Is low‐molecular weight iron dextran really the most risky iron?—Unconvincing data from an unconvincing study

Abstract

The use of intravenous iron has expanded over the past few years as accepted indications for its use have increased. It is now recognized that intravenous iron will raise iron stores faster and more reliably in conditions in which oral iron is unlikely to work or poorly tolerated such as chronic kidney disease, inflammatory bowel disease, heavy uterine bleeding, hereditary hemorrhagic telangiectasia (Osler-Weber-Rendu), pregnancy, and those having undergone bariatric surgery. However, the acceptance of this effective therapy by physicians has been hindered by concerns about safety of iron infusions. The use of early formulations, such as ferric hydroxide, was associated with high levels of labile free iron release and an unacceptably high incidence of serious hemodynamically significant infusion reactions. By the early 1950s, products with carbohydrate cores which bound the elemental iron more tightly, such as high-molecular weight iron dextran-ImFeron, (Fisons, Homes Chapel, England) and later DexFerrum, (American Regent, Shirley, New York)-which are no longer available, and iron sucrose, were much better tolerated but still associated with rare anaphylactic reactions. Newer formulations which release labile free iron much more slowly, such as low-molecular weight iron dextran (INFeD, Pfizer, New York, NY), ferumoxytol (Feraheme, AMAG, Waltham, MA), ferric carboxymaltose (InjectoFer, American Regent, Shirley, NY), and iron isomaltoside (Monofer, Europe only, Pharmacosmos, Haelbeck, Denmark) are much better tolerated and provide the added convenience of being able to be administered safely in complete replacement doses over 15-60 min.While there are many factors to consider in the choice of iron products-expense, numbers of infusions, effectiveness-safety is also a key factor. One iron product did stand out in risk-high-molecular weight iron dextran (DexFerrum) which has been shown in several studies to have reaction rates higher than other iron products [1][2][3]. This formulation was removed from market in 2009. The accumulated data show that lowmolecular weight iron dextran does not share this higher risk. Studies ranging from dialysis database reviews to a European Medical Agency review have shown no difference in risk with low-molecular weight iron dextran versus other iron products [3][4][5].Recently, this notion of equivalent risk was challenged by a study from the FDA which purported to show a significantly higher rate of "anaphylaxis" with iron dextran compared to other iron products [6]. This study examined 688,183 non-dialysis new users of intravenous iron over 10 years in the outpatient Medicare claims database. The anaphylaxis rate for iron dextran was compared to iron gluconate, iron sucrose, and ferumoxytol. The key finding was that the rate of anaphylaxis for iron dextran had an odds ratio 2.6 times higher reaction rate than all nondextran irons-68 vs. 23 per 100,000 persons.However, there are several issues with this study that cast doubt on the conclusion that low-molecular weight iron dextra...

Single‐dose intravenous iron infusion or oral iron for treatment of fatigue after postpartum haemorrhage: a randomized controlled trial

“…iron described as the Fishbane reaction [26,27]. The pathogenesis is unknown, but according to Rampton (2014), it is believed to be a complement activation-related pseudo-allergy (CARPA) triggered by iron nano-particles [28,29].…”

Iron Deficiency Anemia

“…71 The major disadvantage with intravenous iron is infusion reactions, but both the incidence and severity of these is often overstated. 72 These reactions are not true allergic reactions but are related to complement activation by the labile free iron. 73 Recently detailed advice about treating these reactions has been published 74 ; in general, for mild reactions, the infusion is stopped and then resumed at a slower rate once symptoms resolve.…”

The available intravenous iron formulations: History, efficacy, and toxicology

“…The investigators concluded that anaphylaxis was more likely with ID compared with iron sucrose. There are, however, concerns with the study: In the analysis, the authors were unable to distinguish between HMW‐ID and LMW‐ID, both of which continued to be available during the study. The administration of diphenhydramine and epinephrine were used as surrogates for anaphylaxis, and it was impossible to tell if they were used as premedication or as an unnecessary intervention for a minor, self‐limited infusion reaction. The average age of IV iron recipients analyzed was in the 1970s missing many frequent recipients of IV iron, including those with heavy uterine bleeding, pregnancy, bariatric surgery, and inflammatory bowel disease. Dialysis patients were also excluded, eliminating the lion's share of patients who received iron sucrose in the United States during the study period. Most importantly, from the article authors' own supplemental material online, the risk of death on the day of administration was an order of magnitude lower with ID than any of the other iron formulations, effectively contradicting the conclusions of their paper …”

“…Most importantly, from the article authors' own supplemental material online, the risk of death on the day of administration was an order of magnitude lower with ID than any of the other iron formulations, effectively contradicting the conclusions of their paper. 10,11 Recently LMW-ID has been shown to be able to be administered safely and effectively as a 1000 mg dose in 1 hour in 888 patients who received 1266 doses, in a population of patients with iron deficiency caused by heavy uterine bleeding, bariatric surgery, inflammatory bowel disease, hereditary hemorrhagic telangiectasia and pregnancy. 12,13 A recent observational study in 189 oral iron intolerant, iron deficient gravidas in the second and third trimester reported hemoglobin responses in 92% without significant toxicity.…”