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Iron is an essential element and nutrient for the human body functions. Iron deficiency (ID) and iron deficiency anaemia (IDA) are common health problems worldwide. The World Health Organization (2011) estimated 34% of the global population (>2 billion) is affected by anaemia. The most common type of anaemia was ID (50% of total anaemia), which primarily affected women of reproductive age and young children.[[1]]

Although the practice of intravenous (IV) iron to treat iron deficiency and its anaemia has existed for more than six decades,[[2]] its use in primary care centres has, compared to tertiary centres, not been widespread, largely due to historical concern of anaphylaxis and lack of remuneration. Administration of newer (non-dextran) iron formulations allows a complete or near-complete replacement in a single sitting of 15–30 minutes. These newer formulations have an improved safety profile and better tolerability, efficacy and effectiveness compared with oral iron therapy. They are suited for administration in primary care or community practices in a proper setting. This article outlines how to provide iron infusion safely and effectively, along with a brief comparison of the newer formulations (ferric carboxymaltose (FCM), iron sucrose (ISC), iron isomaltoside (IIM) and ferumoxytol (FOT).

Although in most guidelines oral iron remains as a the first-line treatment for replacement of iron, its common side effects (gastric upset and constipation and the need to take it regularly for months to replenish iron stores) often result in non-adherence. Because intramuscular iron injection can cause pain and skin staining and require multiple injections with questionable absorption, it is therefore no longer favourable.

Indications and contraindications

Symptoms specific to ID are relatively uncommon but can include pagophagia (ice craving) or other forms of pica and restless-legs syndrome. Symptoms related to IDA are non-specific: they include fatigue, weakness, tiredness, dizziness, irritability and pale skin, and in severe cases chest pain, palpitations or shortness of breath. Hair and nail disorders such as koilonychia (spoon nails) can also occur in chronic IDA. More importantly, the untreated ID and IDA can eventually impact on cognition, academic achievement, exercise tolerance, work productivity and quality of life.[[3]] ID and IDA should be confirmed by blood count and iron studies with correct interpretation. Although the details of investigation for IDA are beyond the scope of this article, it is always imperative to address the underlying cause while correcting the deficiency.

Infusion offers an alternative route of administration for those in whom oral iron is unsuitable due to intolerance, poor adherence, impracticality or contraindications. Indications for iron infusion include ID and IDA caused by the underlying conditions described in Figure 1.[[4-6]] Figure 2 lists contraindication for infusion.[[4-6]] Precautions include individuals with acute infection, asthma, marked atopy, liver dysfunction or conditions associated with low phosphate in the body. There are insufficient data to support the safety of iron infusion in the first trimester of pregnancy and in children under 14 years of age. Nevertheless, trial infusions of ferric carboxymaltose, iron sucrose and ferumoxytol in children (<14 years) at tertiary centres have shown some promises and is going to have further evaluation.[[ 9–15]]

Figure 1: Indications for iron infusion.

†FID denotes a state in which there is insufficient iron mobilisation for erythropoiesis despite normal or high ferritin concentrations with a low transferrin saturation reflecting inadequate iron availability. Maintaining the ferritin level greater than 100–200 μg/L in some chronic conditions, such as heart failure, is important to improve ventricular function, quality of life and to reduce hospitalisations.[[7,8]]

Figure 2: Contraindications for iron infusion.

Benefits

Intravenous iron rapidly restores iron and expedites haemoglobin synthesis. Newer formulations (Table 1) contain carbohydrate cores that more tightly bind elemental iron,  allowing for a much slower release and providing marginal or fewer reactions.[[1,16]]  They have also demonstrated greater efficacy and effectiveness and, compared to oral therapy and previous parenteral formulations, can improve quality of life and productivity.[[ 6,17,18]] Newer formulations also have the potential save health costs by reducing the frequency of visits to hospital and healthcare providers.[[18–21]]  Some studies have indicated that the newer generations of intravenous iron are underutilised due to historical fears about anaphylaxis that were far more common with high molecular weight iron dextrans (eg, imferon, dexferrum), which are no longer available.[[16,19]] Two narrative reviews and one meta-analysis have suggested a reconsideration of the current paradigm whereby oral iron treatment is considered a first-line therapy;[[16,19,22]] it needs further evaluation with a broad consensus. There are greater than 20 randomised studies in which IV administration of iron offers better tolerability, efficacy and effectiveness compared to oral iron.[[23–28]] One randomised control trial in Australia described the cost of IV use as no more than the cost for oral therapy, in addition to having superior tolerance, efficacy and effectiveness.[[29]]    

Table 1: History of parenteral iron products.[[1,18,19]]

† = Approved by Medsafe and subsided by PHARMAC in New Zealand.

Adverse effects

  • Anaphylaxis is rare but can be life threatening if not managed properly.[[21]] It involves bronchospasm with dyspnoea, angioedema, tachycardia and hypotension. Rates vary according to iron formulation: FCM and ISC (1–10/10,000 cases (≈0.1%–0.01%), IPC (10–100/10,000 cases).[[6,30]] Two review studies, one of which was a meta-analysis, reported that a properly defined serious anaphylaxis are even less than the above rate, if dextran is excluded and drug therapy (adrenaline, antihistamine) is given for minor reactions in the context of practitioners’ fears for further deterioration, which is not uncommon.[[31,32]]    

Less severe or minor reactions include:

  • Facial flushing, urticaria, arthralgia, myalgia, sensation of stiffness in face or limbs.
  • Dizziness, headache, nausea, dysgeusia.
  • Injection site reactions (pain, discoloration of skin). Skin staining usually fades over time, but may be permanent, in which case laser therapy could be considered.[[33]]  It may become a serious issue in young women. See Figure 3 on how to avoid or minimise such an incidence and others.
  • Delayed symptoms may occur one- or two-days post infusion: chills and fever, headache, arthralgia, myalgia, urticaria/rash, angioneurotic oedema.
  • Transient hypophosphatemia may also occur, particularly with FCM.[[30,34]]

Figure 3: Preparation and administration of intravenous iron.

Dosage

The Ganzoni formula (created by Dr Ganzoni of Zurich) usefully estimates a replacement dosage of parenteral iron required (Table 2).[[35]] However, a simplified method of calculation based on current haemoglobin level and body weight can also be used if preferred (Table 2). Each iron product has specific instructions for dilution and duration of infusion, so refer to the specific instruction or local guidelines for each product whenever possible. Generally, FCM (1,000mg) and IIM (1,000–1,500mg) can be given as a single dose over 15–30 minutes.[[36]] As per manufacturer, FOT is to be given 510mg at a time; two trials of 1,020mg infusion over 15–30mins reported no safety concerns, but this needs further appraisal.[[37,38]] ISC requires multiple fraction doses with 100–200mg maximum at a time, which is commonly used in renal dialysis patients.

Table 2: Ganzoni formula and simplified method of calculation for iron dosage.

Comparison

A literature search of comparison studies for four non-dextran formulations (FCM, ISC, IIM and FOT) yielded a total of 22 head-to-head comparisons (n=10,269) and three multi-comparisons (more than two products).[[ 39–63]] The comparisons included various types of studies, such as randomised and clinical trials, cohorts and reviews. The subjects were IDA patients with any cause, such as diet, childbearing and menorrhagia, gastrointestinal disorders, renal failure and cancer. The overall analysis revealed that those four formulations share a comparable safety profile and efficacy overall. However, products that can deliver a replacement with a single large dose rapidly increase blood parameters and offers a more convenient dosing regimen. Hypophosphatemia can be encountered infrequently with FCM and its long-term clinical significance is unknown due to lack of study. Appendix Table 1 illustrates details of comparison with total numbers, methods and subjects of studies.  

Discussion and conclusion  

Apparently, iron infusion with those newer formulations has a better safety profile than old dextran iron and can provide a more convenient and effective alternative to adhering to months of oral iron replacement. Overall, there is little current evidence to recommend a single best iron product for infusion among the four non-dextran products. However, formulations that can deliver a replacement with a single large dose would be more convenient and require fewer visits to healthcare providers. Although anaphylactic reactions are rare with newer non-dextran formulations, close monitoring during administration is recommended for infusion with all IV iron products. Choice of product will be determined by local availability/guidelines, cost and convenience.

Key points:

  • Modern intravenous iron formulations offer an improved safety profile with better tolerability, efficacy and effectiveness compared to oral iron therapy.
  • There is no strong current evidence to recommend a single best iron product for infusion among the four non-dextran formulations.
  • Choice of iron product for infusion will depend on local availability/guidelines, cost and convenience.
  • Two narrative reviews and one meta-analysis suggested a reconsideration of the current paradigm whereby oral iron treatment is considered a first-line therapy; it needs further evaluation.

Summary

Abstract

Aim

Method

Results

Conclusion

Author Information

Dr Tim Aung: FRNZCGP FRACGP: Primary Care Practitioner. Brisbane, QLD. Dr Justin Coleman: MBBS FRACGP MPH: Primary Care Practitioner, Northern Territory. Dr Peter W Davidson: FRACP, PhD: Haematologist (Princess Alexandra Hospital), and Director of QML Pathology. Brisbane, QLD. Dr David J Hetzel: FRACP, PhD: Gastroenterologist, Adelaide, SA. Sandy T Aung, BPharm (UQ): Pharmacist, Logan Hospital, Queensland Health. Brisbane. QLD.

Acknowledgements

Correspondence

Dr Tim Aung, FRNZCGP FRACGP: Primary Care Practitioner. Brisbane, QLD

Correspondence Email

timmynz2006@gmail.com

Competing Interests

Nil.

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29. Khalafallah AA, Hyppa A, Chuang A, Hanna F, Wilson E, Kwok C. A Prospective Randomised Controlled Trial of a Single Intravenous Infusion of Ferric Carboxymaltose vs Single Intravenous Iron Polymaltose or Daily Oral Ferrous Sulphate in the Treatment of Iron Deficiency Anemia in Pregnancy. Semin Hematol. 2018 Oct;55(4):223-234. doi: 10.1053/j.seminhematol.2018.04.006.

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31. Avni T, Bieber A, Grossman A, Green H, Leibovici L, Gafter-Gvili A. The safety of intravenous iron preparations: systematic review and meta-analysis. Mayo Clin Proc. 2015 Jan;90(1):12-23. doi: 10.1016/j.mayocp.2014.10.007.

32. DeLoughery TG. Safety of Oral and Intravenous Iron. Acta Haematol. 2019;142(1):8-12. doi: 10.1159/000496966.

33. Canning ML, Gilmore KA. Iron stain following an intravenous iron infusion. Med J Aust. 2017 Jul 17;207(2):58. doi: 10.5694/mja17.00040.

34. Adkinson NF, Strauss WE, Macdougall IC, Bernard KE, Auerbach M,5, Kaper RF, et al. Comparative safety of intravenous ferumoxytol versus ferric carboxymaltose in iron deficiency anemia: A randomized trial. Am J Hematol. 2018 May;93(5):683-690. doi: 10.1002/ajh.25060.

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40. Laso-Morales MJ, Vives R, Vallejo-Tarrat A, Caló N, Valle-Beltran A, Pontes C. Single dose of intravenous ferric carboxymaltose infusion versus multiple fractionated doses of intravenous iron sucrose in the treatment of postoperative anemia in colorectal cancer patients: study protocol for a randomised controlled trial. Trials. 2019 Jan 7;20(1):23. doi: 10.1186/s13063-018-3125-2.

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Iron is an essential element and nutrient for the human body functions. Iron deficiency (ID) and iron deficiency anaemia (IDA) are common health problems worldwide. The World Health Organization (2011) estimated 34% of the global population (>2 billion) is affected by anaemia. The most common type of anaemia was ID (50% of total anaemia), which primarily affected women of reproductive age and young children.[[1]]

Although the practice of intravenous (IV) iron to treat iron deficiency and its anaemia has existed for more than six decades,[[2]] its use in primary care centres has, compared to tertiary centres, not been widespread, largely due to historical concern of anaphylaxis and lack of remuneration. Administration of newer (non-dextran) iron formulations allows a complete or near-complete replacement in a single sitting of 15–30 minutes. These newer formulations have an improved safety profile and better tolerability, efficacy and effectiveness compared with oral iron therapy. They are suited for administration in primary care or community practices in a proper setting. This article outlines how to provide iron infusion safely and effectively, along with a brief comparison of the newer formulations (ferric carboxymaltose (FCM), iron sucrose (ISC), iron isomaltoside (IIM) and ferumoxytol (FOT).

Although in most guidelines oral iron remains as a the first-line treatment for replacement of iron, its common side effects (gastric upset and constipation and the need to take it regularly for months to replenish iron stores) often result in non-adherence. Because intramuscular iron injection can cause pain and skin staining and require multiple injections with questionable absorption, it is therefore no longer favourable.

Indications and contraindications

Symptoms specific to ID are relatively uncommon but can include pagophagia (ice craving) or other forms of pica and restless-legs syndrome. Symptoms related to IDA are non-specific: they include fatigue, weakness, tiredness, dizziness, irritability and pale skin, and in severe cases chest pain, palpitations or shortness of breath. Hair and nail disorders such as koilonychia (spoon nails) can also occur in chronic IDA. More importantly, the untreated ID and IDA can eventually impact on cognition, academic achievement, exercise tolerance, work productivity and quality of life.[[3]] ID and IDA should be confirmed by blood count and iron studies with correct interpretation. Although the details of investigation for IDA are beyond the scope of this article, it is always imperative to address the underlying cause while correcting the deficiency.

Infusion offers an alternative route of administration for those in whom oral iron is unsuitable due to intolerance, poor adherence, impracticality or contraindications. Indications for iron infusion include ID and IDA caused by the underlying conditions described in Figure 1.[[4-6]] Figure 2 lists contraindication for infusion.[[4-6]] Precautions include individuals with acute infection, asthma, marked atopy, liver dysfunction or conditions associated with low phosphate in the body. There are insufficient data to support the safety of iron infusion in the first trimester of pregnancy and in children under 14 years of age. Nevertheless, trial infusions of ferric carboxymaltose, iron sucrose and ferumoxytol in children (<14 years) at tertiary centres have shown some promises and is going to have further evaluation.[[ 9–15]]

Figure 1: Indications for iron infusion.

†FID denotes a state in which there is insufficient iron mobilisation for erythropoiesis despite normal or high ferritin concentrations with a low transferrin saturation reflecting inadequate iron availability. Maintaining the ferritin level greater than 100–200 μg/L in some chronic conditions, such as heart failure, is important to improve ventricular function, quality of life and to reduce hospitalisations.[[7,8]]

Figure 2: Contraindications for iron infusion.

Benefits

Intravenous iron rapidly restores iron and expedites haemoglobin synthesis. Newer formulations (Table 1) contain carbohydrate cores that more tightly bind elemental iron,  allowing for a much slower release and providing marginal or fewer reactions.[[1,16]]  They have also demonstrated greater efficacy and effectiveness and, compared to oral therapy and previous parenteral formulations, can improve quality of life and productivity.[[ 6,17,18]] Newer formulations also have the potential save health costs by reducing the frequency of visits to hospital and healthcare providers.[[18–21]]  Some studies have indicated that the newer generations of intravenous iron are underutilised due to historical fears about anaphylaxis that were far more common with high molecular weight iron dextrans (eg, imferon, dexferrum), which are no longer available.[[16,19]] Two narrative reviews and one meta-analysis have suggested a reconsideration of the current paradigm whereby oral iron treatment is considered a first-line therapy;[[16,19,22]] it needs further evaluation with a broad consensus. There are greater than 20 randomised studies in which IV administration of iron offers better tolerability, efficacy and effectiveness compared to oral iron.[[23–28]] One randomised control trial in Australia described the cost of IV use as no more than the cost for oral therapy, in addition to having superior tolerance, efficacy and effectiveness.[[29]]    

Table 1: History of parenteral iron products.[[1,18,19]]

† = Approved by Medsafe and subsided by PHARMAC in New Zealand.

Adverse effects

  • Anaphylaxis is rare but can be life threatening if not managed properly.[[21]] It involves bronchospasm with dyspnoea, angioedema, tachycardia and hypotension. Rates vary according to iron formulation: FCM and ISC (1–10/10,000 cases (≈0.1%–0.01%), IPC (10–100/10,000 cases).[[6,30]] Two review studies, one of which was a meta-analysis, reported that a properly defined serious anaphylaxis are even less than the above rate, if dextran is excluded and drug therapy (adrenaline, antihistamine) is given for minor reactions in the context of practitioners’ fears for further deterioration, which is not uncommon.[[31,32]]    

Less severe or minor reactions include:

  • Facial flushing, urticaria, arthralgia, myalgia, sensation of stiffness in face or limbs.
  • Dizziness, headache, nausea, dysgeusia.
  • Injection site reactions (pain, discoloration of skin). Skin staining usually fades over time, but may be permanent, in which case laser therapy could be considered.[[33]]  It may become a serious issue in young women. See Figure 3 on how to avoid or minimise such an incidence and others.
  • Delayed symptoms may occur one- or two-days post infusion: chills and fever, headache, arthralgia, myalgia, urticaria/rash, angioneurotic oedema.
  • Transient hypophosphatemia may also occur, particularly with FCM.[[30,34]]

Figure 3: Preparation and administration of intravenous iron.

Dosage

The Ganzoni formula (created by Dr Ganzoni of Zurich) usefully estimates a replacement dosage of parenteral iron required (Table 2).[[35]] However, a simplified method of calculation based on current haemoglobin level and body weight can also be used if preferred (Table 2). Each iron product has specific instructions for dilution and duration of infusion, so refer to the specific instruction or local guidelines for each product whenever possible. Generally, FCM (1,000mg) and IIM (1,000–1,500mg) can be given as a single dose over 15–30 minutes.[[36]] As per manufacturer, FOT is to be given 510mg at a time; two trials of 1,020mg infusion over 15–30mins reported no safety concerns, but this needs further appraisal.[[37,38]] ISC requires multiple fraction doses with 100–200mg maximum at a time, which is commonly used in renal dialysis patients.

Table 2: Ganzoni formula and simplified method of calculation for iron dosage.

Comparison

A literature search of comparison studies for four non-dextran formulations (FCM, ISC, IIM and FOT) yielded a total of 22 head-to-head comparisons (n=10,269) and three multi-comparisons (more than two products).[[ 39–63]] The comparisons included various types of studies, such as randomised and clinical trials, cohorts and reviews. The subjects were IDA patients with any cause, such as diet, childbearing and menorrhagia, gastrointestinal disorders, renal failure and cancer. The overall analysis revealed that those four formulations share a comparable safety profile and efficacy overall. However, products that can deliver a replacement with a single large dose rapidly increase blood parameters and offers a more convenient dosing regimen. Hypophosphatemia can be encountered infrequently with FCM and its long-term clinical significance is unknown due to lack of study. Appendix Table 1 illustrates details of comparison with total numbers, methods and subjects of studies.  

Discussion and conclusion  

Apparently, iron infusion with those newer formulations has a better safety profile than old dextran iron and can provide a more convenient and effective alternative to adhering to months of oral iron replacement. Overall, there is little current evidence to recommend a single best iron product for infusion among the four non-dextran products. However, formulations that can deliver a replacement with a single large dose would be more convenient and require fewer visits to healthcare providers. Although anaphylactic reactions are rare with newer non-dextran formulations, close monitoring during administration is recommended for infusion with all IV iron products. Choice of product will be determined by local availability/guidelines, cost and convenience.

Key points:

  • Modern intravenous iron formulations offer an improved safety profile with better tolerability, efficacy and effectiveness compared to oral iron therapy.
  • There is no strong current evidence to recommend a single best iron product for infusion among the four non-dextran formulations.
  • Choice of iron product for infusion will depend on local availability/guidelines, cost and convenience.
  • Two narrative reviews and one meta-analysis suggested a reconsideration of the current paradigm whereby oral iron treatment is considered a first-line therapy; it needs further evaluation.

Summary

Abstract

Aim

Method

Results

Conclusion

Author Information

Dr Tim Aung: FRNZCGP FRACGP: Primary Care Practitioner. Brisbane, QLD. Dr Justin Coleman: MBBS FRACGP MPH: Primary Care Practitioner, Northern Territory. Dr Peter W Davidson: FRACP, PhD: Haematologist (Princess Alexandra Hospital), and Director of QML Pathology. Brisbane, QLD. Dr David J Hetzel: FRACP, PhD: Gastroenterologist, Adelaide, SA. Sandy T Aung, BPharm (UQ): Pharmacist, Logan Hospital, Queensland Health. Brisbane. QLD.

Acknowledgements

Correspondence

Dr Tim Aung, FRNZCGP FRACGP: Primary Care Practitioner. Brisbane, QLD

Correspondence Email

timmynz2006@gmail.com

Competing Interests

Nil.

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25. Breymann C, Milman N, Mezzacasa A, Bernard R, Dudenhausen J, et al. Ferric carboxymaltose vs. oral iron in the treatment of pregnant women with iron deficiency anemia: an international, open-label, randomized controlled trial (FER-ASAP). J Perinat Med. 2017 May 24;45(4):443-453. doi: 10.1515/jpm-2016-0050.

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27. Froessler B, Cocchiaro C, Saadat-Gilani K, Hodyl N, Dekker G. Intravenous iron sucrose versus oral iron ferrous sulfate for antenatal and postpartum iron deficiency anemia: a randomized trial. J Matern Fetal Neonatal Med. 2013 May;26(7):654-9. doi: 10.3109/14767058.2012.746299.

28. Vadhan-Raj S, Strauss W, Ford D, Bernard K, Boccia R, Li J, Allen LF. Efficacy and safety of IV ferumoxytol for adults with iron deficiency anemia previously unresponsive to or unable to tolerate oral iron. Am J Hematol. 2014 Jan;89(1):7-12. doi: 10.1002/ajh.23582.

29. Khalafallah AA, Hyppa A, Chuang A, Hanna F, Wilson E, Kwok C. A Prospective Randomised Controlled Trial of a Single Intravenous Infusion of Ferric Carboxymaltose vs Single Intravenous Iron Polymaltose or Daily Oral Ferrous Sulphate in the Treatment of Iron Deficiency Anemia in Pregnancy. Semin Hematol. 2018 Oct;55(4):223-234. doi: 10.1053/j.seminhematol.2018.04.006.

30. Hardy S, Vandemergel X. Intravenous iron administration and hypophosphatemia in clinical practice. Int J Rheumatol. 2015;2015:468675. doi: 10.1155/2015/468675.

31. Avni T, Bieber A, Grossman A, Green H, Leibovici L, Gafter-Gvili A. The safety of intravenous iron preparations: systematic review and meta-analysis. Mayo Clin Proc. 2015 Jan;90(1):12-23. doi: 10.1016/j.mayocp.2014.10.007.

32. DeLoughery TG. Safety of Oral and Intravenous Iron. Acta Haematol. 2019;142(1):8-12. doi: 10.1159/000496966.

33. Canning ML, Gilmore KA. Iron stain following an intravenous iron infusion. Med J Aust. 2017 Jul 17;207(2):58. doi: 10.5694/mja17.00040.

34. Adkinson NF, Strauss WE, Macdougall IC, Bernard KE, Auerbach M,5, Kaper RF, et al. Comparative safety of intravenous ferumoxytol versus ferric carboxymaltose in iron deficiency anemia: A randomized trial. Am J Hematol. 2018 May;93(5):683-690. doi: 10.1002/ajh.25060.

35. Ganzoni AM. Intravenous iron-dextran: therapeutic and experimental possibilities. Schweiz Med Wochenschr. 1970 Feb 14;100(7):301-3.

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37. Auerbach M, Strauss W, Auerbach S, Rineer S, Bahrain H. Safety and efficacy of total dose infusion of 1,020 mg of ferumoxytol administered over 15 min. Am J Hematol. 2013 Nov;88(11):944-7. doi: 10.1002/ajh.23534.

38. Karki NR, Auerbach M. Single total dose infusion of ferumoxytol (1020 mg in 30 minutes) is an improved method of administration of intravenous iron. Am J Hematol. 2019 Jun 2. doi: 10.1002/ajh.25548.

39. Lee S, Ryu KJ, Lee ES, Lee KH, Lee JJ, Kim T. Comparative efficacy and safety of intravenous ferric carboxymaltose and iron sucrose for the treatment of preoperative anemia in patients with menorrhagia: An open-label, multicenter, randomized study. J Obstet Gynaecol Res. 2019 Apr;45(4):858-864. doi: 10.1111/jog.13893.

40. Laso-Morales MJ, Vives R, Vallejo-Tarrat A, Caló N, Valle-Beltran A, Pontes C. Single dose of intravenous ferric carboxymaltose infusion versus multiple fractionated doses of intravenous iron sucrose in the treatment of postoperative anemia in colorectal cancer patients: study protocol for a randomised controlled trial. Trials. 2019 Jan 7;20(1):23. doi: 10.1186/s13063-018-3125-2.

41. Mahey R, Kriplani A, Mogili KD, Bhatla N, Kachhawa G, Saxena R. Randomized controlled trial comparing ferric carboxymaltose and iron sucrose for treatment of iron deficiency anemia due to abnormal uterine bleeding. Int J Gynaecol Obstet. 2016 Apr;133(1):43-8. doi: 10.1016/j.ijgo.2015.09.007.

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43. Naqash A, Ara R, Bader GN. Effectiveness and safety of ferric carboxymaltose compared to iron sucrose in women with iron deficiency anemia: phase IV clinical trials. BMC Womens Health. 2018 Jan 5;18(1):6. doi: 10.1186/s12905-017-0506-8.

44. Christoph P, Schuller C, Studer H, Irion O, De Tejada BM, Surbek D.  Intravenous iron treatment in pregnancy: comparison of high-dose ferric carboxymaltose vs. iron sucrose. J Perinat Med. 2012 May 13;40(5):469-74. doi: 10.1515/jpm-2011-0231.

45. Sharma N, Thiek JL, Natung T, Ahanthem SS. Comparative Study of Efficacy and Safety of Ferric Carboxymaltose Versus Iron Sucrose in Post-partum Anemia. J Obstet Gynaecol India. 2017 Aug;67(4):253-257. doi: 10.1007/s13224-017-0971-x.

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47. Hofman JMG, Eisenga MF, Diepenbroek A, Nolte IM, van Dam B, Westerhuis R, Bakker SJL, Franssen CFM, Gaillard CAJM. Switching iron sucrose to ferric carboxymaltose associates to better control of iron status in hemodialysis patients. BMC Nephrol. 2018 Sep 20;19(1):242. doi: 10.1186/s12882-018-1045-8.

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Iron is an essential element and nutrient for the human body functions. Iron deficiency (ID) and iron deficiency anaemia (IDA) are common health problems worldwide. The World Health Organization (2011) estimated 34% of the global population (>2 billion) is affected by anaemia. The most common type of anaemia was ID (50% of total anaemia), which primarily affected women of reproductive age and young children.[[1]]

Although the practice of intravenous (IV) iron to treat iron deficiency and its anaemia has existed for more than six decades,[[2]] its use in primary care centres has, compared to tertiary centres, not been widespread, largely due to historical concern of anaphylaxis and lack of remuneration. Administration of newer (non-dextran) iron formulations allows a complete or near-complete replacement in a single sitting of 15–30 minutes. These newer formulations have an improved safety profile and better tolerability, efficacy and effectiveness compared with oral iron therapy. They are suited for administration in primary care or community practices in a proper setting. This article outlines how to provide iron infusion safely and effectively, along with a brief comparison of the newer formulations (ferric carboxymaltose (FCM), iron sucrose (ISC), iron isomaltoside (IIM) and ferumoxytol (FOT).

Although in most guidelines oral iron remains as a the first-line treatment for replacement of iron, its common side effects (gastric upset and constipation and the need to take it regularly for months to replenish iron stores) often result in non-adherence. Because intramuscular iron injection can cause pain and skin staining and require multiple injections with questionable absorption, it is therefore no longer favourable.

Indications and contraindications

Symptoms specific to ID are relatively uncommon but can include pagophagia (ice craving) or other forms of pica and restless-legs syndrome. Symptoms related to IDA are non-specific: they include fatigue, weakness, tiredness, dizziness, irritability and pale skin, and in severe cases chest pain, palpitations or shortness of breath. Hair and nail disorders such as koilonychia (spoon nails) can also occur in chronic IDA. More importantly, the untreated ID and IDA can eventually impact on cognition, academic achievement, exercise tolerance, work productivity and quality of life.[[3]] ID and IDA should be confirmed by blood count and iron studies with correct interpretation. Although the details of investigation for IDA are beyond the scope of this article, it is always imperative to address the underlying cause while correcting the deficiency.

Infusion offers an alternative route of administration for those in whom oral iron is unsuitable due to intolerance, poor adherence, impracticality or contraindications. Indications for iron infusion include ID and IDA caused by the underlying conditions described in Figure 1.[[4-6]] Figure 2 lists contraindication for infusion.[[4-6]] Precautions include individuals with acute infection, asthma, marked atopy, liver dysfunction or conditions associated with low phosphate in the body. There are insufficient data to support the safety of iron infusion in the first trimester of pregnancy and in children under 14 years of age. Nevertheless, trial infusions of ferric carboxymaltose, iron sucrose and ferumoxytol in children (<14 years) at tertiary centres have shown some promises and is going to have further evaluation.[[ 9–15]]

Figure 1: Indications for iron infusion.

†FID denotes a state in which there is insufficient iron mobilisation for erythropoiesis despite normal or high ferritin concentrations with a low transferrin saturation reflecting inadequate iron availability. Maintaining the ferritin level greater than 100–200 μg/L in some chronic conditions, such as heart failure, is important to improve ventricular function, quality of life and to reduce hospitalisations.[[7,8]]

Figure 2: Contraindications for iron infusion.

Benefits

Intravenous iron rapidly restores iron and expedites haemoglobin synthesis. Newer formulations (Table 1) contain carbohydrate cores that more tightly bind elemental iron,  allowing for a much slower release and providing marginal or fewer reactions.[[1,16]]  They have also demonstrated greater efficacy and effectiveness and, compared to oral therapy and previous parenteral formulations, can improve quality of life and productivity.[[ 6,17,18]] Newer formulations also have the potential save health costs by reducing the frequency of visits to hospital and healthcare providers.[[18–21]]  Some studies have indicated that the newer generations of intravenous iron are underutilised due to historical fears about anaphylaxis that were far more common with high molecular weight iron dextrans (eg, imferon, dexferrum), which are no longer available.[[16,19]] Two narrative reviews and one meta-analysis have suggested a reconsideration of the current paradigm whereby oral iron treatment is considered a first-line therapy;[[16,19,22]] it needs further evaluation with a broad consensus. There are greater than 20 randomised studies in which IV administration of iron offers better tolerability, efficacy and effectiveness compared to oral iron.[[23–28]] One randomised control trial in Australia described the cost of IV use as no more than the cost for oral therapy, in addition to having superior tolerance, efficacy and effectiveness.[[29]]    

Table 1: History of parenteral iron products.[[1,18,19]]

† = Approved by Medsafe and subsided by PHARMAC in New Zealand.

Adverse effects

  • Anaphylaxis is rare but can be life threatening if not managed properly.[[21]] It involves bronchospasm with dyspnoea, angioedema, tachycardia and hypotension. Rates vary according to iron formulation: FCM and ISC (1–10/10,000 cases (≈0.1%–0.01%), IPC (10–100/10,000 cases).[[6,30]] Two review studies, one of which was a meta-analysis, reported that a properly defined serious anaphylaxis are even less than the above rate, if dextran is excluded and drug therapy (adrenaline, antihistamine) is given for minor reactions in the context of practitioners’ fears for further deterioration, which is not uncommon.[[31,32]]    

Less severe or minor reactions include:

  • Facial flushing, urticaria, arthralgia, myalgia, sensation of stiffness in face or limbs.
  • Dizziness, headache, nausea, dysgeusia.
  • Injection site reactions (pain, discoloration of skin). Skin staining usually fades over time, but may be permanent, in which case laser therapy could be considered.[[33]]  It may become a serious issue in young women. See Figure 3 on how to avoid or minimise such an incidence and others.
  • Delayed symptoms may occur one- or two-days post infusion: chills and fever, headache, arthralgia, myalgia, urticaria/rash, angioneurotic oedema.
  • Transient hypophosphatemia may also occur, particularly with FCM.[[30,34]]

Figure 3: Preparation and administration of intravenous iron.

Dosage

The Ganzoni formula (created by Dr Ganzoni of Zurich) usefully estimates a replacement dosage of parenteral iron required (Table 2).[[35]] However, a simplified method of calculation based on current haemoglobin level and body weight can also be used if preferred (Table 2). Each iron product has specific instructions for dilution and duration of infusion, so refer to the specific instruction or local guidelines for each product whenever possible. Generally, FCM (1,000mg) and IIM (1,000–1,500mg) can be given as a single dose over 15–30 minutes.[[36]] As per manufacturer, FOT is to be given 510mg at a time; two trials of 1,020mg infusion over 15–30mins reported no safety concerns, but this needs further appraisal.[[37,38]] ISC requires multiple fraction doses with 100–200mg maximum at a time, which is commonly used in renal dialysis patients.

Table 2: Ganzoni formula and simplified method of calculation for iron dosage.

Comparison

A literature search of comparison studies for four non-dextran formulations (FCM, ISC, IIM and FOT) yielded a total of 22 head-to-head comparisons (n=10,269) and three multi-comparisons (more than two products).[[ 39–63]] The comparisons included various types of studies, such as randomised and clinical trials, cohorts and reviews. The subjects were IDA patients with any cause, such as diet, childbearing and menorrhagia, gastrointestinal disorders, renal failure and cancer. The overall analysis revealed that those four formulations share a comparable safety profile and efficacy overall. However, products that can deliver a replacement with a single large dose rapidly increase blood parameters and offers a more convenient dosing regimen. Hypophosphatemia can be encountered infrequently with FCM and its long-term clinical significance is unknown due to lack of study. Appendix Table 1 illustrates details of comparison with total numbers, methods and subjects of studies.  

Discussion and conclusion  

Apparently, iron infusion with those newer formulations has a better safety profile than old dextran iron and can provide a more convenient and effective alternative to adhering to months of oral iron replacement. Overall, there is little current evidence to recommend a single best iron product for infusion among the four non-dextran products. However, formulations that can deliver a replacement with a single large dose would be more convenient and require fewer visits to healthcare providers. Although anaphylactic reactions are rare with newer non-dextran formulations, close monitoring during administration is recommended for infusion with all IV iron products. Choice of product will be determined by local availability/guidelines, cost and convenience.

Key points:

  • Modern intravenous iron formulations offer an improved safety profile with better tolerability, efficacy and effectiveness compared to oral iron therapy.
  • There is no strong current evidence to recommend a single best iron product for infusion among the four non-dextran formulations.
  • Choice of iron product for infusion will depend on local availability/guidelines, cost and convenience.
  • Two narrative reviews and one meta-analysis suggested a reconsideration of the current paradigm whereby oral iron treatment is considered a first-line therapy; it needs further evaluation.

Summary

Abstract

Aim

Method

Results

Conclusion

Author Information

Dr Tim Aung: FRNZCGP FRACGP: Primary Care Practitioner. Brisbane, QLD. Dr Justin Coleman: MBBS FRACGP MPH: Primary Care Practitioner, Northern Territory. Dr Peter W Davidson: FRACP, PhD: Haematologist (Princess Alexandra Hospital), and Director of QML Pathology. Brisbane, QLD. Dr David J Hetzel: FRACP, PhD: Gastroenterologist, Adelaide, SA. Sandy T Aung, BPharm (UQ): Pharmacist, Logan Hospital, Queensland Health. Brisbane. QLD.

Acknowledgements

Correspondence

Dr Tim Aung, FRNZCGP FRACGP: Primary Care Practitioner. Brisbane, QLD

Correspondence Email

timmynz2006@gmail.com

Competing Interests

Nil.

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