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`
`Nephrol Dial Transplant (2004) 19: 1576–1580
`DOI: 10.1093/ndt/gfh222
`Advance Access publication 19 March 2004
`
`Original Article
`
`Sodium ferric gluconate complex in haemodialysis patients:
`a prospective evaluation of long-term safety
`
`Beckie Michael1, Daniel W. Coyne2, Vaughn W. Folkert3, Naomi V. Dahl4 and David G. Warnock5,
`Õ
`for the Ferrlecit
`Publication Committee
`
`1Jefferson Medical College, Philadelphia, PA, 2Washington University School of Medicine, St Louis, MO,
`3Albert Einstein College of Medicine/Montefiore Medical Center, Bronx, NY, 4Watson Laboratories, Morristown, NJ and
`5University of Alabama at Birmingham, Birmingham, AL, USA
`
`Abstract
`placebo-
`dose
`single
`Background. A previous
`controlled double-blinded trial showed an extremely
`low (0.4%) intolerance rate of sodium ferric gluconate
`complex
`(SFGC)
`in SFGC-naive haemodialysis
`patients. No large prospective trials have assessed
`the safety of SFGC during repeated exposure in the
`outpatient haemodialysis setting.
`Methods. Chronic haemodialysis patients complet-
`ing the single-dose trial of SFGC were eligible to
`participate in this prospective, multicentre, open-label,
`long-term evaluation of SFGC, designed to record
`adverse events occurring up to 72 h post-dose. Patients
`received as many as 20 ampules (1250 mg total) of
`SFGC at an investigator-determined dose and rate
`over a 9 month evaluation period.
`Results. Among 1412 enrolled patients at 54 centres,
`1321 received 13 151 infusions of SFGC. Most doses
`(94.8%) were 125 mg and the majority were given over
`10 min. Infusion rates ranged from <5 to 125 mg/min.
`There were no life-threatening events. Fifty-one
`patients (3.9%) experienced an adverse event, possibly
`related to SFGC. Of these, one experienced a serious
`event (hypotension). Five patients (0.4%) experienced
`an event
`that precluded SFGC readministration:
`pruritus (three), vasodilatation (one) and loss of
`taste (one). Among 372 patients (28.2%) receiving
`angiotensin-converting enzyme inhibitor (ACEI) ther-
`apy, adverse events were neither more common nor
`more severe than in the other patients.
`Conclusions. Repeated doses of SFGC are very
`well
`tolerated in haemodialysis patients. No life-
`threatening events were observed in over 13 000 doses
`
`Correspondence and offprint requests to: Beckie Michael, DO,
`Clinical Associate Professor of Medicine,
`Jefferson Medical
`College, Director, Dialysis Services, Thomas Jefferson University
`Hospital, 834 Walnut Street, Philadelphia, PA 19107, USA. Email:
`Beckie.Michael@jefferson.edu
`
`administered. Administration of SFGC to patients
`using ACEI is safe and does not increase the incidence
`or severity of adverse events to SFGC.
`
`iron
`iron;
`intravenous
`Keywords: haemodialysis;
`deficiency;
`iron dextran sensitivity;
`sodium ferric
`gluconate complex
`
`Introduction
`
`A major factor limiting achievement of target haemo-
`globin in haemodialysis patients is undiagnosed or
`untreated iron deficiency [1]. Several studies have
`shown that oral iron cannot adequately maintain iron
`stores in haemodialysis patients [2–4]. As a result, the
`use of intravenous iron is necessary to optimally care
`for these patients [1]. Until recently, iron dextran was
`the only form of parenteral iron available in the United
`States. This drug is associated with a significant
`incidence of anaphylactoid reactions [5], limiting its
`utility in treating iron deficiency anaemia. Allergy is
`believed to relate to the dextran moiety of the drug.
`In 1999, sodium ferric gluconate complex in sucrose
`solution (SFGC) was approved by expedited review by
`the US Food and Drug Administration. This drug has
`no dextran component and has an extended history of
`safe use in Europe. Recently, we completed a large
`prospective, double-blinded study that documented the
`safety of a single exposure of SFGC compared with
`concurrent placebo and historical iron dextran controls
`in SFGC-naive haemodialysis patients [6]. Severe
`adverse events with SFGC were reduced by 93%
`compared with iron dextran and were not significantly
`different
`from the incidence or severity of events
`observed with placebo [6].
`Thus, it appears that the safety profile of a single
`exposure to SFGC is excellent. However, it is possible
`that with repeated exposure sensitivity could develop,
`
`Nephrol Dial Transplant Vol. 19 No. 6 ß ERA–EDTA 2004; all rights reserved
`
`

`

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`
`Long-term safety of sodium ferric gluconate complex
`
`as has been observed with iron dextran preparations. In
`addition, a brief case report raised the possibility of
`an interaction between angiotensin-converting enzyme
`inhibitors (ACEI) and intravenous iron, resulting in
`hypotension [7]. Therefore, the purpose of the present
`study is to evaluate the safety of repeated exposure
`to SFGC during its routine clinical use. This paper
`presents the results of a long-term open-label study of
`SFGC in haemodialysis patients.
`
`Subjects and methods
`
`This study was a prospective, open-label, multicentre surveil-
`lance study of
`the safety of repeated doses of SFGC
`administered to iron-deficient adult haemodialysis patients.
`Two subsets of this study have been reported previously: 144
`patients receiving 250–500 mg of SFGC as single infusions [8]
`and 92 patients with prior iron dextran sensitivity [9]. These
`patients are included here for clarity. The primary objectives
`of the study were (i) to evaluate protocol events defined as
`outcome adverse events, life-threatening adverse events or
`allergic adverse events following repeated exposure to SFGC
`in SFGC-tolerant patients and (ii) to compare the incidence of
`adverse events in SFGC-treated patients who were receiving
`ACEI therapy with those patients who were not.
`Patients who completed the preceding single-dose SFGC
`safety study [6] and provided informed consent were invited
`to participate in this study. All centres received approval
`from their respective Institutional Review Boards. Patients
`were enrolled at 54 centres in the United States between
`August 1999 and February 2001 and assigned 20 ampules of
`SFGC, each containing 62.5 mg elemental iron. SFGC dose,
`rate of infusion and frequency were at the local investigator’s
`discretion to mimic routine clinical use of SFGC in the
`outpatient haemodialysis setting.
`Individual patient participation ended when all 20 ampules
`were administered or 9 months had elapsed. Patients were
`assessed by the Study Coordinator for adverse events (an
`unfavourable sign or symptom temporally related to SFGC
`administration) during the dialysis session in which they
`received SFGC and at the dialysis session following. An
`outcome adverse event was any reaction that required
`permanent cessation of SFGC therapy. A life-threatening
`adverse event was any immediate reaction following SFGC
`administration that required the institution of resuscitative
`measures other than those usually used during dialysis to treat
`common intradialytic complications. A serious adverse event
`was any hospitalization or life-threatening event. An allergic
`adverse event was any event the investigator felt, based on the
`patient’s symptoms, to be allergic in nature. Hypotension was
`defined clinically. Patients with symptoms of hypotension
`were to have their blood pressure checked immediately and
`reassessed within 10 min. Events were classified as instanta-
`neous if they occurred during SFGC infusion, immediate if
`after infusion but before dialysis was completed and delayed if
`the event occurred after dialysis was completed and before the
`next dialysis session.
`
`Statistical methods
`
`The percentage of patients experiencing adverse events was
`tabulated by body system and the individual Coding System
`
`1577
`
`for a Thesaurus of Adverse Reaction Terms (COSTART)
`preferred term. The primary and safety analysis was
`conducted on all patients who entered the study and received
`at
`least one dose of SFGC (evaluable population).
`Categorical data were analysed with a two-sided Fisher’s
`exact
`test. All computations were performed using the
`Statistical Analysis System (SAS) v. 6.12.
`
`Results
`
`Demographics
`
`A total of 1412 patients were enrolled at 54 centres and
`91 (6.4%) did not receive SFGC. The demographics
`and baseline characteristics of the remaining 1321
`patients (evaluable population) are shown in Table 1
`and compared with the demographics of the entire US
`haemodialysis population in 1999 [10]. Due to the
`locations of the study sites, blacks and Hispanics are
`over-represented in the study.
`Of the 1321 patients, 129 (9.8%) stopped the study
`prematurely and 119 of these discontinuations were
`unrelated to SFGC. The reasons for withdrawal
`unrelated to SFGC were (a) logistical reasons (83,
`6.3%), including kidney transplantation, transfer to
`another dialysis unit and change to peritoneal dialysis,
`(b) withdrawn consent without an adverse event (28,
`2.1%) and (c) withdrawn consent with an unrelated
`adverse event (8, 0.6%).
`Ten (0.8%) patients discontinued the study due to
`adverse events considered possibly or probably related
`to SFGC: pruritus (three), nausea/vomiting (two),
`diarrhoea, nausea and vomiting (one), vasodilatation
`(one), back pain and nausea (one), abdominal pain
`(one) and loss of taste (one). Four of these reactions
`[pruritus (three) and vasodilatation (one)] were classi-
`fied as intolerance and allergic events. One event (loss
`of taste) was considered an intolerance event, while the
`
`Table 1. Summary of demographic and baseline patient character-
`istics
`
`Characteristic
`
`SFGC study
`(n¼ 1321)
`
`1999 USRDS
`data n
`
`Age (years)a
`Male
`Race
`White
`Black
`Asian
`Hispanic
`Native American
`Other
`Height (cm)a
`Weight (kg)a
`Cause of renal failure
`Diabetes
`Hypertension
`Glomerulonephritis
`Other
`Concomitant ACEI
`
`aData are means±SD.
`
`55.6±15.2
`727 (55)
`
`296 (22.4)
`764 (57.8)
`24 (1.8)
`222 (16.8)
`2 (0.2)
`13 (1.0)
`168±12
`75.2±20.4
`
`457 (34.5)
`492 (37.2)
`136 (10.2)
`268 (20.2)
`372 (28.2)
`
`60
`52.7%
`
`54.2%
`40.4%
`3.6%
`9.7%
`1.8%
`
`168
`74.3
`
`40.2%
`28.3%
`11.6%
`19.9%
`Not available
`
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`1578
`
`remaining five patients had non-serious events that
`were felt not to preclude readministration.
`
`SFGC administration
`
`A total of 13 151 doses of SFGC were administered
`(Table 2). Most SFGC doses (94.7%) were given as
`125 mg per dialysis session. The majority of patients
`(75.5%) received 1000 mg SFGC during the study.
`The majority of doses were administered as 125 mg
`intravenous over 10 min. Rates of administration
`ranged from <5 mg/min (33.5%)
`to 125 mg/min
`(3.7%), though 94% were <15 mg/min. The details of
`the 144 patients receiving 250–500 mg of SFGC have
`been published separately [8].
`
`All adverse events
`
`A total of 260 patients (19.7%) experienced at least one
`adverse event (related and unrelated to SFGC) during
`the study (Table 3). Most events (88%) were of mild or
`moderate intensity and represent events commonly seen
`in haemodialysis patients. Adverse events occurred
`with greatest frequency in the following body systems:
`body as a whole (8.6%); cardiovascular (8.1%); and
`digestive (6.1%). Adverse events reported by 1% of
`
`Table 2. Summary of SFGC administration and related adverse
`events
`
`Exposure category
`
`n (%)
`
`Related
`adverse
`events (n)
`
`Related
`adverse events
`per infusion
`
`13 151
`
`No. of infusions
`Dose (mg/infusion)
`62.5
`3847 (29.3)
`8616 (65.5)
`>62.5–125
`688 (5.2)
`>125
`Rate of infusion (mg/min)
`<5
`4411 (33.5)
`5–<10
`2457 (18.7)
`10–<15
`5494 (41.8)
`15
`780 (5.9)
`
`78
`
`9
`62
`7
`
`43
`6
`27
`2
`
`0.006
`
`0.002
`0.007
`0.010
`
`0.010
`0.002
`0.005
`0.003
`
`Table 3. Overall incidence of adverse events
`
`Type of adverse event
`
`Any adverse eventa
`Related
`Unrelated
`Any serious adverse event
`Related
`Unrelated
`Event precluding re-exposureb
`
`Total n¼ 1321
`n (%)
`
`260 (19.7)
`51 (3.9)
`230 (17.4)
`56 (4.2)
`1 (0.1)
`55 (4.2)
`5 (0.4)
`
`aIndicates total number of patients with one or more adverse event,
`related or unrelated. Some patients had both related and unrelated
`events on different dialysis days. bDrug-intolerant events are
`described in Table 4.
`
`B. Michael et al.
`
`patients were hypotension (4.0%), pain (2.3%), nausea
`(2.0%), headache (2.0%), diarrhoea (1.9%), hyperten-
`sion (1.2%) and vomiting (1.1%). Pruritus was
`reported in 1.1% of patients.
`A total of 56 (4.2%) patients experienced at least one
`serious adverse event and none of these precluded
`readministration of SFGC. One serious event (hypo-
`tension) was considered to be SFGC-related: a 37-year-
`old male receiving an ACEI developed hypotension,
`abdominal pain and vomiting immediately following
`125 mg SFGC given over 2–3 min. He was treated with
`1950 ml saline and the dialysis session was terminated.
`His blood pressure improved and he was sent home
`from the dialysis unit. The patient received six more
`doses of SFGC (125 mg over 12–17 min) without
`incident. Of the 19 patients who died during the
`study, all died >72 h after SFGC infusion and none
`had adverse events felt to be related to the study drug.
`Fifty-one patients (3.9%) experienced a total of 78
`adverse events considered by the investigator to be
`related (probably, possibly or unknown) to SFGC and
`all were classified as mild to moderate in severity. There
`was no correlation between these events and SFGC
`dose, rate of infusion or total exposure to SFGC (Table
`2). Gastrointestinal complaints were the most common
`events (34), followed by hypotension (10), pruritus
`(seven), nervous system disorders (six), vasodilatation
`(three), dyspnoea (three), asthenia (two), chest pain
`(two), pain (two), palpitations/tachycardia (two),
`peripheral oedema (two), taste loss/perversion (two),
`non-specified allergic reaction (one), back pain (one)
`and headache (one).
`
`SFGC drug intolerance and allergic events
`
`SFGC drug intolerance and allergic events are sum-
`marized in Table 4. No life-threatening events were
`observed. Four patients had events characterized as
`both a drug intolerance and an allergic event [pruritus
`(three) and vasodilatation (one)], one patient had a
`non-allergic drug intolerance event only (loss of taste)
`and one patient had an allergic reaction (pruritus) after
`the second dose of SFGC, but received eight additional
`doses without recurrence of symptoms. The four
`patients with pruritus were treated with diphenhydra-
`mine (two intravenously and two orally), with resolu-
`tion of
`symptoms. The patient with symptoms
`characterized as vasodilatation experienced shortness
`of breath and a hot flush around the neck, which
`resolved after 50 mg intravenous diphenhydramine.
`
`Lack of relationship of concomitant ACEI therapy or
`other drugs to adverse events
`
`(28.2%) were receiving
`A total of 372 patients
`concomitant ACEI therapy and 949 (71.8%) were
`not. Table 5 shows the incidence of adverse events in
`the two groups. There was no significant difference in
`the incidence of adverse events, drug intolerance,
`allergic reactions or serious adverse events between
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`
`Long-term safety of sodium ferric gluconate complex
`
`Table 4. Summary of drug intolerance and suspected allergic events
`
`Event
`
`Intensity
`
`Onset
`
`Infusion
`number
`
`Dose (mg)/
`time (min)
`
`Rate
`(mg/min)
`
`Pruritus
`Taste loss
`Vasodilatation
`Pruritus
`Pruritus
`Pruritus
`
`Mild
`Moderate
`Moderate
`Mild
`Moderate
`Mild
`
`Immediate
`Delayed
`Immediate
`Immediate
`Immediate
`Immediate
`
`7
`2
`3
`2
`2
`6
`
`125/30
`125/10
`125/10
`125/30
`250/60
`125/10
`
`4.2
`12.5
`12.5
`4.2
`4.2
`12.5
`
`1579
`
`ACEIa
`
`YES
`NO
`NO
`YES
`NO
`YES
`
`aConcurrent therapy with ACEI.
`
`Table 5. Overall incidence of adverse events (related and unrelated
`to SFGC) in relation to ACEI therapy in patients who experienced
`at least one adverse event during the study
`
`Type of event
`
`Any event
`Drug intolerance
`Allergic event
`Hypotension
`
`ACEI
`(n¼ 372)
`n (%)
`
`86 (23.1)
`2 (0.5)
`3 (0.8)
`12 (3.2)
`
`No ACEI
`(n¼ 949)
`n (%)
`
`174 (18.3)
`3 (0.3)
`2 (0.2)
`41 (4.3)
`
`P-value
`
`0.054
`0.624
`0.139
`0.437
`
`the groups. The most commonly reported adverse event
`in the study was hypotension. Twelve patients (3.2%)
`receiving an ACEI experienced hypotension as com-
`pared with 4.3% of patients who were not (P¼ 0.437).
`Concomitant medication information was collected
`on all 260 patients who had any adverse event (related
`or unrelated) during the study. Among these patients,
`205 (78.8%) were receiving antihypertensive agents, 50
`(19.2%) were receiving antilipaemic agents and 75
`(28.8%) were on antidiabetic therapy. The rates of
`occurrence of drug-related adverse events and outcome
`events were not different among patients receiving these
`concomitant medications and those who were not.
`
`Discussion
`
`in
`Iron deficiency has been shown to be present
`25–37.5% of haemodialysis patients [1]. Oral
`iron
`therapy is usually ineffective in repleting or maintaining
`adequate iron stores in haemodialysis patients receiving
`epoetin [2–4]. Consequently,
`the National Kidney
`Foundation’s Kidney Disease Outcomes Quality
`Initiative guidelines emphasize that the majority of
`haemodialysis patients will require intravenous iron on
`a regular basis [1].
`Parenteral iron therapy can result in a number of
`adverse reactions [5,11,12]. Some, such as nausea, are
`unlikely to be immune-mediated, while others, includ-
`ing rash, dyspnoea and wheezing, appear to represent
`true allergic reactions. Serious allergic (anaphylactic)
`reactions are rare, but can be life-threatening [11]. The
`majority of life-threatening reactions have been asso-
`ciated with iron dextran, with at least 30 deaths
`
`attributed to its use [13]. These adverse events appear
`to be related to the dextran moiety of this preparation.
`In contrast to iron dextran, SFGC has one gluconate
`and four sucrose ligands at
`the five iron oxide
`coordinating positions, resulting in an iron oxide
`polymer rather than iron oxide crystals. Additionally,
`SFGC does not contain any dextran. Our previous
`reports of a double-blinded prospective study of the
`adverse events and safety of a single dose of SFGC also
`demonstrated a low incidence of adverse reactions [6,9].
`Although there was a statistically greater incidence of
`drug intolerance following SFGC as compared with
`placebo, there was no difference in serious adverse
`events or hypotension [6].
`While most serious iron dextran reactions occur
`upon initial exposure to the drug (and even to the test
`dose), reactions can occur after multiple uneventful
`exposures [14]. Fletes et al. [15] found that 30% of iron
`dextran-associated serious adverse reactions occurred
`after repeated administration. Although SFGC has
`been used extensively in Europe for decades with an
`excellent safety record, large prospective clinical studies
`addressing outcomes with repeated exposure have been
`lacking.
`The present study demonstrates repeated adminis-
`tration of SFGC is very well tolerated, with 0.4% of
`haemodialysis patients experiencing an adverse event
`that precluded readministration. These reactions were
`generally mild to moderate in severity. There were no
`life-threatening events observed with over 13 000 doses
`administered. The most common adverse events were
`gastrointestinal symptoms, hypotension and headache,
`events commonly seen in haemodialysis patients
`regardless of drug therapy. There was no evidence
`that the incidence of adverse events increased with
`repeated administration. These results are similar to the
`Õ
`safety study,
`findings of the single exposure Ferrlecit
`where the incidence of drug intolerance in SFGC-naive
`haemodialysis patients was 0.4% [6].
`Rolla et al. [7] suggested concomitant use of ACEI
`might increase the number or severity of reactions to
`intravenous iron products. The use of ACEI has been
`associated with an increased risk of anaphylactoid
`reactions in patients dialysed with certain dialysis
`membranes or sterilizing agents [16,17] and might be
`mediated by increases in bradykinin. The results of this
`study found no increase in the frequency or severity of
`adverse events following repeated SFGC infusion in
`
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`
`1580
`
`ACEI-treated patients and these results are consistent
`with the previous safety study [6].
`This study allowed investigators to determine the
`dose and rate of infusion of SFGC to assess safety
`during routine clinical practice. Although infusion rates
`were 15 mg/min in 5.9% of infusions and doses
`exceeded 125 mg in 5.3% of infusions, the frequency
`and severity of reactions were not increased in these
`subgroups. The 144 patients receiving SFGC at doses
`of 250–500 mg have been discussed in depth previously
`[8]. However, it is suggested that the current infusion
`recommendation (125 mg intravenously over 10 min)
`continues to be followed.
`Repeated administration of SFGC in haemodialysis
`patients is associated with a low incidence of adverse
`events, which does not increase with repeated exposure.
`These reactions are also not influenced by ACEI or
`other common concomitant medications. SFGC was
`demonstrated to have a wide margin of safety in this
`open-label study of routine clinical practice.
`
`Acknowledgements. The additional participating investigators were
`Rajiv Agarwal, MD, Indiana University, Indianapolis, IN; Raul
`Balagtas, MD, Tampa, FL; Daniel C. Batlle, MD, Northwestern
`University Medical School, Chicago,
`IL; Jeffrey Berns, MD,
`University of Pennsylvania; Jose Cangiano, MD, San Juan Bautista
`School of Medicine, San Juan, Puerto Rico; Laura Dember, MD,
`Boston University Medical Center; Devasmita Dev, MD, Veterans
`Administration North Texas Health Care;
`Jorge Diego,
`MD, University of Miami, Miami, FL; Joseph W. Eschbach, MD,
`Northwest Kidney Center, Seattle, WA; Stephen Z. Fadem,
`MD, Houston Kidney Center, Houston, TX; Steven Fishbane, MD,
`Winthrop University Hospital, Mineola, NY; Mary Gellens, MD, St
`Louis University Medical College; Michael Germain, MD, West
`Springfield, MA; Charles Graeber, MD, Newington, CT; Mandeep
`Grewal, MD, Chattanooga, TN; Louisa Ho, MD, Evanston, IL;
`Onyekachi Ifudu, MD, State University of New York; Dennis
`Imperio, MD, Sarasota, FL; Sam James, MD, University of Arizona
`Medical Center; Mark Kaplan, MD, Nashville, TN; Ellie Kelepouris,
`MD, Temple University School of Medicine; Ken Kleinman, MD,
`University of California at Los Angeles; David Leehey, MD, Loyola
`University Medical Center; Jill Lindberg, MD, New Orleans, LA;
`Robert Lynn, MD, Bronx Dialysis Center, New York City, NY;
`Thomas Marbury, MD, Orlando, FL; Ronald Mars, MD, University
`of Florida; Allen R. Nissenson, MD, UCLA School of Medicine, Los
`Angeles, CA; Chamberlain Obialo, MD, Morehouse School of
`Medicine, Atlanta, GA; Chika Oguagha, MD, Nephrology
`Foundation of Brooklyn, New York City, NY; Walter Piering, MD,
`Medical College of Wisconsin; Rasib Raja, MD, Albert Einstein
`Medical Center, Philadelphia, PA; Steven Rosenblatt, MD, San
`Antonio Kidney Diseases Center, San Antonio, TX; Jeff Sands, MD,
`Emory University; Steve Schwab, MD, Duke University Medical
`Center South; Allan Schwartz, MD, Hahnemann University Hospital;
`Andrea J. Shaer, MD, Medical University of South Carolina,
`Charleston, SC; Warren Shapiro, MD, Brookdale, NY; Anupkumar
`Shetty, MD, Henry Ford Health Systems; Jerald Sigala, MD, Orange,
`CA; David Spiegel, MD, University of Colorado Health Sciences
`Center; Richard Swartz, MD, University of Michigan; Nosratola
`Vaziri, MD, University of California Irvine Medical Center; Sergio
`Vega, MD, West Palm Beach, FL; Kevin Vitting, MD, St Joseph’s
`Hospital and Medical Center; Michael Walczyk, MD, Portland, OR;
`Robert Weiss, DO, Temple University; Duane Wombolt, MD,
`Norfolk, VA; Elizabeth Wrone, MD, Palo Alto, CA. This paper was
`supported by a grant from Watson Pharmaceuticals, Inc., to each of
`the participating centres.
`
`Conflict of interest statement. B.M., D.C., V.F. and D.W. have
`conducted research sponsored by Watson Pharmaceuticals, Inc., the
`Õ
`, and/or served on its speakers’ bureau.
`manufacturer of Ferrlecit
`N.D. is Director, Clinical Affairs at Watson Laboratories.
`
`B. Michael et al.
`
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`iron therapy in patients receiving recombinant human
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`Received for publication: 3.10.03
`Accepted in revised form: 18.02.04
`
`