington, MA, USA / Takeda Pharmaceutical Company Limited, Tokyo, Japan) and two in Europe, ferric carboxymaltose (Ferinject®, Vifor Pharma, Zurich, Switzerland) and iron isomaltoside 1000 (Monofer®, Pharmacosmos, Copenhagen, Denmark). In their registrational trials, safety and efficacy were consistent with existing products. Yet, the US FDA delayed approval of ferric carboxymaltose due to unexplained hypophosphatemia at two weeks after injection and an imbalance in cardiovascular events and deaths in the treatment arm compared to placebo. However, it should be noted that none of the deaths in the submitted data were considered related to the administration of the IV iron. And in a recently mandated change in the package insert for ferumoxytol, a bolded warning about potentially life-threatening events was added. In our practice we have administered over 250 doses of 510 mg of ferumoxytol as a 17-second bolus. Three cases of hypotension were observed, all of which resolved with fluid. The same three patients, when given ferumoxytol over one minute, experienced no untoward events.

Premedication, especially with antihistamines, can add to the confusion. Premedication prior to IV iron administration is often given without any data supporting its benefit. There are even published data showing that the majority of adverse events seen when diphenhydramine is used are due to the premedication and often attributed to the IV iron [4]. Antihistamines can cause somnolence, flushing, hypotension and supraventricular tachycardia prompting inappropriate intervention and the conversion of a minor reaction into a serious or life-threatening one. In our practice we routinely administer IV iron without premedication, with the exception of patients with a history of allergy to more than one drug or an allergic diathesis or asthma, in the absence of which we recommend that premedication be avoided.

Based on prospective studies with all the formulations, with the possible exception of high-molecular-weight iron dextran (USA only), where the preponderance of published data suggests caution, and iron isomaltoside (Europe only), for which data is still scanty, serious adverse events are extremely rare. Awareness of the clinical nature of adverse events and avoidance of unnecessary intervention for minor reactions is paramount. A commonly accepted adverse event definition should be adopted by regulatory agencies so that types of events can be calculated. Reporting to a central agency should be mandatory and data reviewed regularly. Until then, one product cannot and should not be considered superior in terms of safety profile [5].

IV iron is safe, and probably much safer than most physicians realize. Proper utilization of this important therapeutic modality offers significant clinical benefit in a host of conditions associated with the need for iron replacement therapy.



1. Wysowski DK, Swartz L, Borders-Hemphill BV, et al. Use of parenteral iron products and serious anaphylactic-type reactions. Am J Hematol 2010;85:650-4.

2. Moniem KA, Bhandari S. Tolerability and efficacy of parenteral iron therapy in hemodialysis patients, a comparison of preparations. Transfus Alternat Transfus Med 2007;9:37-42.

3. Sav T, Tokgoz B, Sipahioglu MH, et al. Is there a difference between the allergic potencies of the iron sucrose and low molecular weight iron dextran? Ren Fail 2007;29:423-6.

4. Barton JC, Barton EH, Bertoli LF, et al. Intravenous iron dextran therapy in patients with iron deficiency and normal renal function who failed to respond to or did not tolerate oral iron supplementation. Am J Med 2000;109:27-32.

5. Auerbach M, Ballard H. Clinical use of intravenous iron: administration, efficacy and safety. Hematology Am Soc Hematol Educ Program 2010:338-47.


Product Information

DexFerrum                    American Regent, Inc. Dexferrum Prescribing Information. [Link]

INFeD / Cosmofer          Watson Pharmaceuticals, Inc. [Link]

                                   Pharcosmos A/S. [Link]

Ferrlecit                        Sanofi-Aventis, Inc. Ferrlecit Prescribing Information. [Link]

Venofer                        American Regent, Inc. [Link]

Feraheme / Rienso         AMAG Pharmaceuticals, Inc. [Link]

Monofer                       Pharmacosmos A/S. [Link]

Ferinject / Injectafer       Vifor Pharma. [Link]