REVIEW URRENT C OPINION
Update on intravenous iron choices Derek S. Larson and Daniel W. Coyne
Purpose of review Iron deficiency is a major factor in the prevalence and severity of anemia in patients with chronic kidney disease (CKD). We review the pathophysiology impairing normal intestinal iron absorption in CKD and compare the characteristics of newer intravenous (i.v.) iron agents to the longstanding i.v. iron products in the market. Recent findings The newer iron products, ferumoxytol, ferric carboxymaltose, and iron isomaltoside, more avidly bind iron, minimizing the release of labile iron during infusions, thus permitting large dose infusions. These irons also have more complex carbohydrate shells than their predecessors, which may also diminish reactions. Newer agents can be routinely administered at higher single doses, in as little as 15 min, with an acceptable safety profile. Summary Newer i.v. iron products permit the rapid, and sometimes complete, repletion of iron-deficient patients with a single dose. However, further studies examining the long-term risks and benefits of i.v. iron repletion are needed. Keywords anaphylaxis, erythropoiesis, hepcidin
INTRODUCTION Iron is essential for numerous physiologic functions, including optimal hemoglobinization during erythropoiesis, the oxygen carrier function of heme in red blood cells, and various enzyme-mediated redox reactions. Labile iron is toxic to cells, and consequently iron circulates in the blood tightly bound to transferrin, resides in cells stored in ferritin, or is bound to enzymes as a cofactor [1]. Iron-deficiency anemia is the most common cause of anemia worldwide, and patients typically have an iron deficit of 800–1400 mg. Oral iron repletes iron stores, but adherence to the prolonged course of therapy is poor because of gastrointestinal side-effects. Intravenous (i.v.) iron therapy is an increasingly attractive option for treatment. Whereas older iron therapies are approved for 200 mg or less per administration, newer iron products are approved for much larger doses including full repletion in a single administration.
body iron requirements [2]. There are no mechanisms for the body to eliminate iron. Under normal conditions, 1–2 mg of iron per day are absorbed via the duodenum, matching the 1–2 mg of iron lost through shedding of intestinal enterocytes, sweat, blood loss, and skin [3]. Despite the essential role of iron, free (or labile) iron is toxic to cells, and consequently must be maintained in a bound or chelated state [1,4]. In the blood, 2–3 mg of iron circulates tightly bound to transferrin, whereas within the cells 3–4 g reside in red blood cells and muscle as heme iron or stored within ferritin in the reticuloendothelial system (RES). Intestinal iron is transported into the duodenal enterocyte which then enters the bloodstream through the basolateral membrane transporter, ferroportin, where it is immediately bound by transferrin. Similarly, iron exits RES storage cells via Renal Division, Washington University, St. Louis, Missouri, USA
REGULATION OF IRON BALANCE The average adult human body contains 3–4 g of iron, and iron deficiency is the most common cause of anemia. Iron homeostasis is dependent upon the tight link between intestinal iron absorption and www.co-nephrolhypertens.com
Correspondence to Daniel W. Coyne, MD, Washington University School of Medicine, 660 South Euclid Avenue, Campus Box 8129, St. Louis, MO 63110, USA. Tel: +1 314 362 7211; fax: +1 314 747 3743; e-mail: [email protected] Curr Opin Nephrol Hypertens 2014, 23:186–191 DOI:10.1097/01.mnh.0000441154.40072.2e Volume 23 Number 2 March 2014
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Update on intravenous iron choices Larson and Coyne
KEY POINTS Intestinal iron absorption is frequently impaired in CKD patients because of elevated hepcidin levels. Oral iron therapy remains the first-line therapy in nondialysis CKD patients, but side-effects limit adherence. Newer i.v. iron products avidly bind iron, minimizing the release of free iron and permitting large dose infusions. Trials of newer i.v. iron products versus iron sucrose have shown similar efficacy and comparable safety with fewer administered doses.
ferroportin [1,3]. Hepcidin, a circulating protein made by the liver, binds to ferroportin and internalizes it, effectively limiting the iron absorption and release of iron from the RES. Hepcidin increases when iron stores increase and during inflammation. Increased hepcidin during inflammation impairs the efficacy of oral iron to treat iron-deficiency anemia in chronic kidney disease (CKD), especially in dialysis patients [5].
THE MAGNITUDE OF IRON DEFICIT IN THE ANEMIC PATIENT Trials have demonstrated i.v. iron can at least partially bypass hepcidin-mediated iron blockade and treat iron-deficiency anemia even in the setting of inflammation [6,7]. Usual doses sufficient to treat iron deficiency and restore iron stores are in the range of 1 g of iron. If given as a single dose, they are referred to as total dose infusions. Total dose infusion may be calculated using one of the two equations shown in Fig. 1.
These equations commonly yield doses in the range of 800–1400 mg. Consequently, some physicians empirically administer 1000 mg to any patient deemed iron deficient, and trials have found this dose is adequate to raise hemoglobin and improve the iron stores [6,8–10].
EFFICACY AND SAFETY OF ALL INTRAVENOUS IRON FORMS Large doses of i.v. iron are efficacious in the treatment of iron-deficiency anemia, even in the setting of hepcidin blockade. Treatment of anemic dialysis patients with 1000 mg of i.v. iron can frequently raise hemoglobin and decrease erythropoiesis-stimulating agent (ESA) doses, and costs [6,8,11,12]. Use of i.v. iron in nondialysis CKD patients has similarly been shown to be efficacious and superior to short courses of oral iron [13,14,15 ]. Treatment of iron deficiency may have benefits well beyond the correction of anemia. A blinded randomized trial of i.v. iron versus placebo in patients with class II and III heart failure found iron-treated patients were significantly more likely to improve heart failure class, functional capacity, 6min walking distance, and quality of life compared with placebo [16]. Comparable improvements in the iron group were observed in all prespecified subgroups, including the 50% of patients who had baseline normal hemoglobin values. Safety endpoints, including cardiovascular events and infections, were not increased in the iron group [16]. Heart failure trials using ESAs to treat anemia have increased hemoglobin, but did not lead to significant functional improvements. Taken together, this suggests that the correction of iron deficiency, rather than correction of anemia, was mediating the observed improvements. A small study of 1000 mg of iron dextran in restless leg syndrome &
Ganzoni formula Total iron dose (mg of iron) = [Weight in Kg x (Desired Hgb in g/dL – Observed Hgb) x 2.4] + (desired iron for storage, commonly 500 mg) Alternate formula Total iron dose (mg of iron) = [2.21 (Desired Hgb in g/dL – Observed Hgb) x lean body weight (LBW) in Kg + (13 x LBW)] The desired Hgb is usually set at 13 g/dL in both equations.
FIGURE 1. Equations to calculate iron deficit. Hb, hemoglobin. 1062-4821 ß 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins
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showed a high rate of improvement in symptoms [17]. All iron products contain warnings that they may cause hypersensitivity reactions, including anaphylactoid reactions, which can be life threatening and fatal. Most reactions occur within 30 min of iron administration, and therefore postadministration monitoring for at least this period is recommended. Symptoms may include hypotension, loss of consciousness, and collapse. All i.v. iron therapies should only be administered where personnel and treatment are available for the management of serious reactions.
OLDER PARENTERAL IRON PRODUCTS AND LIMITATIONS Use of parenteral iron to treat anemia dates back more than a century, but early treatment administered colloidal iron which limited the dose to a few milligrams because of the release of free iron [18–20]. In 1947, chelating the iron as iron saccharide proved a major advance and was followed in 1954 by encapsulating iron in a high molecular weight iron dextran (Imferon) [21–23]. Although the dextran shell of Imferon greatly diminished free iron release, anaphylactic reactions to the product were seen and were probably because of the development of antidextran antibodies resulting
in anaphylaxis. These reactions were common enough to limit the use of the agent and it was removed from the market in 1991 [19].
PRESENT-DAY PARENTERAL IRON AGENTS The characteristics and dosing options for the available i.v. iron products are shown in Table 1. Low molecular weight iron dextran (LMW-ID; INFeD) was introduced in 1992 and has a smaller molecular weight than the Imferon or Dexferrum brand of iron dextran. A test dose of 25 mg is administered at a gradual rate over 30 s, and monitoring is suggested for at least 1 h prior to administering the remainder of the dose [24]. LMW-ID is commonly given as 1 g or total dose infusions. Proper equipment to response to anaphylactic-type reactions is necessary when administering any iron dextran. Total dose infusions are commonly over a 4–6 h period [25]. Although total dose infusions are in common use, they are not Food and Drug Administration (FDA) approved [24]. High molecular weight iron dextran (HMW-ID; Dexferrum) was introduced in 1996, has a molecular weight of 265 kDa. Dosing is similar to LMW-ID. When LMW-ID was briefly unavailable, and HMW-ID was substituted in many facilities, reports to the FDA of adverse reactions from i.v. iron
Table 1. Available intravenous iron formulations, characteristics, and dosing options Molecular weight in kilodaltons (kDa)
Maximum approved single dose, administration time
Common off-label maximal dose and administration time
Iron product generic name (brand name)
Year of U.S. FDA approval
Iron dextran, low molecular weight (INFeD)
1991
165
100 mg over >30 s
1000 mg or more i.v. over 4 h
Yes, 25 mg; monitor 15–30 min
Iron dextran, high molecular weight (Dexferrum)
1996
265
100 mg over >30 s
1000 mg or more i.v. over 4 h
Yes, 25 mg; monitor 15–30 min
Sodium ferric gluconate complex (Ferrlecit, Nulecit)
1999
289–444
125 mg i.v. push over 10 min
250 mg i.v. over 15 min
No
Iron sucrose (Venofer)
2000
34–60
200 mg i.v. over 2–5 mina
300 mg i.v. over 1 h
No
Ferumoxytol (Feraheme)
2009
750 kDa
510 mg i.v., iron sucrose > iron dextran > ferumoxytol [35]. A similar trend for labile iron was observed in in-vivo experiments in rats. Those results are consistent with the study by Jahn et al. [36], which compared the above products to iron isomaltoside and ferric carboxymaltose (FCM). There was a very low level of labile iron release with the three newer iron products and distinctly higher levels with SFGC and iron sucrose. Newer iron products also differ in their carbohydrate shells from each other and their predecessors. As immunologic interactions with the shell are
thought to mediate the most serious allergic reactions, there are many claims that certain iron products are safer than others. However, a review of the available data by the members of the FDA Office of Surveillance and Epidemiology concluded that ‘allergic reactions are possible with all . . . iron products, and it is difficult to determine which product has the largest risk . . .’. Overall, any differences in serious and nonserious reactions between products require large blinded trials to determine [37]. Ferumoxytol (Feraheme) was approved in 2009. It has a polyglucose sorbital carboxymethyl ether shell and a molecular weight of 750 kDa. The recommended dose is 510 mg i.v. injection in less than 1 min followed by a second 510 mg injection 3–8 days later [14,38–40]. One ongoing trial is administering ferumoxytol as 1020 mg infusion over 15 min (clinicaltrials.gov registration number NCT01374919). In randomized, open-label, controlled clinical trials to date, serious hypersensitivity reactions were reported in 0.2% (3/1726) of patients, although these trials exclude patients with multiple drug allergies who are more prone to experience reactions [41]. FCM (Injectafer in the USA and Ferinject in Europe) is a polynuclear iron (III)-hydroxide carbohydrate complex. The structure of the polynuclear iron (III)-hydroxide core resembles that of ferritin and has a molecular weight of 150 kDa. It is approved for adult CKD patients with an oral iron intolerance or unsatisfactory response to oral iron. For patients weighing 50 kg or more, the recommended administration is two 750 doses as slow push or 15 min infusion separated by at least 7 days. Superiority of 1000 mg dose of FCM to oral iron has been demonstrated in open-label trials of nondialysis-dependent CKD patients [42]. Studies of FCM in hemodialysis patients also showed comparable tolerance and efficacy [15 ,43]. The preliminary results of the 12-month treatment trial comparing two different doses of FCM to oral iron in anemic CKD patients (NCT00994318) indicate that a loading dose of 1000 mg of FCM followed by smaller doses of iron to maintain a higher ferritin was statistically superior to lower doses of FCM or prolonged oral therapy in CKD patients. However, oral iron did appear to improve anemia in many patients and would clearly be less costly. Iron isomaltoside 1000 (Monofer in Europe; not approved in the USA) is an investigational agent in the USA. It has a molecular weight of 150 kDa and no test dose is required prior to large dose injections or infusions. The iron is tightly bound within a nonionic isomaltoside carbohydrate matrix, whereas most other i.v. iron preparations use branched polymers to form a carbohydrate shell
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[44]. It was approved in Europe in 2009 for dosing administration up to 20 mg/kg. The safety of iron isomaltoside was assessed in 182 CKD patients and none experienced anaphylaxis or delayed allergic reactions during 584 treatments of 100–200 mg bolus dose injections or total dose infusions [45].
COMPARISON OF NEWER IRON PRODUCTS TO OLDER PRODUCTS Efficacy is directly related to the total dose of iron administered. Any reported differences in efficacy between the products should be viewed with skepticism. Conversely, the acute safety of these agents is related chiefly to their tendency to release bioactive or free iron, which can induce acute hypotension, back pain, and edema. More serious anaphylactoid reactions may reflect the interaction of the immune system with the carbohydrate coating of the iron product and are relatively rare. Lastly, the size and coating of the iron products affects its cellular uptake and disposition, and data suggest that some iron products can lead to transient cellular injury, while other products do not. The safety and tolerability of ferumoxytol is being compared to iron sucrose in at least three trials, involving dialysis and nondialysis CKD patients (clinicaltrials.gov identifier NCT01114204, NCT01052779, and NCT01227616). Two of these trials have been completed, but the results have not thus far been published. The safety and tolerability of FCM was compared to standard medical care (which included iron sucrose or ferric gluconate for most patients) for anemia in dialysis and nondialysis CKD patients by Charytan et al. [15 ]. Serious emergent events were similar among the dialysis patients receiving FCM versus the other irons, but significantly less in the FCM group than the standard care group in nondialysis CKD patients. The authors concluded that FCM was well tolerated and displayed comparable efficacy to the older i.v. iron formulations. The largest trial comparing the products randomized 2584 nondialysis CKD patients to two 750 mg doses of FCM in 1 week or up to 5 infusions of iron sucrose 200 mg in 14 days [46 ]. Unsurprisingly, given the differences in the total iron administered, ferritin and transferrin saturation increased more during the 56 days of treatment in the FCM group, whereas improvements in hemoglobin were similar between the groups. Nausea, hypertension, flushing, dizziness, and dysgeusia were more common following FCM, protocol-defined hypotension was more common following iron sucrose, whereas serious adverse events were similar between the
&&
groups [46 ]. Overall, FCM administered in fewer, larger doses appeared to provide comparable efficacy and safety to iron sucrose. In the above trial, hypophosphatemia was observed in 18.5% of FCM patients versus 0.8% of iron sucrose patients [46 ]. Studies to date suggest that high doses of certain i.v. iron preparations increase fibroblast growth factor-23 (FGF-23) production, leading to marked phosphaturia, depressed endogenous serum calcitriol levels, and hypophosphatemia [47 ]. The effect abates over a few weeks. In the clinical trials where this has been observed, no adverse sequelae have been documented. Anecdotal reports from Japan have shown repeated doses of iron saccharide (an agent not available in the USA) induced osteomalacia, which is likely a consequence of prolonged hypophosphatemia and low calcitriol levels. This highlights the importance of pharmacovigilance and long-term trials to assess the safety of newer and older products. &&
&
CONCLUSION Newer i.v. iron agents avidly bind iron within the complex carbohydrate shells, minimizing the release of free iron during administration. This permits large dose infusions, including total repletion of the iron deficit in a single administration. Comparison trials to date have shown that FCM has a similar safety profile to iron sucrose, whereas the results of trials comparing ferumoxytol to iron sucrose have not yet been published. Given the marked increase in the use of i.v. iron for the treatment of CKD-related anemia, more comparison trials and long-term monitoring of patients for safety are still needed.
&
Acknowledgements None. Conflicts of interest D.W.C. has been a consultant and speaker for the intravenous iron manufacturers Watson, Amag, and Pharmacosmos, and has participated in intravenous iron trials sponsored by those manufacturers.
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REFERENCES AND RECOMMENDED READING Papers of particular interest, published within the annual period of review, have been highlighted as: & of special interest && of outstanding interest 1. Ganz T. Hepcidin and iron regulation, 10 years later. Blood 2011; 117:4425– 4433. 2. Hentze MW, Muckenthaler MU, Andrews NC. Balancing acts: molecular control of mammalian iron metabolism. Cell 2004; 117:285–297. 3. Horl WH. New insights into intestinal iron absorption. Nephrol Dial Transplant 2008; 23:3063–3064.
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Update on intravenous iron choices Larson and Coyne 4. Leong WI, Lonnerdal B. Hepcidin, the recently identified peptide that appears to regulate iron absorption. J Nutr 2004; 134:1–4. 5. Coyne DW. Hepcidin: clinical utility as a diagnostic tool and therapeutic target. Kidney Int 2011; 80:240–244. 6. Coyne DW, Kapoian T, Suki W, et al. Ferric gluconate is highly efficacious in anemic hemodialysis patients with high serum ferritin and low transferrin saturation: results of the Dialysis Patients’ Response to IV Iron with Elevated Ferritin (DRIVE) Study. J Am Soc Nephrol 2007; 18:975–984. 7. Fishbane S, Frei GL, Maesaka J. Reduction in recombinant human erythropoietin doses by the use of chronic intravenous iron supplementation. Am J Kidney Dis 1995; 26:41–46. 8. Fishbane S, Kowalski EA, Imbriano LJ, et al. The evaluation of iron status in hemodialysis patients. J Am Soc Nephrol 1996; 7:2654–2657. 9. Stancu S, Barsan L, Stanciu A, et al. Can the response to iron therapy be predicted in anemic nondialysis patients with chronic kidney disease? Clin J Am Soc Nephrol 2010; 5:409–416. 10. Auerbach M, Winchester J, Wahab A, et al. A randomized trial of three iron dextran infusion methods for anemia in EPO-treated dialysis patients. Am J Kidney Dis 1998; 31:81–86. 11. Pizzi LT, Bunz TJ, Coyne DW, et al. Ferric gluconate treatment provides cost savings in patients with high ferritin and low transferrin saturation. Kidney Int 2008; 74:1588–1595. 12. Lin J, Chang M, Tan D, et al. Short-term small-dose intravenous iron trial to detect functional iron deficiency in dialysis patients. Am J Nephrol 2001; 21:91–97. 13. Van Wyck DB, Roppolo M, Martinez CO, et al. A randomized, controlled trial comparing IV iron sucrose to oral iron in anemic patients with nondialysisdependent CKD. Kidney Int 2005; 68:2846–2856. 14. Provenzano R, Schiller B, Rao M, et al. Ferumoxytol as an intravenous iron replacement therapy in hemodialysis patients. Clin J Am Soc Nephrol 2009; 4:386–393. 15. Charytan C, Bernardo MV, Koch TA, et al. Intravenous ferric carboxymaltose & versus standard medical care in the treatment of iron deficiency anemia in patients with chronic kidney disease: a randomized, active-controlled, multicenter study. Nephrol Dial Transplant 2013; 28:953–964. This trial of anemic CKD patients demonstrated that doses of FCM up to 1000 mg had similar efficacy and safety to older i.v. iron therapy in CKD-HD and CKD-ND patients. 16. Anker SD, Comin Colet J, Filippatos G, et al. Ferric carboxymaltose in patients with heart failure and iron deficiency. N Engl J Med 2009; 361:2436–2448. 17. Ondo WG. Intravenous iron dextran for severe refractory restless legs syndrome. Sleep Med 2010; 11:494–496. 18. Stockman R. The treatment of chlorosis by iron and some other drugs. Br Med J (Clin Res Ed) 1893; 1:942–944. 19. Auerbach M, Ballard H. Clinical use of intravenous iron: administration, efficacy, and safety. Hematology Am Soc Hematol Educ Program 2010; 2010:338–347. 20. Heath CW, Strauss MB, Castle WB. Quantitative aspects of iron deficiency in hypochromic anemia: (The Parenteral Administration of Iron). J Clin Invest 1932; 11:1293–1312. 21. Nissim JA. Intravenous administration of iron. Lancet 1947; 2:49–51. 22. Baird IM, Podmore DA. Intramuscular iron therapy in iron-deficiency anaemia. Lancet 1954; 267:942–946. 23. Danielson BG. Structure, chemistry, and pharmacokinetics of intravenous iron agents. J Am Soc Nephrol 2004; 15 (Suppl. 2):S93–S98. 24. Iron Dextran Injection (INFeD) FDA Package Insert. Morristown: Watson Pharma, Inc. Revised; September 2009. 25. Auerbach M, Chaudhry M, Goldman H, et al. Value of methylprednisolone in prevention of the arthralgia–myalgia syndrome associated with the total dose infusion of iron dextran: a double blind randomized trial. J Lab Clin Med 1998; 131:257–260. 26. McCarthy JT, Regnier CE, Loebertmann CL, et al. Adverse events in chronic hemodialysis patients receiving intravenous iron dextran – a comparison of two products. Am J Nephrol 2000; 20:455–462. 27. Mamula P, Piccoli DA, Peck SN, et al. Total dose intravenous infusion of iron dextran for iron-deficiency anemia in children with inflammatory bowel disease. J Pediatr Gastroenterol Nutr 2002; 34:286–290.
28. Rodgers GM, Auerbach M, Cella D, et al. High-molecular weight iron dextran: a wolf in sheep’s clothing? J Am Soc Nephrol 2008; 19:833–834. 29. Michael B, Coyne DW, Fishbane S, et al. Sodium ferric gluconate complex in hemodialysis patients: adverse reactions compared to placebo and iron dextran. Kidney Int 2002; 61:1830–1839. 30. Folkert VW, Michael B, Agarwal R, et al. Chronic use of sodium ferric gluconate complex in hemodialysis patients: safety of higher-dose (> or ¼250 mg) administration. Am J Kidney Dis 2003; 41:651–657. 31. Coyne DW, Adkinson NF, Nissenson AR, et al. Sodium ferric gluconate complex in hemodialysis patients. II. Adverse reactions in iron dextran-sensitive and dextran-tolerant patients. Kidney Int 2003; 63:217–224. 32. Charytan C, Levin N, Al-Saloum M, et al. Efficacy and safety of iron sucrose for iron deficiency in patients with dialysis-associated anemia: North American clinical trial. Am J Kidney Dis 2001; 37:300–307. 33. Aronoff GR, Bennett WM, Blumenthal S, et al. Iron sucrose in hemodialysis patients: safety of replacement and maintenance regimens. Kidney Int 2004; 66:1193–1198. 34. Charytan C, Schwenk MH, Al-Saloum MM, et al. Safety of iron sucrose in hemodialysis patients intolerant to other parenteral iron products. Nephron Clin Pract 2004; 96:c63–c66. 35. Balakrishnan VS, Rao M, Kausz AT, et al. Physicochemical properties of ferumoxytol, a new intravenous iron preparation. Eur J Clin Invest 2009; 39:489–496. 36. Jahn MR, Andreasen HB, Futterer S, et al. A comparative study of the physicochemical properties of iron isomaltoside 1000 (Monofer(R)), a new intravenous iron preparation and its clinical implications. Eur J Pharm Biopharm 2011; 78:480–491. 37. Wysowski DK, Swartz L, Borders-Hemphill BV, et al. Use of parenteral iron products and serious anaphylactic-type reactions. Am J Hematol 2010; 85:650–654. 38. Ferumoxytol (Feraheme) injection. FDA Package Insert. Waltham: AMAG Pharmaceuticals, Inc.; June 2009. 39. Landry R, Jacobs PM, Davis R, et al. Pharmacokinetic study of ferumoxytol: a new iron replacement therapy in normal subjects and hemodialysis patients. Am J Nephrol 2005; 25:400–410. 40. Spinowitz BS, Schwenk MH, Jacobs PM, et al. The safety and efficacy of ferumoxytol therapy in anemic chronic kidney disease patients. Kidney Int 2005; 68:1801–1807. 41. Lu M, Cohen MH, Rieves D, et al. FDA report: ferumoxytol for intravenous iron therapy in adult patients with chronic kidney disease. Am J Hematol 2010; 85:315–319. 42. Qunibi WY, Martinez C, Smith M, et al. A randomized controlled trial comparing intravenous ferric carboxymaltose with oral iron for treatment of iron deficiency anaemia of nondialysis-dependent chronic kidney disease patients. Nephrol Dial Transplant 2011; 26:1599–1607. 43. Covic A, Mircescu G. The safety and efficacy of intravenous ferric carboxymaltose in anaemic patients undergoing haemodialysis: a multicentre, openlabel, clinical study. Nephrol Dial Transplant 2010; 25:2722–2730. 44. Mace TA, Syed A, Bhandari S. Iron (III) isomaltoside 1000. Expert Rev Hematol 2013; 6:239–246. 45. Wikstrom B, Bhandari S, Barany P, et al. Iron isomaltoside 1000: a new intravenous iron for treating iron deficiency in chronic kidney disease. J Nephrol 2011; 24:589–596. 46. 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 2013; doi: 10.1093/ndt/gft251. [Epub ahead of print] Trial of 2584 CKD-ND patients randomized to two 750 mg doses of FCM or five 200 mg doses of iron sucrose. FCM was more efficacious (expected because of more i.v. iron) and had a similar safety profile. 47. Prats M, Font R, Garcia C, et al. Effect of ferric carboxymaltose on serum & phosphate and C-terminal FGF23 levels in nondialysis chronic kidney disease patients: posthoc analysis of a prospective study. BMC Nephrol 2013; 14:167. doi: 10.1186/1471-2369-14-167. This study demonstrated that 35 of 47 patients administered 1000 mg of FCM as a single dose developed hypophosphatemia at 3 weeks. Other studies suggest this is mediated by a marked increase in FGF23 and a decline in calcitriol levels.
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Update on intravenous iron choices Derek S. Larson and Daniel W. Coyne
Purpose of review Iron deficiency is a major factor in the prevalence and severity of anemia in patients with chronic kidney disease (CKD). We review the pathophysiology impairing normal intestinal iron absorption in CKD and compare the characteristics of newer intravenous (i.v.) iron agents to the longstanding i.v. iron products in the market. Recent findings The newer iron products, ferumoxytol, ferric carboxymaltose, and iron isomaltoside, more avidly bind iron, minimizing the release of labile iron during infusions, thus permitting large dose infusions. These irons also have more complex carbohydrate shells than their predecessors, which may also diminish reactions. Newer agents can be routinely administered at higher single doses, in as little as 15 min, with an acceptable safety profile. Summary Newer i.v. iron products permit the rapid, and sometimes complete, repletion of iron-deficient patients with a single dose. However, further studies examining the long-term risks and benefits of i.v. iron repletion are needed. Keywords anaphylaxis, erythropoiesis, hepcidin
INTRODUCTION Iron is essential for numerous physiologic functions, including optimal hemoglobinization during erythropoiesis, the oxygen carrier function of heme in red blood cells, and various enzyme-mediated redox reactions. Labile iron is toxic to cells, and consequently iron circulates in the blood tightly bound to transferrin, resides in cells stored in ferritin, or is bound to enzymes as a cofactor [1]. Iron-deficiency anemia is the most common cause of anemia worldwide, and patients typically have an iron deficit of 800–1400 mg. Oral iron repletes iron stores, but adherence to the prolonged course of therapy is poor because of gastrointestinal side-effects. Intravenous (i.v.) iron therapy is an increasingly attractive option for treatment. Whereas older iron therapies are approved for 200 mg or less per administration, newer iron products are approved for much larger doses including full repletion in a single administration.
body iron requirements [2]. There are no mechanisms for the body to eliminate iron. Under normal conditions, 1–2 mg of iron per day are absorbed via the duodenum, matching the 1–2 mg of iron lost through shedding of intestinal enterocytes, sweat, blood loss, and skin [3]. Despite the essential role of iron, free (or labile) iron is toxic to cells, and consequently must be maintained in a bound or chelated state [1,4]. In the blood, 2–3 mg of iron circulates tightly bound to transferrin, whereas within the cells 3–4 g reside in red blood cells and muscle as heme iron or stored within ferritin in the reticuloendothelial system (RES). Intestinal iron is transported into the duodenal enterocyte which then enters the bloodstream through the basolateral membrane transporter, ferroportin, where it is immediately bound by transferrin. Similarly, iron exits RES storage cells via Renal Division, Washington University, St. Louis, Missouri, USA
REGULATION OF IRON BALANCE The average adult human body contains 3–4 g of iron, and iron deficiency is the most common cause of anemia. Iron homeostasis is dependent upon the tight link between intestinal iron absorption and www.co-nephrolhypertens.com
Correspondence to Daniel W. Coyne, MD, Washington University School of Medicine, 660 South Euclid Avenue, Campus Box 8129, St. Louis, MO 63110, USA. Tel: +1 314 362 7211; fax: +1 314 747 3743; e-mail: [email protected] Curr Opin Nephrol Hypertens 2014, 23:186–191 DOI:10.1097/01.mnh.0000441154.40072.2e Volume 23 Number 2 March 2014
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Update on intravenous iron choices Larson and Coyne
KEY POINTS Intestinal iron absorption is frequently impaired in CKD patients because of elevated hepcidin levels. Oral iron therapy remains the first-line therapy in nondialysis CKD patients, but side-effects limit adherence. Newer i.v. iron products avidly bind iron, minimizing the release of free iron and permitting large dose infusions. Trials of newer i.v. iron products versus iron sucrose have shown similar efficacy and comparable safety with fewer administered doses.
ferroportin [1,3]. Hepcidin, a circulating protein made by the liver, binds to ferroportin and internalizes it, effectively limiting the iron absorption and release of iron from the RES. Hepcidin increases when iron stores increase and during inflammation. Increased hepcidin during inflammation impairs the efficacy of oral iron to treat iron-deficiency anemia in chronic kidney disease (CKD), especially in dialysis patients [5].
THE MAGNITUDE OF IRON DEFICIT IN THE ANEMIC PATIENT Trials have demonstrated i.v. iron can at least partially bypass hepcidin-mediated iron blockade and treat iron-deficiency anemia even in the setting of inflammation [6,7]. Usual doses sufficient to treat iron deficiency and restore iron stores are in the range of 1 g of iron. If given as a single dose, they are referred to as total dose infusions. Total dose infusion may be calculated using one of the two equations shown in Fig. 1.
These equations commonly yield doses in the range of 800–1400 mg. Consequently, some physicians empirically administer 1000 mg to any patient deemed iron deficient, and trials have found this dose is adequate to raise hemoglobin and improve the iron stores [6,8–10].
EFFICACY AND SAFETY OF ALL INTRAVENOUS IRON FORMS Large doses of i.v. iron are efficacious in the treatment of iron-deficiency anemia, even in the setting of hepcidin blockade. Treatment of anemic dialysis patients with 1000 mg of i.v. iron can frequently raise hemoglobin and decrease erythropoiesis-stimulating agent (ESA) doses, and costs [6,8,11,12]. Use of i.v. iron in nondialysis CKD patients has similarly been shown to be efficacious and superior to short courses of oral iron [13,14,15 ]. Treatment of iron deficiency may have benefits well beyond the correction of anemia. A blinded randomized trial of i.v. iron versus placebo in patients with class II and III heart failure found iron-treated patients were significantly more likely to improve heart failure class, functional capacity, 6min walking distance, and quality of life compared with placebo [16]. Comparable improvements in the iron group were observed in all prespecified subgroups, including the 50% of patients who had baseline normal hemoglobin values. Safety endpoints, including cardiovascular events and infections, were not increased in the iron group [16]. Heart failure trials using ESAs to treat anemia have increased hemoglobin, but did not lead to significant functional improvements. Taken together, this suggests that the correction of iron deficiency, rather than correction of anemia, was mediating the observed improvements. A small study of 1000 mg of iron dextran in restless leg syndrome &
Ganzoni formula Total iron dose (mg of iron) = [Weight in Kg x (Desired Hgb in g/dL – Observed Hgb) x 2.4] + (desired iron for storage, commonly 500 mg) Alternate formula Total iron dose (mg of iron) = [2.21 (Desired Hgb in g/dL – Observed Hgb) x lean body weight (LBW) in Kg + (13 x LBW)] The desired Hgb is usually set at 13 g/dL in both equations.
FIGURE 1. Equations to calculate iron deficit. Hb, hemoglobin. 1062-4821 ß 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins
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showed a high rate of improvement in symptoms [17]. All iron products contain warnings that they may cause hypersensitivity reactions, including anaphylactoid reactions, which can be life threatening and fatal. Most reactions occur within 30 min of iron administration, and therefore postadministration monitoring for at least this period is recommended. Symptoms may include hypotension, loss of consciousness, and collapse. All i.v. iron therapies should only be administered where personnel and treatment are available for the management of serious reactions.
OLDER PARENTERAL IRON PRODUCTS AND LIMITATIONS Use of parenteral iron to treat anemia dates back more than a century, but early treatment administered colloidal iron which limited the dose to a few milligrams because of the release of free iron [18–20]. In 1947, chelating the iron as iron saccharide proved a major advance and was followed in 1954 by encapsulating iron in a high molecular weight iron dextran (Imferon) [21–23]. Although the dextran shell of Imferon greatly diminished free iron release, anaphylactic reactions to the product were seen and were probably because of the development of antidextran antibodies resulting
in anaphylaxis. These reactions were common enough to limit the use of the agent and it was removed from the market in 1991 [19].
PRESENT-DAY PARENTERAL IRON AGENTS The characteristics and dosing options for the available i.v. iron products are shown in Table 1. Low molecular weight iron dextran (LMW-ID; INFeD) was introduced in 1992 and has a smaller molecular weight than the Imferon or Dexferrum brand of iron dextran. A test dose of 25 mg is administered at a gradual rate over 30 s, and monitoring is suggested for at least 1 h prior to administering the remainder of the dose [24]. LMW-ID is commonly given as 1 g or total dose infusions. Proper equipment to response to anaphylactic-type reactions is necessary when administering any iron dextran. Total dose infusions are commonly over a 4–6 h period [25]. Although total dose infusions are in common use, they are not Food and Drug Administration (FDA) approved [24]. High molecular weight iron dextran (HMW-ID; Dexferrum) was introduced in 1996, has a molecular weight of 265 kDa. Dosing is similar to LMW-ID. When LMW-ID was briefly unavailable, and HMW-ID was substituted in many facilities, reports to the FDA of adverse reactions from i.v. iron
Table 1. Available intravenous iron formulations, characteristics, and dosing options Molecular weight in kilodaltons (kDa)
Maximum approved single dose, administration time
Common off-label maximal dose and administration time
Iron product generic name (brand name)
Year of U.S. FDA approval
Iron dextran, low molecular weight (INFeD)
1991
165
100 mg over >30 s
1000 mg or more i.v. over 4 h
Yes, 25 mg; monitor 15–30 min
Iron dextran, high molecular weight (Dexferrum)
1996
265
100 mg over >30 s
1000 mg or more i.v. over 4 h
Yes, 25 mg; monitor 15–30 min
Sodium ferric gluconate complex (Ferrlecit, Nulecit)
1999
289–444
125 mg i.v. push over 10 min
250 mg i.v. over 15 min
No
Iron sucrose (Venofer)
2000
34–60
200 mg i.v. over 2–5 mina
300 mg i.v. over 1 h
No
Ferumoxytol (Feraheme)
2009
750 kDa
510 mg i.v., iron sucrose > iron dextran > ferumoxytol [35]. A similar trend for labile iron was observed in in-vivo experiments in rats. Those results are consistent with the study by Jahn et al. [36], which compared the above products to iron isomaltoside and ferric carboxymaltose (FCM). There was a very low level of labile iron release with the three newer iron products and distinctly higher levels with SFGC and iron sucrose. Newer iron products also differ in their carbohydrate shells from each other and their predecessors. As immunologic interactions with the shell are
thought to mediate the most serious allergic reactions, there are many claims that certain iron products are safer than others. However, a review of the available data by the members of the FDA Office of Surveillance and Epidemiology concluded that ‘allergic reactions are possible with all . . . iron products, and it is difficult to determine which product has the largest risk . . .’. Overall, any differences in serious and nonserious reactions between products require large blinded trials to determine [37]. Ferumoxytol (Feraheme) was approved in 2009. It has a polyglucose sorbital carboxymethyl ether shell and a molecular weight of 750 kDa. The recommended dose is 510 mg i.v. injection in less than 1 min followed by a second 510 mg injection 3–8 days later [14,38–40]. One ongoing trial is administering ferumoxytol as 1020 mg infusion over 15 min (clinicaltrials.gov registration number NCT01374919). In randomized, open-label, controlled clinical trials to date, serious hypersensitivity reactions were reported in 0.2% (3/1726) of patients, although these trials exclude patients with multiple drug allergies who are more prone to experience reactions [41]. FCM (Injectafer in the USA and Ferinject in Europe) is a polynuclear iron (III)-hydroxide carbohydrate complex. The structure of the polynuclear iron (III)-hydroxide core resembles that of ferritin and has a molecular weight of 150 kDa. It is approved for adult CKD patients with an oral iron intolerance or unsatisfactory response to oral iron. For patients weighing 50 kg or more, the recommended administration is two 750 doses as slow push or 15 min infusion separated by at least 7 days. Superiority of 1000 mg dose of FCM to oral iron has been demonstrated in open-label trials of nondialysis-dependent CKD patients [42]. Studies of FCM in hemodialysis patients also showed comparable tolerance and efficacy [15 ,43]. The preliminary results of the 12-month treatment trial comparing two different doses of FCM to oral iron in anemic CKD patients (NCT00994318) indicate that a loading dose of 1000 mg of FCM followed by smaller doses of iron to maintain a higher ferritin was statistically superior to lower doses of FCM or prolonged oral therapy in CKD patients. However, oral iron did appear to improve anemia in many patients and would clearly be less costly. Iron isomaltoside 1000 (Monofer in Europe; not approved in the USA) is an investigational agent in the USA. It has a molecular weight of 150 kDa and no test dose is required prior to large dose injections or infusions. The iron is tightly bound within a nonionic isomaltoside carbohydrate matrix, whereas most other i.v. iron preparations use branched polymers to form a carbohydrate shell
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[44]. It was approved in Europe in 2009 for dosing administration up to 20 mg/kg. The safety of iron isomaltoside was assessed in 182 CKD patients and none experienced anaphylaxis or delayed allergic reactions during 584 treatments of 100–200 mg bolus dose injections or total dose infusions [45].
COMPARISON OF NEWER IRON PRODUCTS TO OLDER PRODUCTS Efficacy is directly related to the total dose of iron administered. Any reported differences in efficacy between the products should be viewed with skepticism. Conversely, the acute safety of these agents is related chiefly to their tendency to release bioactive or free iron, which can induce acute hypotension, back pain, and edema. More serious anaphylactoid reactions may reflect the interaction of the immune system with the carbohydrate coating of the iron product and are relatively rare. Lastly, the size and coating of the iron products affects its cellular uptake and disposition, and data suggest that some iron products can lead to transient cellular injury, while other products do not. The safety and tolerability of ferumoxytol is being compared to iron sucrose in at least three trials, involving dialysis and nondialysis CKD patients (clinicaltrials.gov identifier NCT01114204, NCT01052779, and NCT01227616). Two of these trials have been completed, but the results have not thus far been published. The safety and tolerability of FCM was compared to standard medical care (which included iron sucrose or ferric gluconate for most patients) for anemia in dialysis and nondialysis CKD patients by Charytan et al. [15 ]. Serious emergent events were similar among the dialysis patients receiving FCM versus the other irons, but significantly less in the FCM group than the standard care group in nondialysis CKD patients. The authors concluded that FCM was well tolerated and displayed comparable efficacy to the older i.v. iron formulations. The largest trial comparing the products randomized 2584 nondialysis CKD patients to two 750 mg doses of FCM in 1 week or up to 5 infusions of iron sucrose 200 mg in 14 days [46 ]. Unsurprisingly, given the differences in the total iron administered, ferritin and transferrin saturation increased more during the 56 days of treatment in the FCM group, whereas improvements in hemoglobin were similar between the groups. Nausea, hypertension, flushing, dizziness, and dysgeusia were more common following FCM, protocol-defined hypotension was more common following iron sucrose, whereas serious adverse events were similar between the
&&
groups [46 ]. Overall, FCM administered in fewer, larger doses appeared to provide comparable efficacy and safety to iron sucrose. In the above trial, hypophosphatemia was observed in 18.5% of FCM patients versus 0.8% of iron sucrose patients [46 ]. Studies to date suggest that high doses of certain i.v. iron preparations increase fibroblast growth factor-23 (FGF-23) production, leading to marked phosphaturia, depressed endogenous serum calcitriol levels, and hypophosphatemia [47 ]. The effect abates over a few weeks. In the clinical trials where this has been observed, no adverse sequelae have been documented. Anecdotal reports from Japan have shown repeated doses of iron saccharide (an agent not available in the USA) induced osteomalacia, which is likely a consequence of prolonged hypophosphatemia and low calcitriol levels. This highlights the importance of pharmacovigilance and long-term trials to assess the safety of newer and older products. &&
&
CONCLUSION Newer i.v. iron agents avidly bind iron within the complex carbohydrate shells, minimizing the release of free iron during administration. This permits large dose infusions, including total repletion of the iron deficit in a single administration. Comparison trials to date have shown that FCM has a similar safety profile to iron sucrose, whereas the results of trials comparing ferumoxytol to iron sucrose have not yet been published. Given the marked increase in the use of i.v. iron for the treatment of CKD-related anemia, more comparison trials and long-term monitoring of patients for safety are still needed.
&
Acknowledgements None. Conflicts of interest D.W.C. has been a consultant and speaker for the intravenous iron manufacturers Watson, Amag, and Pharmacosmos, and has participated in intravenous iron trials sponsored by those manufacturers.
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REFERENCES AND RECOMMENDED READING Papers of particular interest, published within the annual period of review, have been highlighted as: & of special interest && of outstanding interest 1. Ganz T. Hepcidin and iron regulation, 10 years later. Blood 2011; 117:4425– 4433. 2. Hentze MW, Muckenthaler MU, Andrews NC. Balancing acts: molecular control of mammalian iron metabolism. Cell 2004; 117:285–297. 3. Horl WH. New insights into intestinal iron absorption. Nephrol Dial Transplant 2008; 23:3063–3064.
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Update on intravenous iron choices Larson and Coyne 4. Leong WI, Lonnerdal B. Hepcidin, the recently identified peptide that appears to regulate iron absorption. J Nutr 2004; 134:1–4. 5. Coyne DW. Hepcidin: clinical utility as a diagnostic tool and therapeutic target. Kidney Int 2011; 80:240–244. 6. Coyne DW, Kapoian T, Suki W, et al. Ferric gluconate is highly efficacious in anemic hemodialysis patients with high serum ferritin and low transferrin saturation: results of the Dialysis Patients’ Response to IV Iron with Elevated Ferritin (DRIVE) Study. J Am Soc Nephrol 2007; 18:975–984. 7. Fishbane S, Frei GL, Maesaka J. Reduction in recombinant human erythropoietin doses by the use of chronic intravenous iron supplementation. Am J Kidney Dis 1995; 26:41–46. 8. Fishbane S, Kowalski EA, Imbriano LJ, et al. The evaluation of iron status in hemodialysis patients. J Am Soc Nephrol 1996; 7:2654–2657. 9. Stancu S, Barsan L, Stanciu A, et al. Can the response to iron therapy be predicted in anemic nondialysis patients with chronic kidney disease? Clin J Am Soc Nephrol 2010; 5:409–416. 10. Auerbach M, Winchester J, Wahab A, et al. A randomized trial of three iron dextran infusion methods for anemia in EPO-treated dialysis patients. Am J Kidney Dis 1998; 31:81–86. 11. Pizzi LT, Bunz TJ, Coyne DW, et al. Ferric gluconate treatment provides cost savings in patients with high ferritin and low transferrin saturation. Kidney Int 2008; 74:1588–1595. 12. Lin J, Chang M, Tan D, et al. Short-term small-dose intravenous iron trial to detect functional iron deficiency in dialysis patients. Am J Nephrol 2001; 21:91–97. 13. Van Wyck DB, Roppolo M, Martinez CO, et al. A randomized, controlled trial comparing IV iron sucrose to oral iron in anemic patients with nondialysisdependent CKD. Kidney Int 2005; 68:2846–2856. 14. Provenzano R, Schiller B, Rao M, et al. Ferumoxytol as an intravenous iron replacement therapy in hemodialysis patients. Clin J Am Soc Nephrol 2009; 4:386–393. 15. Charytan C, Bernardo MV, Koch TA, et al. Intravenous ferric carboxymaltose & versus standard medical care in the treatment of iron deficiency anemia in patients with chronic kidney disease: a randomized, active-controlled, multicenter study. Nephrol Dial Transplant 2013; 28:953–964. This trial of anemic CKD patients demonstrated that doses of FCM up to 1000 mg had similar efficacy and safety to older i.v. iron therapy in CKD-HD and CKD-ND patients. 16. Anker SD, Comin Colet J, Filippatos G, et al. Ferric carboxymaltose in patients with heart failure and iron deficiency. N Engl J Med 2009; 361:2436–2448. 17. Ondo WG. Intravenous iron dextran for severe refractory restless legs syndrome. Sleep Med 2010; 11:494–496. 18. Stockman R. The treatment of chlorosis by iron and some other drugs. Br Med J (Clin Res Ed) 1893; 1:942–944. 19. Auerbach M, Ballard H. Clinical use of intravenous iron: administration, efficacy, and safety. Hematology Am Soc Hematol Educ Program 2010; 2010:338–347. 20. Heath CW, Strauss MB, Castle WB. Quantitative aspects of iron deficiency in hypochromic anemia: (The Parenteral Administration of Iron). J Clin Invest 1932; 11:1293–1312. 21. Nissim JA. Intravenous administration of iron. Lancet 1947; 2:49–51. 22. Baird IM, Podmore DA. Intramuscular iron therapy in iron-deficiency anaemia. Lancet 1954; 267:942–946. 23. Danielson BG. Structure, chemistry, and pharmacokinetics of intravenous iron agents. J Am Soc Nephrol 2004; 15 (Suppl. 2):S93–S98. 24. Iron Dextran Injection (INFeD) FDA Package Insert. Morristown: Watson Pharma, Inc. Revised; September 2009. 25. Auerbach M, Chaudhry M, Goldman H, et al. Value of methylprednisolone in prevention of the arthralgia–myalgia syndrome associated with the total dose infusion of iron dextran: a double blind randomized trial. J Lab Clin Med 1998; 131:257–260. 26. McCarthy JT, Regnier CE, Loebertmann CL, et al. Adverse events in chronic hemodialysis patients receiving intravenous iron dextran – a comparison of two products. Am J Nephrol 2000; 20:455–462. 27. Mamula P, Piccoli DA, Peck SN, et al. Total dose intravenous infusion of iron dextran for iron-deficiency anemia in children with inflammatory bowel disease. J Pediatr Gastroenterol Nutr 2002; 34:286–290.
28. Rodgers GM, Auerbach M, Cella D, et al. High-molecular weight iron dextran: a wolf in sheep’s clothing? J Am Soc Nephrol 2008; 19:833–834. 29. Michael B, Coyne DW, Fishbane S, et al. Sodium ferric gluconate complex in hemodialysis patients: adverse reactions compared to placebo and iron dextran. Kidney Int 2002; 61:1830–1839. 30. Folkert VW, Michael B, Agarwal R, et al. Chronic use of sodium ferric gluconate complex in hemodialysis patients: safety of higher-dose (> or ¼250 mg) administration. Am J Kidney Dis 2003; 41:651–657. 31. Coyne DW, Adkinson NF, Nissenson AR, et al. Sodium ferric gluconate complex in hemodialysis patients. II. Adverse reactions in iron dextran-sensitive and dextran-tolerant patients. Kidney Int 2003; 63:217–224. 32. Charytan C, Levin N, Al-Saloum M, et al. Efficacy and safety of iron sucrose for iron deficiency in patients with dialysis-associated anemia: North American clinical trial. Am J Kidney Dis 2001; 37:300–307. 33. Aronoff GR, Bennett WM, Blumenthal S, et al. Iron sucrose in hemodialysis patients: safety of replacement and maintenance regimens. Kidney Int 2004; 66:1193–1198. 34. Charytan C, Schwenk MH, Al-Saloum MM, et al. Safety of iron sucrose in hemodialysis patients intolerant to other parenteral iron products. Nephron Clin Pract 2004; 96:c63–c66. 35. Balakrishnan VS, Rao M, Kausz AT, et al. Physicochemical properties of ferumoxytol, a new intravenous iron preparation. Eur J Clin Invest 2009; 39:489–496. 36. Jahn MR, Andreasen HB, Futterer S, et al. A comparative study of the physicochemical properties of iron isomaltoside 1000 (Monofer(R)), a new intravenous iron preparation and its clinical implications. Eur J Pharm Biopharm 2011; 78:480–491. 37. Wysowski DK, Swartz L, Borders-Hemphill BV, et al. Use of parenteral iron products and serious anaphylactic-type reactions. Am J Hematol 2010; 85:650–654. 38. Ferumoxytol (Feraheme) injection. FDA Package Insert. Waltham: AMAG Pharmaceuticals, Inc.; June 2009. 39. Landry R, Jacobs PM, Davis R, et al. Pharmacokinetic study of ferumoxytol: a new iron replacement therapy in normal subjects and hemodialysis patients. Am J Nephrol 2005; 25:400–410. 40. Spinowitz BS, Schwenk MH, Jacobs PM, et al. The safety and efficacy of ferumoxytol therapy in anemic chronic kidney disease patients. Kidney Int 2005; 68:1801–1807. 41. Lu M, Cohen MH, Rieves D, et al. FDA report: ferumoxytol for intravenous iron therapy in adult patients with chronic kidney disease. Am J Hematol 2010; 85:315–319. 42. Qunibi WY, Martinez C, Smith M, et al. A randomized controlled trial comparing intravenous ferric carboxymaltose with oral iron for treatment of iron deficiency anaemia of nondialysis-dependent chronic kidney disease patients. Nephrol Dial Transplant 2011; 26:1599–1607. 43. Covic A, Mircescu G. The safety and efficacy of intravenous ferric carboxymaltose in anaemic patients undergoing haemodialysis: a multicentre, openlabel, clinical study. Nephrol Dial Transplant 2010; 25:2722–2730. 44. Mace TA, Syed A, Bhandari S. Iron (III) isomaltoside 1000. Expert Rev Hematol 2013; 6:239–246. 45. Wikstrom B, Bhandari S, Barany P, et al. Iron isomaltoside 1000: a new intravenous iron for treating iron deficiency in chronic kidney disease. J Nephrol 2011; 24:589–596. 46. 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 2013; doi: 10.1093/ndt/gft251. [Epub ahead of print] Trial of 2584 CKD-ND patients randomized to two 750 mg doses of FCM or five 200 mg doses of iron sucrose. FCM was more efficacious (expected because of more i.v. iron) and had a similar safety profile. 47. Prats M, Font R, Garcia C, et al. Effect of ferric carboxymaltose on serum & phosphate and C-terminal FGF23 levels in nondialysis chronic kidney disease patients: posthoc analysis of a prospective study. BMC Nephrol 2013; 14:167. doi: 10.1186/1471-2369-14-167. This study demonstrated that 35 of 47 patients administered 1000 mg of FCM as a single dose developed hypophosphatemia at 3 weeks. Other studies suggest this is mediated by a marked increase in FGF23 and a decline in calcitriol levels.
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