Safety in Iron Management
`
`Steven Fishbane, MD
`
`@ Intravenous (IV) iron therapy has becomean integral part of hemodialysis managementduring the past several
`decades, and the National Kidney Foundation-Kidney Disease OutcomesQuality Initiative guidelines recognize that
`most patients undergoing hemodialysis will require IV iron therapy on a regular basis to reach target hemoglobin
`(Hgb) levels. There now are three IV iron compoundsavailable in the United States: iron dextran, sodium ferric
`gluconate,and iron sucrose. Although all have been proven effective for increasing Hgb/hematocrit levels, recent
`data showdifferencesin their relative safety profiles. During the past two decades, more than 30 deaths have been
`attributed to the use of IV iron dextran. The two newer compounds available in the United States, sodium ferric
`gluconate andiron sucrose, have more favorable safety profiles, with the largest prospective safety comparison to
`date showing sodium ferric gluconate to be similar to placebo in the incidence of serious anaphylactoid-type
`reactions. This article reviews safety data surrounding theIV iron therapies. Am J Kidney Dis 41(S5):S18-S26.
`© 2003 by the National Kidney Foundation,Inc.
`
`INDEX WORDS: Kidney Disease Outcomes Quality Initiative (K/DOQI); iron therapy; sodium ferric gluconate; iron
`sucrose; iron dextran.
`
`LL TREATMENTdecisions that physicians
`make involve the weighing of risks and
`benefits, including nephrologists’ treatment deci-
`sions involving the use of intravenous (IV) iron
`therapy. Benefits of IV iron therapy for hemodi-
`alysis patients are well established; [V iron is
`essential for enabling most tron-deficient hemo-
`dialysis patients to achieve target hemoglobin
`(Hgb)levels of 11 to 12 g/dL (110 to 120 g/L).!
`Correction of anemia may provide numerous
`benefits, including a significant decrease in left
`ventricular mass index and septal wall thickness;
`increased work capacity; improvements in fa-
`tigue, depression,and relationships; reduced hos-
`pitalization; and normalization of increased car-
`diac output.2© Because iron is vital for normal
`energy use by cells and has an important role in
`oxygen delivery and overall health status, it is
`important for hemodialysis patients to maintain
`adequate levels of storageiron.
`Both the European Anemia Best Practices
`Panel’ and the National Kidney Foundation-
`Kidney Disease Outcomes Quality Initiative
`guidelines in the United States! have conducted
`an analysis of risks versus benefits of TV iron
`
`From Winthrop-University Hospital, Mineola, NY.
`Supported by an unrestricted educational grant from
`Watson Pharma, Inc.
`Address reprint requests to Steven Fishbane, MD, Direc-
`tor of Dialysis Services, Winthrop-University Hospital, 200
`Old Country Rd, #135, Mineola, NY 11501. E-muil:
`sfishbane @winthrop.org
`© 2003 by the National Kidney Foundation, Inc.
`0272-6386/03/4106-0504$30.00/0
`doi:10.1016/S0272-638(03)003 73-1
`
`therapyfor the treatment of anemia. In each case,
`it was concluded that IV iron forms a cornerstone
`of hemodialysis therapy. Nevertheless, questions
`remain in some nephrologists’ minds about the
`possible risks associated with IV tron therapy,
`including the risk for adverse reactions, cardio-
`vascular disease (CVD), and infection. Much of
`the concem relates to problems of iron in its
`free-circulating form, in which iron can create
`reactive oxygen species that can result in inflam-
`mation, endothelial damage, and a potential in-
`creased risk for infection. This article discusses
`
`the evidence surrounding the potential risks of
`IV iron therapy.
`
`ADVERSE REACTIONS TO IV IRON THERAPY
`
`Good quantitative data from several analyses
`of adverse reactions to IV iron therapy have
`emerged during the past several years. Although
`a number of adverse reactions have been re-
`ported with the use of IV iron compounds,includ-
`ing injection-site reactions, diarrhea, and nau-
`sea,®” reactions that pose the greatest danger to
`patients and thus are of greatest concern are
`anaphylactoid or allergic-type reactions. These
`are generally characterized by signs and symp-
`tomsthat include urticaria, rash, dyspnea, hypo-
`tension, and, in the most severe cases, shock and
`death. The risk for anaphylactoid reactions ap-
`pears to be greatest with [V iron dextran, prob-
`ably because of the dextran component of the
`compound. High-molecular-weight dextran com-
`plexes alone are known to be antigenic even
`when not complexed to iron.!° Possibly, the im-
`
`$18
`
`American Journal of Kidney Diseases, Vol 41, No 6, Suppl 5 (June), 2003: pp $18-S26
`
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`

`IRON SAFETY
`
`$19
`
`Oxygen
`
`Oxygen Oxygen
`
`Ferric Oxide
`Function
`
`Sucrose
`
`
`
`Oxygen
`
`Oxygen
`
`Sucrose
`
`4. Carboxylate
`| Function
`
`
`
`
`
`
`
`Sucrose
`
`
`Sucrose
`
`
`Ovygen
`
`mm
`
`Oxygen
`
`Ferric Oxide
`Function
`
`
`
`Fig1. Themolecular struc-
`ture of sodium ferric glu-
`conate consists of an iron
`core surrounded by sac-
`charate networks, which are
`linked together by a glu-
`conate function. The result
`is a stable complex of high
`molecular weight (289,000 to
`440,000 d) that resists disso-
`ciation in serum andis non-
`dialyzable. (Data from Watson
`Pharma,Inc.1*)
`
`mune response is caused by a direct effect on
`mast cells and basophils.
`The risk for immediate severe anaphylactoid
`reactions appears to be, at a minimum, approxi-
`mately 0.6% with IV iron dextran, and this agent
`has been associated with a number of deaths
`during the past several decades. A 1980 review
`by Hamstraet al!! examined the use of IV iron
`dextran in 481 hemodialysis patients adminis-
`tered a total of 2,099 doses of 250 or 500 mg. In
`this patient group, life-threatening reactions oc-
`curred in 3 patients (0.6%), characterized by
`respiratory arrest, hypotension, syncope, and
`wheezing. Eight additional patients had delayed
`nonlethal reactions that included myalgia, arthral-
`gia, and pulmonary embolus. These data were
`borne out in later IV iron dextran studies by
`Woodman et al,!? in which anaphylactoid reac-
`tions were seen in 1.8% of 1,260 patients, and by
`Fishbane et al,? in which such reactions were
`seen in 1.7% of 573 patients treated during a
`2-year period.
`Even with IV iron dextran, the expected risk
`for serious anaphylactoid reactions, approxi-
`mately 6/1,000 patients,is relatively low, and the
`risk to the individual patient is low. However, the
`risk is far from negligible, and viewed in the
`context of a large hemodialysis practice that
`treats several hundred patients, it is likely that
`several severe reactions will be encountered over
`the course of time with IV iron dextran. Data by
`Faich and Strobos,!° published in 1999, have
`illustrated this significant risk for potentially
`fatal reactions. Using a database drawing on the
`
`Gluconate Function
`
`US experience with IV iron dextran during a
`two-decade period (1976 to 1996), a total of 196
`serious anaphylactoid reactions and 31 deaths
`were reported with the use of this compound.
`Among patients administered iron dextran who
`experiencedallergic reactions, there was a mini-
`mum case fatality rate of 15.8%. (Because data
`from this study were drawn from retrospective
`reports, many of which did not list final out-
`comes,
`the actual case fatality rate may have
`been even greater.!°)
`The two newer compounds introduced in the
`United States, sodium ferric gluconate and iron
`sucrose, appear to be associated with a far lower
`risk for anaphylaxis. This reducedrisk appearsto
`be related to the absence of dextran chains in
`these molecules; both compounds consist of a
`sucrose network surroundinga ferric ion core. In
`the case of sodium ferric gluconate, sucrose
`networks are linked by a gluconate function to
`create a highly stable nondialyzable macromo-
`lecular complex (Fig 1).
`This reduced risk has been shown in data
`published on sodium ferric gluconate. In 2002,
`Michael et al'* published results of the largest
`prospective safety analysis conducted in hemodi-
`alysis patients. The study, which involved 2,493
`hemodialysis patients, compared the rate of ad-
`verse reactions prospectively with placebo and
`with a historical control group of IV iron dextran
`users. Patients in this study were administered
`placebo or a 125-mg single dose of sodium ferric
`gluconate delivered by IV push at a rate of 12.5
`mg/min during one session and then were crossed
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`S20
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`STEVEN FISHBANE
`
`overto the opposite treatmentat the next session.
`The IV iron dextran comparison was drawn from
`four published trials involving 3,768 drug expo-
`sures to different forms of this compound.
`The rate of life-threatening adverse reactions
`(immediate reactions requiring institution of re-
`suscitative measures) was reduced from 0.61%
`in the IV iron dextran study population to 0.04%
`in the sodium ferric gluconate study population
`(~4/10,000 patients). The relative risk reduction
`was 93% (Table 1).!4 The single life-threatening
`reacuion associated with sodium ferric gluconate
`consisted of shortness of breath, hypotension,
`and lower back pain. It resolved within 20 min-
`utes, enabling the patient to complete the dialysis
`treatment and return home the same day.
`In the placebo-controlled portion of this study,
`there was no significant difference in incidence
`of life-threatening reactions with sodium ferric
`gluconate compared with placebo (Table 2).!*
`Although there wasa statistically significant dif-
`ference in incidence of drug-intolerance events
`(ie, any event that would preclude further study
`drug administration), most of these reactions
`consisted of lower-level gastrointestinal tract re-
`actions.
`Fewer safety data are available on the newest
`agent, TV iron sucrose. Unlike sodium ferric
`gluconate, iron sucrose has not beentested in a
`large-scale prospective studysince its introduc-
`tion in the United States. However, available
`data suggest a similar safety profile. In studies by
`Van Wyckct al® and Charytanct al! involving a
`total of approximately 1,000 doses of 100 mg of
`iron sucrose administered through IV infusion or
`push, no deaths and no potentially fatal anaphy-
`
`Table 1. US Safety Study of Sodium Ferric
`Gluconate: Adverse Events for Sodium Ferric
`Gluconate Versus Iron Dextran
`
`Sodium Ferric
`
`
` Gluconate Iron Dextran P
`
`
`
`0.61, 23/3,768,
`0.04, 1/2,493,
`Life-
`0.36-0.86
`0.00-0.22
`threatening
`0.44, 11/2,493, 2.47, 64/2,589, <0.0001
`Drug
`intolerance 1.87-3.07 0.21-0.71
`
`
`
`0.0001
`
`NOTE. Comparison with iron dextran was taken from
`historical controls in published studies of iron dextran.
`Values expressed as percent, number/total number, 95%
`confidenceinterval.
`
`Reprinted with permission.'4
`
`Table 2. US Safety Study of Sodium Ferric
`Gluconate: Adverse Events for Sodium Ferric
`Gluconate Versus Placebo
`
`Sodium Ferric
`Gluconate
`(N = 2,493)
`
`Placebo
`(N = 2,487)
`
`P
`
`Life-threatening
`Drug intolerance
`
`1 (0.04)
`11 (0.4)
`
`0 (0)
`2 (0.1)
`
`Not available
`0.02
`
`NOTE. Values expressed as number (percent).
`Reprinted with permission.'4
`
`lactoid reactions were attributed to use of this
`compound. In the largest analysis of IV iron
`sucrose use, encompassing 1,004,477 patients
`worldwide from 1992 to 2001, a total of 788
`adverse
`events were reported (incidence,
`0.028%), including 52 anaphylactoid reactions.
`No deaths were reported.'® Data for these two
`compoundsstrongly suggestthat they are signifi-
`cantly safer than IV iron dextran in terms of
`serious adverse reactions, and the use of IV iron
`dextran should be restricted to selected patients
`in whom there is a particular need to treat with
`this compound.
`
`CVD RISK
`
`The link between CVD and TV iron therapy
`has good biological plausibility, at least in theory.
`Iron is an element with a high degree of acute-
`phase reactivity that can lead to a state of in-
`creased oxidative stress. Catalytically active iron
`is involved in the production of hydroxyl radical,
`a damaging reactive oxygen species. Hydroxyl
`radicals, in turn, lead to lipid peroxidation and
`the development of additional lipid-derived free
`radicals, which generate still other free radicals
`in a chain reaction.!”
`Most of the data associating iron with an
`increased risk for CVD have been drawn from
`population-based studies involving serum fer-
`ritin Jevel as a measure of iron stores. A senes of
`Finnish studies by Salonen et al'®?° were among
`the first to test the “iron hypothesis” of an in-
`creased risk for CVD with increased iron stores.
`In these studies, an increased risk for myocardial
`infarction (MI) was found in men with greater
`serumferritin levels compared with those with
`lowerlevels.!® Subsequent studies by this same
`group showedthat regular blood donors had a
`lower average serum ferritin level and decreased
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`IRON SAFETY
`
`$21
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`risk for acute MI over time compared with non—
`blood donors.'?° A large-scale Canadian survey
`by Morrison et al?!
`that followed up nearly
`10,000 participants also showed an increased
`risk for fatal MI in those in the highest category
`of serum ferritin level (175 g/dL).
`Nevertheless, it is exceedingly difficult to draw
`reasoned conclusions from these data about the
`risk for CVD in hemodialysis patients on IV iron
`therapy. First,
`these studies were population-
`based analyses that in most cases involved only
`male patients. An equal number of population-
`based studies that have examined the relation-
`ship between serum ferritin level and MI con-
`cluded there is no increased risk for CVD with
`greater iron stores and no protective effect with
`blood donation.?”°
`Second, serum ferritin levels may not be a
`reliable markerfor actual elevationsin ironstores.
`Chronic inflammatory conditions, such as CVD,
`tend to elevate serum ferritin measures, making
`it questionable whether observational studies are
`measuring an increase in iron levels or results of
`an occult inflammatory process.
`Third, such population-based studies also have
`not controlled for the presence of hemochromato-
`sis, a hereditary disorder that results in massive
`accumulation of storage iron over a period of
`decades. Because this disorderis fairly common
`(1 of 300 Caucasians are homozygous for the
`Cys282Tyr mutation of HIE, one of the genes
`involved in hemochromatosis), failure to control
`for its presence may influcnce the outcomes of
`population-based analyses.
`Finally, population-based studies involving
`body iron stores contribute little to our knowl-
`edge of the specific CVD risk associated with [V
`iron therapy in hemodialysis patients. The few
`studies to date conducted in the hemodialysis
`population tended to showa slight, but signifi-
`cant, increase in relative risk (~ 1.1 to 2.4).?7??
`However, this modest increase in risk must be
`weighed against
`the serious and well-docu-
`mented health consequencesof failing to correct
`iron-deficiency anemiain these patients.
`
`RISK FOR INFECTION
`
`Iron is crucial for survival in most organisms
`and is necessary for erythrocyte production and
`the making and storage of adenosine triphos-
`phate. Oxidative phosphorylation,
`the produc-
`
`Oo
`
`i
`Tyr191
`OngoS
`AspSe Tyr 93
`
`His 252
`
`Fig 2. An iron-protein complex. Such complexes
`tend to be large glycoprotein complexes wrapped
`around a central core of iron that protects the body
`from exposureto free iron.
`
`is highly dependent on
`tion of usable energy,
`iron. Therefore, the body strives to obtain iron
`and is very resistant to tron elimination. Of the
`estimated 4,000 mg of iron in the body, only
`approximately | mg/d is lost in healthy individu-
`als. Nevertheless, the potent oxidizing ability of
`iron makesit a potentially toxic compound in the
`body in its free form. Because of this potential
`toxicity, the majority of iron that is not actively
`circulating as Hgb in red blood cells is safely
`sequestered in the form of ferritin and hemosid-
`erin in macrophages of the reticuloendothelial
`system (RES). Molecules that hold iron tend to
`be very large, containing a central core of iron
`with a proteinaceous envelope that insulates the
`body from the iron atom (Fig 2). In healthy
`individuals, free iron rarcly is a problem. Con-
`versely, in cases of hemochromatosis, in which
`serumferritin levels can increase to more than
`10,000 ng/mL,the body is presented with unman-
`ageable levels of free iron.
`In hemodialysis patients on IV iron therapy,
`althoughironis introduceddirectly into the circu-
`lation as opposedto the gastrointestinal tract, the
`body generally retains its ability to protect against
`free-iron release by taking up the iron-carbohy-
`drate complex into the RES in its bound form.In
`the RES, iron is dissociated from its carbohy-
`drate ligand, stored as ferritin or hemosiderin,
`and only then is turned over to transferrin, the
`body’s primary serum buffer against free iron,
`for delivery to the erythroid marrow for use in
`Hgb production. A series of pharmacokinetic
`analyses by Seligman et al®° and Kimkoetal?!
`showed that sodium ferric gluconate delivered at
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`S22
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`STEVEN FISHBANE
`
`
`
`> 8
`80—
`
`
`
`
`
`Transferrin
`
`Saturation(%
`PatientsWith(JFree
`Iron(%)
`
`
`
`= 1
`
`50
`
`180
`
`210
`
`0
`
`30
`
`60
`
`T
`90
`
`F
`120
`
`Time (min)
`
`60
`50
`40
`
`30
`20
`10
`
`0
`
`
`T
`te
`T
`Te
`“Tv
`“e
`30
`60
`90
`120
`150
`180
`
`210
`
`0
`
`Time (min)
`
`(A) Transferrin
`3.
`Fig
`saturation and (B) percent-
`age of patients with free iron
`after administration of iron
`sucrose, 100 mg, by IV push.
`Reprinted with permission.**
`
`a dose of 125 mg by IV infusion or push follows
`this normal pathwayof iron distribution. In these
`studies,
`the sodium ferric gluconate complex
`was taken up directly by the RES before being
`delivered back to transferrin. Release offree iron
`directly into the circulation was negligible, and
`no transferrin oversaturation was observed, even
`at an infusion rate greater than 15 mg/min. After
`the iron was taken up by the RES, turnoverto
`transferrin was orderly: The majority of iron
`(~80%) was delivered back to transferrin and
`made available to the erythroid marrow within
`24 hoursof infusion.*°*!
`An increasing number of studies during the
`past 2 years have shownthat the same protection
`against free-iron release may not be seen with [V
`iron sucrose. A pharmacokinetic study by Daniel-
`son et al*’ showed that iron sucrose follows two
`pathways after administration: Although part of
`the iron is transported directly to the RES inits
`carbohydrate-bound complex, a portion is re-
`leased directly into the circulation, existing as
`nontransferrin-bound free tron. Subsequent stud-
`ies have shown the potential detrimental effects
`of this method ofiron release in terms of infec-
`tion risk and oxidative damage. In 2000, Parkki-
`nen et al** published results of an elegant series
`of studies on the release of free iron with iron
`sucrose and risk for infection. This study ana-
`lyzed 12 stable hemodialysis patients with fer-
`
`ritin levels less than 400 ng/mL who received
`treatment with 100 mg of iron sucrose adminis-
`tered by IV push. Transferrin saturation was
`measuredat 5, 30, 90, and 210 minutespostinjec-
`tion, and serum iron was measured by meansof
`two spectrophotometric methods using ferozine
`and ferene-S as the chromogenic agents.
`Transferrin saturation increased rapidly imme-
`diately after injection (Fig 3A),** a phenomenon
`that would only occur if iron was moving di-
`rectly to transferrin. Transferrin saturation contin-
`ucd to increase, averaging morc than 80% within
`3.5 hours. In addition, there was a consistent
`increase in number of patients with measurable
`free iron in the circulation as detected by bleomy-
`cin assay, climbing to 50% at 3.5 hours (Fig
`3B).*
`These findings have several clinical implica-
`tions. First, patients with lowertransferrin levels
`(which may occur in hemodialysis patients be-
`cause of inadequate transferrin production in the
`liver) are likely at greater risk for having free
`iron in the circulation with IV iron sucrose.
`Second, the presence of free iron in the circula-
`tion may increase the risk for infection. This
`increased risk was shown bythis group by intro-
`ducing Staphylococcus epidermidis into serum
`samples in patients with free iron. Although S$
`epidermidis normally does not grow in serum in
`the absence of free iron,
`the organism grew
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`IRON SAFETY
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`$23
`
`Adding apotransferrin to the sera-inhibited staph growth
`
`
`
`
`
`
`
`~t¢-3.5 h sample with
`apotransterrin
`added; growth
`index 0
`
`~@-Serum sample
`before IV iron:
`growth index 0
`
`—-Normal serum:
`growth index0
`
`—A- Serum sample
`3.5 h after IV iron;
`growth index 0.4
`
`Fig 4. Growth of Staphy-
`lococcus epidermidis in se-
`rum samplesof patients with
`catalytically active free iron
`after administration of IV iron
`sucrose. The addition of apo-
`transferrin to bind free iron
`reduced the growth of S epi-
`dermidis to normal
`levels.
`Reprinted with permission.**
`
`rapidly in samples from patients with free iron
`and in direct proportion to the level of free iron
`in serum (Fig 4).** Adding apotransferrin to the
`samples to bind free iron prevented S epidermi-
`dis growth in these samples. The investigators
`concluded from this study that an iron sucrose
`dose of 100 mg delivered by IV push maybe too
`large.
`Damiani et al*+ compared clinical infection
`outcomes between IV iron sucrose and sodium
`ferric gluconate in a study of 61 hemodialysis
`patients treated at a single center. Baseline char-
`acteristics of the two patient groups were similar,
`with the exception of a greater mean recombi-
`nant human erythropoietin dose at baseline in the
`iron sucrose group. At follow-up, there were no
`significant differences in recombinant human
`erythropoietin dose requirements or Hgb levels.
`However, at months 6 and 8, transferrin satura-
`tions and serum ferritin levels were greater in the
`iron sucrose group. The infection rate in the iron
`sucrose group was significantly greater than in
`the sodium ferric gluconate group: 1 for every 10
`patient-months versus | for every 17 patient-
`months.*4
`Zager et al®° conducted a series of in vitro
`studies of four [TV iron compounds: iron sucrose,
`sodium ferric gluconate, iron dextran, and iron
`oligosaccharide (which is not available in the
`United States). Using isolated mouse proximal
`tubule segments and cultured human proximal
`tubule (HK-2) cells,
`the researchers assessed
`oxidant injury through malondialdehyde (MDA)
`generation, as well as lethal cell injury through
`
`Times (hours)
`
`lactate dehydrogenase (LDH) release and cell
`proliferation/viability through tetrazolium dye
`(MTT)assay. All four IV iron compounds were
`found to cause some degree of lipid peroxida-
`tion, measured by MDA generation, with iron
`dextran and iron oligosaccharide causing slightly
`greater levels of oxidation than the other two
`compounds.
`However, when cellular toxicity was exam-
`ined based on LDHrelease, IV iron sucrose was
`shown to cause a dramatic increase in mouse
`proximal tubule cell death compared with the
`other three compounds (which were similar to
`placebo; lig 5).*° This significant increasein cell
`death with IV iron sucrose also was seen in
`human proximal tubule cclls, measured by both
`LDH release (Fig 6A) and MITuptake (Fig
`6B).*> The response was robustly dose depen-
`dent.
`Two additional studies, both published in 2002,
`have addressed the issue of free tron and oxida-
`tive stress with IV iron sucrose. Kooistra et al°°
`examined effects of iron sucrose in IV push
`administration of 100 mg in 6 minutes in 10
`hemodialysis patients. In these patients, an in-
`crease in transferrin saturation ranging from 26%
`to 491% was observed. A slower infusion (100
`mg in 60 minutes) did not affect the increase in
`transferrin saturation; abundant free iron was
`seen in both methods of administration. In a
`study by Rooyakkers*’ involving 20 healthy vol-
`unteers administered IV iron sucrose, 100 mg in
`60 minutes, a 400% increase in non-transferrin-
`bound iron was seen, accompanied by an in-
`
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`
`
`P<0.002
`(9)} OSLDHRelease
`
`
`Glue
`” Dext |
`Fe (i mg/mL)
`
`Fig 5. Cell death in mouse proximal tubule cells
`shownbythe percentage of LDH release with four IV
`iron preparations(iron oligosaccharide [OS], sodium
`ferric gluconate [Gluc], iron dextran [Dext], and iron
`sucrose [Sucr]) compared with placebo. Abbreviation:
`Cont, continued. Reprinted with permission.*°
`
`30
`
`25
`
`& 20
`
`——$$——
`
`
`
`0.5 mg/mL
`[]0.42 mg/mL|
`M0 mg/mL.
`
`
`
`STEVEN FISHBANE
`
`crease in superoxide levels ranging from 53%to
`70%. Moreover, Tovbin et al?® studied iron su-
`crose at a dose of 100 mg administered to 19
`hemodialysis patients on high-flux dialysis
`therapy. They found significant increases in pro-
`tein oxidation. Recently, Drtieke et al*? studied
`79 hemodialysis patients administered IV iron
`sucrose and foundsignificant evidence for oxida-
`tive stress and acceleration of atherosclerosis in
`proportion to the amountof iron sucrose admin-
`istered.
`
`CONCLUSIONS
`
`Viewedtogether, these data show several po-
`tential risks of IV iron administration, including
`anaphylaxis, CVD, and increasedrisk for infec-
`tion. Risks for adverse events generally have
`been quantifiable, with the newer IV iron com-
`
`L
`
`t
`a
`
`.
`
`*
`
`
`
`
`.
`.
`|
`Fe Gluc
`Fe Sucr
`
`
`k
`
`ok
`
`%
`
`2
`
`.
`Fe Gluc
`
`
`
`
`
`
`
`
`fi mo/mi
`0.5 mg/mL
`Fig 6. Lethalcell injury to
`(10.12 mg/mL
`cultured human proximal tu-
`HB 0.06 mg/m bule (HK-2) cells determined
`by (A) LDH release and (B)
`MTT uptake with varying
`dosesof iron (Fe) oligosac-
`charide (OS), sodium ferric
`gluconate (Gluc),
`iron dex-
`tran (Dext), and iron sucrose
`(Sucr). For (A), *P < 0.05 and
`TP < 0.001. For (B), *P <
`0.001. Modified and reprinted
`with permission.25
`
`ok
`
`te
`
`
`
`
`
`
`Fe Suer
`
`PGR2020-00009
`PharmacosmosA/S v. American Regent, Inc.
`Petitioner Ex. 1040 - Page 7
`
`@
`3157
`cc
`
`10—
`
`5A
`
`5 an
`
`0
`
`A
`
`<
`od
`ae
`a
`=
`E
`s
`
`O-
`
`B
`
`PGR2020-00009
`Pharmacosmos A/S v. American Regent, Inc.
`Petitioner Ex. 1040 - Page 7
`
`

`

`IRON SAFETY
`
`S25
`
`pounds, sodiumferric gluconate and iron su-
`crose, having a lower incidence ofallergic and
`anaphylactoid-type reactions. A numberofstud-
`ies during the past 2 years have pointed to a risk
`for free-iron release and infection with iron su-
`crose. Further research is needed to quantify the
`risk of this free-iron release in terms of clinical
`outcomes. Nevertheless, in weighing risks ver-
`sus benefits of IV iron therapy, it is clear that [V
`iron is not only a beneficial component of hemo-
`dialysis, but also a necessary one for the majority
`of patients who are iron deficient. Specific risks
`and benefits should be balanced on an individual
`patient basis.
`
`REFERENCES
`
`1. National Kidney Foundation: K/DOQI Clinical Prac-
`tice Guidelines for Anemia of Chronic Kidney Disease,
`2000. Am J Kidney Dis 37:$182-S238, 2001 (suppl 1)
`2. Cannella G, La Canna G, Sandrini M,et al: Reversal of
`left ventricular hypertrophy following recombinant human
`erythropoietin treatment of anaemic dialysed uraemic pa-
`tients. Nephrol Dial Transplant 6:31-37, 1991
`3. Lim VS: Recombinant human erythropoietin in predi-
`alysis patients. Am J Kidney Dis 18:534-S37, 1991 (suppl 1)
`4. Churchill DN, Muirhead N, Goldstein M,et al: Effect
`of recombinant human erythropoietin on hospitalization of
`hemodialysis patients. Clin Nephrol 43:184-188, 1995
`5. Powe NR, Griffiths RI, Watson AJ, et al: Lffect of
`recombinant erythropoietin on hospital admissions, readmis-
`sions, length of stay, and costs of dialysis patients. JAm Soc
`Nephrol 4:1455-1465, 1994
`6. Harnett JD, Kent GM, Foley RN, Parfrey PS: Cardiac
`function and hematocrit level. Am J Kidney Dis 25:S3-S7,
`1995 (suppl 1)
`7. Jacobs C, Hérl WH, Macdougall IC, et al: European
`Best Practice Guidelines 9-13: Anaemia management. Neph-
`rol Dial Transplant 15:$33-S42, 2000 (suppl 4)
`8. Van Wyck DB, Cavallo G, Spinowitz BS: Safety and
`efficacy of iron sucrose in patients sensitive to iron dextran:
`North American Clinical Trial. Am J Kidney Dis 36:88-97,
`2000
`
`9. Fishbane S, Ungureanu V-D, Maesaka JK, Kaupke CJ,
`Lim V, Wish J: The safety of intravenous iron dextran in
`hemodialysis patients. Am J Kidney Dis 28:529-534, 1996
`10. Faich G, Strobos J: Sodium ferric gluconate complex
`in sucrose: Safer intravenous iron therapy than iron dex-
`trans. Am J Kidney Dis 33:464-470, 1999
`11. Hamstra RD, Block MH, Schocket AL: Intravenous
`iron dextran in clinical medicine. JAMA 243:1726-1731,
`1980
`12. Woodman J, Shaw RJ, Shipman AJ, Edwards AM: A
`surveillance programme on a long-established product: Im-
`feron (iron dextran BP). Pharmaceut Med 1:289-296, 1987
`13. Watson Pharma, Inc: Data on file. Morristown, NJ,
`Watson Pharma, Inc
`14. 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
`61:1830-1839, 2002
`15. Charytan C, Levin N, Al-Saloum M, Hafeez T, Gag-
`non S, Van Wyck DB: Efficacy and safety of iron sucrose for
`iron deficiency in patients with dialysis-associated anemia:
`North American Clinical Trial. Am J Kidney Dis 37:300-
`307, 2001
`16. Macdougall I, Bailie G, Richardson D,et al: World-
`wide safety profile of iron sucrose injection (Venofer):
`Analysis of 1,004,477 patients from 1992 to 2001. Presented
`at: ASN World Congress of Nephrology, October 13-17,
`2001, San Francisco, CA
`17. Besarab A: Iron and cardiac discase in the end-stage
`renal disease setting. Am J Kidney Dis 34:S18-S24, 1999
`(suppl 2)
`18. Salonen JT, Nyyssonen K, Korpela H, et al: High
`stored iron levels are associated with cxcess risk of myocar-
`dial infarction in Eastern Finnish men. Circulation 86:803-
`811, 1992
`19. Salonen JT, Korpela H, NyyssénenK,et al: Lowering
`of body iron stores by blood Ictting and oxidation resistance
`of serum lipoproteins: A randomized cross-overtrial in male
`smokers. J Intern Med 237:161-168, 1995
`20. Salonen JT, Tuomainen T-P, Salonen R, T.akka TA,
`Nyyssénen K: Donation of blood is associated with reduced
`risk of myocardial infarction: The Kuopio Ischaemic Heart
`Disease Risk Factor Study. Am J Epidemiol 148:445-451,
`1998
`
`21. Morrison HI, Semenciw RM, Mao Y, Wigle DT:
`Serum iron and risk of fatal acute myocardial infarction.
`Epidemiology 5:243-246, 1994
`22. Manttéri M, Manninen V, Huttunen JK, et al: Serum
`ferritin and ceruloplasmin as coronary risk factors. Eur
`Heart J 15:1599-1603, 1994
`23. Reunanen A, Takkunen H, Knekt P, Seppanen R,
`Aromaa A: Bodyiron stores, dietary iron intake and coro-
`nary heart disease mortality. J Intern Med 238:223-230,
`1995
`
`24. Danesh J, Appleby P: Coronary heart disease and iron
`status: Meta-analyses of prospective studies. Circulation
`99:852-854, 1999
`25. Sempos CT, Looker AC, Gillum RF, McGee DL,
`Vuong CV, Johnson CL: Serum ferritin and death from all
`causes and cardiovascular disease: The NHANESI Mortal-
`ity Study. Ann Epidemiol 10:441-448, 2000
`26. Ascherio A, Rimm EB, Giovannucci E, Willett WC,
`Stampfer MJ: Blood donations and risk of coronary heart
`disease in men. Circulation 103:52-57, 2001
`27. Collins A, Ebben J, Ma J, Xia H: IV iron dosing
`patterns and mortality. J Am Soc Nephrol 9:205A, 1998
`(abstr)
`28. Besarab A, Bolton WK, Browne JK: Theeffects of
`normal as compared with low hematocrit values in patients
`with cardiac disease who are receiving hemodialysis and
`epoetin. N Engl J Med 339:584-590, 1998
`29. Feldman HI, Santanna J, Guo W,et al: Iron adminis-
`tration and clinical outcomes in hemodialysis patients. J Am
`Soc Nephrol 13:734-744, 2002
`30. Seligman P, Schleicher R, Meyer G, et al: Fast IV
`iron: Sodium ferric gluconate complex (SFGC)is safe with
`
`PGR2020-00009
`PharmacosmosA/S v. American Regent, Inc.
`Petitioner Ex. 1040 - Page 8
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`PGR2020-00009
`Pharmacosmos A/S v. American Regent, Inc.
`Petitioner Ex. 1040 - Page 8
`
`

`

`$26
`
`STEVEN FISHBANE
`
`no “free” iron toxicity. J Am Soc Nephrol 11:278A, 2000
`(abstr)
`31. Kimko HC, Karhu D, Nissenson A, Strobos J,
`Seligman P: Evidence for iron delivery to erythroid
`marrow by sodium ferric gluconate complex (Ferrlecit®).
`J Am Soc Nephrol 11:297A-298A, 2000 (abstr)
`32. Danielson BG, Salmonson T, Derendorf H, Geisser P:
`Pharmacokinetics of iron(III)-hydroxide sucrose complex
`after a single intravenous dose in