Clinical data for intravenous iron - debunking the hype around hypersensitivity

Maureen Achebe, Thomas G DeLoughery, Maureen Achebe, Thomas G DeLoughery

Abstract

Background: Reluctance to use intravenous (IV) iron for the treatment of iron deficiency continues due to a perceived high risk of severe hypersensitivity reactions (HSRs). Additionally, it has been hypothesized that 'dextran-derived' IV iron products (e.g., ferumoxytol [FER] and ferric derisomaltose/iron isomaltoside 1000 [FDI]) have a higher risk of severe HSRs than 'non-dextran-derived' products (e.g., ferric carboxymaltose [FCM] and iron sucrose [IS]). In the present analysis, HSR data from head-to-head randomized controlled trials (RCTs) with IV iron products were evaluated to determine if differences in safety signals are present among these IV iron formulations.

Study design and methods: Reported serious or moderate-to-severe HSR incidence data from five RCTs (FIRM; FERWON-NEPHRO/-IDA; PHOSPHARE-IDA04/-IDA05) were used to calculate risk differences with 95% confidence intervals (CIs) for FER, FCM, FDI, and IS. The rates and risk differences for these HSRs were compared.

Results: The analysis included data for 5247 patients: FER (n = 997), FCM (n = 1117), FDI (n = 2133) and IS (n = 1000). Overall rates of serious or moderate to severe HSRs were low (0.2%-1.7%). The risk differences (95% CIs) showed small differences between the IV iron formulations: FER versus FCM, -0.1 (-0.8 to 0.6); FDI versus IS, 0.1 (-0.3 to 0.5); FDI versus FCM, -0.9 (-3.7 to 1.9).

Conclusion: RCT evidence confirms a low risk of serious or moderate to severe HSRs with newer IV iron formulations and no significant differences among existing commercially available products. Thus, RCT data show that the supposed classification of dextran-derived versus non-dextran-derived IV iron products has no clinical relevance.

Conflict of interest statement

The authors have disclosed no conflicts of interest.

© 2020 The Authors. Transfusion published by Wiley Periodicals LLC on behalf of AABB.

Figures

Fig. 1.
Fig. 1.
The risk of serious or moderate to severe HSRs associated with the use of IV iron products – data from the FIRM, FERWON, and PHOSPHARE studies. CI = confidence interval; FCM = ferric carboxymaltose; FDI = ferric derisomaltose/iron isomaltoside 1000; FER = ferumoxytol; HSR = hypersensitivity reaction; IS = iron sucrose.
Fig. 2.
Fig. 2.
Algorithm for the management of immediate infusion reactions. Adapted from: Rampton et al.,4 Lim et al.,22 Macdougall et al.,23 and Simons et al. 24 [Color figure can be viewed at wileyonlinelibrary.com]

References

    1. Mueller MM, Van Remoortel H, Meybohm P, et al. ICC PBM Frankfurt 2018 Group. Patient blood management: recommendations from the 2018 Frankfurt Consensus Conference. JAMA 2019;321:983‐97.
    1. Auerbach M, DeLoughery T. Single‐dose intravenous iron for iron deficiency: a new paradigm. Hematology Am Soc Hematol Educ Program 2016;2016:57‐66.
    1. Jahn MR, Andreasen HB, Fütterer S, et al. A comparative study of the physicochemical properties of iron isomaltoside 1000 (Monofer), a new intravenous iron preparation and its clinical implications. Eur J Pharm Biopharm 2011;78:480‐91.
    1. Rampton D, Folkersen J, Fishbane S, et al. Hypersensitivity reactions to intravenous iron: guidance for risk minimization and management. Haematologica 2014;99:1671‐6.
    1. Macdougall IC, Vernon K. Complement activation‐related pseudo‐allergy: a fresh look at hypersensitivity reactions to intravenous iron. Am J Nephrol 2017;45:60‐2.
    1. Neiser S, Wilhelm M, Schwarz K, et al. Assessment of dextran antigenicity of intravenous iron products by an immunodiffusion assay. Port J Nephrol Hypert 2011;25:219‐24.
    1. Neiser S, Schwarz K, Wilhelm M, et al. Reply to the letter to the editor by Johannes Ring and Rudi Valenta on the article “Assessment of dextran antigenicity of intravenous iron products by an immunodiffusion assay”. Port J Nephrol Hypert 2012;26:311‐2.
    1. OCEBM Levels of Evidence Working Group. The Oxford 2011 Levels of Evidence. Available at: .
    1. Adkinson NF, Strauss WE, Macdougall IC, et al. Comparative safety of intravenous ferumoxytol versus ferric carboxymaltose in iron deficiency anemia: a randomized trial. Am J Hematol 2018;93:683‐90.
    1. Auerbach M, Henry D, Derman RJ, et al. A prospective, multi‐center, randomized comparison of iron isomaltoside 1000 versus iron sucrose in patients with iron deficiency anemia; the FERWON‐IDA trial. Am J Hematol 2019;94:1007‐14.
    1. Bhandari S, Kalra PA, Berkowitz M, et al. Safety and efficacy of iron isomaltoside 1000/ferric derisomaltose versus iron sucrose in patients with chronic kidney disease: the FERWON‐NEPHRO randomized, open‐label, comparative trial. Nephrol Dial Transplant 2020. pii: gfaa011. 10.1093/ndt/gfaa011 [Epub ahead of print].
    1. Wolf M, Rubin J, Achebe M, et al. Effects of iron isomaltoside vs ferric carboxymaltose on hypophosphatemia in iron deficiency anemia: two randomized clinical trials. JAMA 2020;323:432‐43.
    1. Available from: .
    1. Hetzel D, Strauss W, Bernard K, et al. A phase III, randomized, open‐label trial of ferumoxytol compared with iron sucrose for the treatment of iron deficiency anemia in patients with a history of unsatisfactory oral iron therapy. Am J Hematol 2014;89:646‐50.
    1. Macdougall IC, Strauss WE, McLaughlin J, et al. A randomized comparison of ferumoxytol and iron sucrose for treating iron deficiency anemia in patients with CKD. Clin J Am Soc Nephrol 2014;9:705‐12.
    1. Macdougall IC, Strauss WE, Dahl NV, et al. Ferumoxytol for iron deficiency anemia in patients undergoing hemodialysis. The FACT randomized controlled trial. Clin Nephrol 2019;91:237‐45.
    1. Derman R, Roman E, Modiano MR, et al. A randomized trial of iron isomaltoside versus iron sucrose in patients with iron deficiency anemia. Am J Hematol 2017;92:286‐91.
    1. Center for Drug Evaluation and Research . Medical review of Injectafer (VIT‐45, ferric carboxymaltose injection; FCM) for the treatment of iron deficiency anemia (203565Orig1s000). 2013. Available at: .
    1. Avni T, Bieber A, Grossman A, et al. The safety of intravenous iron preparations: systematic review and meta‐analysis. Mayo Clin Proc 2015;90:12‐23.
    1. Pollock RF, Biggar P. Indirect methods of comparison of the safety of ferric derisomaltose, iron sucrose and ferric carboxymaltose in the treatment of iron deficiency anemia. Expert Rev Hematol 2020;13:187‐95.
    1. Auerbach M, Adamson JW. How we diagnose and treat iron deficiency anemia. Am J Hematol 2016;91:31‐8.
    1. Lim W, Afif W, Knowles S, et al. Canadian expert consensus: management of hypersensitivity reactions to intravenous iron in adults. Vox Sang 2019;114:363‐73.
    1. Macdougall IC, Bircher AJ, Eckardt KU, et al. Conference Participants. Iron management in chronic kidney disease: conclusions from a “Kidney Disease: Improving Global Outcomes” (KDIGO) Controversies Conference. Kidney Int 2016;89:28‐39.
    1. Simons FE, Ardusso LR, Bilò MB, et al. World Allergy Organization. World Allergy Organization guidelines for the assessment and management of anaphylaxis. World Allergy Organ J 2011;4:13‐37.
    1. European Medicines Agency . New recommendations to manage risk of allergic reactions with intravenous iron‐containing medicines. 2013. [cited 2020 Jan 21]. Available from: .
    1. Bircher AJ, Auerbach M. Hypersensitivity from intravenous iron products. Immunol Allergy Clin North Am 2014;34:707‐23 x‐xi.
    1. Zoller H, Schaefer B, Glodny B. Iron‐induced hypophosphatemia: an emerging complication. Curr Opin Nephrol Hypertens 2017;26:266‐75.
    1. Detlie TE, Lindstrøm JC, Jahnsen ME, et al. Incidence of hypophosphatemia in patients with inflammatory bowel disease treated with ferric carboxymaltose or iron isomaltoside. Aliment Pharmacol Ther 2019;50:397‐406.

Source: PubMed

Sponsoren und Mitarbeiter

Krankheiten

Drogeninterventionen

3
Abonnieren