Nephrol Dial Transplant (2004) 19: 1571–1575
`DOI: 10.1093/ndt/gfh185
`
`Original Article
`
`Downloaded from https://academic.oup.com/ndt/article-abstract/19/6/1571/1857376 by Harvard Law School Library user on 02 October 2019
`
`On the relative safety of parenteral iron formulations
`
`Glenn M. Chertow1, Phillip D. Mason2, Odd Vaage-Nilsen3 and Jarl Ahlme´ n4
`
`1Division of Nephrology, Department of Medicine, University of California San Francisco, San Francisco, CA, USA,
`2Oxford Kidney Unit, Churchill Hospital, Oxford, UK, 3Nebo a/s, Holbaek, Denmark and 4Department of Renal
`Medicine, Skaraborgs Hospital, Sko¨ vde, Sweden
`
`Abstract
`Background. Intravenous iron is usually required to
`optimize the correction of anaemia in persons with
`advanced chronic kidney disease and end-stage renal
`disease. Randomized clinical trials may have insuffi-
`cient power to detect differences in the safety profiles
`of specific formulations.
`Methods. We obtained data from the US Food and
`Drug Administration on reported adverse drug events
`(ADEs) related to the provision of three formulations
`of intravenous iron during 1998–2000. We estimated
`the relative risks [odds ratios (OR)] of ADEs asso-
`ciated with the use of higher molecular weight iron
`dextran and sodium ferric gluconate complex com-
`pared with lower molecular weight iron dextran using
`2  2 tables.
`Results. The total number of reported parenteral iron-
`related ADEs was 1981 among 21 060 000 doses
`administered, yielding a rate of 9.4  10
`5, or 94
`per million. Total major ADEs were significantly
`increased among recipients of higher molecular
`weight iron dextran (OR 5.5, 95% CI 4.9–6.0) and
`sodium ferric gluconate complex (OR 6.2, 95% CI
`5.4–7.2) compared with recipients of lower molecular
`weight iron dextran. We observed significantly higher
`rates of
`life-threatening ADEs,
`including death,
`anaphylactoid reaction, cardiac arrest and respiratory
`depression among users of higher molecular weight
`compared with lower molecular weight iron dextran.
`There was insufficient power to detect differences in
`life-threatening ADEs when comparing lower molecu-
`lar weight iron dextran with sodium ferric gluconate
`complex.
`iron-related ADEs are rare.
`Conclusions. Parenteral
`Using observational data, overall and most specific
`
`Correspondence and offprint requests to: Glenn M. Chertow, MD,
`MPH, Department of Medicine Research, University of California
`San Francisco, UCSF Laurel Heights Suite 430, 3333 California
`Street, San Francisco, CA 94118-1211, USA. Email: chertowg@
`medicine.ucsf.edu
`
`ADE rates were significantly higher among recipients
`of higher molecular weight iron dextran and sodium
`ferric gluconate complex than among recipients of
`lower molecular weight iron dextran. These data may
`help to guide clinical practice, as head-to-head clinical
`trials comparing different formulations of intravenous
`iron have not been conducted.
`
`iron dextran; par-
`Keywords: adverse drug events;
`enteral iron; sodium ferric gluconate complex
`
`Introduction
`
`Despite the use of recombinant erythropoietin, anae-
`mia remains a significant problem for patients with
`advanced chronic kidney disease (CKD) and end-stage
`renal disease (ESRD).
`Iron deficiency commonly
`complicates both conditions, and tends to be more
`severe among individuals on haemodialysis [1]. Blood
`loss
`into the haemodialyser
`system and routine
`discarding of small aliquots (5–10 ml) of blood (in
`patients using indwelling catheters) account for a large
`fraction of the blood loss seen in the haemodialysis
`population. Occult
`gastrointestinal haemorrhage,
`anticoagulation-related blood loss and accidental
`blood loss from arteriovenous fistulae and grafts
`also contribute to blood loss and iron deficiency. On
`average, maintenance haemodialysis is associated with
`a loss of at least 1–1.5 g of elemental iron each year [2].
`Oral iron preparations have proved ineffective and
`relatively poorly tolerated in the ESRD population
`[3]. Comparative studies of oral versus parenteral
`iron administration have unequivocally established
`the superiority of intravenous preparations in replacing
`iron stores [4]. As a result, the use of parenteral
`iron in conjunction with erythropoietin has become
`standard practice in most maintenance haemodialysis
`programmes worldwide, and has been endorsed by
`professional societies in the USA, Europe and else-
`where [1,5].
`
`Nephrol Dial Transplant Vol. 19 No. 6 ß ERA–EDTA 2004; all rights reserved
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`1572
`
`During the 1980s and 1990s, several fomulations of
`iron dextran were commercially available in the USA.
`While effective at repleting iron stores, enthusiasm for
`the use of these agents was tempered by the risk of
`adverse drug events (ADEs), especially anaphylaxis,
`associated with their use. Newer, non-dextran formula-
`tions of iron have been introduced, and have been
`marketed as equally effective and safer than iron
`dextran formulations.
`Fletes et al. [6] recently reported on the frequency of
`iron dextran-related ADEs during a 6-month period
`using data derived from Fresenius Medical Care North
`America Clinical Variance Reports. In the current
`study, we aimed to extend our inquiry to the entire US
`haemodialysis population, using data reported to the
`US Food and Drug Administration (FDA) and
`obtained from the World Health Organization. Incor-
`porating reports filed during the calendar years
`1998–2000, we sought to estimate overall ADEs for
`two iron dextran preparations that differ in the molec-
`ular weight and structure of the dextran moiety (InFedÕ
`and DexferrumÕ) and for sodium ferric gluconate
`complex (FerrlecitÕ). We also sought to determine the
`relative frequency of specific ADEs. Since parenteral
`iron-related ADEs are rare, population-based cohort
`analyses are necessary to provide valid estimates of
`safety.
`
`Materials and methods
`
`iron-related ADEs reported to the FDA
`All parenteral
`during the calendar years 1998–2000 were obtained from the
`World Health Organization in Uppsala, Sweden. Deaths
`were reviewed in detail and duplicates were eliminated.
`Specific ADEs were categorized according to the FDA’s
`system organ class criteria and summarized. Detailed clini-
`cal information, including dialysis status, on the affected
`individuals was not available.
`The ADE rate was determined by dividing the number
`of overall or specific ADEs by the number of dose vials
`dispensed. The vial size of sodium ferric gluconate complex
`(62.5 mg) is lower than the vial size of the two iron dextran
`preparations (100 mg). Therefore, unadjusted ADE rates,
`and ADE rates adjusted per 100 mg of iron dispensed for the
`ferric gluconate in sucrose solution, were calculated.
`We classified 17 types of ADEs as serious ADEs. These
`included: death,
`cardiac arrest, myocardial
`infarction,
`coma, anaphylactic shock, anaphylactoid reactions, seizures,
`arrhythmia, apnoea, respiratory depression,
`tachycardia,
`bradycardia, allergic reaction, hypertension, hypotension,
`cyanosis and urticaria. We further subclassified ADEs into
`life-threatening (death, anaphylactoid reactions, cardiac
`arrest and respiratory depression) and non-life-threatening
`ADEs (all others). Low molecular weight
`iron dextran
`(InFedÕ in the USA, CosmoferÕ outside the USA) was used
`as the referent group. The relative risks [odds ratios (ORs)] of
`ADEs associated with high molecular weight iron dextran
`(DexferrumÕ)
`and sodium ferric
`gluconate
`complex
`(FerrlecitÕ) use were estimated from 2  2 tables. The level
`of statistical significance was determined by the Yates-
`corrected 2 test. Confidence intervals (CIs) were computed
`
`using the method of Fleiss [7]. Two-tailed P-values <0.05
`were considered statistically significant.
`
`G. M. Chertow et al.
`
`Results
`
`Frequency of ADEs
`
`The total number of reported parenteral iron-related
`ADEs was 1981 among 21 060 000 doses admini-
`stered, yielding a rate of 9.4  10–5, or 94 per million.
`Twenty-one individuals died in association with an
`ADE (0.0001%). The number of patients affected by
`parenteral iron-related ADEs was lower than the actual
`number of ADEs. The average number of ADEs
`reported per patient was 3.6, 3.0 and 3.1 for
`FerrlecitÕ, DexferrumÕ and InFedÕ, respectively.
`
`Relative frequency of ADEs by formulation
`
`Table 1 shows the actual number of reported ADEs
`associated with each iron formulation. The latter two
`columns show the ORs and 95% CIs for each ADE
`comparing FerrlecitÕ and DexferrumÕ with InFedÕ.
`Total ADEs were significantly increased among reci-
`pients of higher molecular weight iron dextran (OR 5.5,
`95% CI 4.9–6.0) and sodium ferric gluconate complex
`(OR 6.2, 95% CI 5.4–7.2) compared with lower
`molecular weight iron dextran. The odds of death
`associated with the use of higher molecular weight
`compared with lower molecular weight iron dextran
`was 3.6 (1.4–9.4). The risks of other specific ADEs
`(including life-threatening and non-life-threatening
`ADEs) were increased 2- to 12-fold in persons given
`higher molecular weight compared with lower mole-
`cular weight
`iron dextran. The risks of non-life
`threatening ADEs (including other allergic reactions,
`back pain, chest pain, dyspnoea and vomiting, among
`others) were increased 4- to 14-fold in persons given
`sodium ferric gluconate complex. In contrast, the risks
`of life-threatening ADEs (death, anaphylactoid reac-
`tion, cardiac arrest and respiratory depression) were
`not
`significantly different when comparing lower
`molecular weight
`iron dextran and sodium ferric
`gluconate complex, due in part to the low number of
`events. Figure 1 summarizes the overall serious ADE
`rate per million doses (normalized to 100 mg intrave-
`nous iron per dose).
`
`Inclusion of non-specified ADEs
`
`There were 221 iron dextran-related ADEs reported by
`generic name only and five iron gluconate-related
`ADEs reported by generic name only (including two
`deaths). If we were to assign all 221 iron-dextran-
`related ADEs to the low molecular weight iron dextran
`group (InFedÕ) group, we would not extinguish the
`increase in ADE risk associated with alternative
`formulations. Under these extreme assumptions, the
`OR and 95% CI for DexferrumÕ for all ADEs would
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`The relative safety of parenteral iron formulations
`
`Table 1. Major ADEs by parenteral iron formulation
`
`1573
`
`ADE
`
`FerrlecitÕ
`(n ¼ 1 083 000)
`
`DexferrumÕ
`(n ¼ 5 058 000)
`
`InFedÕ
`(n¼ 14 919 000)
`
`OR FerrlecitÕ
`vs InFedÕ
`
`OR DexferrumÕ
`vs InFedÕ
`
`Death
`Anaphylactoid reaction
`Allergic reaction
`Facial oedema
`Pruritus
`Urticaria
`Back pain
`Cardiac arrest
`Chest pain
`Tachycardia
`Hypotension
`Dyspnoea
`Respiratory depression
`Nausea
`Vomiting
`Sweating
`Total
`
`1
`3
`7
`1
`10
`5
`15
`0
`23
`2
`23
`18
`0
`15
`9
`5
`271
`
`11
`14
`4
`10
`57
`24
`94
`25
`87
`24
`72
`107
`13
`43
`23
`32
`1112
`
`9
`28
`13
`5
`19
`10
`23
`14
`33
`10
`35
`57
`7
`21
`9
`9
`598
`
`1.5 (0.1–11.7)
`1.5 (0.4–5.0)
`7.4 (2.7–19.9)
`2.8 (0.1–23.9)
`7.3 (3.1–16.4)
`6.9 (2.1–21.8)
`9.0 (4.5–17.3)
`0 (0–5.1)
`9.6 (5.5–13.8)
`2.8 (0.4–13.3)
`9.1 (5.2–15.8)
`4.4 (2.5–7.6)
`0 (0–10.8)
`9.8 (4.8–19.9)
`13.8 (5.0–37.7)
`7.7 (2.2–24.9)
`6.2 (5.4–7.2)
`
`3.6 (1.4–9.4)
`1.5 (0.7–2.9)
`0.9 (0.3–3.0)
`5.8 (1.9–19.7)
`8.8 (5.1–15.4)
`7.0 (3.2–15.7)
`12.1 (7.5–19.5)
`5.3 (2.6–10.7)
`7.8 (5.5–11.8)
`7.0 (3.2–15.7)
`6.1 (4.0–9.3)
`5.5 (4.0–7.7)
`2.3 (1.0–4.9)
`6.0 (3.5–10.5)
`7.5 (3.3–17.4)
`10.5 (4.8–23.6)
`5.5 (4.9–6.0)
`
`Two additional deaths were reported in association with iron dextran (formulation unknown). If the additional deaths were associated with
`InFedÕ, the OR and 95% CI for FerrlecitÕ vs InFedÕ would be 1.3 (0.1–9.3).
`
`Total reported serious ADEs
`per million doses of 100 mg
`57.9
`
`49.6
`
`11.6
`
`Dexferrum®
`
`Ferrlecit®
`
`INFeD®
`
`60
`
`50
`
`40
`
`30
`
`20
`
`10
`
`0
`
`Fig. 1.
`
`be reduced to 4.0 (3.7–4.3), and for FerrlecitÕ to 4.6
`(4.0–5.3).
`
`Consideration of alternative vial size and total ADEs
`
`The results outlined above normalize results per
`100 mg iron equivalent. If one were to assume that
`FerrlecitÕ were administered only in 62.5 mg incre-
`ments, then the OR and 95% CI per dose (rather than
`per 100 mg) would be reduced from 6.2 (5.4–7.2) to 4.2
`(3.6–4.9). If one were to assume that Ferrlecit were
`administered only in 125 mg increments, then the OR
`and 95% CI per dose would be increased to 7.8
`(6.7–9.0).
`
`Discussion
`
`The efficacy of parenteral iron in supporting erythro-
`poiesis is indisputable [1]. While several reports on the
`safety data of parenteral iron preparations have been
`published, the study designs and clinical settings have
`varied widely. Older studies included solely non-ESRD
`patients and many described ADEs with formulations
`of intravenous iron that are no longer commercially
`available [8]. Few studies have directly compared
`different formulations of parenteral iron until recently
`[9,10].
`Fletes et al. [6] aimed to determine the incidence
`iron dextran-related ADEs in clinical practice,
`of
`and to attempt to characterize risk factors and describe
`outcomes associated with iron dextran-related ADEs.
`The authors identified 165 suspected ADEs among
`841 252 intravenous
`iron dextran administrations
`during a 6-month study period, corresponding to
`an overall rate of 0.000196%, or 20 per 100 000
`doses. While some differences between the cases
`and the >85 000 patient cohort were statistically
`significant,
`the authors were unable to identify
`clinically significant differences in patient characteris-
`tics associated with iron dextran-related ADEs. A
`post hoc analysis revealed an 8-fold higher ADE rate
`associated with the use of the higher molecular weight
`iron dextran formulation (DexferrumÕ) that could not
`be explained by differences in patient or facility
`characteristics.
`McCarthy et al. [11] described iron dextran-related
`ADEs during 665 courses of parenteral iron dextran
`given to 254 patients over a 5-year period. The
`higher molecular weight iron dextran was associated
`with a significantly higher ADE rate than a lower
`molecular weight formulation, with rates of 11 out of
`197 (5.6%) vs 10 out of 468 (2.1%) (P ¼ 0.02). There
`were no differences
`in haemoglobin or
`serum
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`1574
`
`ferritin concentrations (i.e. efficacy) between the two
`groups.
`More recently, Michael et al. [12] reported on the
`results of a placebo-controlled randomized trial using
`sodium ferric gluconate complex (FerrlecitÕ) in hae-
`modialysis patients. Overall event rates were extremely
`low. Compared with placebo, there was a significant
`increase in drug intolerance associated with FerrlecitÕ
`administration (intolerance defined as an ADE pre-
`cluding re-exposure). The authors reported a highly
`significant difference in ADE rates between iron
`dextran and sodium ferric gluconate complex (2.47 vs
`0.44%, P<0.0001). These findings led the authors to
`state that ‘routine use of iron dextran in hemodialysis
`patients should be discontinued’.
`A more careful examination of the control studies
`is warranted. Four studies were pooled in what the
`authors described as a meta-analysis, although no
`information was provided on study quality, hetero-
`geneity or other factors that might indicate appropri-
`ateness for meta-analytic study. Hamstra et al.
`[8]
`reported on the frequency of life-threatening events
`occurring in 471 patients and 10 prisoners with iron
`deficiency, with or without other non-renal auto-
`immune or inflammatory diseases. This study used
`ImferonÕ, a high molecular weight
`iron dextran
`formulation that was recalled by the FDA in 1990,
`and soon after withdrawn from the market. The doses
`of iron dextran given in this study were typically in the
`250–500 mg range. A second control formulation was
`FeridexÕ, an aqueous colloid of superparamagnetic
`iron oxide associated with dextran used as a radio-
`contrast medium (for magnetic resonance imaging)
`[13]. FeridexÕ has never been used therapeutically for
`correction of iron deficiency anaemia or in the context
`of ESRD. Indeed, publications describing the efficacy
`of Feridex in imaging have concentrated on persons
`with focal hepatic lesions (e.g. hepatocellular carci-
`noma, hepatic metastases) [14]. Faich and Strobos [15]
`refer to unpublished data from a 100-hospital network
`database, where the authors considered the simulta-
`neous administration of iron dextran and intravenous
`epinephrine during hospitalization as an ADE. The
`authors provided no detail on the five alleged events,
`and failed to distinguish among different iron dextran
`formulations. The fourth control was a well-conducted
`open label trial of a lower molecular weight iron
`dextran formulation (InFedÕ) in 573 haemodialysis
`patients treated over a 2-year period [16]. Twenty-seven
`of 573 (4.7%) patients experienced ADEs, of which
`four
`(0.7%) were classified as
`serious
`(requiring
`hospitalization). While the ADE rate appears higher,
`the unit of evaluation was the patient, rather than a
`dose, as in the study of Michael et al. [12]. If one were to
`conservatively estimate the number of doses of iron
`dextran administered over 2 years at 20 per patient
`(providing 1 g of elemental iron per year, less than usual
`losses), then the overall ADE rate per dose of iron
`dextran would be 0.24%. The rate of iron dextran-
`related ADEs precluding re-exposure
`from the
`Fishbane et al. study was not calculated, but was
`
`G. M. Chertow et al.
`
`probably <0.24%. In contrast, 3.9% of subjects who
`received a single dose of sodium ferric gluconate
`complex (FerrlecitÕ) in the study of Michael et al. [12]
`experienced an ADE considered by the investigator to
`be possibly or probably related to the study drug, a
`value
`significantly higher
`than placebo (2.5%,
`P ¼ 0.0006).
`Multiple investigators have explored the associations
`among laboratory proxies of iron status and out-
`comes in the haemodialysis population, and have
`generally shown hyperferritinaemia to be associated
`with increased mortality and morbidity. Whether this
`association relates to iron overload or associated
`inflammation is unclear. Fewer
`epidemiological
`studies have focused on the provision of intravenous
`iron and associated outcomes. Feldman et al.
`[17]
`reported an 11% increase in the risk of death and 12%
`increase in the risk of hospitalization associated with
`the provision of >10 vials of intravenous iron over a
`6-month period in a study of >5000 patients with
`ESRD in the USA. The formulations used in this study
`were not reported.
`Immediate or short-term toxicities of iron have been
`attributed jointly to the effect of free iron on oxidative
`stress, and the relative protective and allergic effects of
`the carbohydrate shields (e.g. dextran, gluconate and
`sucrose). The most comprehensive experimental study
`in this area was published by Zager et al. [18] who
`compared three commercially available iron formula-
`tions (low molecular weight iron dextran and sodium
`ferric gluconate complex, described above, along with
`iron sucrose) and iron oligosaccharide, on in vitro
`proxies of oxidative injury. Briefly, all parenteral agents
`were pro-oxidant, although the relative effects of
`different
`formulations depended on the particular
`experimental model
`tested. While provocative,
`the
`experimental data available to date cannot explain the
`findings we have observed.
`There are several
`important limitations to these
`analyses. We had no detailed clinical information on
`the patients treated with parenteral iron. We could not
`learn whether the patients treated had ESRD, CKD or
`other conditions associated with iron deficiency (e.g.
`blood loss due to menorrhagia) and inflammation (e.g.
`rheumatoid arthritis and other autoimmune diseases).
`However, patients on haemodialysis account for the
`vast majority of intravenous iron infused in the USA
`(A. J. Collins, personal communication). Confounding
`by indication or provider preference cannot be ruled
`out, but is unlikely to account for a multiple fold
`increase in the risk of parenteral iron-related ADEs.
`The differences between higher and lower molecular
`weight iron dextran formulations have been identified
`previously [6,11]. It is possible that clinicians may have
`been more vigilant with patients exposed to sodium
`ferric gluconate complex (FerrlecitÕ) since this agent
`had not been widely used in ESRD, so that the fraction
`of cases reported may have been higher. However, a
`reporting bias is unlikely to explain the large observed
`inter-agent differences. Given the voluntary nature
`of ADE reporting,
`it is likely that all ADEs were
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`References
`
`1. NKF-K/DOQI Clinical Practice Guidelines for Anemia of
`Chronic Kidney Disease: update 2000. Am J Kidney Dis 2001;
`37 [1 Suppl 1]: S182–S238
`2. Nissenson AR, Strobos J. Iron deficiency in patients with renal
`failure. Kidney Int Suppl 1999; 69: S18–S21
`3. Wingard RL, Parker RA, Ismail N, Hakim RM. Efficacy of
`oral
`iron therapy in patients receiving recombinant human
`erythropoietin. Am J Kidney Dis 1995; 25: 433–439
`4. Macdougall IC. Strategies for iron supplementation: oral versus
`intravenous. Kidney Int Suppl 1999; 69: S61–S66
`5. Horl WH,
`Jacobs C, Macdougall
`IC, Valderrabano F,
`Parrando I, Thompson K. European best practice guidelines
`14–16: inadequate response to epoetin. Nephrol Dial Transplant
`2000; 15 [Suppl 4]: 43–50
`6. Fletes R, Lazarus JM, Gage J, Chertow GM. Suspected iron
`dextran-related adverse drug events in hemodialysis patients.
`Am J Kidney Dis 2001; 37: 743–749
`7. Fleiss JL. Confidence intervals for the odds ratio in case–control
`studies: the state of the art. J Chronic Dis 1979; 32: 69–77
`8. Hamstra RD, Block MH, Schocket AL. Intravenous iron
`dextran in clinical medicine. J Am Med Assoc 1980; 243:
`1726–1731
`9. Kosch M, Bahner U, Bettger H, Matzkies F, Teschner M,
`Schaefer RM. A randomized, controlled parallel-group trial on
`efficacy and safety of iron sucrose (Venofer) vs iron gluconate
`(Ferrlecit)
`in haemodialysis patients treated with rHuEpo.
`Nephrol Dial Transplant 2001; 16: 1239–1244
`safety of
`10. Fishbane S, Kowalski EA. The
`comparative
`intravenous iron dextran, iron saccharate, and sodium ferric
`gluconate. Semin Dial 2000; 13: 381–384.
`11. McCarthy JT, Regnier CE, Loebertmann CL, Bergstralh EJ.
`Adverse events
`in chronic hemodialysis patients
`receiving
`intravenous iron dextran—a comparison of two products. Am J
`Nephrol 2000; 20: 455–462
`12. 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 2002; 61:
`1830–1839
`13. http://www.berleximaging.com/pdf/Feridex.pdf
`14. Schultz JF, Bell JD, Goldstein RM, Kuhn JA, McCarty TM.
`Hepatic tumor imaging using iron oxide MRI: comparison with
`computed tomography, clinical impact, and cost analysis. Ann
`Surg Oncol 1999; 6: 691–698
`15. Faich G, Strobos J. Sodium ferric gluconate complex in
`sucrose: safer intravenous iron therapy than iron dextrans. Am
`J Kidney Dis 1999; 33: 464–470
`16. Fishbane S, Ungureanu VD, Maesaka JK, Kaupke CJ, Lim V,
`Wish J. The safety of intravenous iron dextran in hemodialysis
`patients. Am J Kidney Dis 1996; 28: 529–534
`17. Feldman HI, Santanna J, Guo W et al. Iron administration and
`clinical outcomes in hemodialysis patients. J Am Soc Nephrol
`2002; 13: 734–744
`18. Zager RA, Johnson AC, Hanson SY, Wasse H. Parenteral iron
`formulations: a comparative toxicologic analysis and mechan-
`isms of cell injury. Am J Kidney Dis 2002; 40: 90–103
`19. http://www.accessdata.fda.gov/scripts/medwatch/
`20. Lasser KE, Allen PD, Woolhandler SJ, Himmelstein DU,
`Wolfe SM, Bor DH. Timing of new black box warnings and
`withdrawals for prescription medications. J Am Med Assoc
`2002; 287: 2215–2220
`
`Received for publication: 10.11.03
`Accepted in revised form: 4.2.04
`
`The relative safety of parenteral iron formulations
`
`underascertained, especially more minor ADEs. Major
`ADEs, such as those listed in Table 1, would be more
`likely to be reported under any circumstances. We did
`not include data on iron sucrose, since it was rarely
`used during the time frame studied. These analyses
`should be updated after sufficient patient-years of iron
`sucrose exposure. Finally,
`the data used for the
`analyses were not derived from a randomized clinical
`trial. However, for exceptionally rare events such as
`serious parenteral
`iron-related ADEs, data from
`ongoing clinical practice may be more sound than
`data from clinical trials, since the power of clinical trials
`to detect rare but clinically important events is usually
`severely limited. These results highlight the importance
`of ongoing vigilance and active reporting of ADEs [19].
`Lasser et al. [20] showed that >10% of drugs approved
`by the FDA between 1975 and 1999 either acquired a
`new black box warning, or were withdrawn from the
`market.
`In summary, using data obtained from the FDA
`Medwatch programme, we demonstrated an increase in
`the risk of ADEs when comparing higher vs lower
`molecular weight iron dextran formulations, and when
`comparing sodium ferric gluconate complex with lower
`molecular weight iron dextran. While the absolute
`ADE risk was low, the magnitude of the increased risks
`exceeded what might be expected from confounding or
`reporting biases. Since large-scale, long-term clinical
`trials comparing various parenteral iron formulations
`may not be practical (due to limited power and great
`expense), these data may be used to guide clinical
`decision making. We identified no benefit and an
`increase in risk associated with higher molecular weight
`relative to lower molecular weight iron dextran. We
`were unable to confirm or refute the contention that
`non-dextran formulations of parenteral
`iron are
`associated with a reduced risk of death, anaphylactoid
`reactions, cardiac arrest or respiratory depression.
`Additional research will be required to determine the
`optimal formulation, dose and schedule of parenteral
`iron in haemodialysis patients.
`
`Acknowledgements. Presented in part as an oral communication
`at the World Congress of Nephrology, Berlin, Germany (June 9,
`2003).
`
`Conflict of interest statement. O.V.-N. is employed by Nebo a/s, a
`Danish company responsible for the marketing of CosmoFerÕ, a
`lower molecular weight iron dextran. O.V.-N. was included as a
`co-author of the manuscript with the unanimous approval of the
`other authors, because of his intellectual contributions. G.M.C.
`conducted the statistical analyses, and the authors collectively were
`responsible for data interpretation, without influence by O.V.-N. or
`any other employee or affiliate of Nebo a/s.
`
`PGR2020-00009
`Pharmacosmos A/S v. American Regent, Inc.
`Petitioner Ex. 1032 - Page 5
`
`