Iron in hematology: Danger with IV iron: Real or perceived?
Authors: Michael Auerbach
Journal: American Journal of Hematology (2014)

To the editor: This is the first of a series or monthly updates on the treatment of iron deficient states. This regular column will address in real time relevant issues concerning indications and therapeutic modalities for the use of iron supplements. Questions and comments from the AJH readership are welcome. Iron deficiency is associated with fatigue, dietary abnormalities including pagophagia, decreased work performance, restless legs syndrome, and sleep disturbance and most strikingly in neonates, delayed growth and development and an increment in cognitive and behavioral abnormalities up to 10 years after iron repletion 1. In the past decade, the medical community has witnessed incremental increases in the use of intravenous (IV) iron for conditions where oral iron is not tolerated, ineffective or contraindicated. This paradigm shift in the treatment of one of the most common maladies on earth was at least in part, motivated by the development and availability of four new formulations in which the carbohydrate core binds iron more tightly, allowing slower release for erythropoiesis, minimizing infusion related hypersensitivity reactions, and allowing complete replacement dosing in 15–60 min 2, not possible with the more widely used salts, iron sucrose, and ferric gluconate which release higher amounts of free iron after administration. These include low molecular weight (LMW) iron dextran, ferumoxytol, ferric carboxymaltose, and iron isomaltoside. Millions of doses in patients on dialysis, those with inflammatory bowel disease, previous bariatric surgery, heavy uterine bleeding, gravidas, and other well individuals intolerant of oral iron, have been given seamlessly with marginal toxicity. Nonetheless, safety concerns abound, many of which are fueled by publications reporting differences in the safety profile of available formulations based on methodologies, such as spontaneous adverse event reporting, that have been specifically proscribed by regulatory agencies 3. Further confounding safety concerns, was the use of high molecular weight (HMW) iron dextran, which was associated with a significant increase in serious adverse events 4. Minor infusion reactions consisting of mild arthralgias of the chest and flank or flushing occur infrequently with all of the formulations. These reactions routinely abate without therapy and serum tryptase levels are always normal. Without any evidence to support its use, diphenhydramine is used as premedication. This antihistamine can cause somnolence, hypotension, diaphoresis, and tachycardia often ostensibly attributed to the iron. It is, therefore, not surprising that practitioners with pre-existing notions of danger with IV iron, frequently intervene with pressors, and more antihistamines, converting minor infusion reactions into hemodynamically significant serious adverse events (SAEs). In all prospective comparisons between LMW ID, ferric carboxymaltose, and ferumoxtol to iron sucrose, no negative safety signal was identified with the new formulations. The same conclusion can be drawn with large intrainstitutional retrospective analyses 5. Recently, ferric carboxymaltose was compared to the no longer available and more dangerous HMW ID, which erroneously concluded that ferric carboxymaltose was safer than iron dextran 6. Until such a comparison is made to LMW iron dextran, no conclusion can or should be inferred. In conclusion, the new formulations of IV iron are extremely safe, and probably much safer than most physicians realize. When proper interpretation and management of minor infusion reactions is understood and undertaken, serious adverse events are vanishingly rare with an estimated incidence of <1:200,000 doses 4. Hematologists should be more familiar with the available formulations, their profiles, and administration. Michael Auerbach Auerbach Hematology and Oncology, 9110 Philadelphia Rd Suite 314, Baltimore, Maryland 21237