Guideline 2.6 – Administration of IV Iron – Safety Recommendations

All forms of IV iron may be associated with acute adverse events (AEs). Immune mechanisms (including IgE-mediated responses or complement activation-related pseudo-allergy) may have a role in some cases (1). Anaphylactoid reactions appear to occur more frequently with high molecular weight iron dextran (2). The rate of life-threatening reactions to iron dextran administration is 0.6% to 0.7% (3,4). Labile or free iron reactions occur more frequently with non-dextran forms of iron (4). These reactions, also known as Fishbane reactions, are infusion rate related and are characterised by facial flushing, back pain and chest tightness sometimes accompanied with dyspnoea. They can often be mistaken for anaphylaxis, however symptoms often disappear following cessation of the infusion. Patients should have their vital signs monitored following cessation of the infusion and if symptoms have disappeared, can continue the therapy at a lower infusion rate. This does not exclude the patient form receiving that form of IV iron in the future, however a slower rate of infusion would be required for subsequent treatment. (1)

In one study, a total of 2534 people receiving haemodialysis were directly observed after double-blind exposure to intravenous sodium ferric gluconate (SFGC) or placebo. One participant in each of the SFGC and placebo groups experienced anaphylactoid reactions. Additional cases with characteristics possibly consistent with anaphylaxis occurred in 0.4% of intravenous SFGC–treated participants and 0.1% of placebo-treated participants. The results suggest that there is a relatively low rate of anaphylaxis with non-dextran irons and that the reactions are generally easily managed (5, 6). A retrospective cohort study compared anaphylaxis rates between five IV iron preparations: iron dextran, ferumoxytol, ferric gluconate, iron sucrose and ferric carboxymaltose. The adjusted IRs for anaphylaxis per 10 000 first administrations were 9.8 cases (95% CI: 6.2 to 15.3 cases) for iron dextran, 4.0 cases (CI: 2.5 to 6.6 cases) for ferumoxytol, 1.5 cases (CI: 0.3 to 6.6 cases) for ferric gluconate, 1.2 cases (CI: 0.6 to 2.5 cases) for iron sucrose, and 0.8 cases (CI: 0.3 to 2.6 cases) for ferric carboxymaltose (7).

In the IRONMAN trial, 1127 people with heart failure with HFrEF and iron deficiency were recruited to either receive IV ferric derisomaltose (n=559) or usual care (n=568) (8). There were no differences between the two groups and the rate of serious adverse events. Only one person in the study had an infusion related reaction, reported to have experienced vomiting, back pain and dizziness after commencing infusion, but recovered fully after overnight observation (8). The MHRA has issued an updated guidance on the use of parenteral iron. This was in response to concerns raised as a result of serious and rarely fatal hypersensitivity reaction, particularly in pregnant women. These reactions can occur even when a previous administration has been tolerated (including a negative test dose). The risk of hypersensitivity is increased in people with: known allergies (including drug allergies); immune or inflammatory conditions (e.g., systemic lupus erythematous, rheumatoid arthritis); or those with a history of severe asthma, eczema, or other atopic allergy. As a result, the MHRA updated guidelines recommend that (9):

• IV iron should be administered in strict accordance with the posology and method of administration described in the product information for each individual product (note that advice varies between products).
• Caution is needed with every dose of intravenous iron that is given, even if previous administrations have been well tolerated.
• IV iron products should only be administered when staff trained to evaluate and manage anaphylactic or anaphylactoid reactions—as well as resuscitation facilities—are immediately available.
• Recipients should be closely monitored for signs of hypersensitivity during and for at least 30 minutes after every administration of an IV iron product.
• In people with increased risk of hypersensitivity, treatment with IV iron products should only be considered if the benefits are clearly judged to outweigh the potential risks.

References

1. Rampton D, Folkersen J, Fishbane S et al. Hypersensitivity reactions to intravenous iron: guidance for risk minimization and management. Haematologica. 2014 Nov;99(11):1671-6.
2. Novey HS, Pahl M, Haydik I et al. Immunologic studies of anaphylaxis to iron dextran in patients on renal dialysis. Ann Allergy 1994; 72:224-228.
3. Hamstra RD, Block MH, Schocket AL. Intravenous iron dextran in clinical medicine. JAMA 1980; 243:1726- 1731.
4. Fishbane S, Ungureanu VD, Maesaka JK, et al. The safety of intravenous iron dextran in haemodialysis patients. Am J Kidney Dis 1996; 28:529-534.
5. Agarwal R, Vasavada N, Sachs NG et al. Oxidative stress and renal injury with intravenous iron in patients with chronic kidney disease. Kidney Int 2004; 65:2279- 2289.
6. Michael B, Coyne DW, Fishbane S, et al; Ferrlecit Publication Committee. Sodium ferric gluconate complex in haemodialysis patients: adverse reactions compared to placebo and iron dextran. Kidney Int. 2002 May;61(5):1830-9.
7. Dave CV, Brittenham GM, Carson JL, Setoguchi S. Risks for Anaphylaxis with Intravenous Iron Formulations: A Retrospective Cohort Study. Ann Intern Med. 2022;175(5):656-664.
8. Kalra PR, Cleland JGF, Petrie MC, et al. Intravenous ferric derisomaltose in patients with heart failure and iron deficiency in the UK (IRONMAN): an investigator-initiated, prospective, randomised, open-label, blinded-endpoint trial. Lancet. 2022;400(10369):2199-2209. doi:10.1016/S0140-6736(22)02083-9
9. MHRA Drug Safety Update (2013) Intravenous iron and serious hypersensitivity reactions: strengthened recommendations https://www.gov.uk/drug-safety-update/intravenous-iron-and-serioushypersensitivity- reactions-strengthened-recommendations (accessed 29/08/2023)

Parenteral iron administration to people receiving haemodialysis has been shown to result in a reduction of circulating TNFα levels (1). In addition, chronic iron loading has been associated with an impaired immune response of circulating monocytes to ex vivo stimulation with lipo-poly saccharide (LPS) (2). Excess iron inhibits anti-microbial effector pathways of macrophages (3, 4). This is exerted via blockade of LPS and interferon-gamma (IFNJ) inducible immune pathways, while production of macrophage de-activating cytokines such as interleukin10 (IL10) is increased (5, 6). The effect of iron on immune function could be dependent on the iron preparation; one study has shown that iron sucrose had more prominent effects on monocyte differentiation than other clinically available compounds (7).

Ishida and Johansen critically reviewed available literature regarding the association between iron and infection in people receiving HD (8). The authors identified studies that evaluated the association between the risk of infection, serum ferritin levels (13 studies) and iron usage (24 studies). Thirteen studies with sample sizes ranging from 61 to 2,662 have examined the link between serum ferritin and infection in haemodialysis patients. Among the 13 studies, nine studies reported an association, and four studies did not find an association between serum ferritin and infection. Among the studies that identified an association, high serum ferritin (typically defined as >500 or 1,000 microgram/L) was associated with higher incidence of bacterial infection or infection-related mortality. The incidence of bacterial infection ranged from 0.34 to 0.59 infections per patient-year (in studies evaluating the rate of infection) and 0.93% to 61.9% (in studies evaluating the proportion with infection) in the higher serum ferritin groups and 0.09 to 0.18 infections per patient-year and 0% to 37% in the lower serum ferritin groups. The authors concluded that these studies suggest an excess of 16 to 50 infections per 100 patient-years in the higher compared with the lower serum ferritin groups. In studies that expressed the association between serum ferritin and bacterial infection as ratios, higher serum ferritin was independently associated with a 1.5 to 3.1-fold higher incidence of bacterial infection or infection-related mortality. Among the 24 studies that evaluated the relationship between iron therapy and infection, twenty-two studies were observational with sample sizes ranging from 21 to 309,219 participants. Twelve of these studies found an association between any iron usage, higher dose or frequency of iron usage and infection or infection-related mortality.

One study compared mortality with different dosing patterns of IV iron (9). Based on data from 117,050 people receiving HD, the study evaluated the effect of bolus versus maintenance IV iron dosing during repeated 1- month exposure periods on risks of mortality and infection-related hospitalisation during the subsequent 3 months. In multivariable additive risk models, compared to maintenance dosing (median monthly dose 200 mg), bolus dosing (median 700 mg) was associated with an increased risk of infection-related hospitalisation (risk difference, 25 additional events/1000 patient-years; 95% CI: 16 to 33), with the risk being largest among patients with a catheter or history of recent infection. An association between bolus dosing and infection-related mortality was also observed. In contrast, maintenance and low-dose iron (125 mg) dosing were not associated with increased risks of infection-related hospitalisation or mortality outcomes when compared with no iron.

A multicentre study prospectively evaluated the association between serum ferritin levels and IV iron usage with adverse outcomes and mortality among 1086 Japanese people receiving chronic HD. By using Cox proportional hazard models and time-dependent variables, there was a significantly higher risk of infection with higher (above 100 microgram/L) compared to lower (below 100 ng/dl) serum ferritin levels, and with high (≥50 mg/week) and even low (<50 mg/week) doses of IV iron compared with no IV iron; they also reported significantly higher risk of death among people with high-amplitude ferritin fluctuations (serum ferritin level consistently above 100 microgram/L or upward trend from below to above 100 microgram/L) compared with those with low ferritin level (10).

In a study involving 626 people with pre-dialysis CKD. People were treated with intravenous ferric carboxymaltose (with a high and low ferritin target) or oral iron for 52 weeks. The percentage of deaths, myocardial infarctions, and infections was not significantly different between oral iron– treated and IVI-treated participants. However, the study was not powered to evaluate safety of parenteral iron (11).

Post-hoc analysis studied adverse events between the three arms. The incidence of one or more adverse events was 91.0, 100.0 and 105.0 per 100 patient-years in the high ferritin, low ferritin and oral iron groups, respectively. The incidence of adverse events with a suspected relation to study drug was 15.9, 17.8 and 36.7 per 100 patient-years in the three groups; for serious adverse events, the incidence was 28.2, 27.9 and 24.3 per 100 patient-years. The incidence of cardiac disorders and infections was similar between groups (12).

In a study evaluating the safety of parenteral iron therapy in 10,169 people receiving haemodialysis in the United States; after adjusting for 23 demographic and comorbidity characteristics among 5833 people included in the multivariable analysis; bills for ≤10 vials of iron over 6 months showed no adverse effect on survival when compared with none, but bills for >10 vials showed a statistically significant elevated rate of death (13). Bills for ≤10 vials of iron over 6 months also showed no significant association with hospitalisation (adjusted = 0.92; 95% CI: 0.83 to 1.03; P = 0.15), but bills for >10 vials showed statistically significant elevated risk. More intensive dosing was associated with diminished survival and higher rates of hospitalisation, even after extensive adjustment for baseline comorbidity (13).

A subsequent analysis of 32,566 Fresenius Inc. people receiving haemodialysis by the same authors did not find an association between IVI iron dose and risk of death after adjusting for time-varying measures of iron treatment and fixed and time-varying measures of morbidity (14).

Kalantar-Zadeh et al. studied 58,058 DaVita Inc. people receiving dialysis (15). For people who received 400 mg of IVI per month, the risk for death was found to be lower compared with people with no IV iron administered. By contrast, doses >400 mg per month were associated with an increased risk of death (15).

Kshirsagar et al. studied 117,050 people receiving haemodialysis. No association was found between dose of IVI iron and short-term risk of myocardial infarction, stroke, or death (16).

A prospective observational study by Hoen et al. followed 988 people receiving HD from 19 French centres for 6 months. There were 51 episodes of bacteraemia, but no association with either IV iron dosing or serum ferritin concentration was detected (17). A more recent study from the same group in 985 people receiving dialysis patients, demonstrated no significant increase in infection rates (18).

In the IRONMAN trial, 1127 people with heart failure and reduced ejection fraction (HFrEF) and iron deficiency were recruited to either receive IV ferric derisomaltose (n=559) or usual care (n=568). It was found that between the two groups, there were a similar rates of infections (25% vs 29%. HR – 3.12; 95% CI: -8.30 to 2.06. p=0.24). Deaths due to infections were also similar in the two groups (6% vs 5%. HR 1.22, 95% CI: 0.74 to 2.02. p=0.43) as were hospitalisations due to infection (n= 175 vs 213. HR 0.82, 95% CI: 0.62 to 1.08. p=0.16) (19).

The PIVOTAL trial randomised 2141 people receiving HD who were within the first year of receiving haemodialysis to a high dose proactive iron regimen (400 mg monthly) or a low dose reactive regimen (0-400 mg monthly) based of TSAT and ferritin, showing a high dose iron regimen was superior in reducing rates of non-fatal MI, non-fatal stroke, hospitalisation due to heart failure or death (20). Secondary analysis sought to address concerns around increasing infection rates in patients receiving IV iron. Secondary endpoints included infection, hospitalisation for infection and death from infection. It was found that there was no significant difference in secondary endpoints in the high dose vs low dose iron groups.

Results for “all infection episodes,” there were 508 first events (46.5%) in the proactive high-dose group versus 477 first events (45.5%) in the low-dose group (HR, 0.98; 95% CI: 0.87 to 1.11; P=0.80). Results for “hospitalisations for infections” were 323 first events (29.6%) in the proactive high-dose arm versus 307 first events (29.3%) in the reactive low-dose arm (HR, 0.99; 95% CI: 0.82 to 1.16; P=0.92). Results for “death from infections,” showed 46 events (4.21%) in the proactive high-dose arm versus 41 first events (3.91%) in the reactive low-dose arm (HR, 1.04; 95% CI: 0.69 to 1.59; P=0.84). Participants with central venous catheter were more likely to experience an infection, however no differences in all three infection endpoints (in relation to the treatment arms) were seen in those people dialysing via central venous access vs arteriovenous fistula (20, 21).

Meta-analysis from Hougen et al. also supported PIVOTAL findings by comparing infection rates from four RCT studies using high dose IV iron regimens (>400 mg a month) vs low dose IV iron or no iron regimens in people receiving haemodialysis (22). This study concluded that there were no differences in infection rates in the high dose iron group (n=743; relative risk, 1.02; 95% confidence interval, 0.74 to 1.41). Eight observational studies using high dose IV iron regiments (>200 mg a month) showed no increase in infection risk (n=135,532; pooled hazard ratio, 1.13; 95% confidence interval, 0.99 to 1.28) (22).

Meta-analysis from Shah A et al. reviewed 154 RCTs looking at risk of infection with intravenous iron vs oral iron or no iron across various disease states. This study found that intravenous iron was associated with an increased risk of infection when compared with oral iron or no iron (RR, 1.17; 95% CI: 1.04-1.31; I2 = 37%; moderate certainty of evidence) most significantly in those with inflammatory bowel disease (IBD). Across the trials, there were significant variation in in how infection was defined or reported, leading to inconsistent reporting across the studies. There were no differences observed in mortality between the groups (23).

References

1. Weiss, G., Meusburger, E., Radacher, G., et al. 2003. Effect of iron treatment on circulating cytokine levels in ESRD patients receiving recombinant human erythropoietin. Kidney Int 64:572-578.
2. Sonnweber, T., Theurl, I., Seifert, M., et al. 2011. Impact of iron treatment on immune effector function and cellular iron status of circulating monocytes in dialysis patients. Nephrol Dial Transplant 26:977-987.
3. Nairz, M., Schroll, A., Sonnweber, T et al, G. 2010. The struggle for iron – a metal at the host-pathogen interface. Cell Microbiol 12:1691-1702.
4. Ganz, T. 2009. Iron in innate immunity: starve the invaders. Curr Opin Immunol 21:63-67.
5. Fritsche, G., Nairz, M., Werner, E.R et al. 2008. Nramp1-functionality increases iNOS expression via repression of IL-10 formation. Eur J Immunol 38:3060-3067.
6. Weiss, G., and Goodnough, L.T. 2005. Anemia of chronic disease. N Engl J Med 352:1011- 1023.
7. Fell, L.H., Zawada, A.M., Rogacev, K.S., et al. 2014. Distinct immunologic effects of different intravenous iron preparations on monocytes. Nephrol Dial Transplant 29:809-822.
8. Ishida JH, Johansen KL. Iron and infection in haemodialysis patients. Semin Dial. 2014; 27 (1): 26-36.
9. Brookhart MA, Freburger JK, Ellis AR, et al. Infection risk with bolus versus maintenance iron supplementation in haemodialysis patients. J Am Soc Nephrol. 2013 Jun; 24(7):1151-8.
10. Kuragano T, Matsumura O, Matsuda A, et al. Association between hemoglobin variability, serum ferritin levels, and adverse events/mortality in maintenance hemodialysis patients. Kidney Int. 2014 Oct;86(4):845-54
11. Macdougall IC, Bock AH, Carrera F, et al; FIND-CKD Study Investigators. FIND-CKD: a randomized trial of intravenous ferric carboxymaltose versus oral iron in patients with chronic kidney disease and iron deficiency anaemia. Nephrol Dial Transplant. 2014 Nov;29(11):2075-84.
12. Roger SD, Gaillard CA, Bock AH, et al. Safety of intravenous ferric carboxymaltose versus oral iron in patients with nondialysis-dependent CKD: an analysis of the 1-year FIND-CKD trial. Nephrol Dial Transplant. 2017;32(9):1530-1539. doi:10.1093/ndt/gfw264
13. Feldman HI, Santanna J, Guo W, et al. Iron administration and clinical outcomes in haemodialysis patients. J Am Soc Nephrol. 2002 Mar;13(3):734-44.
14. Feldman HI, Joffe M, Robinson B, et al. Administration of parenteral iron and mortality among haemodialysis patients. J Am Soc Nephrol. 2004 Jun;15(6):1623-32.
15. Kalantar-Zadeh K, Regidor DL, McAllister CJ et al. Time-dependent associations between iron and mortality in haemodialysis patients. J Am Soc Nephrol. 2005 Oct;16(10):3070-80.
16. Kshirsagar AV, Freburger JK, Ellis AR, et al. Intravenous iron supplementation practices and short-term risk of cardiovascular events in haemodialysis patients. PLoS One. 2013 Nov 1;8(11):e78930.
17. Hoen B, Paul-Dauphin A, Hestin D, et al. EPIBACDIAL: a multicentre prospective study of risk factors for bacteraemia in chronic haemodialysis patients. J Am Soc Nephrol 1998; 9: 869- 876.
18. Hoen B, Paul-Dauphin A, Kessler M: Intravenous iron administration does not significantly increase the risk of bacteraemia in chronic haemodialysis patients. Clin Nephrol 2002, 57(6):457-461.
19. Kalra PR, Cleland JGF, Petrie MC, et al. Intravenous ferric derisomaltose in patients with heart failure and iron deficiency in the UK (IRONMAN): an investigator-initiated, prospective, randomised, open-label, blinded-endpoint trial. Lancet. 2022;400(10369):2199-2209. doi:10.1016/S0140-6736(22)02083-9
20. Macdougall IC, Bhandari S, White C, et al. Intravenous Iron Dosing and Infection Risk in Patients on Hemodialysis: A Prespecified Secondary Analysis of the PIVOTAL Trial. J Am Soc Nephrol. 2020;31(5):1118-1127. doi:10.1681/ASN.2019090972
21. Macdougall I, Bhandari S, White C, Anker SD, Farrington K, Kalra PA, McMurray JJ, Murray H, Steenkamp R, Tomson CRV, Wheeler CD, Winearls CG, Ford I on behalf of the PIVOTAL Study investigators. Intravenous iron dosing and Infections in patients on Haemodialysis. A prespecified secondary analysis of the PIVOTAL Trial. Journal of American Society of Nephrology 2020 31 (5), 1118-1127.
22. Hougen I, Collister D, Bourrier M, et al. Safety of Intravenous Iron in Dialysis: A Systematic Review and Meta-Analysis. Clin J Am Soc Nephrol. 2018;13(3):457-467. doi:10.2215/CJN.05390517
23. Shah AA, Donovan K, Seeley C, et al. Risk of Infection Associated with Administration of Intravenous Iron: A Systematic Review and Meta-analysis [published correction appears in JAMA Netw Open. 2022 Jan 4;5(1):e2146637]. JAMA Netw Open. 2021;4(11):e2133935. Published 2021 Nov 1. doi:10.1001/jamanetworkopen.2021.33935

The most commonly used oral treatments for iron deficiency anaemia often cause gastrointestinal side effects, leading to discontinuation of treatment. Gastrointestinal side effects most often occur due to the conversion of bivalent iron into trivalent iron, along with the formation of reactive oxygen species (ROS). However, due to the nature of vascular access, intravenous iron administration is not well-accepted by many people who are not receiving haemodialysis and furthermore can lead to high non bound (labile) iron levels in the circulation, resulting in ROS generation.

To address these concerns, nanosized iron preparations have been developed. Reducing the particle size of iron compounds increases their surface area, improving solubility in gastric juice and enhancing absorption. Novel iron preparations like sucrosomial iron, ferric citrate, and ferric maltol offer high bioavailability and good tolerance, making them suitable options for anaemia in chronic kidney disease.

In summary, the available evidence suggests that the following alternative oral iron preparations may have several benefits in the treatment of anaemia in people with CKD, including increasing haemoglobin levels, improving iron parameters, and reducing the need for intravenous iron and erythropoietin-stimulating agents. However, the specific effects can vary among studies, and further research is needed to clarify optimal use and long-term safety. Physicians should consider individual patient factors and preferences when deciding on the use of newer iron preparations as part of an anaemia management strategy in people with CKD.

Alternative Preparations:

Ferric Citrate

Ferric citrate is used in people with CKD undergoing dialysis primarily for phosphate binding but is also employed off-label as an iron supplement.

There have been two meta-analyses of ferric citrate and treatment of anaemia. One analysis of nine studies found that ferric citrate significantly increased haemoglobin levels compared to active control drugs (mean difference 0.43 g/dL) or placebo (mean difference 0.39 g/dL) (1). A second meta-analysis of five studies showed that ferric citrate substantially increased haemoglobin levels compared to the comparator group (mean difference 0.65 g/dL) along with improvements in other laboratory parameters such as iron, ferritin, transferrin saturation, and bicarbonate levels (2).

In a sequential, randomised trial, subjects on ferric citrate achieved higher mean iron parameters (ferritin = 899±488 ng/ml; transferrin saturation = 39%±17%) compared to subjects on active control (ferritin = 628±367 ng/ml; transferrin saturation = 30%±12%). Haemoglobin levels were also statistically higher on ferric citrate (3).

A 12-week, double-blind, placebo-controlled trial of ferric citrate of 149 participants with eGFR <60 mL/min/1.73m2, Hb, 90-120 g/L; TSAT ≤30%, ferritin ≤300 ng/mL). Ferric citrate treatment increased mean transferrin saturation (TSAT) from 22% ± 7% to 32% ± 14% and increased haemoglobin levels (from 105 ± 8 to 110 ± 10 g/L) compared to placebo (4).

The ASTRIO trial randomised 93 people who were undergoing HD and being treated with non-iron-based phosphate binders and ESA to receive 24 weeks of ferric citrate or to continue their non-iron-based phosphate binders. While Hb and Hct were not significantly changed, the ferric citrate group experienced a significant decrease ESA dose requirement compared to the control group (5).

In a prospective study of 60 participants on HD treated with lanthanum carbonate, participants were randomly assigned to 2 groups: lanthanum carbonate or switch to ferric citrate. The ferric citrate group had significantly increased serum iron, serum ferritin, transferrin saturation, and significantly decreased ESA doses compared to the control group (6).

A randomised double-blind clinical trial in adults with NDD-CKD and iron deficiency anaemia to compare the safety and efficacy of oral ferric citrate (n=117) versus placebo (n=115) was performed (7). Ferric citrate-treated patients had a significantly higher proportion achieving a ≥10 g/L increase in haemoglobin, with a safety profile similar to the placebo group (7). A further analysis of this study found that ferric citrate showed a greater treatment effect on patients with lower baseline ferritin levels, resulting in a greater rate of haemoglobin rise (8).

A small RCT of 60 adults with moderate to severe NDD-CKD (eGFR 15-45 ml/min/1.73m2) comparing ferric citrate and ferrous sulphate led to greater increases in transferrin saturation and ferritin compared to ferrous sulphate, but there was no significant difference in haemoglobin levels and the incidence of adverse events did not differ between treatment arms (9).

In 441 subjects with end-stage kidney failure, ferric citrate (FC) increased ferritin and transferrin saturation levels, reduced intravenous iron use, and lowered ESA requirements (10). Subjects were randomised to ferric citrate, sevelamer carbonate and/or calcium acetate and followed for 52 weeks. Subjects on FC had increased ferritin and TSAT levels by week 12 and needed less IV iron and less cumulative ESA over 52 weeks (10).

Ferric Maltol

Ferric maltol is a compound composed of ferric iron and maltol, a naturally occurring sugar derivative commonly found in various food products. This complex remains tightly bound in the intestinal tract until it reaches the point of absorption. At this stage, iron exhibits a stronger attraction to iron transport receptors on the surface of intestinal cells, leading to its separation from maltol. This unique mechanism ensures that there is no unbound or free iron in the gut, reducing the risk of generating harmful hydroxyl radicals and minimising the potential for gastrointestinal side effects. Iron uptake from ferric maltol is subject to saturation and relies on the presence of iron transport receptors, ensuring controlled and efficient absorption.

AEGIS-CKD is a phase 3, double-blind, randomised, placebo-controlled trial, where participants were given oral ferric maltol at 30 mg or placebo twice daily for 16 weeks (2:1 randomisation), followed by ferric maltol at 30 mg twice daily for up to 36 weeks (all patients) (11). 167 participants were randomised, with 111 receiving ferric maltol and 56 receiving a placebo. At week 16, haemoglobin significantly increased with ferric maltol compared to placebo. Ferritin, transferrin saturation, and serum iron levels also increased with ferric maltol but declined with placebo. Haemoglobin levels remained stable up to week 52 in patients continuing ferric maltol, and they increased in patients switching from placebo to ferric maltol. The most common adverse events were gastrointestinal, and adverse events led to treatment withdrawal in a small percentage of patients, with slightly more in the placebo group (11).

Ferric Pyrophosphate (FPC)

FPC is a complex iron salt which is administered along with dialysate. Two phase 3 trials, CRUISE 1 and 2, involving 599 iron-replete participants receiving chronic haemodialysis having been performed (12). Participants received dialysate containing FPC-iron or a standard dialysate (placebo) for up to 48 weeks. Results showed that Hb concentration was maintained in the FPC group but decreased in the placebo group (0.4 g/dL decrease, p < 0.001). Placebo treatment also resulted in larger decreases in CHr and serum ferritin compared to FPC treatment. The proportions of patients with adverse events were similar in both treatment groups (12).

A Chinese study investigated the pharmacokinetics and safety of FPC in subjects with and without HD. In healthy subjects, the peak serum concentration was reached at the end of the infusion, with a Cmax of 33.46 μmol/L at a Tmax of 4.09 hours. In people receiving HD, there were differences in Cmax and Tmax between two doses of FPC. Adverse events were reported in both healthy subjects and people receiving HD, with a limited number of incidences (13).

Sucrosomial Iron

Sucrosomial iron comprises ferric pyrophosphate enclosed within a membrane made of phospholipids and sucrose esters of fatty acids.

In a randomised trial of 99 participants with CKD and iron deficiency anaemia (Hb ≤120 g/L, ferritin ≤100 ng/mL, TSAT ≤25%) were divided into two groups: one received oral liposomal iron (30 mg/day) and the other intravenous (IV) iron gluconate (total dose of 1000 mg, infused weekly) for 3 months. The IV iron group showed a faster increase in haemoglobin levels compared to the liposomal iron group during the first month of treatment, but both groups had similar haemoglobin levels by the end of the 3-month treatment period. After discontinuation of iron treatment, haemoglobin levels remained stable in the IV group but returned to baseline in the liposomal iron group. The incidence of adverse events was significantly lower in the oral liposomal iron group (14).

Hypophosphataemia

Hypophosphataemia is a known side effect of intravenous iron preparations as listed in the SmPCs of IV iron products. It is a common side effect with ferric carboxymaltose (FCM) (15). As detailed in their SmPC, symptomatic hypophosphataemia leading to osteomalacia and fractures requiring clinical intervention including surgery has been reported in the post marketing setting. Patients should be asked to seek medical advice if they experience worsening fatigue with myalgias or bone pain. Serum phosphate should be monitored in patients who receive multiple administrations at higher doses or long-term treatment, and those with existing risk factors for hypophosphataemia. In case of persisting hypophosphataemia, treatment with ferric carboxymaltose should be re-evaluated.

Acute features can include muscle pain and weakness as well as fatigue, although often can be asymptomatic (16). There is evidence that hypophosphataemia, secondary to IV iron therapy can lead to long term issues with bone metabolism, presenting as osteomalacia and fractures (16).

Wolf et al. made the first link between FCM causing a rise in Fibroblast growth factor 23 (FGF23), s hormone which regulates phosphate and vitamin D, causing a decrease in phosphate levels, calcitriol and calcium, with an increase in PTH levels. This study compared FCM to iron dextran treatment, measuring the difference in FGF23 and phosphate levels in people with iron deficiency, secondary to heavy uterine bleeding. Authors reported a significant rise in iFGF23 following treatment with FCM, but not iron dextran (r = 0.59; p < 0.001), with corresponding decrease in phosphate (r = −0.50; p = 0.002). Differences in vitamin D, calcium and PTH were not significant. Hypophosphataemia was reported to continue for up to 80 days (17).

Following on from this study, sub-analysis of the FIRM trial compared FGF23 and phosphate levels in a trial of FCM vs ferumoxytol in which hypophosphataemia was significantly decreased in the FCM group vs ferumoxytol group (<2.0 mg/dl, 50.8% vs. 0.9%; <1.3 mg/dl, 10.0% vs. 0.0%; P < 0.001), continuing for up to 5 weeks after FCM administration in 29.1% of participants. FCM only increased the FGF23 concentrations, which lead to a significant decrease in calcium (mean difference between iron treatment groups in change from baseline to week 2, 0.37 mg/dl; 95%CI 0.25–0.50; P < 0.001) and vitamin D (mean within-patient percentage change from baseline to week 2, –60.4 ± 25.9% vs. – 2.5 ± 28.0%; P < 0.001), with a rise in PTH levels (18).

PHOSPHARE-IDA trials compared phosphate levels in people receiving ferric derisomaltose (FDI) or FCM, finding that incidence of hypophosphataemia was significantly higher in the FCM group vs the FDI group (74.4% versus 8.0%, respectively; p < 0.001), showing a significant rise in FGF23, a decrease in calcium and increase in PTH levels in the FCM group, as previously reported (19). Sub-analysis showed 57% of patients in the FCM group (vs 0% in FDI group) experienced persistent hypophosphataemia, with associated changes in bone metabolism biomarkers (20).

PHOSPHARE-IBD similarly showed higher rates of hypophosphataemia in the FCM group vs FDI group in the IBD population- 8.3% FDI vs 51.0% FCM (adjusted risk difference: -42.8% (95% CI: -57.1% to – 24.6%) p<0.0001) (21).

Literature review by Schafer B et al. looked at 42 prospective clinical trials, which found that people, who have received FCM, are more likely to experience hypophosphataemia than those who have received FDI, with an incidence of 42% vs 4% across 42 clinical trials (95% CI: 36-58% vs. 95% CI: 2- 5%). Significantly decreased levels in serum phosphate were also seen when comparing the two treatments, a decrease in 0.4mmol/L with FCM vs a decrease in 0.06mmol/L with FDI, with hypophosphataemia reportedly persisting after 3 months of treatment with FCM (7). The only significant predictor of experiencing hypophosphataemia being the severity of anaemia at time of treatment, with no significant link seen between IV iron treatment in CKD (18,22). However, FGF23 has been reported to increase after IV iron therapy in people with CKD, with a decrease in active vitamin D levels (23), despite higher baseline levels of FGF23 in patients with CKD, affecting bone metabolism long term (24).

Glaspy J et al. published a literature review that included 40 trials reviewing all of the IV iron products on the US market at the time. This included iron dextran, ferric gluconate, FCM, ferumoxytol and iron sucrose. This review found that people without CKD and who receive higher doses of iron are more likely to experience hypophosphataemia (25). As with previous findings, FCM treatment was associated with the highest rate of reported hypophosphataemia (25).

Kidney transplant recipients can experience hypophosphataemia within the first 3 months post transplantation (secondary to phosphaturia), which is associated with high levels of FGF23 and PTH. This normalises in the recovery period and increasing again with declining graft function, leading to adverse effects on the cardiovascular system, graft function and bone metabolism (26). 23 kidney transplant recipients received FCM, showing an average decrease in phosphate levels of 0.27 mmol/l (p = 0.003). 56.5% of participants experienced hypophosphataemia, with severe Hypophosphataemia (<0.5 mmol/L) seen in 34.8% of people. Hypophosphataemia persisted in 38.5% of patients with median normalisation of levels at 41 days (27). This shows that kidney transplant recipients should receive FCM with caution and close monitoring (28).

References

1. Li L, Zheng X, Deng J, Zhou J, Ou J, Hong T. Ferric citrate for the treatment of hyperphosphatemia and anemia in patients with chronic kidney disease: a meta-analysis of randomized clinical trials. https://dx.doi.org/10.1080/0886022X.2022.2094273
2. Choi YJ, Noh Y, Shin S. Ferric citrate in the management of hyperphosphataemia and iron deficiency anaemia: a meta-analysis in patients with chronic kidney disease.Br J Clin Pharmacol. 2021;87(2):414-426.doi:10.1111/bcp.14396
3. Lewis JB, Sika M, Koury MJ, Chuang P, Schulman G, Smith MT, Whittier FC, Linfert DR, Galphin CM, Athreya BP, Nossuli AK, Chang IJ, Blumenthal SS, Manley J, Zeig S, Kant KS, Olivero JJ, Greene T, Dwyer JP; Collaborative Study Group. Ferric citrate controls phosphorus and delivers iron in patients on dialysis. J Am Soc Nephrol. 2015 Feb;26(2): 493-503. doi: 10.1681/ASN.2014020212. Epub 2014 Jul 24. PMID: 25060056; PMCID: PMC4310662.
4. Block GA, Fishbane S, Rodriguez M, et al. A 12-week, double-blind, placebo-controlled trial of ferric citrate for the treatment of iron deficiency anemia and reduction of serum phosphate in patients with CKD stages 3-5. Am J Kidney Dis. 2015;65(5):728–736.
5. Yokoyama K, Fukagawa M, Akiba T, et al. Randomised clinical trial of ferric citrate hydrate on anaemia management in haemodialysis patients with hyperphosphataemia: ASTRIO study. Sci Rep. 2019;9(1):8877.
6. Maruyama N, Otsuki T, Yoshida Y, et al. Ferric citrate decreases fibroblast growth factor 23 and improves erythropoietin responsiveness in hemodialysis patients. Am J Nephrol. 2018;47(6):406–414.
7. Fishbane S, Block GA, Loram L, et al. Effects of ferric citrate inpatients with nondialysis-dependent CKD and iron deficiency anemia. J Am Soc Nephrol. 2017;28(6):1851- 1858.doi:10.1681/asn.201610105315.
8. Pergola PE, Fishbane S, LeWinter RD, et al. Hemoglobin response to ferric citrate in patients with nondialysis-dependent chronic kidney disease and iron deficiency anemia. Am J Hematol. 2018;93(6):E154-E156.doi:10.1002/ajh.2508817.
9. Womack R, Berru F, Panwar B, Gutierrez OM. Effect of ferric citrate versus ferrous sulfate on iron and phosphate parameters in patients with iron deficiency and CKD: a randomized trial. Clin J Am Soc Nephrol. 2020;15(9):1251-1258.doi:10.2215/cjn.1529121920.
10. Umanath K, Jalal DI, Greco BA, Umeukeje EM, Reisin E, Manley J, Zeig S, Negoi DG, Hiremath AN, Blumenthal SS, Sika M, Niecestro R, Koury MJ, Ma KN, Greene T, Lewis JB, Dwyer JP. Ferric Citrate Reduces Intravenous Iron and Erythropoiesis-Stimulating Agent Use in ESRD. Journal of the American Society of Nephrology. 26(10):2578-87, 2015 Oct. https://dx.doi.org/10.1681/ASN.2014080842
11. Pergola PE, Kopyt NP. Oral Ferric Maltol for the Treatment of Iron-Deficiency Anemia in Patients With CKD: A Randomized Trial and Open-Label Extension. American Journal of Kidney Diseases. 78(6):846-856.e1, 2021 12. https://dx.doi.org/10.1053/j.ajkd.2021.03.020
12. Fishbane SN, Singh AK, Cournoyer SH, et al. Ferric pyrophosphate citrate (Triferic™) administration via the dialysate maintains hemoglobin and iron balance in chronic hemodialysis patients. NephrolDialTransplant.2015;30(12):2019-2026. doi:10.1093/ndt/gfv277
13. Gan L, Xie P, Tan Y, Wei G, Yuan X, Lu Z, Pratt R, Zhou Y, Hui AM, Li K, Fang Y, Zuo L. Pharmacokinetics and Safety of Ferric Pyrophosphate Citrate in Chinese Subjects with and without Hemodialysis-Dependent Stage 5 Chronic Kidney Disease. Drugs R D. 2022 Jun;22(2):119-129. doi: 10.1007/s40268-022-00384-5.
14. Pisani A, Riccio E, Sabbatini M, Andreucci M, Del Rio A, Visciano B. Effect of oral liposomal iron versus intravenous iron for treatment of iron deficiency anaemia in CKD patients: a randomized trial. Nephrol Dial Transplant. 2015;30(4):645652.doi:10.1093/ndt/gfu357
15. Ferinject (ferric carboxymaltose). Summary of product characteristics. Vifor Pharma UK Ltd; Nov 2020.
16. Zoller H, Schaefer B, Glodny B. Iron-induced hypophosphatemia: an emerging complication. Curr Opin Nephrol Hypertens. 2017;26(4):266–275.
17. Wolf M, Koch TA, Bregman DB. Effects of iron deficiency anemia and its treatment on fibroblast growth factor 23 and phosphate homeostasis in women. J Bone Miner Res. 2013;28(8):1793–1803.
18. Wolf M, Chertow GM, Macdougall IC, et al. Randomized trial of intravenous iron-induced hypophosphatemia. JCI Insight. 2018;3(23):e124486.
19. 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):432–443.
20. Wolf M, Schaefer B, Zoller H. Persistent hypophosphatemia after ferric carboxymaltose is associated with persistent changes in biomarkers of bone metabolism. Blood. 2020;136(Suppl 1):13–14.
21. Zoller H, Wolf M, Blumenstein I, et al. Hypophosphataemia following ferric derisomaltose and ferric carboxymaltose in patients with iron deficiency anaemia due to inflammatory bowel disease (PHOSPHARE-IBD): a randomised clinical trial. Gut. 2023 Apr;72(4):644-653.
22. Schaefer B, Tobiasch M, Viveiros A, et al. Hypophosphataemia after treatment of iron deficiency with intravenous ferric carboxymaltose or iron isomaltoside-a systematic review and meta-analysis. Br J Clin Pharmacol. 2021;87(5):2256-2273.
23. Huang LL, Lee D, Troster SM, et al. A controlled study of the effects of ferric carboxymaltose on bone and haematinic biomarkers in chronic kidney disease and pregnancy. Nephrol Dial Transplant. 2018;33(9):1628–1635.
24. Musgrove J, Wolf M. Regulation and effects of FGF23 in chronic kidney disease. Annu Rev Physiol. 2020;82(1):365–390.
25. Glaspy JA, Lim-Watson MZ, Libre MA, et al. Hypophosphatemia associated with intravenous iron therapies for iron deficiency anemia: a systematic literature review. Ther Clin Risk Manag. 2020;16:245–259.
26. Baia LC, Heilberg IP, Navis G, et al. NIGRAM investigators. Phosphate and FGF-23 homeostasis after kidney transplantation. Nat Rev Nephrol. 2015;11(11):656–666.
27. Sari V, Atiqi R, Hoorn EJ, et al. Ferric carboxymaltose-induced hypophosphataemia after kidney transplantation. Neth J Med. 2017;75(2):65–73.
28. Blumenstein I, Shanbhag S, Langguth P, et al. Newer formulations of intravenous iron: a review of their chemistry and key safety aspects – hypersensitivity, hypophosphatemia, and cardiovascular safety. Expert Opin Drug Saf. 2021;20(7):757-769.