Real-world comparative safety of ferric derisomaltose and ferric carboxymaltose: an analysis of hypersensitivity reactions

Authors

Abstract

Aim The comparative risk of hypersensitivity reactions (HSRs) between two high-dose intravenous iron formulations, ferric derisomaltose (FDI) and ferric carboxymaltose (FCM), is not well-established in real-world settings. This study directly compared the incidence and characteristics of HSRs between these agents.
Materials and Methods A retrospective, single-center cohort study was conducted at King Abdulaziz University Hospital, Jeddah. We included a cohort of 120 adult patients who received either FDI (n=60) or FCM (n=60) between August and October 2024. The timing of the HSRs was used to categorize them as infusion-related (Fishbane-type), early (≤24 hours), or delayed (24-72 hours).
Results In the primary analysis, the overall incidence of any HSR showed a trend to be higher in the FDI group than it was in the FCM group (31.7% vs 15.0%; odds ratio [OR] 2.63; p=0.051). Delayed HSRs were numerically higher in the FDI group (p=0.085). However, the association of drug type with HSR was no longer significant after adjustment for pregnancy status in a stratified analysis. It is important to note that there were no severe or life-threatening reactions in either group.
Discussion In this real-world analysis of patients, while an unadjusted comparison showed a trend towards a higher incidence of HSRs with FDI, this association did not remain after adjusting for pregnancy status. Both FDI and FCM have an overall positive safety profile for severe events, but highlight the need for larger prospective trials to confirm formulation-specific risk and evaluate patient factors such as pregnancy.

Keywords

Introduction

Iron deficiency anemia (IDA) is the most prevalent nutritional disorder in the world and is responsible for considerable morbidity and impaired quality of life. Oral iron is the first-line treatment; however, it is often limited in its use to tolerance and efficacy, especially within the spectrum of chronic inflammation or malabsorption [1]. Third-generation intravenous (IV) iron preparations are now an established option for IV iron therapy, allowing rapid and effective iron replacement. Ferric carboxymaltose (FCM, Ferinject®) and ferric derisomaltose (FDI, Monofer®) are widely utilized among these advanced agents [2]. These iron-carbohydrate nanoparticle complexes are designed to strongly bind iron to facilitate iron repletion for the safety of the patient with less toxicity from the lability of free iron. The improved stability allows infusion of a total iron dose in a single encounter for improved adherence [3].
Safety associated with these iron formulations is now well characterized, especially regarding the risk of serious hypersensitivity reactions (HSRs), which are exceedingly rare. High-quality evidence from randomized controlled trials (RCTs) and meta-analyses using standardized definitions to adjudicate events underpins safety. For example, Kennedy et al. published a systematic review and meta-analysis and reported an incidence of serious or severe HSRs for both drugs at 0.14% (FDI) and 1.08% (FCM) [4]. The FERWON-IDA trial reported adjudicated serious or severe HSRs of 0.3% for the same drug, FDI [5].
While this is reassuring information regarding severe events, another safety narrative has begun to unfold from real- world observational studies, which have evaluated all types of HSRs, including mild/moderate infusion reactions. Several retrospective cohort studies have repeatedly shown that the incidence of mild to moderate HSRs was seen to be significantly higher with FDI compared to FCM. In the study by Mulder et al., there were HSR 8.7% of FDI administrations compared to 2.1% for FCM, and in the study of Lucas et al., rates were 10.3% for FDI compared to 2.4% for FCM. Similarly, Bager et al. also stated that mild HSRs were four times higher with FDI (10.7%) compared with FCM (2.5%) [6, 7, 8]. This difference appears driven by transient, self-limiting infusion reactions (Fishbane reaction) that are certainly a type of complement activation- related pseudoallergy (CARPA) rather than true IgE-mediated anaphylaxis [9]. The discordance in the RCT data for severe reactions and observational data for milder events creates an important knowledge gap related to their comparative tolerability of these agents in routine practice.
Thus, this study aimed to add further real-world evidence by comparing the incidence, characteristics, and predictors of HSRs in association with the use of FDI and FCM in the cohort of patients treated at a single tertiary center.

Materials and Methods

This study was a single-center, retrospective cohort study completed as part of care at King Abdulaziz University Hospital, a tertiary care center located in Jeddah, Saudi Arabia. All adult patients who received IV iron therapy during the study period from August 1 to October 31, 2024, were included. Eligible participants were adult patients (14 years and older) who received at least one dose of either FCM or FDI for the treatment of non-anemic iron deficiency (NAID) or IDA. Dialysis patients were not included as iron sucrose was the institutional standard of care for this population during the study period. Patients with a known history of severe allergies to any parenteral iron formulation were also excluded from the analysis.
Subjects were initially recognized through the pharmacy infusion logs. All data obtained from the medical record was collected on a standardized data collection form from the electronic medical record (EMR). Data included patient demographics, gestational status with trimester designation, relevant comorbidities, and details of any infusion-related reactions. Iron infusions were administered based on the Summary of Product Characteristics (SPC) with ferric derisomaltose diluted in 100 mL of saline infused over 20–30 minutes and ferric carboxymaltose infused into a bag of 100 mL of sodium chloride 0.9% (to satisfy stability, dilutions to concentrations less than 2 mg/mL are not allowable) infused over 15 minutes.
The primary outcome was the incidence, type, and timing of infusion-related reactions. Reactions were categorized using a standardized classification to classify reactions into three categories: 1) Fishbane-type reactions, transient flushing, myalgia, or back pain with infusion, 2) Early HSR: occurring within 24 hours of infusion (e.g., urticaria, dyspnea), or 3) Delayed HSR: occurring between 24 and 72 hours of infusion (e.g., fever, arthralgia, rash) and were collected through a follow up phone call with patients. HSR responses were classified in an objective way utilizing the Ring and Messmer classification system [9, 10].
All descriptive and inferential statistics were performed in IBM SPSS (version 28.0, IBM Corp., Armonk, NY). A formal sample size calculation was not conducted because of the retrospective nature of the study. The primary comparison of hypersensitivity reaction rates between the treatment groups was performed using Fisher’s exact test. Odds ratios (OR) with 95% confidence intervals (CI) were calculated to quantify the association. In addition, due to an imbalance in pregnancy status between groups, a stratified analysis was conducted based on the Cochran-Mantel-Haenszel test to control for pregnancy as a potential confounding variable. Statistical significance was assumed with a p-value of less than 0.05 in all analyses.
Ethical Approval
This study was approved by the Ethics Committee of the Unit of Biomedical Ethics at King Abdulaziz University Hospital (Date: 2025-09-15, No:353-25).

Results

Patient Characterization
A total of 120 patients were analyzed, as there were 60 in each group (FDI, FCM). The patient characteristics are summarized in Table 1. The mean age for the cohort was 36.2 years, and nearly all patients identified as female sex (96.7%). In the FDI group, pregnancy was a more common clinical indication compared to the FCM group (26.7% vs 8.7% respectively).
Incidence and Type of Hypersensitivity Reactions
A total of 28 of 120 patients (23.3%) experienced one or more HSRs. For the primary outcome of any HSR, the odds were 2.63 times higher in the FDI group than in the FCM group. This result was borderline statistically significant (31.7% [19/60] vs 15.0% [9/60]; OR 2.63, 95% CI 1.09-6.35, p=0.051). The largest difference was observed for delayed HSR, where the incidence was twice the rate reported in the FDI group (23.3% [14/60] vs 10.0% [6/60]; OR 2.74, 95% CI 0.99-7.54, p = 0.085). Fishbane and early HSR reactions were more frequent in the FDI group numerically, but did not reach statistical significance (Figure 1). The most commonly reported events for FCM were flushing and fatigue, while with FDI, it was chest pain, shortness of breath, and abdominal pain. A complete breakdown of reaction types and their associated odds ratios is presented in Table 2. No severe reactions (Ring and Messmer Grade III/IV) occurred, and all were managed conservatively.
Stratified Analysis by Pregnancy Status
There was an imbalance in pregnancy status between treatment groups, and thus a stratified analysis was undertaken. After the adjustment for pregnancy, it did not find an association between the IV iron formulation and delayed hypersensitivity reactions (p = 0.096).

Discussion

The findings of a single-center, retrospective study in a real- world Saudi cohort show that administration of FDI resulted in a significantly higher rate of infusion-related reactions versus FCM. Our main finding of 31.7% of patients receiving FDI experiencing a reaction vs. 15.0% after FCM added to an emerging body of international evidence that is surprisingly consistent. The rates we have reported closely resemble the findings of Mulder et al. from the Netherlands (8.7% FDI vs. 2.1% FCM), Lucas et al. in Australia (10.3% FDI vs. 2.4% FCM), and Bager et al. in Denmark, who reported a four-fold greater rate of mild HSR with FDI [6, 7, 8]. It should be noted that our absolute rate is higher than those reported in the prior studies, possibly reflecting our enhanced institutional awareness and systematic reporting, but the relative difference is consistent and documents a similar pattern of reaction rates observed in routine clinical care from different health care systems. The consistency of the findings from these comparative observational studies, which capture the total spectrum of HSR, contrasts with the data, especially that which summarises large-scale RCT and meta-analyses, which only capture adjudicated severe reactions. Using high adjudication criteria, Kennedy et al. reported a very low incidence of serious HSR for both formulations, as low as 0.14% for FDI versus 1.08% for FCM [4]. This was also evident in the recent evaluation of the FERWON-IDA trial of patients with acute coronary syndrome, demonstrating an adjudicated serious HSR rate of only 0.3%; along with an indirect treatment comparison which had the same conclusion, with the FDI group having a lower risk of serious HSRs [5, 11]. Our study supports this dichotomy as we did not observe any severe or life-threatening (Ring and Messmer Grade III/IV) reactions [10]. This degree of safety serves to emphasize a relevant paradox within the literature, in which both drugs are quite safe in terms of rare, life- threatening events. Still, tolerability characteristics regarding milder infusion reactions are very different when using either intervention, even among sensitive populations like pregnancy [12]. The type of evidence also matters in this regard. Ehlken et al. provided evidence of a higher reporting rate of severe HSRs for FDI, using pharmacovigilance databases. While evidence is useful, the analyses done, based on spontaneous reports, have considerable methodological flaws, such as reporting bias and being unable to provide true incidence data [13]. This was challenged, or addressed, in a direct rebuttal by Schaffalitzky de Muckadell & Strom, ultimately championing a higher emphasis on RCT data of higher quality that should be prioritized [14]. Our study findings from continuous cohort review support the data from other real-world studies rather than the conclusions based on pharmacovigilance reporting systems [6, 7, 8]. Besides, the nature of events seen through our study may imply a specific mechanism. We went through the events based on symptoms of transient flushing (‘hives’), myalgia, and chest tightness, all being associated with CARPA, also known as Fishbane, compared to a true IgE-mediated allergy [9]. This mechanism of ‘non-allergic’ nature also appears to be causing infusion reactions primarily, with other reports suggesting this mechanism is more evident when using the allergic type of mechanism, which is linked to the nanoparticle structure of the IV iron [2, 15, 16]. The unique physicochemical characteristics of the iron-carbohydrate complexes likely account for the divergent reaction patterns [3, 17]. While our investigation was limited to HSRs, the clinical choice between the preparations is the result of a broader consideration of benefits and harm related to their use. One important difference between the drugs is the risk of treatment-emergent hypophosphatemia. The head-to-head PHOSPHARE trials clearly showed that FCM had substantially higher rates of hypophosphatemia incidence than FDI (approximately 75% vs. 8%) [18]. This common biochemical anomaly is often prolonged and even symptomatic and is an important clinical consideration [2, 19]. Consequently, consideration of a greater incidence of mild or transient HSRs with the use of FDI compared to severe biochemical disturbance with the use of FCM.

Limitations

The main advantage of this study is the addition of real- world data from a non-Western population. However, there are several limitations due to the retrospective, single-center design. A major limitation is our uncertainty regarding potential confounding variables. Our overall analysis showed a trend towards an increased rate of reactions with Monofer®, and our stratified analysis indicated that this trend was eliminated when controlling for pregnant patients. This indicates that the small sample of pregnant patients we had was not sufficient for statistical power to determine if the first trend was actually an effect of the drug or not, due to some event that occurred during pregnancy. The issue highlights the need for larger studies to obtain definitive safety data for this population. Furthermore, we had other unmeasured confounders and reporting biases, and our smaller patient population meant we were not able to conduct a more complex multivariable analysis to identify other independent risk factors. Besides, we were not able to measure serum phosphate as a routine protocol for this parameter did not exist for outpatients at our center.

Conclusion

This study found that there was a significantly greater incidence of mild to moderate HSRs with FDI than with FCM. There were no serious adverse events, which is reassuring and highlights the excellent overall safety profile of current IV iron preparations; this conclusion is supported by larger cohort studies and trials in more vulnerable populations, such as pregnancy. Clinicians should consider that FDI has an increased likelihood of transient infusion reactions in the context of safety, while hypophosphatemia risk with FCM treatment. Future prospective studies are warranted to confirm these formulation-specific differences.

References

1. Aleem A, Alsayegh F, Keshav S, et al. Consensus statement by an expert panel on the diagnosis and management of iron deficiency anemia in the Gulf Cooperation Council Countries. Med Princ Pract. 2020;29(4):371-81.
   PubMed Google Scholar
2. Van Doren L, Steinheiser M, Boykin K, Taylor KJ, Menendez M, Auerbach M. Expert consensus guidelines: Intravenous iron uses, formulations, administration, and management of reactions. Am J Hematol. 2024;99(7):1338-48.
   PubMed Google Scholar
3. Bhandari S, Pereira DIA, Chappell HF, Drakesmith H. Intravenous irons: From basic science to clinical practice. Pharmaceuticals (Basel). 2018;11(3):82.
   PubMed Google Scholar
4. Kennedy NA, Achebe MM, Biggar P, Pöhlmann J, Pollock RF. A systematic literature review and meta-analysis of the incidence of serious or severe hypersensitivity reactions after administration of ferric derisomaltose or ferric carboxymaltose. Int J Clin Pharm. 2023;45(3):604-12.
   PubMed Google Scholar
5. Auerbach M, Henry D, Derman RJ, Achebe MM, Thomsen LL, Glaspy J. 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(9):1007-14.
   PubMed Google Scholar
6. Mulder MB, van den Hoek HL, Birnie E, van Tilburg AJP, Westerman EM. Comparison of hypersensitivity reactions of intravenous iron: iron isomaltoside-1000 (Monofer) versus ferric carboxy-maltose (Ferinject). A single center, cohort study. Br J Clin Pharmacol. 2019;85(2):385-92.
   PubMed Google Scholar
7. Lucas S, Chauhan A, Hurley C, et al. Intravenous administration of ferric derisomaltose is associated with a higher incidence of infusion reactions than ferric carboxymaltose, and unaffected by dilution volume. Intern Med J. 2025;55(8):1293-300.
   PubMed Google Scholar
8. Bager P, Hvas CL, Dahlerup JF. Drug-specific hypophosphatemia and hypersensitivity reactions following different intravenous iron infusions. Br J Clin Pharmacol. 2017;83(5):1118-25.
   PubMed Google Scholar
9. Szebeni J, Fishbane S, Hedenus M, et al. Hypersensitivity to intravenous iron: classification, terminology, mechanisms and management. Br J Pharmacol. 2015;172(21):5025-36.
   PubMed Google Scholar
10. Ring J, Messmer K. Incidence and severity of anaphylactoid reactions to colloid volume substitutes. The Lancet. 1977;309(8009):466-9.
    PubMed Google Scholar
11. 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(2):187-95.
    PubMed Google Scholar
12. Khalafallah A, Hyppa A, Chuang A, et al. A prospective randomised controlled trial of a single intravenous infusion of ferric carboxymaltose, versus single intravenous iron polymaltose or daily oral ferrous sulphate in the treatment of iron deficiency anaemia in pregnancy. Semin Hematol. 2018;55(4):223-34.
    PubMed Google Scholar
13. Ehlken B, Nathell L, Gohlke A, Bocuk D, Toussi M, Wohlfeil S. Evaluation of the Reported Rates of Severe Hypersensitivity Reactions Associated with Ferric Carboxymaltose and Iron (III) Isomaltoside 1000 in Europe Based on Data from EudraVigilance and VigiBase between 2014 and 2017. Drug Saf. 2019;42(3):463- 71.
    PubMed Google Scholar
14. Schaffalitzky de Muckadell P, Strom CC. Comment on ‘Reported severe hypersensitivity reactions after intravenous iron administration in the European Economic Area (EEA) before and after implementation of risk minimization measures’. Drug Saf. 2020;43(5):503-5.
    PubMed Google Scholar
15. Rampton D, Folkersen J, Fishbane S, et al. Hypersensitivity reactions to intravenous iron: guidance for risk minimization and management. Haematologica. 2014;99(11):1671-6.
    PubMed Google Scholar
16. Gómez-Ramírez S, Shander A, Spahn DR, et al. Prevention and management of acute reactions to intravenous iron in surgical patients. Blood Transfus. 2019;17(2):137-45.
    PubMed Google Scholar
17. Geisser P, Burckhardt S. The pharmacokinetics and pharmacodynamics of iron preparations. Pharmaceutics. 2011;3(1):12-33.
    PubMed Google Scholar
18. 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(5):432-43.
    PubMed Google Scholar
19. Snook J, Bhala N, Beales ILP, et al. British Society of Gastroenterology guidelines for the management of iron deficiency anaemia in adults. Gut. 2021;70(11):2030-51.
    PubMed Google Scholar

Declarations

Additional Information

Publisher’s Note
Bayrakol MP remains neutral with regard to jurisdictional and institutional claims.

Rights and Permissions

Creative Commons License

This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License (CC BY-NC 4.0). To view a copy of the license, visit https://creativecommons.org/licenses/by-nc/4.0/

View full license details →

About This Article