Structure, Chemistry, and Pharmacokinetics of Intravenous
`Iron Agents
`
`J Am Soc Nephrol 15: S93–S98, 2004
`
`BO G. DANIELSON
`Department of Renal Medicine, University Hospital, Uppsala, Sweden
`
`Structure and Chemistry
`All intravenous (IV) iron agents are colloids that consist of
`spheroidal iron-carbohydrate nanoparticles. At the core of each
`particle is an iron-oxyhydroxide gel. The core is surrounded by
`a shell of carbohydrate that stabilizes the iron-oxyhydroxide,
`slows the release of bioactive iron, and maintains the resulting
`particles in colloidal suspension. IV iron agents share the same
`core chemistry but differ from each other by the size of the core
`and the identity and the density of the surrounding carbohy-
`drate. Differences in core size and carbohydrate chemistry
`determine pharmacologic and biologic differences, including
`clearance rate after injection, iron release rate in vitro, early
`evidence of iron bioactivity in vivo, and maximum tolerated
`dose and rate of infusion.
`Early experience demonstrated the hazards posed by admin-
`istering inorganic ferric (Fe⫹3) iron unprotected by carbohy-
`drate. Profound toxicity limited parenteral free ferric iron ad-
`ministration to 8 mg (1), the approximate total iron-binding
`capacity of transferrin in the plasma of an adult. Formulations
`that present ferric iron as colloidal ferric hydroxide permitted
`higher doses, but common and severe hypotensive reactions
`precluded routine use (2). Chelating the colloidal ferric hy-
`droxide particles with a carbohydrate proved a major advance
`in improving parenteral iron safety. Investigators who prepared
`their own saccharated ferric hydroxide administered as much
`as 1000 mg of iron intravenously over 15 min. Adverse reac-
`tions occurred but apparently were not severe because they
`responded to only “an electric blanket and a fluid ounce of
`brandy” (3). These reports led to the first commercially avail-
`able iron-carbohydrate compounds, including iron dextrin (4),
`saccharated iron oxide (Proferrin; Sharp & Dohme, Inc., Phil-
`adelphia, PA) (5), iron dextran (6,7), iron sucrose (8), and
`ferric gluconate (9,10).
`IV iron agents that currently are available in North America
`include only iron sucrose, ferric gluconate, and two iron dex-
`tran formulations. We focus discussion here primarily on
`agents in these three classes. However, multiple other paren-
`teral iron-carbohydrate compounds for IV and intramuscular
`administration have been produced over the past 50 yr. Most
`
`Correspondence to Dr. Bo G. Danielson, Renapharma, P.O. Box 938, S-751 09
`Uppsala, Sweden. Phone: 46-18-4784050; Fax: 46-18-4784099; E-mail:
`bo.danielson@renapharma.se
`1046-6673/1512-0093
`Journal of the American Society of Nephrology
`Copyright © 2004 by the American Society of Nephrology
`
`DOI: 10.1097/01.ASN.0000143814.49713.C5
`
`are not currently marketed. Some of these agents differ by
`trade name but share identical chemistry, whereas others share
`the same generic name but differ chemically. Compounding
`the potential for confusion, published reports may reference
`either trade name or generic class but not both. Thus, to assist
`interpretation of the literature and minimize confusion, Table 1
`lists IV iron agents by generic class, trade name, and current
`availability. The table includes packaging information because
`the older literature frequently cites iron doses by volume ad-
`ministered rather than by milligrams.
`Use of low molecular weight (LMW) dextran to chelate high
`molecular weight ferric oxyhydroxide particles produced iron
`dextran. Iron dextran (Imferon; Fisons Ltd., Loughborough,
`Leicestershire, UK) was first available in the United States and the
`United Kingdom for intramuscular administration in 1955 (11)
`and for IV use in 1971. It was withdrawn from the world market
`in 1996. Early reports confirmed that iron dextran could be ad-
`ministered in doses as high as 2 to 3 g given intravenously over 4
`to 10 min (12). More caution followed closely, when investigators
`found that patients who received iron dextran infusions were
`prone, at times fatally so, to anaphylaxis (13,14). Moreover,
`patients who were given high-dose iron dextran experienced se-
`vere reactions related to either total iron dose or rate of iron
`infusion (15). Two other forms of iron dextran remain available in
`the United States, one of which was introduced recently in Europe
`(Table 1).
`Iron sucrose was first used in 1949 in Europe (8). Iron
`sucrose has been administered in IV push doses up to 200 mg
`over 2 to 5 min and in IV infusion doses up to 500 mg over 2
`to 4 h. Iron sucrose is available in North America, Europe, and
`most countries worldwide.
`To our knowledge, IV administration of ferric gluconate was
`first reported in 1977 (16,17). Ferric gluconate has been ad-
`ministered 125 mg over 10 min and up to 250 mg over 1 to 4 h.
`Ferric gluconate is available in the United States and several
`European countries.
`
`Molecular Weight and Chemistry
`As a result of differences in core size and carbohydrate
`chemistry, IV iron agents differ by overall molecular weight.
`Because molecular mass determinations depend highly on
`method, reported results for a single agent may differ substan-
`tially. Thus, direct comparative studies are best suited to assess
`relative particle sizes of IV iron agents. Two studies provide
`the needed information for the agents in the three generic
`classes considered here: iron dextran Imferon (73 kD), iron
`dextran INFeD (96 kD), and iron dextran Dexferrum (265 kD);
`
`Pharmacosmos, Exh. 1048, p. 1
`
`

`

`S94
`
`Journal of the American Society of Nephrology
`
`J Am Soc Nephrol 15: S93–S98, 2004
`
`Intramuscularuseonly
`
`100mg/2mlWithdrawn
`
`AstraZeneca,UnitedKingdom
`
`68countries
`
`100mg/5ml
`
`ViforInternational,St.Galen,Switzerland
`
`Alsoreferredtoassaccharatediron
`Alsoreferredtoasirondextrin
`
`oxide
`
`Japan
`Withdrawn
`Withdrawn
`
`40mg/2ml
`20mg/ml
`20mg/ml
`
`Yoshitomi,Osaka,Japan
`Neopharma,AschauimChiemgau
`Laevosan,Austria
`
`SouthAmerica,Australia
`
`100mg/2ml
`
`ViforInternational,St.Galen,Switzerland
`
`Israel,Hungary
`
`62.5mg/5mlUnitedStates,Germany,Italy,
`
`Cologne,Germany
`
`Rhone-PoulencRorer,A.Nattermann&Cie,
`WatsonPharmaceuticals,Corona,CA
`
`SeeDexferrum
`
`Introducedin1996
`
`SameasINFeD
`Introducedin1992
`marketsby1996
`
`100mg/2ml
`50mg/1ml
`100mg/2ml
`50mg/1ml
`100mg/2mlUnitedStates
`
`Canada
`
`Canada
`
`Europe(5countries)
`
`100mg/2ml
`100mg/2mlUnitedStates
`
`WithdrawnfromUSmarket1990,other
`
`100mg/2mlWithdrawn
`
`Sabex,Boucherville,Quebec,Canada
`
`AmericanRegent,Shirley,NY
`
`AmericanRegent,Shirley,NY
`Distributor:Nebo,Denmark
`
`Pharmacosmos,Holbæk,Denmark.
`WatsonPharmaceuticals,Corona,CA
`
`LoughboroughLeicestershire,UK
`FisonsLtd.PharmaceuticalDivision,
`
`JapanandotherAsiancountries
`
`40mg/10ml
`
`DainippoinPharmaceutical,Tokyo,Japan
`
`Venofer
`
`Ironsucrose
`
`Jectofer
`
`Ironsorbitol
`
`Fesin
`FerrumVitis
`Ferrivenin
`
`Ironsaccharate
`
`Maltofer
`
`Ironpolymaltose
`
`Ferrlecit
`
`Ferricgluconate
`
`Infufer
`
`DexIron
`
`Dexferrum
`
`Cosmofer
`INFeD
`
`Imferon
`
`Irondextran
`
`Blutal
`
`Notes
`
`Availability
`
`Packaging
`
`Producer/Distributor
`
`GenericClass/TradeName
`
`Table1.Parenteralironagentscitedinpublishedliterature,bygenericclassandcurrentavailability
`
`Chondroitinsulfateironcolloid
`
`Pharmacosmos, Exh. 1048, p. 2
`
`

`

`J Am Soc Nephrol 15: S93–S98, 2004
`
`Chemistry of IV Iron Agents
`
`S95
`
`Table 2. Particle size, core size, and shell carbohydrate in three IV iron agents(20)a
`
`Particle
`
`Core
`
`Diameter
`(nm)b
`
`3 ⫾ 1
`7 ⫾ 4
`30 ⫾ 10
`
`Shape
`
`Spheroid
`Spheroid
`Spheroid
`
`Diameter
`(nm)
`
`2 ⫾ 1
`3 ⫾ 2
`20–35 ⫻ 6d
`
`Shape
`
`Shell Carbohydrate
`
`Spheroid
`Spheroid
`Ellipsoid
`
`Bound gluconate, loosely associated sucrose
`Bound sucrose
`Bound dextran polysaccharide
`
`Ferric gluconate
`Iron sucrose
`Iron dextranc
`
`a IV, intravenous.
`b Mean ⫾ SD.
`c Dexferrum.
`d Major ⫻ minor axes.
`
`(18) and iron dextran Imferon (103 kD), iron sucrose (43 kD),
`and ferric gluconate (38 kD) (19). Together, these results
`establish the relative molecular weight of the currently avail-
`able IV iron compounds to be as follows: iron dextran Dex-
`ferrum ⬎ iron dextran INFeD ⬎⬎ iron sucrose ⬎ ferric
`gluconate.
`Imaging of iron-carbohydrate nanoparticles using atomic
`force microscopy distinguishes the iron-oxyhydroxide core
`from the carbohydrate shell and permits direct determina-
`tion of core size. Atomic force microscopy imaging (20)
`confirms that
`the relative diameters of the overall
`iron-
`carbohydrate particles follow the sequence observed for
`overall molecular weight (iron dextran ⬎⬎ iron sucrose ⬎
`ferric gluconate; Table 2) and further establishes that the
`relative diameters of the mineral cores follow the same
`sequence as those of the complete molecule. This has im-
`portant implications for core surface area available for bio-
`active iron release (Labile Iron, Chapter 3).
`Overall molecular weight affects two biologic characteristics
`of IV iron agents that are directly relevant to therapeutic use in
`patients: Rate of release of iron from the ferric hydroxide core
`and rate of clearance of agent from the plasma after IV admin-
`istration. Iron release in vitro is related to total molecular
`weight in an inverse log-log manner; in short, the smaller the
`particle size, the more rapid the release of iron (19). The
`clinical implications of this effect are related to bioactive iron
`manifestations explored in detail elsewhere (Labile Iron, Chap-
`ter 3).
`
`Pharmacokinetics and Internal Iron Disposition
`After
`IV injection,
`iron-carbohydrate agents mix with
`plasma, then enter the reticuloendothelial system (RES) di-
`rectly from the intravascular fluid compartment. Resident
`phagocytes of the liver, spleen, and bone marrow remove iron
`agent from the circulating plasma. Within phagocytes, iron is
`released from the iron-carbohydrate compound into an LMW
`iron pool. LMW iron either is incorporated by ferritin into
`intracellular iron stores or is released from the cell to be taken
`up by the extracellular iron-binding protein transferrin. Trans-
`ferrin delivers iron to transferrin receptors on the surface of
`erythroid precursors, and the resulting internalization of the
`
`iron-transferrin-transferrin receptor complex supplies iron for
`hemoglobin synthesis and maturation of the red cell.
`The precise cellular events by which iron-carbohydrate com-
`pounds are taken up by RES phagocytes and thereby cleared
`from plasma have not been elucidated. The observation that
`plasma clearance of iron dextran follows first-order kinetics
`after IV doses up to 500 mg but zero-order kinetics at higher
`doses suggests that the clearance mechanism is saturable (Fig-
`ure 1) (21). No information is available on the pharmacokinet-
`ics of iron sucrose after doses ⬎100 mg or ferric gluconate
`⬎125 mg (22).
`The initial volume of distribution of iron sucrose (3.4 L)
`(23), like that of both forms of iron dextran (3.5 L or 55 ml/kg),
`(24) is equivalent to plasma volume. This is further evidence
`that early, direct donation of iron to transferrin is limited and
`relatively inconsequential at
`low iron doses. The reported
`initial volume of distribution of ferric gluconate (6.0 to 6.4 L)
`(22) is approximately twice the plasma space, a result that
`cannot readily be explained.
`The clearance rate of IV iron agents from plasma ranges
`from rapid to very slow, depending on the molecular weight of
`the agent. In general, the lower the overall molecular weight,
`the more rapid the clearance of agent from plasma after an IV
`dose (Figure 2). It is interesting that studies that compared two
`iron dextran agents determined that the agent with the greater
`molecular weight showed the slower plasma iron clearance rate
`and longer half-life in plasma (data on file; American Regent,
`Shirley, NY). Thus, the sequence for plasma half-life follows
`the sequence for molecular weight: iron dextran Dexferrum ⬎
`iron dextran INFeD ⬎⬎ iron sucrose ⬎ ferric gluconate.
`If the rate of uptake of IV iron into the RES depends on
`molecular weight, then the rate of transfer of iron from the RES
`into circulating red cells seems to depend on the severity of
`iron deficiency, the rate of erythropoiesis, or circulating factors
`that influence those disorders. When the patient is profoundly
`iron deficient, incorporation of iron from IV iron agent into red
`cell precursors proceeds rapidly and is relatively complete
`within 2 to 4 wk (5,25). In the absence of evidence of iron
`deficiency, donation of iron from RES to red cells after IV iron
`administration is blunted (26), and in patients with cancer or
`inflammation, little or no erythron iron uptake may occur
`
`Pharmacosmos, Exh. 1048, p. 3
`
`

`

`S96
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`Journal of the American Society of Nephrology
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`J Am Soc Nephrol 15: S93–S98, 2004
`
`(Figure 3) (5,21,27). Sequestration and impaired release of
`both endogenous and external iron from resident macrophages
`of the RES defines RES blockade.
`
`Figure 1. Effect of intravenous (IV) iron dose on plasma disappear-
`ance of 59Fe-labeled iron dextran. At doses up to 500 mg, iron dextran
`disappearance shows first-order kinetics. At higher doses, disappear-
`ance kinetics are zero-order. Although the mechanism of clearance of
`iron-carbohydrate compounds is not known, these results suggest that
`the process can be saturated. Adapted from reference 21.
`
`The precise mechanism of RES blockade is unclear. Hepci-
`din, an iron-regulatory peptide, is released by hepatic paren-
`chymal cells in response to inflammation or iron loading.
`Because hepcidin acts to decrease intestinal iron absorption
`and limit macrophage iron release, it is a likely candidate to
`explain features of RES blockade that characterize iron dispo-
`sition in patients with chronic kidney disease (CKD), that is,
`impaired absorption of oral iron and a low transferrin satura-
`tion despite a high serum ferritin. No information is available,
`however, on the role of hepcidin in patients with CKD. Neither
`are results available on the effect of hepcidin on the fate and
`availability of intravenously injected iron. The amount of iron
`incorporated into circulating red cells subtracted from the dose
`of IV iron administered yields a semiquantitative estimate of
`the remaining, stainable, macrophage iron in bone marrow
`aspirates (21). The finding that iron-deficient patients may
`relapse after IV iron administration despite persistent stainable
`iron in marrow (5,28,29) suggests that some of the injected iron
`remains within cells as hemosiderin or intact, unmetabolized
`iron agent (30), deep forms of iron storage not readily acces-
`sible for erythropoiesis. Given the same iron loading dose,
`experimental animals show higher RES iron levels after iron
`dextran and iron polymaltose than after ferric gluconate and
`iron sucrose, suggesting that the rate of metabolism and utili-
`zation of IV iron may be lower for agents with higher mole-
`cular weights. Whatever the explanation, early iron utilization
`
`Figure 2. Molecular weight and plasma half-life of IV iron agents. Sources for molecular weights include the only available studies that
`compared two or more agents: Lawrence (18), Geisser et al. (19), and Kudasheva et al. (20). Sources for plasma half-life results include the
`following: For iron dextran Dexferrum and INFeD (data on file; American Regent), iron dextran Imferon (21), iron sucrose (25), and ferric
`gluconate (26). The plasma half-life of an IV iron-carbohydrate compound is directly related to its molecular weight.
`
`Pharmacosmos, Exh. 1048, p. 4
`
`

`

`J Am Soc Nephrol 15: S93–S98, 2004
`
`Chemistry of IV Iron Agents
`
`S97
`
`Laboratory Testing. Because iron-carbohydrate com-
`pounds interfere with clinical laboratory determination of se-
`rum iron, it follows from pharmacokinetics that serum iron and
`transferrin saturation should be tested after most or all of the IV
`iron agent has been cleared: No earlier than 7 d after admini-
`stration of a 100-mg dose of iron dextran, 2 wk after a 500-mg
`dose of iron dextran, and 24 to 48 h after a 125-mg dose of
`ferric gluconate or a 100-mg dose of iron sucrose.
`
`References
`1. Heath CW, Strauss MB, Castle WB: Quantitative aspects of iron
`deficiency in hypochromic anemia. J Clin Invest 11: 1293–1312,
`1932
`2. Goetsch AT, Moore CV, Minnich V: Observations on the effect
`of massive doses of iron given intravenously to patients with
`hypochromic anemia. Blood 1: 129 –142, 1946
`3. Nissim JA: Intravenous administration of iron. Lancet 1: 49 –51,
`1947
`4. Fierz F: Contribution concerning the intravenous iron therapy.
`Investigations with Ferrum-Hausmann. Praxis 22: 469 – 472,
`1950
`5. Beutler E: The utilization of saccharated Fe59 oxide in red cell
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`6. Martin LE, Bates CM, Beresford CR, Donaldson JD, McDonald
`FF, Dunlop D, Sheard P, London E, Twigg GD: The pharma-
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`macol 10: 375–382, 1955
`7. Nissim JA: Deposition of iron in the testes after administration of
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`8. Paschen HW: Efficient anaemia treatment with large intravenous
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`9. Samochowiec L: [Experimental studies of enteric absorption of
`sodium ferric gluconate]. Clin Ter 56: 341–345, 1971
`10. Wittmann G: [Treatment of iron deficiency with Ferrlecit 100].
`Med Welt 24: 1141–1144, 1973
`11. McCurdy PR, Rath CE, Meerkrebs GE: Parenteral iron therapy:
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`injection. N Engl J Med 257: 1147–1153, 1957
`12. Marchasin S, Wallerstein RO: The treatment of iron-deficiency
`anemia with intravenous iron dextran. Blood 23: 354 –358, 1964
`13. Becker CE, MacGregor RR, Walker KS, Jandl JH: Fatal ana-
`phylaxis after intramuscular iron-dextran. Arch Intern Med 65:
`745–748, 1966
`14. Zipf RE: Fatal anaphylaxis after intravenous iron dextran.
`J Forensic Sci 20: 326 –333, 1975
`15. Wallerstein RO: Intravenous iron-dextran complex. Blood 32:
`690 – 695, 1968
`16. Hadnagy C, Markus T, Szurkos I: [Sideroblast content of the
`bone marrow at the end of pregnancy or 1st days of puerperium,
`respectively]. Zentralbl Gynakol 99: 1106 –1107, 1977
`17. Hadnagy C, Andreicut S, Binder P: [Geophagia sideropenica].
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`18. Lawrence R: Development and comparison of iron dextran prod-
`ucts. PDA J Pharm Sci Technol 52: 190 –197, 1998
`19. Geisser P, Baer M, Schaub E: Structure/histotoxicity relationship
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`1992
`20. Kudasheva DS, Lai J, Ulman A, Cowman MK: Structure of
`carbohydrate-bound polynuclear iron oxyhydroxide nanopar-
`
`Figure 3. Whole-blood radioactivity after IV injection of 59Fe-labeled
`iron dextran (250 mg) in two anemic patients. Initial iron disappear-
`ance from plasma is similar in the two patients, but reappearance of
`59Fe in circulating red blood cells is both more rapid and more
`complete in the iron-deficient patient compared with the patient with
`lung cancer. Adapted from reference 27.
`
`for erythropoiesis may be variable and incomplete after IV iron
`administration in patients with dialysis-dependent CKD (31).
`In short, the bulk of iron in iron-carbohydrate compounds
`after IV injection passes into RES cells and is either retained
`for later use or released from intracellular compartments to
`extracellular transferrin for delivery to marrow. A small frac-
`tion, however, likely bypasses the intracellular steps and do-
`nates iron directly to transferrin in plasma. Approximately 1 to
`2% of the iron contained in iron dextran is available to bind
`directly to transferrin in vitro (21,32). Although this fraction is
`low compared with that observed for iron sucrose (4 to 5%)
`and ferric gluconate (5 to 6%) (32), it is sufficient to saturate
`unbound iron-binding capacity in vivo (21) after rapid IV
`administration of ⬎500 mg of iron dextran.
`
`Clinical Implications
`Dosing. Differences in pharmacokinetics among IV iron
`agents have direct implications for determining dosing fre-
`quency, treatment duration, and laboratory testing intervals.
`Determining dosing frequency is important if, as in current
`practice, the total prescribed dose (often 1000 mg) is to be
`administered in divided doses. A reasonable dosing frequency
`for iron dextran agents, given plasma half-lives ranging from
`30 to 60 h, would be every 2 to 7 d, a schedule convenient for
`patients who are undergoing hemodialysis (once to thrice
`weekly). However, ferric gluconate and iron sucrose, with 1-
`and 8-h half-lives, respectively, could be given as frequently as
`every 24 h, permitting a dosing frequency more suitable for
`hospitalized patients. To calculate the treatment duration in
`days, divide the total prescribed dose (mg) by the maximum
`tolerated single dose (mg), and multiply by the chosen treat-
`ment interval (days). Again, in practice, actual dosing intervals
`may be longer than minimal for logistical reasons, just as IV
`push doses, although lower than IV infusion doses, may be
`preferred for convenience.
`
`Pharmacosmos, Exh. 1048, p. 5
`
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`26. Ferrlecit Product Package Insert, Corona, CA, Watson Pharma-
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`27. Grimes AJ, Hutt MSR: Metabolism of fe-dextran complex in
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`31. Roe DJ, Harford AM, Zager PG, Wiltbank TB, Kirlin L, Della
`Valle AM, Van Wyck DB: Iron utilization after iron dextran
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`
`Pharmacosmos, Exh. 1048, p. 6
`
`