Newer formulations of intravenous iron: a review of their chemistry and key safety aspects–hypersensitivity, hypophosphatemia, and cardiovascular safety

Expert Opinion on Drug Safety

Volumn 20, Issue 7, 2021, Pages 757-769

  Blumenstein, Irina ^a   Shanbhag, Satish ^b,c   Langguth, Peter ^d   Kalra, Philip A ^e,f   Zoller, Heinz ^g   Lim, Wendy ^h  

^a UNIVERSITY HOSPITAL FRANKFURT   (Germany)

^b Cancer Specialists of North Florida   (United States)

^c JOHNS HOPKINS UNIVERSITY SCHOOL OF MEDICINE   (United States)

^d JOHANNES GUTENBERG UNIVERSITY   (Germany)

^e SALFORD ROYAL NHS FOUNDATION TRUST   (United Kingdom)

^f UNIVERSITY OF MANCHESTER   (United Kingdom)

^g INNSBRUCK MEDICAL UNIVERSITY   (Austria)

^h MCMASTER UNIVERSITY   (Canada)

Author keywords

Anemia; ferric carboxymaltose; ferric derisomaltose; ferumoxytol; heart failure; hypersensitivity; hypophosphatemia; intravenous iron; iron deficiency; iron isomaltoside

Indexed keywords

IRON DERIVATIVE;

CARDIOVASCULAR DISEASE; CHEMISTRY; DRUG HYPERSENSITIVITY; HUMAN; HYPOPHOSPHATEMIA; INTRAVENOUS DRUG ADMINISTRATION; IRON DEFICIENCY ANEMIA;

ADMINISTRATION, INTRAVENOUS; ANEMIA, IRON-DEFICIENCY; CARDIOVASCULAR DISEASES; DRUG HYPERSENSITIVITY; HUMANS; HYPOPHOSPHATEMIA; IRON COMPOUNDS;

EID: 85106329524     PISSN: 14740338     EISSN: 1744764X     Source Type: Journal    
DOI: 10.1080/14740338.2021.1912010     Document Type: Review

References (106)

1. Auerbach M, Ballard H., Clinical use of intravenous iron: administration, efficacy, and safety. Hematology Am Soc Hematol Educ Program. 2010; 2010 (1): 338–347.
2. Auerbach M, DeLoughery T. Single-dose intravenous iron for iron deficiency: a new paradigm. Hematology Am Soc Hematol Educ Program. 2016; 2016 (1): 57–66.
3. Auerbach M, Coyne D, Ballard H. Intravenous iron: from anathema to standard of care. Am J Hematol. 2008; 83 (7): 580–588.
4. 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 (3): 480–491.
5. Monofer (ferric derisomaltose). Summary of product characteristics. Pharmacosmos UK Ltd; Sep 2020.
6. Monoferric (ferric derisomaltose). Product information. Pharmacosmos A/S; Jul 2020.
7. Ferinject (ferric carboxymaltose). Summary of product characteristics. Vifor Pharma UK Ltd; Nov 2020.
8. Injectafer (ferric carboxymaltose). Prescribing information. Vifor International, Inc; Sep 2020.
9. Feraheme (ferumoxytol). Prescribing information. AMAG Pharmaceuticals, Inc; Sep 2020.
10. European Medicines Agency. Public statement. Rienso: withdrawal of the marketing authorisation in the European Union. EMA/437901/2015; EMEA/H/C/2215. 10 Jul 2015. [cited 2021 Jan 27]. Available from: https://www.ema.europa.eu/en/documents/public-statement/public-statement-rienso-ferumoxytol-withdrawal-marketing-authorisation-european-union_en.pdf
11. Kalra PA, Bhandari S. Safety of intravenous iron use in chronic kidney disease. Curr Opin Nephrol Hypertens. 2016; 25 (6): 529–535.
12. Danielson BG. Structure, chemistry, and pharmacokinetics of intravenous iron agents. J Am Soc Nephrol. 2004; 15 (Suppl 2): S93–S98.
13. Rottembourg J. The non-biologic-complex-drug concept. Int J Biopharm Sci. 2018; 1 (1): 104.
14. Borchard G, Flühmann B, Mühlebach S. Nanoparticle iron medicinal products–Requirements for approval of intended copies of non-biological complex drugs (NBCD) and the importance of clinical comparative studies. Regul Toxicol Pharmacol. 2012; 64 (2): 324–328.
15. WO 2007/081744 A2–Methods and compositions for administration of iron. International Application No. PCT/US2007/000176. International filing date: 2007 Jan 8; [cited 2021 Jan 27]. Available from: https://patents.google.com/patent/WO2007081744A2/en.
16. US 9,376,505 B2–Aqueous iron carbohydrate complexes, their production and medicaments containing them. Application No. 13/556,733. International filing date: 2012 Jul 24; [cited 2021 Jan 27]. Available from: https://patents.google.com/patent/US9376505B2/en.
17. Sigma-Aldrich. Product Specification. Maltodextrin 4.0–7.0. Product Number: 419672. [cited 2020 Sep 17]. Available from: https://www.sigmaaldrich.com/catalog/substance/maltodextrin12345905036611?lang=en®ion=GB.
18. US 8,501,158 B2–Polyol and polyether iron oxide complexes as pharmacological and/or MRI contrast agents. Application No. 12/963,308. Filing date: 2010 Dec 8; [cited 2021 Jan 27]. Available from: https://patents.google.com/patent/US8501158B2/en.
19. US 8,895,612 B2–Methods and compositions for administration of iron. Application No. 14/100,717. Filling date: 2013 Dec 9; [cited 2021 Jan 27]. Available from: https://patents.google.com/patent/US8895612B2/en.
20. Neiser S, Rentsch D, Dippon U, et al. Physico-chemical properties of the new generation IV iron preparations ferumoxytol, iron isomaltoside 1000 and ferric carboxymaltose. Biometals. 2015; 28 (4): 615–635.
21. British Pharmacopoeia 2017. Volume III. Jan 2017.
22. De Belder AN., Dextran. © Amersham Biosciences AB 2003.
23. Fütterer S, Andrusenko I, Kolb U, et al. Structural characterization of iron oxide/hydroxide nanoparticles in nine different parenteral drugs for the treatment of iron deficiency anaemia by electron diffraction (ED) and X-ray powder diffraction (XRPD). J Pharm Biomed Anal. 2013; 86: 151–160.
24. Nikravesh N, Borchard G, Hofmann H, et al. Factors influencing safety and efficacy of intravenous iron-carbohydrate nanomedicines: from production to clinical practice. Nanomedicine. 2020; 26: 102178.
25. Sidhu PS, Gilkes RJ, Cornell RM, et al. Dissolution of iron oxides and oxyhydroxides in hydrochloric and perchloric acids. Clays Clay Miner. 1988; 29 (4): 269–276.
26. Kruszewski M. Labile iron pool: the main determinant of cellular response to oxidative stress. Mutat Res. 2003; 531 (1–2): 81–92.
27. Garbowski MW, Bansal S, Porter JB, et al. Intravenous iron preparations transiently generate non-transferrin-bound iron from two proposed pathways. Haematologica. 2020.
28. 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.
29. 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 (5): 683–690.
30. 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 (9): 1007–1014.
31. 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. 2021; 36 (1): 111–120.
32. Wolf M, Auerbach M, Kalra PA, et al. Safety of ferric derisomaltose and iron sucrose in patients with iron deficiency anemia: the FERWON-IDA/NEPHRO trials. Am J Hematol. 2021; 96 (1): E11–E15.
33. 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): 187–195.
34. Wysowski DK, Swartz L, Borders-Hemphill BV, et al. Use of parenteral iron products and serious anaphylactic-type reactions. Am J Hematol. 2010; 85 (9): 650–654.
35. European Medicines Agency (EMA). Rapid response to BMJ. Re: pandemrix vaccine: why was the public not told of early warning signs. EMA/659264/2018. 2018 [cited 2021] Jan 27. Available from: https://www.ema.europa.eu/en/documents/other/european-medicines-agency-rapid-response-british-medical-journal-pandemrix_.pdf
36. OCEBM Levels of evidence working group. The Oxford 2011 Levels of Evidence.
37. Rampton D, Folkersen J, Fishbane S, et al. Hypersensitivity reactions to intravenous iron: guidance for risk minimization and management. Haematologica. 2014; 99 (11): 1671–1676.
38. Lim W, Afif W, Knowles S, et al. Canadian expert consensus: management of hypersensitivity reactions to intravenous iron in adults. Vox Sang. 2019; 114 (4): 363–373.
39. Achebe M, DeLoughery TG. Clinical data for intravenous iron–debunking the hype around hypersensitivity. Transfusion. 2020; 60 (6): 1154–1159.
40. Macdougall IC, Bircher AJ, Eckardt KU, et al. Iron management in chronic kidney disease: conclusions from a “Kidney Disease: Improving Global Outcomes” (KDIGO) controversies conference. Kidney Int. 2016; 89 (1): 28–39.
41. Macdougall IC, Vernon K. Complement activation-related pseudo-allergy: a fresh look at hypersensitivity reactions to intravenous iron. Am J Nephrol. 2017; 45 (1): 60–62.
42. Szebeni J, Fishbane S, Hedenus M, et al. Hypersensitivity to intravenous iron: classification, terminology, mechanisms and management. Br J Pharmacol. 2015; 172 (21): 5025–5036.
43. 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): 137–145.
44. Zoller H, Schaefer B, Glodny B. Iron-induced hypophosphatemia: an emerging complication. Curr Opin Nephrol Hypertens. 2017; 26 (4): 266–275.
45. Schaefer B, Meindl E, Wagner S, et al. Intravenous iron supplementation therapy. Mol Aspects Med. 2020; 75: 100862.
46. Schaefer B, Tobiasch M, Viveiros A, et al. Hypophosphatemia after treatment of iron deficiency with intravenous ferric carboxymaltose or iron isomaltoside–a systematic review and meta‐analysis. Br J Clin Pharmacol. 2020.
47. 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.
48. 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.
49. Wolf M, Chertow GM, Macdougall IC, et al. Randomized trial of intravenous iron-induced hypophosphatemia. JCI Insight. 2018; 3 (23): e124486.
50. 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.
51. Iqbal TH, Wolf M, Schaffalitzky de Muckadell P, et al. PHOSPHARE studies: important changes in phosphate homeostasis and bone metabolism after IV iron. Poster presented at the British Society of Gastroenterology (BSG) Annual Meeting, Glasgow, 17–20 Jun, 2019.
52. Emrich IE, Lizzi F, Siegel JD, et al. Hypophosphatemia after high-dose iron repletion with ferric carboxymaltose and ferric derisomaltose–the randomized controlled HOMe aFers study. BMC Med. 2020; 18 (1): 178.
53. 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 (4): 397–406.
54. 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.
55. Stöhr R, Sandstede L, Heine GH, et al. High-dose ferric carboxymaltose in patients with HFrEF induces significant hypophosphatemia. J Am Coll Cardiol. 2018; 71 (19): 2270–2271.
56. Fang W, Kenny R, Rizvi QU, et al. Hypophosphataemia after ferric carboxymaltose is unrelated to symptoms, intestinal inflammation or vitamin D status. BMC Gastroenterol. 2020; 20 (1): 183.
57. Amanzadeh J, Reilly RF, Jr. Hypophosphatemia: an evidence-based approach to its clinical consequences and management. Nat Clin Pract Nephrol. 2006; 2 (3): 136–148.
58. Geerse DA, Bindels AJ, Kuiper MA, et al. Treatment of hypophosphatemia in the intensive care unit: a review. Crit Care. 2010; 14 (4): R147.
59. Gravelyn TR, Brophy N, Siegert C, et al. Hypophosphatemia-associated respiratory muscle weakness in a general inpatient population. Am J Med. 1988; 84 (5): 870–876.
60. Fukumoto S. Phosphate metabolism and vitamin D. Bonekey Rep. 2014; 3: 497.
61. Hardy S, Vandemergel X. Intravenous iron administration and hypophosphatemia in clinical practice. Int J Rheumatol. 2015; 2015: 468675.
62. Imel EA, Econs MJ. Approach to the hypophosphatemic patient. J Clin Endocrinol Metab. 2012; 97 (3): 696–706.
63. Pasquali M, Tartaglione L, Rotondi S, et al. Calcitriol/calcifediol ratio: an indicator of vitamin D hydroxylation efficiency? BBA Clin. 2015; 3: 251–256.
64. Penido MG, Alon US. Phosphate homeostasis and its role in bone health. Pediatr Nephrol. 2012; 27 (11): 2039–2048.
65. Prié D, Ureña Torres P, Friedlander G. Latest findings in phosphate homeostasis. Kidney Int. 2009; 75 (9): 882–889.
66. Schaefer B, Glodny B, Zoller H. Blood and bone loser. Gastroenterology. 2017; 152 (6): e5–e6.
67. Zhao Y, Li Z, Shi Y, et al. Effect of hypophosphatemia on the withdrawal of mechanical ventilation in patients with acute exacerbations of chronic obstructive pulmonary disease. Biomed Rep. 2016; 4 (4): 413–416.
68. Blazevic A, Hunze J, Boots JMM. Severe hypophosphataemia after intravenous iron administration. Neth J Med. 2014; 72 (1): 49–53.
69. Fierz YC, Kenmeni R, Gonthier A, et al. Severe and prolonged hypophosphatemia after intravenous iron administration in a malnourished patient. Eur J Clin Nutr. 2014; 68 (4): 531–533.
70. Anand G, Schmid C. Severe hypophosphataemia after intravenous iron administration. BMJ Case Rep. 2017; 2017: bcr2016219160.
71. Ifie E, Oyibo SO, Joshi H, et al. Symptomatic hypophosphataemia after intravenous iron therapy: an underrated adverse reaction. Endocrinol Diabetes Metab Case Rep. 2019; 2019 (1): 19-0065.
72. Harris RE, Armstrong L, Curtis L, et al. Severe hypophosphataemia following ferric carboxymaltose infusion in paediatric patients with inflammatory bowel disease. Frontline Gastroenterol. 2019; 11 (4): 324–326.
73. Vasquez-Rios G, Chapel A, Philip I, et al. Life-threatening hypophosphatemia following intravenous iron infusion. Nefrologia. 2020; S0211-6995 (20):30071-0.
74. Bart G, Glemarec J, Lerhun M, et al. A rusty man … or how iron can be responsible for bone pain. Symptomatic hypophosphataemic osteomalacia after iron carboxymaltose treatment. The Rheumatologist’s Newsletter. No. 428; 2017.
75. Burckhardt P. Iron-induced osteomalacia. Osteologie. 2018; 27 (1): 20–23.
76. Klein K, Asaad S, Econs M, et al. Severe FGF23-based hypophosphataemic osteomalacia due to ferric carboxymaltose administration. BMJ Case Rep. 2018. DOI: 10.1136/bcr-2017-222851.
77. Fragkos KC, Sehgal V, Rogers J, et al. Hypophosphataemia after intravenous iron therapy with ferric carboxymaltose–real world experience from a tertiary centre in the UK. GastroHep. 2020; 2 (5): 205–214.
78. Musgrove J, Wolf M. Regulation and effects of FGF23 in chronic kidney disease. Annu Rev Physiol. 2020; 82 (1): 365–390.
79. 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.
80. Sari V, Atiqi R, Hoorn EJ, et al. Ferric carboxymaltose-induced hypophosphataemia after kidney transplantation. Neth J Med. 2017; 75 (2): 65–73.
81. Ferinject (ferric carboxymaltose). Prescribing information [Brazil]. Vifor (International) Inc; Sep 2020.
82. GOV.UK. Drug safety update. Ferric carboxymaltose (Ferinject): risk of symptomatic hypophosphataemia leading to osteomalacia and fractures. [cited 2020 Nov 16]. Available from: https://www.gov.uk/drug-safety-update/ferric-carboxymaltose-ferinject-risk-of-symptomatic-hypophosphataemia-leading-to-osteomalacia-and-fractures.
83. Kang CK, Pope M, Lang CC, et al. Iron deficiency in heart failure: efficacy and safety of intravenous iron therapy. Cardiovasc Ther. 2017; 35 (6): e12301.
84. Cairo G, Bernuzzi F, Recalcati S. A precious metal: iron, an essential nutrient for all cells. Genes Nutr. 2006; 1 (1): 25–39.
85. Anderson GJ, Vulpe CD. Mammalian iron transport. Cell Mol Life Sci. 2009; 66 (20): 3241–3261.
86. Panth N, Paudel KR, Parajuli K. Reactive oxygen species: a key hallmark of cardiovascular disease. Adv Med. 2016; 2016: 9152732.
87. Anker SD, Comin Colet J, Filippatos G, et al. Ferric carboxymaltose in patients with heart failure and iron deficiency. N Engl J Med. 2009; 361 (25): 2436–2448.
88. Ponikowski P, Van Veldhuisen DJ, Comin-Colet J, et al. CONFIRM-HF investigators. Beneficial effects of long-term intravenous iron therapy with ferric carboxymaltose in patients with symptomatic heart failure and iron deficiency. Eur Heart J. 2015; 36 (11): 657–668.
89. Van Veldhuisen DJ, Ponikowski P, Van Der Meer P, et al. Effect of ferric carboxymaltose on exercise capacity in patients with chronic heart failure and iron deficiency. Circulation. 2017; 136 (15): 1374–1383.
90. Ponikowski P, Kirwan B-A, Anker SD, et al. Ferric carboxymaltose for iron deficiency at discharge after acute heart failure: a multicentre, double-blind, randomised, controlled trial. Lancet. 2020; 396 (10266): 1895–1904.
91. Onken JE, Bregman DB, Harrington RA, et al. Ferric carboxymaltose in patients with iron-deficiency anemia and impaired renal function: the REPAIR-IDA trial. Nephrol Dial Transplant. 2014; 29 (4): 833–842.
92. Onken JE, Bregman DB, Harrington RA, et al. A multicenter, randomized, active-controlled study to investigate the efficacy and safety of intravenous ferric carboxymaltose in patients with iron deficiency anemia. Transfusion. 2014; 54 (2): 306–315.
93. Macdougall IC, White C, Anker SD, et al. Intravenous iron in patients undergoing maintenance hemodialysis. N Engl J Med. 2019; 380 (5): 447–458.
94. Agarwal R, Kusek JW, Pappas MK. A randomized trial of intravenous and oral iron in chronic kidney disease. Kidney Int. 2015; 88 (4): 905–914.
95. Bhandari S, Kalra PA, Coyne DW. Data confusion. Kidney Int. 2015; 88 (6): 1445.
96. Macdougall IC, Roger SD. New data on the safety of IV iron–but why the discrepancy with FIND-CKD? Kidney Int. 2015; 88 (6): 1445–1446.
97. Charles-Edwards G, Amaral N, Sleigh A, et al. Effect of iron isomaltoside on skeletal muscle energetics in patients with chronic heart failure and iron deficiency. Circulation. 2019; 139 (21): 2386–2398.
98. ClinicalTrials.gov. Intravenous iron supplement for iron deficiency in cardiac transplant recipients (IronIC). NCT03662789. 2 Mar 2020.
99. ClinicalTrials.gov. Intravenous iron supplement for iron deficiency in patients with severe aortic stenosis (IIISAS). NCT04206228. 3 Apr 2020.
100. ClinicalTrials.gov. Intravenous iron treatment in patients with heart failure and iron deficiency: IRONMAN (IRONMAN). NCT02642562. 6 Oct 2020.
101. ClinicalTrials.gov. Intravenous iron in patients with systolic heart failure and iron deficiency to improve morbidity & mortality (FAIR-HF2). NCT03036462. 8 May 2020.
102. ClinicalTrials.gov. Randomized placebo-controlled trial of FCM as treatment for heart failure with iron deficiency (HEART-FID). NCT03037931. 3 Nov 2020.
103. Kassebaum NJ, Jasrasaria R, Naghavi M, et al. A systematic analysis of global anemia burden from 1990 to 2010. Blood. 2014; 123 (5): 615–624.
104. Global Burden of Disease (GBD) 2016. Disease and injury incidence and prevalence collaborators. Global, regional, and national incidence, prevalence, and years lived with disability for 328 diseases and injuries for 195 countries, 1990–2016: a systematic analysis for the Global Burden of Disease Study 2016. Lancet. 2017; 390 (10100): 1211–1259.
105. Amarnani R, Travis S, Javaid MK. Novel use of burosumab in refractory iron-induced FGF23-mediated hypophosphataemic osteomalacia. Rheumatology (Oxford). 2020; 59 (8): 2166–2168.
106. CRYSVITA (burosumab). Summary of product characteristics. [cited 2020 Nov 4]. Available from: https://www.ema.europa.eu/en/documents/product-information/crysvita-epar-product-information_en.pdf