NU RI
`
`ION-
`
`)
`
`THE INTERNATIONAL JOURNAL OF
`APPLIED AND BASIC NUTRITIONAL SCIENCES
`
`Volume 11
`
`Translated Abstracts
`
`Marchi April
`
`1995
`
`* Editorial Comments
`
`II
`
`Number
`
`2
`
`and Nutrition
`
`Current Concepts in Clinical Nutrition
`Nutritional Considerations
`and Management
`of the Child
`with Human Immunodeficiency
`Virus Infection
`ROBIN A. HENDERSON,
`PHD. RD. AND JOSE M. SAAVEDRA, MD
`
`121 *
`
`*
`
`Applied Nutritional Investigations
`Small Intestinal Malabsorption
`and Colonic
`Fe~entation
`of Resis~ant Starch ,and Resistant
`129
`Peptides
`to Short-Cham Fatty Acids
`tNGE NORDGAARD. MD. PER BR0BECH MORTENSEN. MD. PHD.
`AND ANNA MARlA LANGKILDE, MD
`Leucine Metabolism and Body Cell Mass in
`Cystic Fibrosis
`ROSS W. SHEPHERD. MD. TERRY L. HOLT. PHD.
`LESLIE P. JOHNSON.
`PHD. PAUL QUIRK. BSC. AND
`BRIAN J. THOMAS.
`PHD
`WarIarin and Reduced Central Venous Thrombosis
`in Home Total Parenteral Nutrition Patients
`MANJAKKOLLAt
`P. VEERABAGU. MD.
`JANET TUTTLE·NEWHALL.
`MD. ROY MALIAKKAL. MD.
`RN. AND EDWARD A. MASCIOLI, MD
`CHARLOTTE CHAMPAGNE,
`A Simple Technique
`to Reduce Ventilator-Dependent
`Errors in Oxygen Consumption Measurements
`ROLAND N. DlCKERSON.
`PHARMD.
`JAMES E. MURRELL, CRTI,
`REX O. BROWN. PHARMD. KENNETH A. KUDSK. MD. AND
`KENNETH V. LEEPER,
`JR, MD
`
`138
`
`142
`
`145*
`
`Basic Nutritional Investigations
`Glycerol Gluconeogenesis
`in Fasting Humans
`HIDEFUMI BABA. MD, XIAO-JUN ZHANG, MD, AND
`ROBERT R. WOLFE. PHD
`A Significant Methotrexate-Glutamine
`Pharmacokinetic
`Interaction
`SCOlTL.
`CHARLAND.
`PHARMD. DAVID L. BARTLETT. MD,
`AND MICHAEL H. TOROSIAN, MD
`
`149
`
`154*
`
`International Ward Rounds in Clinical Nutrition
`Metabolic Management
`of Hyper- and Hypocalcemia
`.... 159
`SHEEBA BALAN. BSC, KRISHNAN SRlRAM, MBBS, FRCS(C), FACS,
`AND V. JAYANTHI. MSC
`
`Review Article
`Parenteral
`Iron Dextran Therapy: A Review
`DAVID L. BURNS. MD. EDWARD A. MASCIOLI. MD. AND
`BRUCE R. BISTRIAN. MD. PHD
`
`Roundtable
`in Assessing
`of Visceral Protein Status
`Measurement
`and Energy Malnutrition:
`Standard of Care Prealbumin
`in Nutritional Care Consensus Group*
`
`*For an additional perspective,
`
`see Editorial Comments
`
`.163
`
`Protein
`
`169
`
`Pediatric Gastroenterology
`JAY A. PERMAN, MD
`of Starch and Protein:
`Colonic Fermentation
`An End to All Resistance?
`GEORGE GRIMBLE. MD
`Possible Mechanism(s)
`of Glutamine-Mediated
`Protection
`v. SUZANNE KLIMBERG. MD
`Technical Aspects of Metabolic Measurements
`RICHARD D. BRANSON. RRT
`Clinton Health Care Reform •.•The Inside Track
`Carrots and Sticks
`177
`GREGG S. MEYER. MD, MSC
`Public Policy and Nutrition Practice
`To Keep Jane WelI...She Needs
`Integrated
`Patient-Centered
`Care
`ALISON B. KJNG. PHD
`Random Bytes
`Simple Linear Regression Correlation
`MARCELLO PAGANO. PHD
`NutritionlMetabolism Classic With•..
`Neuropsychiatric
`Disorders Caused by Cobalamin
`Deficiency
`in Absence of Anemia or Macrocytosis
`I. LINDENBAUM.
`B.B. HEALTON, D.G. SAVAGE,
`I.C.M. BRUST.
`T.!. GARRETI,
`E.R. PODELL.
`P.O. MARCELL,
`S.P. STABLER,
`R.H. ALLEN
`... Prospective Overview
`NORMAN G. EGGER. MD, AND KARL E. ANDERSON. MD
`1994 John M. Kinney Annual International
`Award for Nutrition and Metabolism
`Book Reviews
`•..And In the Next Issue
`Contents of Sister Journals
`Calender of Events
`Guidelines for Publishing Symposium
`Proceedings
`Supplement
`Years Later:
`The Skeleton in the Hospital Closet-20
`Malnutrition
`in Patients with OI Disease, Cancer
`and AIDS
`
`172
`
`173
`
`175
`
`176
`
`Host
`
`178
`
`179
`
`181
`
`180
`
`183
`
`187
`
`153
`
`.189
`
`190
`
`VI
`
`191
`
`PGR2020-00009
`Pharmacosmos A/S v. American Regent, Inc.
`Petitioner Ex. 1030 - Page 1
`
`

`

`REVIEW ARTICLE
`
`Nutrition Vol. II, No.2, 1995
`
`Parenteral Iron Dextran Therapy: A Review
`
`DAVID L. BURNS, MD, EDWARD A. MASCIOLI, MD, AND BRUCE R. BISTRIAN, MD, PHD
`
`of Medicine, New England Deaconess Hospital,
`From the Nutrition Support Service, Department
`Harvard Medical School, Boston, Massachusetts, USA
`
`Date accepted: 30 November
`
`1994
`
`ABSlRACT
`treatment of iron deficiency anemia that is refractory to
`Iron dextran was introduced more than 30 yr ago for the parenteral
`Iron dextran is a preparation of ferric hydroxide complexed with a low molecular weight fraction of dextran.
`oral therapy.
`Iron
`deficiency anemia is one of the most common nutritional deficiency diseases and occurs worldwide secondary to inadequate
`dietary iron, usually with excessive gastrointestinal blood losses. Repletion of iron stores is often complicated by intolerance to
`oral
`iron supplementation
`and may require parenteral
`iron. Parenteral
`iron can be administered via the intramuscular or
`intravenous route either directly or as an additive to total parenteral nutrition. Both routes of administration can cause various
`side effects and a test dose is recommended before therapeutic administration to assess the risk for anaphylaxis. Although the
`efficacy and safety of parenteral
`iron dextran have been convincingly demonstrated, supplementation may be contraindicated in
`the setting of infection. Nutrition 1995; 11:163-168
`
`Key words: iron, dextran, iron deficiency, total parenteral nutrition, infection, side effects
`
`INTRODUCTION
`Iron dextran first became available in 1952 and was initially
`administered to children with iron deficiency.
`Iron dextran was
`hailed as effective
`and safe therapy that could be administered
`regardless of the patient's
`ability to take oral
`iron supplements.
`The drug was administered intramuscularly
`by multiple injections
`with a low incidence of adverse reactions.
`In 1963, Basul' was
`the first
`to describe total dose infusion (TDI) of iron dextran to
`replenish iron stores completely with one parenteral dose of iron.
`In 1973,
`the Food and Drug Administration
`approved
`the
`intravenous
`route of administration
`of iron dextran for patients
`with documented iron deficiency.
`and low
`hydroxide
`of ferric
`Iron dextran
`is a complex
`The dextran
`molecular mass (5,000 to 10,000 daltons) dextran.
`iron dextran
`serves as a protective
`lipophilic colloid.
`Parenteral
`is commercially
`available
`as a sterile solution
`containing
`50 g
`elemental
`iron/L that is predominantly
`in the ferric state.
`It is
`Iron deficiency
`is the most common cause of anemia.
`estimated that >500 million people worldwide
`are iron deficient
`-20 million
`with
`in the United
`States
`alone.?
`Chronic
`gastrointestinal blood loss is the most prevalent etiologic factor in
`adults with iron deficiency anemia. Other
`factors
`include iron-
`poor diets,
`impaired iron absorption, and in hospitalized
`patients,
`nosocomial
`anemia from repeated phlebotomy.v'
`The mainstay
`of therapy is repletion of iron stores through the oral or parenteral
`route although diagnosis,
`and where indicated,
`treatment of the
`underlying etiology are essential.
`
`DIAGNOSIS OF IRON DEFICIENCY
`by
`of iron deficiency
`is made serologically
`The diagnosis
`noninvasive means and is characterized
`by three phases.
`Initially,
`iron store depletion
`is associated
`with increased
`gut
`iron
`absorption,
`decreased
`serum iron,
`increased
`serum transferrin,
`and decreased serum ferritin. This is followed by iron-deficient
`erythropoiesis
`that
`is associated with a serum iron to transferrin
`saturation
`<16%, an erythrocyte
`protoporphyrin
`concentration
`<100 mglL, and a serum ferritin concentration <12 ~gIL without
`recognizable
`anemia. The third phase is iron deficiency anemia,
`characterized
`by hypochromic,
`microcytic
`red blood celIs.5,6
`Classically,
`the histopathological
`diagnosis of iron deficiency is
`based on the absence of stainable iron in the bone marrow.
`
`IRON BALANCE AND ABSORPTION
`iron is -4-5 g with
`a daily
`body content
`of
`total
`The
`of 1 mg absorbed/day
`in normal men and normal,
`requirement
`nonmenstruating women.
`Iron requirements
`are based on daily
`obligate
`losses
`from the skin, desquamation
`of gastrointestinal
`mucosal cells, and microscopic bleeding from the gut and kidney.
`During menstruation,
`iron losses may increase by an additional
`I
`mg/day.
`The average dietary iron intake in the United States is 5-7 mg
`per 1000 kcaI. Healthy people absorb 5-10% of dietary iron:
`the
`Recommended
`Dietary Allowance
`(RDA)
`is 15 mg.
`In iron
`deficiency
`or in late pregnancy,
`absorption
`can increase
`to
`10-20% or 4-6 rug/day." The recommended
`daily dose for oral
`to maximally replete iron stores is 180-220
`iron supplementation
`
`. Correspondence to: E. A. Mascioli, MD, New England Deaconess Hospital, 194 Pilgrim Road, Boston, MA 02215, USA.
`
`163
`
`PGR2020-00009
`Pharmacosmos A/S v. American Regent, Inc.
`Petitioner Ex. 1030 - Page 2
`
`

`

`164
`
`TABLE!.
`
`INDICATIONS FOR PARENTERAL IRON DEXTRAN
`
`Indications
`syndrome
`Malabsorption
`Short bowel syndrome
`Chronic bowel obstruction
`Inflammatory bowel disease
`Long-term total parenteral nutrition
`Chronic. uncorrected bleeding
`Hemodialysis. particularly with erythropoietin treatment
`Relative indications
`High intake of antacids,
`Oral iron intolerance
`Noncompliance with oral regimen
`
`tea, or clay
`
`iron. but this may be limited by gastrointestinal
`mg elemental
`intolerance. Thus. with supplementation,
`iron absorption can be
`increased to a maximum of 40-50 mg/day, which is given most
`commonly as ferrous sulfate in 325-mg tablets that contain -60
`mg elemental
`iron. Different
`salts of oral
`iron exist, but side
`effects are due [0 the amount of oral iron and not to the salt.
`In the acidic medium of the stomach,
`inorganic
`iron is
`solubilized,
`ionized to the ferrous form, and chelated. Ascorbic
`acid, amino acids, and some sugars promote iron absorption by
`forming iron chelates
`that are taken up by the small bowel."
`Impaired gastric acid secretion occurs in elderly patients as the
`result
`of age-related
`achlorhydria
`and in patients
`after
`gasrrecromles.!
`Such individuals have impaired iron absorption
`that is related to decreased solubilization and chelation of dietary
`iron.
`in the duodenum and
`is most efficient
`Iron absorption
`iron is more readily
`Divalent
`ferrous
`proximal
`jejunum.
`ferric iron because of its low solubility at
`adsorbed than trivalent
`the alkaline pH of intestinal
`fluid. Once ferrous iron traverses
`the mucus layer to the mucosal brush border,
`it is oxidized to the
`ferric form.
`Iron absorption consists of two phases: uptake of
`luminal
`iron into small bowel mucosal
`cells and subsequent
`release into the circulation.
`Ferric iron in the plasma is taken up
`in a ratio of two iron molecules per molecule of
`by transferrin
`transferrin,"
`and heme
`in hemoglobin, myoglobin,
`Heme iron, present
`Iron.''' This is
`enzymes,
`is better absorbed
`than is elemental
`related to a different mechanism of absorption.
`Heme can be
`directly taken up by the mucosal cells after globin is removed.
`Lower
`socioeconomic
`populations
`such as in the Third World
`often have diets that are poor in heme iron, resulting in reduced
`iron availability. 11
`system release iron
`in the reticuloendothelial
`Macrophages
`red blood cells to
`resulting
`from the destruction
`of senescent
`80-90% of iron
`transferrin
`for reutilization.
`Approximately
`bound to transferrin is destined for hemoglobin production within
`for I mg of the
`t~e ery~ro?Iast.6
`Dietary absorption accounts
`cIrculat~ng Iron p~ol of 30--35 milligrams that cycles daily.
`to
`~adlOlabeled non dextran injected into patients
`localizes
`the liver, spleen, and sacrum before being incorporated into red
`cell hemoglobin. The half-life for clearance of radiolabeled iron
`dextran from the serum of iron-deficient
`subjects ranges from 5.9
`h to 2.5 days, and -40% is bound to transferrin within 11 h. The
`rate of plasma
`clearance
`is unrelated
`to the degree of iron
`deficiency.I':'!
`
`PARENTERAL IRON DEXTRAN THERAPY
`
`IRON
`FOR PARENTERAL
`INDICATIONS
`The oral route of iron therapy is preferred to the parenteral
`route on the basis of ease of administration, much reduced cost,
`and fewer
`side effects.
`Table I lists common conditions
`that
`often require parenteral
`iron dextran treatment.
`The principal
`indication for parenteral
`iron dextran is the failure to respond to
`oral
`iron supplementation
`in patients with iron deficiency
`anemia.
`Common
`reasons
`for
`failure
`include
`poor
`iron
`absorption,
`oral
`intolerance
`usually
`related
`to significant
`or
`gastrointestinal
`side effects
`such as severe
`constipation
`of
`diarrhea, and patient noncompliance.
`Extensive consumption
`gut
`antacids,
`clay,
`tea, coffee,
`or phytates
`in bran inhibit
`iron
`absorption
`and may reduce
`the efficacy
`of enteral
`or
`therapy.
`13.14 As previously
`mentioned,
`achlorhydria
`gastrectomy
`reduce
`dietary
`iron
`availability.
`Dietary
`manipulation with exclusion of these inhibitors of iron absorption
`and attention to gastrointestinal
`intolerance may improve oral
`iron compliance
`and absorption,
`thus avoiding
`the risks of
`parenteral supplementation.
`Hypoproliferative
`anemia is a common side effect of end-
`stage renal disease in patients undergoing hemodialysis
`and it is
`secondary to decreased
`endogenous
`erythropoietin
`production.
`Hemodialysis
`results
`in chronic blood loss with a negative
`iron
`of 1-2 g/yr.
`balance
`Patients
`with
`uremia may
`have
`gastrointestinal
`intolerance
`to oral
`iron repletion and restoration
`of hemoglobin
`to the normal
`level may necessitate
`parenteral
`supplementation.
`IS This need has become particularly
`apparent
`therapy."
`during the era of recombinant
`human erythropoietin
`Finally,
`iron dextran may be indicated
`for patients
`with
`significant blood loss after major surgery. Many such patients
`are unable to tolerate
`sufficiently
`rapid oral
`repletion
`or may
`decline red cell transfusions despite requiring rapid restoration of
`
`TABLE II.
`
`SIDE EFFECTS AND COMPLICATIONS OF
`PARENTERAL IRON DEXTRAN
`
`Short-term (intramuscular or intravenous administration)
`Anaphylaxis
`Urticaria
`Hypotension
`Nausea or emesis
`Bronchospasm
`Pruritus
`Fever
`Seizures
`Arthralgia
`Headache
`Myalgia
`Flushing
`Lymphadenopathy
`Phlebitis
`Chest, back, or abdominal pain
`Rigors
`Long-term
`Iron overload (intravenous and intramuscular)
`Complications of intramuscular administration
`Chronic pain at the site of injection
`Skin staining
`Local skin atrophy
`Abscess
`Sarcoma formation
`
`PGR2020-00009
`Pharmacosmos A/S v. American Regent, Inc.
`Petitioner Ex. 1030 - Page 3
`
`

`

`r
`
`PARENTERAL IRON DEXTRAN THERAPY
`
`iron stores for hemoglobin production.
`
`ADVERSE EFFECTS
`and
`to iron dextran infusion are variable
`reactions
`Adverse
`can be graded
`from mild or transient
`to severe
`or even life-
`threatening
`anaphylaxis
`(Table
`II). Most
`reactions
`occur
`immediately
`during administration
`of the test dose and may
`include dyspnea; headache;
`flushing;
`chest, abdominal,
`or back
`pain;
`nausea;
`emesis;
`bronchospasm;
`fever;
`seizures;
`hypotension;
`urticaria;
`and anaphylaxis.
`Delayed
`reactions
`occurring 1-3 days later
`include myalgia,
`arthralgia,
`phlebitis,
`and lymphadenopathy.
`reviewed the existing literature on 2400
`In 1968, wallerstein'"
`patients who received intravenous
`iron dextran and reported an
`overall adverse reaction rate of 1-2%. The intramuscular
`and
`intravenous
`routes of administration
`had similar
`incidences
`of
`side effects.
`In addition
`to acute
`systemic
`adverse
`effects,
`rhabdomyolysis
`and late sarcoma formation have been reported
`with intramuscular
`iron dextran administration.Jv'?
`Hamstra et a1.15studied 481 patients given an intravenous
`iron
`dextran dose of 250-500 mg at a rate of <I00 mg/min. Overall,
`125 patients
`(26%) experienced
`a reaction, most of which were
`mild. Eight were delayed reactions
`characterized
`by arthralgia,
`myalgia,
`fever,
`adenopathy,
`thrombophlebitis,
`pulmonary
`embolism,
`or erythema
`nodosum.
`Three
`of 481 patients
`developed life-threatening
`anaphylactoid
`reactions
`characterized
`by hypotension,
`cyanosis,
`syncope, bronchospasm,
`purpura, and
`respiratory
`arrest.
`Severe reactions were associated with large
`iron doses given to small patients and were also more frequent
`in
`women with collagen vascular disease."
`to exacerbate
`TDIs of iron dextran
`have been reported
`symptoms of rheumatoid
`arthritis and collagen vascular disease
`and have been associated with a greater
`incidence of anaphylaxis
`In a study of 11 patients with
`in patients with these conditions.
`rheumatoid arthritis who were given TDIs, Blake et a1.20found
`that
`two patients
`had anaphylactic
`reactions
`and nine had an
`exacerbation of synovitis.
`to have induced
`has been reported
`Iron dextran
`infusion
`systemic
`lupus erythematosus
`in a patient with a history
`of
`polyarthritis
`but no serologic
`evidence
`of lupus;"
`After
`intravenous
`administration
`of iron dextran,
`the patient developed
`a malar
`rash, polyarthritis,
`periungual
`vasculitis,
`elevated
`erythrocyte
`sedimentation
`rate, positive antinuclear
`antibody, and
`antidouble stranded DNA antibody. The proposed mechanism of
`the increased likelihood of adverse reactions
`to iron dextran in
`patients with collagen vascular disease include a hypersensitivity
`to dextran, a toxic effect of iron on synovium by generation of
`free
`radicals
`and
`peroxidation
`of
`lipids,22,23
`and
`reticuloendothelial
`system blockade
`resulting
`in a secondary
`immune complex synovitis."
`Auerbach
`et aJ.25 studied 87 patients with iron deficiency
`anemia and absent bone marrow iron stores
`to define
`adverse
`reactions and the optimal
`rate of infusion of TDIs and to assess
`the role of premedication.
`Two patients
`had anaphylactoid
`reactions
`in response
`to the test dose.
`Their
`symptoms were
`relieved with intravenous diphenhydramine, methylprednisolone,
`and subcutaneous
`epinephrine. Delayed transient
`reactions
`such
`as myalgia, arthralgia, and fever occurred in 37 patients and were
`controlled with nonsteroidal
`anti-inflammatory
`agents.
`The
`group concluded that
`the TDI method was safe if there was no
`reaction to the test dose and the infusion rate did not exceed 6
`mg/min. Premedication was not necessary for the relatively low
`incidence
`of severe
`side
`effects,
`but diphenhydramine,
`epinephrine, and methylprednisolone
`should be available.
`is
`The incidence
`of anaphylactic
`reactions
`to iron dextran
`variable and ranges from 0.6% to 2.3%, whereas the incidence of
`
`165
`
`at 0.2% to 0.3%.26
`is estimated
`reactions
`acute hypersensitivity
`Patients with underlying rheumatoid
`arthritis or collagen vascular
`disease
`are at greater
`risk for severe systemic or anaphylactoid
`reactions.
`
`IRON DEXTRAN ADMINISTRATION
`IN1RAMUSCULAR
`or
`Parenteral
`iron can be administered
`either
`intramuscularly
`is limited to 2 ml or
`intravenously.
`Intramuscular
`administration
`100 mg iron per
`injection
`and patients
`often require multiple
`doses
`to replete
`iron stores.
`Iron dextran manufacturers
`recommend
`that
`all patients
`receive
`a 0.5 ml
`(25 mg)
`intramuscular
`test dose
`before
`therapeutic
`iron
`dextran
`administration.
`A period y 1 h of observation
`should
`elapse
`before therapeutic
`dosing. Both the test and therapeutic
`doses
`should be given by deep intramuscular
`injection into the buttock
`via the Z-track
`technique
`(displacement
`of the skin laterally
`before injection).25,27
`should be avoided in patients
`Intramuscular
`administration
`with coagulation
`defects or inadequate muscle bulle Generally
`patients may experience
`local
`symptoms
`of persistent
`pain,
`subcutaneous
`atrophy,
`skin staining,
`necrosis,
`sterile
`abscess
`formation, or late occurrence of sarcoma in addition to systemic
`effects.18,28
`side
`Because
`of
`local
`complications
`and
`unpredictable
`intramuscular
`absorption,
`the American Medical
`Association Drug Evaluations
`discourages
`intramuscular
`iron
`dextran administration
`in favor of the intravenous
`route."
`
`IRON DEXTRAN ADMINISTRATION
`INTRAVENOUS
`Iron dextran can be administered
`intravenously
`as undiluted
`injection, or as a TDI or an additive to total parenteral nutrition
`(TPN). Undiluted iron dextran is given with a test dose of I to 2
`drops (-2 mg) followed in 15 min by an additional
`test dose of
`25 mg (0.5 ml).
`If no reaction is evident, a total of 100 mg (2 ml)
`may be given daily at a rate <50 mg/min (I mllmin).
`of the total
`If
`larger
`iron doses
`are required,
`infusion
`calculated dose should be done as a single administration. A TOI
`of iron dextran is the dose of iron required to replete iron stores
`in one infusion. The dose of iron required to replenish stores and
`to normalize
`hemoglobin
`(Hb)
`is calculated
`by the following
`equation."
`
`Iron (mg) ; 0.3 x weight (Ibs) x
`[100 - (actual Hh (g/dl) x 100)/desired Hh]
`
`in 500-1000 ml
`be diluted
`dose should
`The therapeutic
`in water. A few milliliters
`physiologic
`saline or 5% dextrose
`should be slowly infused as a test and if no reaction occurs after
`15 min observation,
`the solution can be administered at a rate of
`1 Lover
`4-6 h. Because
`of the small but significant
`risk of
`anaphylaxis,
`patients should be observed closely. Manufacturers
`recommend
`that emergency medications
`including
`epinephrine
`equipment be readily available.26,27.29
`and resuscitative
`
`EFFICACY OF IRON DEXTRAN TOTAL DOSE INFUSION
`Ashby'? gave TDIs of iron dextran to 79 surgical patients with
`iron deficiency anemia:
`the range of iron doses was not specified,
`nor was a control group available.
`Initial average hemoglobin
`concentration was 83 gIL, which increased
`significantly
`to 125
`gIL 30 days after
`iron infusion.
`No serious
`adverse
`reactions
`occurred, but two patients did report
`transient arthralgias.
`with
`Iron
`deficiency
`anemia
`is common
`in children
`TDIs
`inflammatory
`bowel disease. Halpin et aJ.33 administered
`and
`of
`iron dextran
`to six children
`with Crohn's
`disease
`ulcerative
`colitis after correction
`of weight
`loss and nutritional
`deficiencies with TPN. The children tolerated the infusion with
`no reactions.
`The doses
`ranged from 275 to 840 mg elemental
`
`PGR2020-00009
`Pharmacosmos A/S v. American Regent, Inc.
`Petitioner Ex. 1030 - Page 4
`
`

`

`e_
`
`G
`
`- 11'
`
`166
`
`PARENTERAL IRON DEXTRAN THERAPY
`
`iron. All patients achieved a satisfactory increase in hemoglobin
`with an average rise of 35 gIL.
`and
`gynecologic
`51 surgical.
`Mays and Mays34 studied
`obstetric patients with depleted iron stores. TDls ranged from
`1000 to 4500 mg elemental
`iron. One week after infusion the
`was 19 gIL. No adverse
`average
`increase
`in hemoglobin
`reactions were reported.
`
`added to TPN in six patients with
`iron dextran
`of high-dose
`massive
`acute blood loss and in two patients with chronic
`anemia. The maximum dose of iron dextran per liter of TPN was
`500 mg and the maximum total iron dose administered was 7000
`mg over 5 days in this series. The acute blood loss group had an
`average increase in hemoglobin of 56 gIL over 23 days, and the
`chronic anemia patients had an increase of 68 gIL over 121 days.
`
`CONSIDERATION OF IRON
`PHARMACOLOGIC
`SUPPLEMENTATION
`OF TPN
`Commercially available trace elements are routinely added to
`TPN admixtures.
`In the United States, commercial
`trace element
`formulations do not contain iron, however, products available in
`Europe may contain 1-2.5 mg.
`studied TPN admixtures of
`In 1978, Hauer and Kaminski"
`dextrose,
`lipid, and water
`amino acids in protein hydrolysates,
`and found that
`the concentration
`of iron varied from 0.025 to
`1.370 mg/L, which may have been related to contamination
`in
`production.
`Sayers et at.36 tested the addition of ferrous citrate to
`TPN.
`In vitro iron citrate was stable in TPN and was available to
`transferrin, with a mean availability in vivo of 81%. Wan and
`Tsallas37 in 1980 demonstrated stability over a period of 3 rna of
`diluted iron dextran at a concentration of 0.5 mg/ml with benzyl
`alcohol.
`TPN solutions containing lipid or three-in-one admixtures are
`subject
`to physicochemical
`restrictions.
`All commercially
`available lipid preparations use an anionic egg yolk phosphatide
`emulsifier. Care should be taken when adding trivalent cations
`such as ferric iron to three- in-one admixtures, The surface charge
`of Iipid particles can be neutralized,
`causing breakdown of the
`admixture,
`coalescence
`of the lipid droplets,
`and cracking or
`creaming
`of
`the lipid
`component.
`38 Recommendations
`concerning the compatibility
`of iron in three-in-one
`admixtures
`vary between
`the two major American
`providers
`of lipid
`emulsion.
`At our institution,
`lipid-containing
`TPN has been
`limited to 2 mg iron dextran per bag, and 10 rug in nonlipid bags,
`although this is an area of current
`investigation.
`
`EFFICACY OF IRON DEXTRAN
`SUPPLEMENTATION
`IN TPN
`support of patients
`TPN is a valuable tool. for the nutritional
`who are unable to tolerate sufficient enteral nutrition, The daily
`recommendation
`for parenteral
`iron supplementation ranges from
`0.5 to 3.9 mg/day.39-41 Patients who are nutritionally
`replete
`before initiation
`of TPN may develop a negative iron balance
`with depletion of iron stores. This is due to an estimated loss of 1
`mg iron daily in normal adults with the additional
`contribution
`from blood Joss due to surgery or phlebotomy."
`Norton et al.43 prospectively
`studied 42 patients
`receiving
`TPN to evaluate the optimal
`iron dextran dose to restore serum
`Four treatment groups received either 0, 25,
`iron concentrations.
`97.5,
`or 175 mg iron weekly
`in their
`TPN.
`Before
`supplementation with TPN, all four groups had low serum iron
`concentrations,
`total iron binding capacity, and hemoglobin.
`The
`patients
`supplemented with 87.5 and 175 mg/wk had increased
`after 3 wk of TPN. However, 80% of
`serum iron concentrations
`the group receiving 175 mg/wk had serum iron concentrations
`greater than the upper
`limit of normal. No untoward reactions
`occurred and no significant
`increase in the risk of infection was
`observed. They concluded that 87.5 mg iron supplemented
`in
`TPN per week was safe and consistently
`raised serum iron
`concentrations
`to the normal range over a 3-wk period.
`.Poner et al." demonstrated the relative safety of lower doses
`?f iron dextran (~ mg/day) in TPN. in a patient
`intolerant
`to rapid
`iron dextran adrmmstration. Dudnck et al.45 investigated the use
`
`IRON OVERLOAD
`in excess iron
`The improper administration
`of iron can result
`administered
`stores. The body's
`ability to excrete parenterally
`iron is limited,
`and the reticuloendothelial
`system sequesters
`excess iron, resulting in hepatosplenic
`siderosis.
`Iron overload
`has been observed
`in hemodialysis
`patients
`and in long-term
`home TPN patients receiving modest doses (2 mg) of daily iron
`(D.B., personal communicauonj.w"
`
`IRON AND INFECTION
`is
`and iron deficiency
`between
`infection
`The relationship
`unclear and there is controversy within the literature."
`Studies
`suggest decreased infectious
`risk in iron-deficient
`children given
`iron-fortified milk compared with control
`subjects,
`but
`it
`is
`unclear what
`role poverty, malnutrition,
`and problems
`in
`experimental design may have played.49,5o
`iron
`are
`response
`Several
`components
`of the immune
`mediated
`and may be depressed
`in the setting of deficiency.
`Kuvibidila et aJ.51fed-mice iron-deficient diets and demonstrated
`atrophy of the thymus with depletion of thymocytes.
`Chandra'?
`showed impaired numbers of circulating
`blood neutrophils
`and
`capacity for generation
`of the oxidative burst necessary
`to kill
`phagocytized bacteria in iron-deficient patients.
`response
`Infection or sepsis initiates a systemic inflammatory
`(SIR),
`the goals of which are to limit injury, aid tissue repair, and
`augment
`immunity. Classic responses include fever, hypotension,
`tachycardia,
`hyperglycemia,
`increased protein catabolism,
`and
`decreased
`iron-transferrin
`saturation.
`Elevated
`release
`of
`cytokines
`are the hallmark
`and include
`interleukin-L,
`tumor
`necrosis
`factor, and interleukin-fi.U These occur
`in conjunction
`with elevated
`concentrations
`of glucagon,
`cortisol,
`and
`epinephrine
`and serve to mediate the metabolic
`cascade of the
`SIR.
`iron
`of parenteral
`to the administration
`A potential side effect
`is an increased risk for infectious complications.>'
`Children with
`kwashiorkor-type malnutrition
`and low serum transferrin who
`were
`given
`nutritional
`support
`that
`included
`oral
`iron
`supplements
`had a higher mortality rate than did children with
`normal
`serum transferrin
`concentrations
`who were given
`comparable
`nutritional
`interventions.
`Septicemia with Yersinia
`enterocolitica
`has been reported in healthy children who took
`overdoses of oral
`iron.56
`Iron-deficient
`Somali nomads
`treated
`with oral
`iron demonstrated
`a greater
`than five-fold increase
`in
`infectious
`complications
`compared with those who received
`placebos; most of the complications
`represented
`reactivation
`of
`underlying malaria, brucellosis, or tuberculosis.?
`of body
`Several authors
`report
`that
`in vitro supplementation
`fluids, such as plasma, with iron overcomes natural
`immunity."
`In general, doubling the saturation of the iron-binding protein in
`animal models yields a marked increase in the growth of various
`pathogens. Microorganisms
`require iron for growth and most
`acquire iron from their host. Microbes
`synthesize iron transport
`proteins or siderophores
`that compete with transferrin
`for free
`iron. 59 Depressed
`serum iron values have been documented
`during
`infectious
`diseases.
`Proposed mechanisms
`include
`decreased
`intestinal
`iron absorption
`and cytokine-mediated
`sequestration
`of iron into tissue stores, predominantly with the
`
`PGR2020-00009
`Pharmacosmos A/S v. American Regent, Inc.
`Petitioner Ex. 1030 - Page 5
`
`

`

`PARENTERAL IRON DEXTRAN THERAPY
`
`167
`
`flux 'Of iron into the reticuloendothelial
`system and the liver.58-tiO
`Given these data, use of either oral or parenteral
`iron in the
`patient at high risk of serious
`infection
`should be discouraged
`pending further study.
`
`SUMMARY
`iron
`safety and efficacy profiles of parenteral
`The acceptable
`iron
`dextran have been demonstrated.
`The use of parenteral
`should be limited to patients with documented
`iron deficiency
`anemia
`and failed
`oral
`iron
`repletion.
`All
`parenteral
`
`for the low dose of 2 mg
`except
`of iron dextran,
`administration
`provided in TPN, should be preceded by a test dose to evaluate
`susceptibility
`to systemic reactions.
`Patients
`should be observed
`closely and emergency
`resuscitative
`equipment
`and medication
`including
`epinephrine
`should be immediately
`available.
`Care
`should be taken in calculation
`of the replacement
`dose to avoid
`iron overload.
`In patients with underlying
`infection,
`the benefits
`of iron repletion need to be weighed against
`the potential
`risk of
`exacerbating infectious complications.
`
`REFERENCES
`
`in iron
`
`1 Am Med Assoc
`
`1. Basu SK, Rapid administration of iron-dextran in late pregnancy.
`Lancet 1963;1:1430
`2. Finch CA, Huebers H. Medical progress, perspectives
`metabolism. NEnglJMed
`1982;306:1520
`3. Eyster E, Bemene 1. Nosocomial
`anemia.
`1973;223:73
`4. Cook J, Finch CA. Assessing the iron status of a population. Am 1
`Clin Nutr 1979;32:2115
`5. Lipschitz DA, Cook 10. Finch CA. A clinical evaluation of ferritin
`as an index of iron stores. N Engl 1Med 1974;290:1213
`6. Woods S, DeMarco T, Friedland M. Iron metabolism. Am 1
`GastroenterolI990;85:1
`7. Cook JD. Morek TA. Lynch SR. The inhibitory effect of soy
`products on nonheme iron absorption in man. Am J Clin Nutr
`1981;34:2622
`8. Conrad ME, Schade SG. Ascorbic acid in iron absorption: a role for
`hydrochloric acid and bile. Gastroenterology 1968;55:35
`9. Cavill J, Jacobs A, Worwood M. Diagnostic methods for iron status.
`Ann Clin Biochem 1986;23:168
`10. Hallberg L. Bioavailability of dietary iron in man. Annu Rev Nutr
`1981;1:123
`II. Kamakakom K. Cavill I,Jacobs A. The metabolism of intravenously
`administered iron-dextran. Br J HaematoI1973;25:637
`12. Wood JK, Milner PFA, Pathak UN. The metabolism of iron-dextran
`given as a total dose infusion to iron deficient Jamaican subjects. Br
`JHaematoI1968;14:119
`13. Tumlund JR, Smith RG, Kretsch Ml, et at. Milk's effect on the
`bioavailabllity of iron from cereal-based diets in young women by
`use of in vitro and in vivo methods. Am J Clin Nutr 1990;52:373
`14. Hallberg L. Rossander L, Skanberg AB. Phytates and the inhibitory
`effect of bran on iron absorption
`in man. Am J Clin Nutr
`1987;45:988
`Intravenous iron dextran in
`15. Hamstra RD, Block NM, Schocket AL.
`clinical medicine. J Am Med Assoc 1980;243:1726
`16. Grutzmacher P, Tsobanelis T, Roth P, et al. Effect of recombinant
`human erythropoietin on iron balance in maintenance hemodialysis:
`theoretical" considerations, clinical experience and consequences.
`Clin NephroI1992;38:S92
`17. Wallerstein RO.
`Intravenous
`1968;32:690
`18. Greenberg O. Sarcoma after intramuscular iron injection. Br Med 1
`1976;3: 1508
`after
`19. Foulkes WD, Sewry C, Calam 1. et a1. Rhabdomyolysis
`intramuscular
`iron dextran in malabsorption. Ann Rheum Dis
`1991;50:184
`20. Blake DR, Lunec 1, Ahem M, et al. Effect of intravenous iron
`dextran on rheumatoid synovitis. Ann Rheum Dis 1985;44:183
`21. Oh VMS. Iron dextran and systemic lupus erythematosus. Br Med J
`1992;305:1000
`22. Blake DR. Hall NO, Bacon PA, et aJ. The importance of iron in
`rheumatoid disease. Lancet 1981;2:1142
`23. Reddy PS, Lewis M. The adverse effect of intravenous iron-dextran
`in rheumatoid arthritis. Arthritis Rheum 1969;12:454
`24. Ron D. The reticuloendothelial
`system and rheumatoid arthritis.
`Lancet 1979;2:901
`25. Auerbach M. Witt D, Toler W, et al. Clinical use of the total dose
`intravenous infusion of iron dextran. J Lab Clin Med 1988;111:566
`26. Physicians' Desk Reference. Montvale, NJ:Medic