\
`
`The Treatment of Iron-Deficiency Anemia
`with Intravenous Iron Dextran
`
`By SIDNEY MARCHASIN AND RALPH 0. WALLERSTEIN
`
`I N THE THERAPY of iron-deficiency anemia, iron given orally is safe, ef(cid:173)
`
`fective, inexpensive, and is usually the treatment of choice, but occasional(cid:173)
`ly when a rapid replenishment of iron stores is desired, administration by the
`parenteral route is indicated. Heath, Strauss and Castle, 1
`in 1938, showed
`that when 16-32 mg. of iron as ferric ammonium citrate is injected subcuta(cid:173)
`neously or intramuscularly, practically the total amount is utilized for hemo(cid:173)
`globin formation.
`Two iron compounds, iron ascorbate2 and colloidal ferric hydroxide,3 have
`been given intravenously in doses of 10 mg., but both proved to be unstable
`and toxic. The introduction of saccharated iron oxide4 and dextriferron (iron
`dextrin)G about 15 years ago provided improved preparations for intravenous
`use, for as much as 500 mg. could be injected without causing serious toxic
`reactions. In 1954, a new compound, iron-dextran complex ( lmferon), was
`found to be effective when given intramuscularly.6 Most published accounts
`have dealt with intramuscular administration of this preparation. In one of
`the few reports on the intravenous use of iron dextran, Callender and Smith7
`described toxic reactions in two patients who had been given 50 mg. parenter(cid:173)
`ally, and suggested further study of its administration by the intravenous
`route. The present investigation deals with the intravenous use of iron-dextran
`in very large amounts in 45 patients. Most of the injected iron stayed in the
`blood stream for several hours, was well tolerated and eventually utilized. A
`preliminary report has been published.8
`
`MATERIALS AND METHODS
`
`The subjects consisted of 37 patients with iron-deficiency anemia and eight patients
`with acute gastrointestinal bleeding. The diagnosis in all cases was supported by the
`lack of marrow hemosiderin and usually by the characteristic blood picture, low serum
`iron levels and high total iron-binding capacity. Bone marrow smears were obtained by
`aspiration; hemosiderin was determined as previously described.9 Serum iron was de(cid:173)
`termined by the method of Kok and Wild,10 slightly modified by using 0.2 N hydrochloric
`acid as diluent, and by boiling the specimen for 5 minutes before adding trichloracetic
`acid. Using this method, 1: 10 in vitro dilutions of Imferon in serum gave serum iron con(cid:173)
`centrations of 5119 µg. / ml., which agreed well with the stated Imferon concentration of
`50 mg.{ml., and with values obtained in our laboratory of 50.40 mg./ ml. when undiluted
`Imferon was first digested for 20 minutes in 2 ml. chloric acid.
`
`From the Hematology Research Laboratory, Children's Hospital, and the Hematology
`Unit (San Francisco General Hospital), University of California School of Medicine, San
`Francisco, Calif.
`Supported by grants (2A-5103 and A-2887) from the United States Public Health
`Service.
`Submitted May 20, 1963; accepted for publication. Sept. 17, 1963.
`
`3.54
`
`BLUou, VoL. 23, No. 3 ( MARCH), 1964
`
`Pharmacosmos, Exh. 1005, p. 1
`
`

`

`J
`
`IN'lllAVJ,;NOUS IRON DEXTllAN
`
`3,55
`
`All patients were given undiluted iron-dextran intravenously. The compound was ad(cid:173)
`ministered in a single dose of 200()-3()00 mg. ( 6 patients ) , 1000 mg. ( 18 patients), 100-
`500 mg. ( 7 patients), and in repeated doses of 250-500 mg., 2-4 times in 2 weeks ( 6
`patients) . Iron was given by slow intravenous drip infusion to the first few patients; the
`remainder received the preparation by injection over a 4-10 minute period. One patient
`( F. C.), who had continued blood loss from congenital telangiectasis, received a second
`dose of 3000 mg. 2 months after the first injection. Five of the patients had been treated
`with intramuscularly administered iron-dextran 2-6 months before the intravenous injec(cid:173)
`tion. Eight additional patients with severe acute gastrointestinal bleeding received 500-
`2000 mg. of iron-dextran introduced directly into the transfusion bottle. The patients were
`carefully observed for 48 hours for untoward local or systemic effects and change in vital
`si~rns. Frequent serum iron determinations were made in some cases.
`The concentration of iron in the urine was determined after the administration of iron(cid:173)
`dcxtran in 3 patients.
`
`RESULTS
`No untoward local reactions were observed. Accidental perivascular in(cid:173)
`filtration in one patient caused only minor, transient discomfort. One patient
`developed a delayed systemic reaction, characterized by shaking chills and
`mild abdominal cramps, approximately 8 hours after intravenous injection of
`1000 mg. of iron-dextran; however, she did not develop fever and had no
`objective abdominal signs or symptoms; she had a similar reaction when iron(cid:173)
`dextrnn was again given intravenously 1 week later. None of the other pa(cid:173)
`tients had any discomfort or change in vital signs.
`Serum iron levels usually reached a peak in 10 minutes, then gradually de(cid:173)
`dined from levels as high as 95,000 µ.g. per 100 ml. to 100 µg. per 100 ml. or
`less in 2 to 4 weeks (fig. 1). Serum samples with an iron content in excess
`of 12,000 µ.g. per 100 ml. appeared hrown to the naked eye; concentrations of
`6000 µg . per 100 ml. did not discolor the serum.
`Most of the injected iron could be accounted for in the plasma (table 1).
`For example, in patient F. C., the pretreatment serum iron level was 29 µg./
`100 ml. Immediately after administration of 3000 mg. of iron-dextran, th~
`serum iron level rose to 86,750 µg./100 ml.; at 10 minutes it was 95,000 µg./
`100 ml., at 1 hour 91,000 µg./100 ml., and at 24 hours 78,500 r~g. During th<.•
`first week, the plasma levels decreased in linear fashion at a rate of 525.6 µg./
`hour. At 5 weeks, the serum iron level had fallen to 40 µg. / 100 ml Only 41
`µg. were excreted in the urine during the first 24 hours. In 2 other patients
`urinary excretion of iron was less than 100 µg. per day for 72 hours. Stainable
`iron examined in one patient was present in the hone marrow at 12 hours
`hut not at 6 hours.
`
`DISCUSSION
`Toxic reactions to intravenously administered iron occur when ionized
`iron exceeds plasma iron-binding capacity. Normally transferrin, the iron-bind(cid:173)
`ing beta-2 globulin, can chelate 8 to 10 mg. or iron. Modern iron preparations
`for parenteral use owe their lack of toxicity to the complexing of iron with a
`large, relatively stable colloidal molecule. Iron-dextran 11 is a combination of
`colloidal ferric hydroxide with dextran of a molecular weight of approximately
`
`Pharmacosmos, Exh. 1005, p. 2
`
`

`

`100.000
`
`MARCHASIN AND W ALLERSTEIN"
`
`~1".C,
`- - - S.M.
`0---0 VG
`
`20
`IS
`DAYS
`Fig. 1.-Disappearance rate of serum iron after intravenous administration of
`iron-dextran.
`
`25
`
`30
`
`35
`
`0
`
`5
`
`10
`
`2000 to 8000. The solution contains 5 per cent iron and has a pH of 6. The
`complex is a weakly negatively charged molecule, whose stability, in con(cid:173)
`trast to saccharated iron oxide, does not depend on an absorbed layer of
`strongly charged irons. Clinically, the stability of iron dextran is demonstrated
`by the lack of untoward symptoms even when plasma iron levels are extremely
`high. Despite these levels, iron is not lost in urine and stool in significant
`amounts, and appears in the marrow only after 6-12 hours. Early plasma Ie,·els
`can account for practically all the injected iron (table l); it probably is re(cid:173)
`moved slowly by the reticuloendothelial cells.
`The indications for the intravenous use of iron-dextran are similar to those
`for the intramuscular route. Parenteral iron may be given to patients who
`are ( l) unwilling to take iron by the oral route, ( 2) unable to tolerate it
`well (e.g., patients with peptic ulcer, regional ileitis or ulcerative colitis),
`( 3 } unable to absorb iron well (e.g., in sprue ) , and ( 4 ) to patients who lose
`relatively large amounts of blood from gastrointestinal lesions that are not
`amenable to surgical treatment (e.g., congenital telangiectasia, inoperable
`cancer and blood loss of obscure origin). Occasionally, parenteral iron may
`be used in patients who fail to respond to oral administration; in these individ-
`
`Pharmacosmos, Exh. 1005, p. 3
`
`

`

`INTRAVENOUS IRON DEXTRAN
`
`357
`
`Table 1.-Serum Iron Levels after Intravenous Administration of Iron-Dextran
`Patient
`
`Weight in Kg.
`Estimated plasma volume in ml.
`Mg. of iron administered
`Predicted peak in µ.g.
`Actual peak in µ.g.
`Per cent of peak value
`
`F. C.
`57.3
`2,865
`3,000
`104,700
`86,750
`62.4
`
`S.M.
`53
`2,650
`1,500
`56,600
`48,900
`87
`
`R.M.
`54
`2,700
`1,000
`37,050
`24,250
`78
`
`E.C.
`50
`2,500
`2,000
`80,000
`81,000
`101
`
`V.G.
`57
`2,850
`2,000
`70,200
`54,000
`77
`
`uals it is imperative to make a thorough re-evaluation of the diagnosis before
`proceeding with parenteral therapy. The intravenous route has some ad(cid:173)
`vantage over intramuscular injection in ( 1) bedridden, immobilized patients
`who have greatly reduced lymph flow and decreased absorption of iron-dex(cid:173)
`tran from the muscle depot, ( 2) asthenic patients without much muscle mass,
`( 3 ) patients requiring multiple, relatively large injections of iron who find
`that intramuscular administration causes discomfort, and ( 4) patients with
`severe blood loss from idiopathic thrombocytopenic purpura who may have
`tissue bleeding after intramuscular injections.
`
`SUMMARY
`Iron-dextran, in doses up to 3000 mg., was administered intravenously by
`single injection to 37 patients with iron deficiency and to 8 additional pa(cid:173)
`tients with acute gastrointestinal bleeding. No serious untoward effects were
`observed. One patient developed chills and mild abdominal cramps 8 hours
`after injection. Most of the iron could be accounted for in the circulating
`blood immediately after the injection. Iron was cleared from the plasma slowly
`for 3 weeks after the administration. lron-dextran appears to be a safe and
`well-tolerated intravenous preparation. It is especially useful in the treatment
`of iron-deficiency in immobilized patients and individuals with sma1l muscle
`mass.
`
`SuMMARIO IN INTERLINGUA
`Dextrano a ferro, in doses de usque a 3.000 mg, esseva administrate per via
`intravenose in injectiones unic a 37 patientes con carentia de ferro e a 8
`patientes additional con acute sanguination gastrointestinal. Nulle serie effectos
`adverse esseva observate. Un del patientes disveloppava algor e leve grados de
`crampas abdominal 8 horas post le injection. Le plus grande parte del ferro
`poteva esser retraciate in le circulation de sanguine immediatemente post le
`injection. Ferro esseva catabolisate ex le plasma lentemente durante 3 septi(cid:173)
`manas post le administration. Dextrano a ferro pare esser un salve e ben(cid:173)
`tolerate preparato intravenose. Illo es particularmente utile in le tractamento
`de carentia de ferro in immobilisate patientes e subjectos con minime massas
`muscular.
`
`ACKNOWLEDGMENT
`\Ve are grateful to Miss Joyce Atkinson for performing th!' iron determinations.
`
`Pharmacosmos, Exh. 1005, p. 4
`
`

`

`358
`
`MARCHASIN AND W ALLERSTEI.N
`
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`
`Sidney Marclwsin, M.D., U.S.P.H.S. Hematology Trainee,
`Hematology Research Laboratory, Children's Hospital, and
`the Hematology Unit (San Francisco GeneTal Hospital), Uni(cid:173)
`versity of California, School of Medicine, San Francisco, CaUf.
`
`Ralph O. Wallerstein, M.D., Hematology Research Laboratory,
`Children's Hospital, the Hematology Unit (San Francisco
`General Hospital), Associate Clinical Professor of Medicine,
`Universitl.J of California. School of Medicine, San Francisco,
`Calif.
`
`Pharmacosmos, Exh. 1005, p. 5
`
`