Modern Intravenous Iron Therapy: A Review on Safety and Practical Aspects

Review Article

Ann Hematol Oncol. 2022; 9(6): 1413.

Modern Intravenous Iron Therapy: A Review on Safety and Practical Aspects

Juillerat P1,13*, Angelillo-Scherrer A2, Surbek D3, Restellini S4, Biedermann L5, Rogler G5, Vavricka SR5,6, Schoepfer A7, Burri E8, Degen L9, Seibold F10,11, Mottet C12, Maillard MH7, Michetti P7,13, Battegay E14#, and Stein J15,16#

1Department of Gastroenterology, Clinic for Visceral Surgery and Medicine, Inselspital, Bern University Hospital, University of Bern, Switzerland

2Department of Haematology and Central Haematology Laboratory, Inselspital, Bern University Hospital, University of Bern, Switzerland

3Department of Gynecology and Obstetrics, Inselspital, Bern University Hospital, Switzerland

4Department of Gastroenterology and Hepatology, Geneva University Hospitals and University of Geneva, Switzerland

5Department of Gastroenterology and Hepatology, University Hospital Zurich, University of Zurich, Switzerland

6Center of Gastroenterology and Hepatology, Switzerland

7Division of Gastroenterology and Hepatology, Centre Hospitalier Universitaire Vaudois and University of Lausanne, Switzerland

8Gastroenterology and Hepatology, University Medical Clinic, Cantonal Hospital Baselland, Switzerland

9University Center for Gastrointestinal and Liver Diseases, St. Clara Hospital and University Hospital, Switzerland

10Department of Gastroenterology, Kantonspital Fribourg, Switzerland

11Department of Gastroenterology, Praxis Balsiger, Seibold und Partner am Lindenhofspital, Switzerland

12Department of Gastroenterology, Centre Hospitalier du Valais Romand (CHVR), Switzerland

13Crohn and Colitis Center, Gastroentérologie Beaulieu SA, Switzerland

14Innovation Hub, International Center for Multimorbidity and Complexity, University of Zurich, Switzerland, and Department of Psychosomatic Medicine, University Hospital Basel, Switzerland

15DGD Clinics Sachsenhausen, Frankfurt/Main, Germany

16Crohn Colitis Centre Rhein-Main, Frankfurt/Main, Germany

#These authors have contributed equally to this article

*Corresponding author: Pascal Juillerat, Clinic for Visceral Surgery and Medicine Inselspital, Bern University Hospital Freiburgstrasse 38, CH-3010 Bern, Switzerland

Received: October 27, 2022; Accepted: November 26, 2022; Published: December 03, 2022


Introduction: Intravenous iron formulations have been approved in Europe and North America for the treatment of iron deficiency if oral iron is not tolerated or not efficacious. Recently-developed intravenous iron formulations exhibit specific physicochemical and immunological properties, with distinct bioavailability, efficacy and safety profiles.

Area of Interest: intravenous iron formulations safety and tolerability were reviewed in the framework of a Swiss expert meeting. This work focused on the specificity of each compound with emphasis on the practical aspects of its use.

Expert Opinion: Adverse reactions in response to IV formulations can be categorized into two main types: hypophosphataemia and hypersensitivity. Hypophosphatemia follows administration of ferric carboxymaltose at a higher rate in comparison to other formulations, but is mostly mild, transient and asymptomatic. However, the decrease in serum phosphate following repeated administration of iron preparations can affect bone health, particularly in patients at risk for osteomalacia. Severe hypersensitivity reactions are the most lifethreatening adverse reactions to intravenous iron supplementation. Iron (III)- isomaltoside 1000 seems to induce severe hypersensitivity more often (RR 5.6 - 16.2) than ferric carboxymaltose. Further studies are needed to address issues of long-term safety in high dose and prolonged administration of intravenous iron preparations in case of chronic diseases.

Keywords: Iron; Intravenous; Efficacy; Haemoglobin; Anaemia; Safety; Hypophosphatemia; Hypersensitivity


AE: Adverse Events; CHF: Chronic Heart Failure; CKD: Chronic Kidney Disease; Hb: Haemoglobin; IBD: Inflammatory Bowel Disease; ID: Iron Deficiency; IDA: Iron Deficiency Anaemia; IV: Intravenous; SD: Standard Deviation


It took several decades to transform a highly toxic colloidal solution of Intravenous (IV) ferric hydroxide that had elicited severe adverse reactions into commercially available parenteral iron preparations that enable high doses of IV iron to be administered in a short lapse of time and with a comparatively low risk of adverse effects. Iron (III) sucrose, one of the first commercially available intravenous iron compounds, went into clinical use in Europe in 1949 [1]. High molecular weight iron dextran followed in the 1950s but its usage was stopped due to anaphylactic reactions following administration, except in clinical conditions offering no alternative [2]. In 1977, IV administration of ferric gluconate [3], and in the 1990s low molecular weight iron dextran went into clinical use, the latter with a lower risk of severe adverse drug reactions [4]. Near 2000, three “new- or thirdgeneration” iron preparations entered clinical use: ferumoxytol, ferric carboxymaltose and iron (III)-isomaltoside 1000. Their high stability enables a total replacement dose to be administered in just one or two infusions. Nevertheless, each of these products exhibits particular physicochemical and immunological properties which have led to distinctive clinical outcomes and safety profiles [5]. This review focuses on ferric carboxymaltose and iron (III)-isomaltoside 1000 as the current “new generation” IV iron preparations mainly used in Europe. It is out of the scope of this article to provide practical approaches regarding diagnosis of ID and detailed advises on its treatment in specific therapeutic areas.

Physicochemical and Immunological Properties of Intravenous Iron

All IV iron preparations are colloidal suspensions of nanoparticles. They consist of a polynuclear core of iron (III) oxyhydroxide surrounded by a carbohydrate ligand (“shell”). The carbohydrate shell stabilizes the core and thus protects against further polymerization. The shell also slows the continuous release of bioactive iron, which is toxic at excessive concentrations leading to oxidative stress [6,7]. Parenteral iron products qualify as non-biological complex drugs because their level of complexity exceeds small synthetic drugs by far. They are, however, less complex than molecules produced in living systems, such as antibodies. Nevertheless, iron core and iron shell carbohydrate complexes are intricate, unique and difficult to manufacture [8]. They require very specific conditions and a highly controlled and sophisticated environment for their production. Thus, the smallest variation in the manufacturing process, such as changes in pH, temperature, material sources, or reaction time could critically influence the physicochemical characteristics and properties of the final product, including molecular weight or particle size distribution, valence state of iron, surface charge, or crystallinity [8]. The resulting structures of the iron core and iron shell, as well as the size and size distribution of the particles affect bioavailability, toxicity and clinical features of IV iron preparations [9,10].

Efficacy and Clinical Outcomes

Data from head-to-head trials on the efficacy of different IV iron formulations is limited. (Table 1) summarizes effects and indirect comparisons of IV iron formulations, mainly based on network metaanalyses [11-14]. Clinical potency of distinct IV iron formulations can differ depending on the specific indication for therapeutic use and the clinical outcome selected. Thus, iron (III) isomaltoside has shown a higher increase of hemoglobin from baseline compared to ferric carboxymaltose in anaemic patients intolerant to oral iron, but failed to show superiority among those patients with an increase in haemoglobin of ≥ 2g/dL [12]. Ferumoxytol and ferric carboxymaltose at monthly doses of 1020 mg and 750-1500 mg, respectively, were shown to be particularly potent in anaemic patients with Chronic Kidney Disease (CKD) [11]. Indirect comparisons with other intravenous irons based on studies using oral iron as a control indicate that ferric carboxymaltose might show superiority over other IV iron formulations regarding haemoglobin increase [15]. In IBD patients, only ferric carboxylmaltose, but not iron (III) sucrose or iron (III) isomaltoside 1000, has shown statistically significant superiority versus oral iron [12]. This data is specific for patients with IBD and may not apply to IDA from other causes. Considering many uncertainties about distinct efficacy and outcomes of different preparations, further head-to-head trials are needed in order to provide better evidence regarding the efficacy of different IV iron formulations [12].