Ferumoxytol as a New, Safer, Easier-to-Administer Intravenous Iron: Yes or No?

Use of intravenous iron for the management of anemia in chronic kidney disease (CKD) and dialysis patients has repeatedly been shown to increase hemoglobin levels and lower the dose of erythropoiesis-stimulating agents (ESAs). Each of the currently available formulations of intravenous iron has limitations related to safety or convenience. The currently available preparations are all iron-carbohydrate complexes or colloids based on small spheroidal iron-carbohydrate particles developed to shield bioactive free iron. Each particle consists of a core made of an iron-oxyhydroxy gel surrounded by a shell of carbohydrate that stabilizes the gel, slows the release of iron, and maintains the resulting particles in colloidal suspension. The molecular weight of the iron complex reflects the size of the iron core and the surrounding carbohydrate. There are currently 2 iron-dextran formulations and 2 nondextran formulations (iron salts), as well as 2 new compounds under consideration. These compounds are described in more detail in Table 1.

Table 1. Intravenous Iron Preparations

		Currently Available Intravenous Iron Preparations1, 2, 3, 4				Investigational Agents (not FDA approved)5, 6, 7
	Trade Name	DexFerrum	INFeD	Ferrlecit	Venofer	Ferumoxytol	Injectafer
	Manufacturer	American Regent, Inc	Watson Pharmaceuticals, Inc	Watson Pharmaceuticals, Inc	American Regent, Inc	AMAG Pharmaceuticals	American Regent, Inc
	Carbohydrate	High-molecular-weight dextran	Low-molecular-weight dextran	Gluconate	Sucrose	Polyglucose sorbitol carboxymethylether	Carboxymaltose
	Molecular weight measured by manufacturer (Da)	265,000	165,000	289,000-440,000	34,000-60,000	750,000	150,000
	Total-dose or >500-mg infusion	Yes	Yes	No	No	Yes	Yes
	Premedication	TDI only	TDI only	No	No	No	No
	Test dose required	Yes	Yes	No	No	No	No
	Iron concentration (mg/mL)	50	50	12.5	20	50	30
	Vial volume (mL)	1-2	2	5	5	NA	NA
	Black box warning	Yes	Yes	No	No	NA	NA
	Preservative	None	None	Benzyl alcohol	None	None	None

Note: Ferric gluconate and iron sucrose are also referred to as iron salts. Abbreviations: NA, not applicable; TDI, total-dose infusion.

The usual dose for repletion of iron stores is 1,000 to 1,500 mg. While high- and low-molecular-weight preparations of iron dextran can be given as a total dose infusion (eg, 1,000 to 1,500 mg) over 60 to 90 minutes, there are concerns about anaphylactic reactions. The iron salts ferric gluconate and iron sucrose do not appear to cause anaphylaxis, but higher doses result in other acute reactions, precluding total dose infusions. In this issue of the American Journal of Kidney Diseases, Singh and colleagues8 report the safety results of ferumoxytol, an investigational form of intravenous iron, which can be given as 510 mg intravenously in less than 1 minute. This study compared adverse reactions to ferumoxytol to placebo, but not to other forms of intravenous iron, and excluded patients more likely to develop drug reactions. Before we can conclude that ferumoxytol is the perfect combination of safety and convenience, it is worth reviewing the safety of the other available intravenous irons and comparing those results to this recent ferumoxytol study.

Intravenous iron in combination with ESA to reach the target hemoglobin concentration is now the standard of care for anemia in CKD. Iron dextran was the most widely used intravenous iron until the introduction of ferric gluconate, and then iron sucrose, to the US market. Shortly thereafter, the use of iron dextran in dialysis patients plummeted due to the view that iron dextran carried a greater risk of severe reactions. Newer information suggests low-molecular-weight iron dextran is much safer than high-molecular-weight iron dextran, with the latter agent accounting for an overwhelming majority of reported serious adverse events to iron dextran in a retrospective analysis by Chertow and colleagues of 50 million doses of intravenous iron.9 In this analysis, low-molecular-weight iron dextran had serious reaction rates of less than 1 in 200,000, similar to the iron salts. Retrospective analyses from spontaneous reporting systems lead to systematic underreporting of the actual incidence of drug reactions, but the similarity between reaction rates reported with low-molecular-weight iron dextran and the iron salts undermine the view that the newer irons are clearly safer. Further, many identified serious adverse events were unable to be classified by brand and were subsequently assigned equally between high-molecular-weight and low-molecular-weight iron dextran for the final analysis. It is therefore likely that this underestimated the toxicity of the high-molecular-weight preparation while overestimating the toxicity of low-molecular-weight iron dextran. During a brief period of time when low-molecular-weight iron dextran was unavailable, necessitating the use of high-molecular-weight iron dextran in dialysis centers in the United States, there was an 1,100% increase in serious adverse events related to intravenous iron reported to the US Food and Drug Administration (data obtained by the author through a Freedom of Information Act request).10

The safety of intravenous iron is not only limited by anaphylaxis and other acute reactions. In vitro and animal studies by Zager and colleagues showed the iron salts induce cellular injury while low-molecular-weight iron dextran does not at comparable to higher doses.11, 12 A beautiful series of studies in patients with CKD stages 3 and 4 have demonstrated that 100 mg of iron sucrose induces increased markers of oxidative stress and causes transient proteinuria and enzymuria.13, 14, 15 On further analysis, the increase in proteinuria was characterized as albuminuria. Further, the albumin molecule itself was damaged, such that a ladder pattern was seen on western blots.16 This laddering of albumin was also time dependent and resolved over 24 hours. In contrast, although 250 mg of ferric gluconate increased oxidative stress, it did not significantly increase proteinuria.13, 14 These data are consistent with Zager's preclinical studies and with a study by Pai et al, which showed increased non–transferrin-bound (free) iron and markers of oxidative stress after a single dose of either iron sucrose or ferric gluconate compared with iron dextran.17

The study by Singh and colleagues evaluated the safety, efficacy, and ease of administration of ferumoxytol, 255 or 510 mg, over 17 to 60 seconds in patients with CKD stages 1 to 5 and 5D. They reported only 1 serious adverse event to ferumoxytol in 750 patients studied, suggesting a better safety profile than reported with iron dextran. This anaphylactoid reaction occurred in a patient with multiple drug allergies. In addition, the authors suggested that the high doses given over such a short period of time provides for a greater ease of administration than exists with the currently available iron salts and iron dextrans.

In their discussion, Singh and colleagues state that iron dextran is associated with a 1.7% incidence of anaphylactoid reactions, referencing data published prior to the study by Chertow and colleagues9 and prior to the increased awareness of the toxicity differences between high- and low-molecular-weight preparations of iron dextran, though they note that “there are data to suggest that low-molecular-weight iron dextran may be better tolerated than high-molecular-weight iron dextran.” Many iron experts are more forceful, noting huge differences in toxicity between the 2 iron dextrans, and more than 15 publications that proscribe the use of the high-molecular-weight formulation.10, 18 Two recent publications urge the US Food and Drug Administration to remove high-molecular-weight iron dextran from the pharmacopoeia.10, 19

Although the ferumoxytol safety profile appears better than the retrospective chart review of low-molecular-weight iron dextran and comparable to the iron salts, 2 prospective comparison studies of low-molecular-weight iron dextran versus iron sucrose found no differences in efficacy or toxicity.20, 21 Lastly, the 5.2% incidence of minor infusion-related side effects seen with ferumoxytol represents a nearly 10- to 20-fold increase over such events seen with ferric gluconate, iron sucrose, and low-molecular-weight iron dextran.22

Ferumoxytol, with a modified dextran shell, may not be as safe as suggested by Singh et al's report, as the study excluded all patients who had an allergy to iron products or to 2 or more drugs. This greatly limits the likelihood of a drug reaction, because such patients are known to have increased sensitivity to even chemically dissimilar drugs.23 A large double-blind safety study of ferric gluconate found reactions to both drug and placebo were 7-fold more common among those with a history of iron dextran allergy.24 Singh et al report the anaphylactoid reaction to ferumoxytol occurred in a man with “multiple drug allergies,” which is inconsistent with the study's own exclusion criteria, but highlights the higher reaction rate among predisposed individuals. Lastly, the ferumoxytol study, unlike the ferric gluconate study trial, did not exclude patients receiving antihistamines, which can mimic, or glucocorticoids, which can mask, drug reactions.25

Cumulatively, these studies call into question the wisdom of abandoning low-molecular-weight iron dextran as first-line therapy in dialysis patients.18 Low-molecular-weight iron dextran also has the advantage of being able to be given as a single total-dose infusion of 1 g over 1 to 2 hours, while the maximal single dose of iron salts is significantly less. In my practice, in the past 15 months we have given over 150 total-dose infusions of 1,000 to 1,500 mg of low-molecular-weight iron dextran in 60 to 90 minutes to patients with iron deficiency from a wide variety of disease states, without incident. Although the efficacy, toxicity profile, and marked increased ease of administration of ferumoxytol provide an exciting new avenue for investigation for those interested in the role of intravenous iron in treating anemia across many disease states, ferumoxytol should be compared to the other iron formulations in unselected patient populations before yet another premature conclusion is drawn about safety and efficacy of intravenous iron products.

In conclusion, the clinical community's larger perception of risk associated with all intravenous irons is antiquated and incorrect.10 While the perception of adverse event rates are driven higher by high-molecular-weight iron dextran, low-molecular-weight iron dextran, and to a lesser extent the 2 iron salts, suffer the stigma. The folklore surrounding the toxicity of intravenous iron will only end with prospective, randomized, controlled, comparative clinical trials.