--- C:
`
`merican Journal of
`Kidney Diseases
`
`■ Plasmapheresis Therapy for Henoch-Schonlein Purpura Nephritis
`■ Ramipril and Urinary Protein Excretion ■ Safer Intravenous Iron Therapy
`■ Pediatric Patients on Dialysis
`
`NF The Official Journal of the
`
`National Kidney Foundation
`
`W. B . Saunders Company
`
`• A Division of Harcourt Brace & Company
`
`

`

`NF TheOfficialJournalofthe
`
`National Kidney Foundation
`
`VOL 33, NO 3, MARCH 1999
`
`CONTENTS
`
`American Journal ol Kldney Diseases
`
`*ANNOUNCEMENTS .................... ..................... ................... .......... ...... ...................... ...... xlii
`
`*OF NEPHROLOGY AND NEPHROLOGISTS
`
`Peritoneal Dialysis: The State of the Art in Europe
`................... ................ ......... .. ......... ..... ............•. ... .............. ....................................
`Claudio Ronco
`
`ORIGINAL INVESTIGATIONS
`
`Plasmapheresis as the Sole Therapy for Rapidly Progressive Henoch-Schonlein
`Purpura Nephritis in Children
`Motoshi Hattori, Katsumi Ito, Taiwo Konomoto, Hiroshi Kawaguchi, Toshimasa Yoshioka,
`and Miyuhi Khano -········· ······················· ····················•·············· ······· ·············· ········ ······················· 427
`Expression of Interferon-Inducible Mx-Proteins in Patients With IgA Nephropathy
`or Henoch-Schonlein Purpura
`Jurgen Floege, Michael Burg, Abdul N. Al Masri, Hermann Joseph Grone, and Peter von Wussow
`
`4 34
`
`Renal Manifestations of Concurrent Systemic Lupus Erythematosus and HIV
`Infection
`Benjamin G. Chang, Glen 5. Marlwwitz, Surya V Seshan, Robert L. Seigle,
`........................ .......................... .... .. .... ........................ ..... .......................... 441
`and Vivette D. D'Agati
`A Subdepressor Low Dose of Ramipril Lowers Urinary Protein Excretion Without
`Increasing Plasma Potassium
`Taha Keilani, Farhad R. Danesh, William A. Schlueter, Agostino Molteni, and Daniel Batlle ....... .... 450
`Urinary Protein Excretion and Serum Tumor Necrosis Factor in Diabetic Patients
`With Advanced Renal Failure: Effects of Pentoxifylline Administration
`Juan F. Navan-a, Carmen Mora, Antonio Rivero, Eduardo Gallego, Jesus Chahin, Manuel Macia,
`............................... ................................... ........ .................... 458 ·
`Maria L. Mendez, and Javier Garcia
`Sodium Ferric Gluconate Complex in Sucrose: Safer Intravenous Iron Therapy Than
`Iron Dextrans
`I Editorial, p. 595 1
`Gerald Faich andJur Strobos
`
`....................................... ...................... .............................. ...... ... ..... 464
`
`* Asterisked items and all abstracts are available in both the print and electronic editions of the Journal.
`Cover □ lu tration: Hist logical and immunofluoresceoce analysis of wild-type and CCSP-/- ki.dney tissue.
`The morphological characteri tics of wild-type (A, C, E, G I, K, M, and 0) and CCSP-/- (B, D F H J L, N
`and P renal tissue were compared at_ month A, B E F 1, J M and N) and 12 montbs (C, D, G, H, K, L 0 ,
`and P). Th histological tain used in this analysis were hematoxylin and eosin A-D)., sirius red (I-L and
`(M-P). Fibronectin was detected by lmmunofluorescence (E-H) using a previou ly characterized goat
`PA
`in J through L indicate sirjus red- tained ba ement membrane. No
`antiiibronectin antibody. Arrow
`differences were noted between wiJd-type and CCSP-/- Li sue at either age. See Reynolds et al, p. 541.
`
`

`

`Sodium Ferric Gluconate Complex in Sucrose:
`Safer Intravenous Iron Therapy Than Iron Dextrans
`
`Gerald Faich, MD, MPH, and Jui Strobos, MD, JD
`
`• Use of recombinant human erythropoietin in patients with end-stage renal disease has highlighted iron defi(cid:173)
`ciency as the major cause of resistant anemia. The current mainstay of intravenous (IV) iron replacement therapy,
`iron dextran, has been shown in prior studies to have a risk of serious life-threatening anaphylaxis of just under 1
`per 100 patients exposed. The current study assessed the safety profile of an alternative IV iron, sodium ferric
`gluconate complex in sucrose (Ferrlecit), as compared with iron dextrans. Sodium ferric gluconate complex in sucrose,
`a unique chemical preparation, has been in use since 1959, principally in Europe, at a rate of approximately 2.7 million IV
`doses per year (1992 to 1996) in Germany and Italy alone. For iron dextran, usage in the United States was comparable(cid:173)
`principally renal hemodialysis-and estimated from market sources at 3.0 million doses per year (1995). From 1976 to
`1996, there were 74 allergic adverse events reported for sodium ferric gluconate complex in sucrose to the World
`Health Organization (WHO), German Health Bureau, and the manufacturer (all combined). For the years 1992 to
`1996, sodium ferric gluconate complex in sucrose had an allergy event reporting rate of 3.3 allergy episodes per
`million doses per year compared with a similar rate of 8.7 reported allergy events per million doses per year for iron
`dextran in the United States in 1995. Case fatalities for sodium ferric gluconate complex in sucrose and iron dextran
`within these reports were then compared. For sodium ferric gluconate complex in sucrose, there were no reports of
`deaths over the entire period (1976 to 1996). However, for iron dextrans, there were 31 fatalities among 196
`allergy/anaphylaxis cases reported in the United States between 1976 and 1996, yielding a case-fatality rate of
`15.8%. These data show that sodium ferric gluconate complex in sucrose, when compared with iron dextrans in
`comparably sized patient usage populations with similar total rates of reporting of allergic events, has a signifi(cid:173)
`cantly lower reported mortality rate (P < 0.001). Thus, the data justify usage of sodium ferric gluconate complex in
`sucrose as the safer iron replacement therapeutic agent.
`© 1999 by the National Kidney Foundation, Inc.
`
`INDEX WORDS: Iron-deficiency anemia; iron dextran; sodium ferric gluconate complex in sucrose; sodium ferric
`gluconate complex in sucrose; renal hemodialysis.
`
`Editorial, p. 595
`
`I N THE FAST, anemia associated with chronic
`
`renal failure was treated with blood transfu(cid:173)
`sion, which bore many of the risks and hazards
`associated with other organ transplantations, such
`as immunologic disease or the tntbsmission of
`infectious agents. With the advent of erythropoi(cid:173)
`etin replacement with recombinant human eryth(cid:173)
`ropoietin (rHuEPO), the need for exposure to
`allogeneic blood has virtually disappeared for
`this patient population. Administration of
`rHuEPO may expose underlying iron deficiency,
`particularly in the hemodialysis population, which
`
`From Pharmaceutical Safety Assessments, Inc, Narberth,
`PA; and Olsson, Frank and Weeda, P.C. , Washington , DC.
`Received January 26, 1998; accepted in revised form
`September4, 1998.
`Study s11pportfunds provided by R & D Laboratories, Inc.
`and Schein Pharmaceuticals.
`Address reprint requests to fur Strobos, MD, JD, Olsson.
`Frank and Weeda. P.C., 1400 16th St, ,VW, Suite 400,
`Washin gton, DC 20036. E-mail: jstrobos@ojivlaw.com
`© 1999 by the National Kidney Fo1111dario11. Ille.
`0272 -6386/99/3303-0006$3. 00/0
`
`suffers substantial blood loss. 1 Usage of intrave(cid:173)
`nous iron formulations for the therapy of iron(cid:173)
`deficiency anemia has increased in the renal
`hemodialysis population with the advent of
`rHuEPO. Identification of appropriate and safer
`methods of iron administration have, therefore,
`become imperative.
`Much of the iron stores are in red blood cells
`(RBCs). Hemodialysis patients lose RBCs from
`repeated laboratory blood testing, needle punc(cid:173)
`tures, shunt revisions, blood retention in the
`dialyzer and tubing, and the bleeding diathesis
`associated with the use of anticoagulants. For
`instance, hemodialysis patients typically lose up
`to 15 to 25 rnL of whole blood at each dialysis
`treatment. 2 Administration of rHuEPO itself may
`increase iron use and, consequently, iron needs
`because of the increase in iron maintained in
`circulating RBCs. 3 Hemodialysis patients have
`been shown to have yearly loses of up to 6 to 8 g
`of iron. 4 A number of studies have shown the
`ineffectiveness of oral iron supplements in meet(cid:173)
`ing this demand even under conditions designed
`to optimize effectiveness.5-7
`Recently, Dialysis Outcomes Quality Initia(cid:173)
`tive (DOQI) guidelines from the National Kid-
`
`464
`
`American Journal of Kidney Diseases, Vol 33, No 3 (March) , 1999: pp 464-470
`
`

`

`SODIUM FERRIC GLUCONATE COMPLEX IN SUCROSE INJECTION
`
`465
`
`ney Foundation emphasize that oral iron therapy
`has been shown to be ineffective in meeting this
`increased demand for iron in the hemodialysis
`patient population. Further, the DOQI guidelines
`point out that target hematocrits have not been
`met, perhaps because fewer than 50% of dialysis
`patients meet erythropoietin and iron dosing rec(cid:173)
`ommendations. 8 These guidelines have also iden(cid:173)
`tified the difficulties in diagnosing iron defi(cid:173)
`ciency using currently available testing methods.
`One reason that intravenous iron may not be
`used more widely in patients who fail to achieve
`target hematocrits may be that intravenous iron
`dextrans have been known to cause life-threaten(cid:173)
`ing and fatal anaphylaxis. Adequate therapeutic
`usage of intravenous iron products in the United
`States may, therefore, be inhibited by safety
`concerns. There have been several reviews to
`assess the quantitative risk of serious or life(cid:173)
`threatening reaction to iron dextran. Hamstra et
`al9 retrospectively examined the experience of
`481 patients who received a total of 2,099 intra(cid:173)
`venous doses of 250 or 500 mg of iron dextran.
`There were three life-threatening (0.6% of pa(cid:173)
`tients) and 12 non-life-threatening (2.6% of pa(cid:173)
`tients) immediate systemic reactions. Thus, pro(cid:173)
`portionately, 20% of allergic systemic reactions
`were life threatening. Woodman et al1° identified
`an anaphylactoid rate of 1.8% among 1,260
`patients given iron dextran. Fishbane et al 11 con(cid:173)
`ducted a retrospective chart review of 573 hemo(cid:173)
`dialysis patients administered iron dextran in
`which they identified 10 mild anaphylactoid
`(1.7%) reactions and four serious reactions (0.7%)
`(29% of allergic reactions were serious).
`Examination of an electronic hospital records
`database from a 100-hospital network indicated a
`similar rate of anaphylaxis to iron dextran admin(cid:173)
`istration in patients on hemodialysis. 12 In these
`data, there were 549,705 hospital discharges dur(cid:173)
`ing a 6-month period in 1996. Among these,
`there were 5,979 patients with a diagnosis of
`renal hemodialysis, of which 474 received iron
`dextran during their hospital stay. Five of these
`474 patients also received epinephrine during the
`same hospital stay. Under the assumption that
`administration of both iron dextran and epineph(cid:173)
`rine in the same hospital stay must be to. treat
`anaphylaxis, the calculated rate of anaphylaxis
`from iron dextran is 1. 1 %.
`Deaths of anaphylaxis after iron dextran admin-
`
`istration are thought to be associated with the
`iron- carbohydrate or iron-dextran complex that
`may be immunogenic. * However, ferric ion to
`carbohydrate ligands are common to all prepara(cid:173)
`tions of intravenous iron in use internationally,
`and anaphylaxis rates appear to vary from prod(cid:173)
`uct to product. There have been scattered reports
`of self-limited hypotension and flushing in three
`patients who had received sodium ferric glu(cid:173)
`conate complex in sucrose (Ferrlecit), but these
`cases do not bear the hallmarks of a true anaphy(cid:173)
`lactic reaction. 13•14 Alternatively, then, anaphy(cid:173)
`laxis may be caused by the high-molecular(cid:173)
`weight dextran component itself. High-molecular(cid:173)
`weight dextran complexes alone are known to be
`potent antigens even when not complexed to
`iron.1s Sodium ferric gluconate complex in su(cid:173)
`crose is also-a relatively high-molecular-weight
`complex (=350,000 daltons) composed of iron
`(ill) oxide hydrate directly bonded to sucrose
`with a chelating gluconate function in a molar
`ratio of two iron molecules to one gluconate
`molecule.t The product does not have signifi(cid:173)
`cant, if any, polysaccharide (eg, dextran) content.
`Dextrans are thought to be immunogenic even to
`na'ive patients because of cross-reactivity of the
`dextran to native antibodies formed to polysac(cid:173)
`charides produced by gastrointestinal organ(cid:173)
`isms.1s Therefore, sodium ferric gluconate com(cid:173)
`plex in sucrose may not share the antigenicity of
`the iron dextrans.
`In light of the differences in chemical compo(cid:173)
`sition in iron products and the possibility that
`there is a different relative risk for .serious ad(cid:173)
`verse reactions, we sought to examine available
`dat_a on the severity of allergic reactions to iron
`products. In particular, we examined the postmar(cid:173)
`keting experience for sodium ferric gluconate
`
`*The package insert for INFeD® contains the following
`black box warning:
`The parenteral use of complexes of iron and carbohydrates
`has resulted in anaphylactic-type reactions. Deaths associ(cid:173)
`ated with such administration have been reported. Therefore,
`INFeD should be used only in those patients in whom the
`indications have been clearly established and laboratory
`investigations confirm an iron-deficient state not amenable
`to oral iron therapy.
`tKeppler B, University of Vienna (personal communica(cid:173)
`tion) ; sodium ferric gluconate complex in sucrose, a Rhone(cid:173)
`Poulenc Rorer product, will be distributed by Schein Pharma(cid:173)
`ceutical, Inc./R&D Laboratories, Inc, in the United States
`and selected countries.
`
`

`

`466
`
`FAICH AND STROBOS
`
`complex in sucrose and iron dextran, one with
`iron complexed to sucrose/gluconate and, in the
`other, to dextran. Over the period examined,
`there have been two different formulations of
`iron dextran marketed in the United States.t
`Data for each were combined, because reporting
`databases do not distinguish the formulations.
`Systematic underreporting of adverse events
`by health professionals to national authorities or
`to the manufacturer makes estimates of absolute
`risk based on spontaneous surveillance impre(cid:173)
`cise and unreliable. 16 Historically, therefore, post(cid:173)
`marketing surveillance of adverse-event reports
`are useful primarily for identifying a signal indica(cid:173)
`tive of a specific safety concern rather than
`quantifying the rate of occurrence. Underreport(cid:173)
`ing also varies by time, country, reporter, adverse
`event, and specific drug within class usage.17
`Iron dextrans are sold primarily in the United
`States and United Kingdom and have been avail(cid:173)
`able for more than 30 years. They are not used in
`Germany and are not available in Italy. Sodium
`ferric gluconate complex in sucrose has been
`sold primarily in Germany and Italy since 1959
`and is not currently available in the United States
`or United Kingdom. Adverse-event databases
`are, therefore, unlikely to be useful to compare
`absolute rates of reported adverse events be(cid:173)
`tween two drug products that do not share the
`same market and have both been marketed for
`many years.
`The existence of sufficient reports of allergic
`events should, however, permit a ct,mparison of
`relative severity of reactions. The reaction in
`question is well defined, serious, and rapidly
`follows drug administration, which should en(cid:173)
`hance reporting frequency. Generally, acute se(cid:173)
`vere events in all settings are preferentially re(cid:173)
`ported as compared with reporting of delayed(cid:173)
`onset or minor reactions. Stated differently, even
`if there were significant unknown variations in
`the absolute rate of reporting of allergic/anaphy(cid:173)
`lactoid reactions among German and Italian dialy(cid:173)
`sis management physicians for sodium ferric
`gluconate complex in sucrose as compared with
`similar US physicians for iron dextran, there
`would not be preferential reporting of mild
`events-and no reporting of anaphylactic
`deaths-among one group. Highly immunogenic
`
`:j:INFeD® became available in 1992; Imferon was with(cid:173)
`drawn in 1991.
`
`agents only rarely produce fatal reactions, which
`are a fractional subset of serious or life-threaten(cid:173)
`ing reactions that, in turn, are a fractional subset
`of all immunologic reactions. If there were suffi(cid:173)
`cient total allergic/anaphylactoid events re(cid:173)
`ported, a "within-report" comparison of relative
`severity (case fatality rate) would allow for analy(cid:173)
`sis of the comparative safety of the two products
`under the assumption that deaths are more likely
`or equally likely to be reported than milder
`reactions.
`
`MATERIALS AND METHODS
`
`To determine use patterns and provide denominators for
`rate calculations, data on use of the two products were
`obtained from marketing sources and manufacturers. Ad(cid:173)
`verse event reports and listings were obtained from the
`World Health Organization (WHO; Uppsala, Sweden) Col(cid:173)
`laborating Center for Drug Monitoring, Rhone-Poulenc Rorer
`GmBH (the manufacturer of sodium ferric gluconate in
`sucrose; Cologne, Germany), Schein Pharmaceutical, Inc. (a
`manufacturer of an iron dextran; Florham Park, NJ), and the
`German Health Ministry (Koln, Germany).
`
`RESULTS
`
`Total Drug Exposure Estimates
`Sodium Ferric Gluconate Complex in Su(cid:173)
`crose. Sodium ferric gluconate complex in su(cid:173)
`crose was first introduced for intravenous use in
`1959. Sodium ferric gluconate complex is recom(cid:173)
`mended for administration by slow direct intrave(cid:173)
`nous push of 62.5 mg over 10 to 20 minutes.
`Volume of use for sodium ferric gluconate com(cid:173)
`plex in sucrose in units of 2 or 5 mL from 1992 to
`1996 was made available by the manufacturer
`(Fig 1). Three countries (Germany, Italy, and
`Spain) account for 97% of total units sold in all
`countries in 1996. The manufacturer advised that
`90% of Italian sales represent oral usage as a
`dietary supplement. Data provided by the manu(cid:173)
`facturer and sources within the-German nephrol(cid:173)
`ogy community indicated that German usage
`was predominantly in renal hemodialysis pa(cid:173)
`tients. 18 Of the approximately 45,000 hemodialy(cid:173)
`sis patients in Germany-a figure that has been
`increasing slowly throughout the 1990s-these
`sources indicated that 60% to 75% (20,000 to
`30,000) are managed with regular or mainte(cid:173)
`nance intravenous iron supplementation at, on
`average, one ampule per week per patient. This
`accounts for 1.3 million ampules per year in
`Germany or over 80% of total sodium ferric
`
`

`

`SODIUM FERRIC GLUCONATE COMPLEX IN SUCROSE INJECTION
`
`467
`
`2500000 -
`
`2000000
`
`1500000
`
`1000000
`500000
`
`0
`
`Fig 1. Sodium ferric glu(cid:173)
`conate complex in sucrose
`units sold by country and
`year. •saudi Arabia repre(cid:173)
`sents 960,542 of these. **Fig(cid:173)
`ures represent 10% of sold
`units in Italy; the rest are
`taken orally.
`
`gluconate complex in sucrose usage in Germany,
`for which total drug exposure is approximately
`1.5 million parenteral doses per year. Based on the
`manufacturer's estimate of 10% parenteral usage in
`Italy, drug exposure in Italy constitutes an addi(cid:173)
`tional 1.2 million parenteral doses per year, for a
`total of 2. 7 million exposures per year. The relatively
`recent introduction of sodium ferric gluconate com(cid:173)
`plex in sucrose into Spain and the historic dearth
`of reporting of adverse events in Spain led to
`exclusion of Spanish usage for the current study.
`Iron Dextran. Sales data for iron dextran
`were obtained from commercial data maintained
`by IMS that indicate that 2,593,800 vials were
`sold in 1995. This database underrepresents total
`sales because large, direct institutional purchases
`are not included. An estimated drug exposure
`figure of 3.0 million doses per year was con(cid:173)
`firmed by the only US manufacturer of iron
`dextran for 1995 as reasonably accurate. Data
`from the manufacturer and market surveys of
`usage in the United States indicated that 80% to
`90% of iron dextran sold is generally used within
`the end-stage renal disease community. The pen(cid:173)
`etration of maintenance dosing in the United
`States for 1995 was, however, less than 50%. 19
`
`Cumulative Allergic and Anaphylactic
`Adverse Events
`Sodium Ferric Gluconate Complex in Sucrose.
`All allergic adverse events from patient exposure
`to sodium ferric gluconate complex in sucrose in
`
`- - --=-;-- _ __j
`
`■ Germany
`■ Italy
`□ Other
`- - - - - .1 ■ Total
`
`1995 1996
`
`both Italy and Germany for 1976 to 1996 inclu(cid:173)
`sively derived from electronic databases made
`available from the manufacturer, reports pro(cid:173)
`vided by the German Health Ministry, and case
`report forms compiled by the manufacturer's
`quality assurance program in Germany are com(cid:173)
`piled in Table 1. These listings and reports were
`consistent with each other and largely duplica(cid:173)
`tive. To assure completeness, the WHO Collabo(cid:173)
`rating Center for Drug Monitoring (Uppsala,
`Sweden) database was also polled. Only 11 WHO
`reports were found, and eight of these were
`duplicative of reports in Table 1.
`Allergic (rash or flushing without edema or
`hypotension) or anaphylactoid (hypotension, col(cid:173)
`lapse, edema, cardiac arrest, dyspnea) reactions
`are tabulated together (Table 1). To ensure meth(cid:173)
`odological validity, multiple reports from a single
`clinical site with identical symptoms were ex(cid:173)
`cluded. As a result, 17 patients with "flush and
`dyspnea" from one practice and 10 reports of
`"shock-like condition" from one clinic were
`excluded. Inclusion of these events would not
`have changed the results because no deaths were
`reported from either site. These reports are, how(cid:173)
`ever, consistent with published and other informa(cid:173)
`tion on sodium ferric gluconate complex in su(cid:173)
`crose that certain patients may experience
`flushing or hypotension that appears to resolve
`within 1 hour. Most suspected allergic or anaphy(cid:173)
`lactoid reactions were immediate. A few delayed
`
`

`

`468
`
`FAICH AND STROBOS
`
`Table 1. Allergic/Anaphylactoid Reports for Sodium
`Ferric Gluconate Complex-Italy and Germany
`Combined (1976-1996)
`
`Year
`
`Number
`
`Deaths
`
`Known Survival
`or Recovery
`
`1976
`1977
`1978.
`1979
`1980.
`1981
`1982
`1983
`1984
`1985
`1986t
`1987
`1988
`1989
`1990
`1991
`1992
`1993
`1994
`1995:f:
`1996
`Total
`
`2
`2
`2
`2
`2
`3
`1
`
`11
`1
`
`2
`4
`8
`25
`6
`74
`
`0
`
`2
`2
`2
`2
`2
`3
`
`11
`1
`
`2
`4
`8
`24
`4
`71
`
`•Excludes anomalous data-17 patients with "flush and
`dyspnea" from one practice; 1 O patients with poorly de(cid:173)
`scribed "shock-like condition" from one clinic; results would
`not be changed were data included because no deaths
`were reported.
`tSeveral group reports from single practice.
`:f:See text on production component.
`
`reactions were also included (eg, hyperventila(cid:173)
`tion 14 hours postinjection). Care was taken to
`count duplicate or triplicate listings only once
`(eg, three 1994 reports for "shivering, fever,
`weakness" in one patient and separately re(cid:173)
`corded under each term were counted as one
`case). Based on the 1992 to 1996 data of 45
`reports over 5 years and an estimated rate of use
`of 13.5 million ampules sold (5 years X 2.7
`million doses sold per year), the reporting rate of
`allergic reaction for sodium ferric gluconate com(cid:173)
`plex in sucrose was 3.3 per million doses.
`German and Italian Sodium Ferric Gluconate
`Complex in Sucrose Reporting Sensitivity. As
`given in Table 1, reports for anaphylactoid reac(cid:173)
`tions to sodium ferric gluconate complex in
`sucrose in Italy and Germany increased precipi(cid:173)
`tously in 1995, going from 8 in 1994 to 25 in
`1995 and then dropping to 6 in 1996. This
`
`increase in reported reactions prompted a de(cid:173)
`tailed investigation of batch production records.
`The ,only identified change was in the commer(cid:173)
`cial source of sucrose for a batch manufactured
`on April 27, 1995. All commercial sources of
`sucrose met European Pharmacopeial standards,
`but retrospective evaluation with high-pressure
`liquid chromatography and other methods identi(cid:173)
`fied the presence of high-molecular-weight poly(cid:173)
`saccharides, probably alpha-1,6-glucans, at the
`limits of detection in batches of raw material
`from the new source. 20 When production re(cid:173)
`verted to the original source, reported events
`dropped. Since then, raw material testing has
`included ethanol separation to detect any polysac(cid:173)
`charide content.
`The 1994 to 1996 data on sodium ferric glu(cid:173)
`conate complex in sucrose support two conclu(cid:173)
`sions. First, the German and Italian reporting
`systems are sensitive to changes in incidence of
`allergic or anaphylactoid reactions. Second, the
`episode is consistent with the hypothesis that
`polysaccharides, such as dextran, are the primary
`causative factor in the production of type I imme(cid:173)
`diate hypersensitivity or anaphylactoid reactions
`from intravenous iron compounds.
`Iron Dextran. There are 196 WHO reports
`of allergy or anaphylactoid reaction in the United
`States from 1976 to 1996. These data were re(cid:173)
`viewed by the manufacturer of one iron dextran
`marketed in the United States during this period
`and found to be consistent with their internal
`data. A display of the WHO database for allergic
`or anaphylactoid reactions to iron dextran for the
`United States by year from 1976 through 1996 is
`provided in Table 2. Using the 1995 data of 26
`reports and 3 million doses sold, the reporting
`rate of allergic reaction for iron dextran is 8.7 per
`million doses.
`
`Fatality Rates
`During the 21-year period from 1976 to 1996
`for which data are available for both iron dextran
`and sodium ferric gluconate complex in sucrose,
`there were 74 reports of suspected allergic or
`anaphylactoid reactions for sodium ferric glu(cid:173)
`conate complex in Italy and Germany and 196
`comparable reports for iron dextran in the United
`States, This represents an adequate database to
`examine severity for these reports in terms of
`case fatality rates. For sodium ferric gluconate
`
`

`

`SODIUM FERRIC GLUCONATE COMPLEX IN SUCROSE INJECTION
`
`469
`
`Table 2. Allerglc/Anaphylactic Reports for Iron
`Dextran-United States (1976-1996)
`
`Year
`
`1976
`1977
`1978
`1979
`1980
`1981
`1982
`1983
`1984
`1985
`1986
`1987
`1988
`1989
`1990
`1991
`1992
`1993
`1994
`1995
`1996
`Total
`
`Number
`
`Deaths
`
`Known Survival
`or Recovery
`
`3
`3
`1
`4
`4
`2
`7
`8
`8
`5
`10
`3
`5
`13
`16
`14
`6
`16
`26
`26
`16
`196
`
`2
`
`2
`1
`2
`
`2
`2
`
`2
`2
`7
`4
`31
`
`3
`
`4
`3
`5
`3
`2
`0
`0
`0
`1
`0
`0
`2
`5
`1
`2
`36
`
`complex in sucrose, there were no reports of
`deaths among 74 reported allergic episodes. For
`these, only three had unknown outcomes. By
`contrast, for iron dextran, there were 31 known
`deaths reported among a total of 196 allergic
`events reported for a minimum case fatality rate
`of 15.8% (Table 3) (P < 0.001 by chi-squared,
`substituting one for zero cases for sodium ferric
`gluconate complex in sucrose). This is a minimal
`rate because approximately 60% (129) of iron
`dextran reports did not list outcomes, so addi(cid:173)
`tional -deaths may have occurred and not been
`reported.
`
`Table 3. Allergy and Anaphylaxis Reports tor Sodium
`Ferric Gluconate Complex in Sucrose
`and Iron Dextran
`
`Case
`Fatality
`No. of
`No_ of Unknown Rate
`No_ of
`(%)
`Reports Deaths Outcomes
`
`196
`
`31
`
`129
`
`15.8*
`
`74
`
`0
`
`3
`
`0
`
`Iron dextrans
`Sodium ferric gluconate
`complex in sucrose
`
`*P< 0.001 .
`
`DISCUSSION AND CONCLUSION
`
`Parenteral drug exposure in the United States
`for iron dextran roughly parallels parenteral drug
`exposure for sodium ferric gluconate complex in
`sucrose in Italy and Germany. Estimated US
`exposure in 1995 for iron dextran was 3.0 mil(cid:173)
`lion doses per year. Estimated exposure for so(cid:173)
`dium ferric gluconate complex in sucrose from
`1992 through 1996 in Italy and Germany was 2.7
`million doses per year. In recent years, the spon(cid:173)
`taneously reported allergic reaction event rate for
`these drugs was calculated as 3.3 allergy epi(cid:173)
`sodes per million doses sold for sodium ferric
`gluconate complex in sucrose and 8.7 allergy
`episodes per million doses sold for iron dextran.
`These data confirm that there is extensive
`usage of both sodium ferric gluconate complex
`in sucrose and iron dextran for intravenous iron
`replacement therapy. In both settings, in the last
`5 years, usage has been largely in the well(cid:173)
`supervised renal hemodialysis patient popula(cid:173)
`tion. The volume of reporting of allergic adverse
`events-196 reports for iron dextran and 7 4 for
`sodium ferric gluconate complex in sucrose -has
`been constant over time and sufficient to permit
`analysis of the severity of illness resulting from
`exposure to the two products. Comparative as(cid:173)
`sessment of the propmtion of deaths "within
`reports" of allergic or anaphylactoid reactions
`for sodium ferric gluconate complex in sucrose
`versus iron dextrans shows that sodium ferric
`gluconate complex in sucrose is the safer formu(cid:173)
`lation, because it has a substantially lower case
`fatality rate. Given the difference in the composi(cid:173)
`tion of the two products, this result suggests that
`fatal anaphylaxis reported from intravenous iron
`products may be the result of the dextran compo(cid:173)
`nent. The finding of no deaths in 7 4 reported
`episodes of allergic reactions with sodium ferric
`gluconate complex in sucrose, compared with 31
`deaths in 196 reports for iron dextran, is suffi(cid:173)
`ciently great to overwhelm any effects due to
`differential use ( eg, age, sex, and maintenance)
`and reporting artifacts.
`The case fatality rate among iron dextran
`reports is similar to the case severity rates re(cid:173)
`ported in the literature of 20% to 29% severe-to(cid:173)
`total cases of anaphylaxis. 9•11 This similarity sup(cid:173)
`ports the study's assumption that death and severe
`reactions are reported at nearly the same rate as
`less severe allergic reactions. The sensitivity of
`
`

`

`470
`
`FAICH AND STROBOS
`
`the German and Italian reporting systems to a
`temporary increase in events also supports the
`study assumptions.
`The superior safety of sodium fe1Tic gluconate
`complex in sucrose may allow clinicians to imple(cid:173)
`ment DOQI recommendations for maintenance
`intravenous iron therapy to achieve a better out(cid:173)
`come for dialysis patients.
`
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`13. P