`INTRAVENOUS USE: A SHORT REPORT TO THE WORLD HEALTH ORGANIZATION
`ADVISORY COMMITTEE ON THE SAFETY OF MEDICINES.
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`From: Peter I Folb
`Date: 18th October 2004
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`Background
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` 1. At a meeting of the WHO Expert Committee on the Use of Essential Medicines, held
` some time early in 2004 or late 2003, it was decided to delete iron dextran from the
`WHO list of Essential Medicines. It is understood that the decision was not based on
`evidence, and it is assumed but not verified that the misgivings of the expert committee
`would have been with the safety of iron dextran administered parenterally. No
`replacement for iron dextran was recommended by the expert committee.1 The WHO
`Advisory Committee on the Safety of Medicines is seeking the evidence for such a
`decision and recommendations for replacement of iron dextran by an alternative
`formulation of iron for intravenous use, provided the evidence would support such a
`recommendation. The formulation concerned would be likely to be iron sucrose for
`intravenous administration.2 In preparing this report a full literature search has been
`conducted, and Meyler’s Side Effects of Drugs 14th and 13th editions were consulted.
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`2. Parenteral iron is probably used too widely; there are few indications for its prescription.
`These include: intractable gastrointestinal intolerance to the oral product, hyperemesis
`in pregnancy, very severe blood loss, and possibly ulcerative colitis. A low iron binding
`capacity (due for example to prior saturating iron therapy or malnutrition), folic acid
`deficiency and an allergic constitution predispose the patient to adverse reactions to
`parenteral iron3.
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`Safety profiles of iron dextran and of iron sucrose
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`3.
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`Fletes et al (2001) have reported on iron dextran-related adverse drug events following
`intravenous iron dextran administrations in the United States between October 1998
`and March 1999. Of 841 252 IV iron dextran administrations to patients with end-
`stage renal disease there were 165 reported suspected adverse drug events,
`corresponding to an overall rate of 0.000196%, or approximately 20 per 100 000 doses.
`18 patients (11%) required hospitalisation and 1 patient (0.6%) died. Dyspnoea
`(43%), hypotension (23%), and neurological symptoms (23%) were the most common
`major ADEs. In summary, when used strictly for the right indication serious adverse
`reactions to IV iron dextran are rare. Iron dextran-related ADEs are difficult to predict.
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`1 Email dated March 02, 2004 from Dr Mary Couper to members of the WHO advisory committee on the safety of
`medicines.
`2 This report will not deal further with intramuscular administration of iron formulations, the use of which is becoming
`obsolete because of their adverse safety profile.
`3 Refer Meyler’s Side Effects of Drugs 13th edition p596 and 14th edition p699.
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`In a web site posted statement on the safety of iron sucrose for intravenous
`administration 4 , it is clear that the overall experience with IV iron sucrose is
`considerably less than with iron dextran. Exposure to the drug (as Venofer) has been
`documented in 231 patients undergoing chronic haemodialysis in clinical trials and in
`1 051 patients undergoing haemodialysis in two post-marketing safety studies. As at
`10.10.2004, the safety of intravenous iron sucrose (as Venofer) had been documented
`in a total of 1 282 patients. Two (2) patients have experienced mild or moderate
`hypersensitivity reactions.
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`In a North American clinical trial of the safety and efficacy of iron sucrose for iron
`deficiency in patients with dialysis-associated anaemia there were no serious adverse
`drug reactions to IV iron sucrose in 77 enrolled patients, including those with previous
`iron dextran sensitivity (the number of the latter is not clear), other drug allergies, or
`concurrent angiotensin-converting enzyme inhibitor use (iron sucrose was administered
`in this study as 1 000 mg in 10 divided doses by IV push, without a test dose)
`(Charytan C et al., 2001).
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`In a review Bailie et al (2000) suggest, but fail to establish, that iron sucrose and iron
`gluconate may have less adverse effect profiles when compared with iron dextran.
`They point out that additional clinical experience is required to establish the role for
`these new iron products (Bailie et al, 2000).
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`Hoigne et al (1998), in reviewing the experience of patients exposed to iron hydroxide
`sucrose complex given intravenously (altogether around 8 100 patient-years were
`assessed, with exposure to approximately 160 000 ampoules of iron sucrose, each
`containing 100 mg elementary iron) not a single life threatening reaction was observed.
`The authors suggest that the relatively good tolerance to intravenous iron sucrose in
`patients with chronic renal insufficiency may be due either to reduced immune
`competence in patients with chronic renal insufficiency and/or to the preparation itself,
`or probably both. Their findings need confirmation.
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`Faich and Strobos (1999) have reviewed 74 allergic adverse events attributed to
`sodium ferric gluconate complex and reported to the WHO, German Health Bureau, and
`the manufacturer (combined). An adverse event reporting rate of 3.3 allergy episodes
`per million doses per year over the period 1976 to 1996 was compared with 8.7
`reported allergy events per million doses per year with iron dextran in the United
`States in 1996. There were no case fatality reports for sodium ferric gluconate over
`the entire period; for iron dextrans over the same period there was a case fatality rate
`of 15.8% of 196 allergy/anaphylaxis cases. The authors concluded that sodium ferric
`gluconate is safer than iron dextrans as an iron replacement agent. However, the
`difficulty with the conclusion is that the extent of use of the two preparations would
`have been quite different; in 1996 an estimated 3 million doses of iron dextran were
`given, but the figure for other iron preparations for IV use is not known.
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`9.
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`Other reports attesting to the safety of iron sucrose are those of: van Wyck et al
`(2000) – no serious adverse drug reactions in a total of 223 doses of iron sucrose, 184
`by IV push, 39 intravenously; Hudson and Comstock (2001); Nissenson and Charytan
`(2003) – they find that further prospective work is necessary to determine whether iron
`sucrose and iron gluconate are safer than iron dextran in dialysis patients; Charytan et
`al (2004), who found that iron sucrose is safe and well tolerated in haemodialysis
`patients intolerant to iron dextran or sodium ferric gluconate (there were 130 such
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`4 Refer: www.rxlist.com/cgi/generic2/venofer_ad.htm (last accessed 18th October 2004).
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`patients intolerant to other iron preparations, none of whom suffered a serious reaction
`to iron sucrose); Bastani et al (2004) who describe in a retrospective study the
`incidence of side effects with high-dose ferric gluconate complex in sucrose (Ferrlecit)
`in patients with severe chronic renal failure (they found that significant untoward
`reactions occurred in 10-30% of patients in a dose-dependent fashion – altogether 40
`treatments were analysed in this study); Breymann et al (2001) who found that iron
`sucrose was safe given with adjuvant recombinant erythropoietin for the treatment of
`resistant iron-deficiency anaemia during pregnancy resistant to orally administered iron
`given alone; Bastani et al (2002), who found that 5 patients who had previously had a
`severe, potentially life threatening reaction to intravenous iron dextran preparation
`tolerated iron sucrose with no untoward effects; Coyne et al (2003), who found that of
`143 patients who had previously been intolerant to iron dextran and were exposed to
`sodium ferric gluconate complex 3 had a suspected allergic event, including 1 with a
`serious reaction (0.7%) but there were no serious adverse events in 2 194 iron
`dextran-tolerant patients, and a history of dextran sensitivity also predisposed to
`allergic reactions to placebo in 2 patients – the results suggested host idiosyncrasy;
`Fishbane (2003) who in a review article suggested that iron sucrose and sodium ferric
`gluconate have more favourable safety profiles than iron dextran; Eichbaum et al
`(2003), who found no difference in the number of adverse reactions to iron dextran
`given by infusion (total number of reactions 20.5% of 39 infusions in 32 patients, 2.6%
`severe) and iron gluconate (total number of reactions 23% of 26 infusions in 4 patients,
`0% severe); Chertow et al (2004) who found an estimated 94 adverse reactions
`reported with parenteral iron preparations, but no significant difference between the
`different formulations of iron (high molecular weight iron dextran, lower molecular
`weight iron dextran, and sodium ferric gluconate complex) – they point out that head
`to head comparative clinical trials have not been conducted.
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`It would be important to know whether the basis of the severe adverse allergic
`reactions experienced with iron dextran are attributable to the dextran component. If
`that were the case, formulations without dextran might be expected to be safer.
`However, the situation is not that clear. The following is understood:
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`i.
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`ii.
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`iii.
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`Patients with a history of allergy may be at risk of developing undesired
`immunological reactions such as asthma attacks, following parenteral iron
`administration; however, the incidence of such reactions seems to be low,
`and the risk probably also exists with other iron compounds as well (Meyler
`14th edition, page 701).
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`Iron toxicity may be expected if the amount of free iron that is released into
`the plasma exceeds plasma iron-binding capacity (this is more likely to occur
`when using iron sorbitol – citric acid complex (iron sorbitex), since the iron is
`less firmly bound than with iron dextran (Meyler 14th edition, page 701).
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`Several conditions associated with low iron-binding capacity such as
`malnutrition and previous or simultaneous oral iron therapy appear to
`predispose to these toxic reactions. In addition, folic acid deficiency has
`been reported to be a predisposing factor (Side Effects of Drugs, Annual 9,
`516); the likely mechanism here is a disturbance of iron utilization secondary
`to folic acid deficiency that results in an increased saturation of iron-binding
`capacity.
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`Mechanisms and risk situations
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`10.
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`iv.
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`their
`in
`formulations differ experimentally
`iron
`Different parenteral
`comparative toxicity and potential for cytotoxicity in a manner that is related
`directly to the potential of the iron contained in them to cause free radical
`generation and severe adenosine triphosphate depletion; iron sucrose has
`greater potential for that than iron dextran (Zager et al, 2002).
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`Conclusions and recommendations
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`11.
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`In the absence of head-to-head comparative clinical trials it cannot be stated with
`confidence that iron sucrose (or any other formulation of iron for intravenous
`administration) is clearly safer than iron dextran. At least part of the negative safety
`record of iron dextran is linked with its extensive use over the past 30 to 40 years.
`From this record it can be said that the incidence of severe adverse effects is roughly
`quantifiable, and is not negligible (vide supra). The outcome of anaphylactic reactions
`to iron dextran is occasionally fatal. Although fatal anaphylactic reactions to iron
`sucrose do not appear to have been described, and they have been with iron dextran,
`this does not necessarily mean that they would not occur in comparable numbers if the
`extent of use of iron sucrose and iron dextran, respectively, were similar.
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`12. Although dextran itself is immunogenic, and potentially responsible for allergic
`reactions including anaphylaxis and anaphylactoid reactions, the mechanism(s) of
`toxicity of iron dextran are not necessarily attributable to its dextran component.
`Equally, or more, likely would be the availability of free iron after administration.
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`13. Comparisons of the safety of iron dextran for intravenous administration with other iron
`formulations do not allow of a clear recommendation in favour of iron sucrose, even
`though it might be argued that there is a prima facie case. It is noted that in a
`number of publications the authors suggest that further work would be necessary for
`this matter to be resolved.
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`14.
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`In general, intravenous (and other parenteral) administration of iron appears to be
`excessive and not justified by the indications, which are strictly limited. A public health
`initiative aimed at reducing the number of severe adverse reactions to parenteral iron
`would require a stricter approach to the indications for use of parenteral iron
`administration.
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`4
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`Acknowledgment
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`The author is grateful to Joe Talmud, Medicines Information Centre of the University of Cape
`Town, for his assistance in compiling the background literature for this report.
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`REFERENCES
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`
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`Bailie GR, Johnson CA, Mason NA (2000). Parenteral iron use in the management of anemia in
`end-stage kidney disease patients. Am. J. Kidney Dis., 35, 1-12.
`
`Bastani B, Rahman S, Gellens M (2002). Lack of reaction to ferric gluconate in haemodialysis
`patients with a history of a severe reaction to iron dextran. ASAIO J., 48, 404-406.
`
`Bastani B, Jain A, Pandurangan G (2003). Incidence of side-effects associated with high-dose
`ferric gluconate in patients with severe chronic renal failure. Nephrology, 9, 47-48.
`
`Breymann C, Visca E, Huch R and Huch A (2001). Efficacy and safety of intravenously
`administered iron sucrose with and without adjuvant recombinant human erythropoietin for the
`treatment of resistant iron-deficiency anemia during pregnancy. Am. J. Obstet. Gynecol., 184,
`662-667.
`
`Charytan C, Levin N, Al-Saloum M, Hafeez T, Gagnon S, Van Wyck DB (2001). Efficacy and
`safety of iron sucrose for iron deficieincy in patients with dialysis-associated anemia : North
`American clinical trial. Am. J. Kidney Dis., 37, 300-307.
`
`Charytan C, Schwenk MH, Al-Saloum MM, Spinowitz BS (2004). Safety of iron sucrose in
`haemodialysis patients intolerant to other parenteral iron products. Nephron Clin Pract., 96, 63-
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`
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`Chertow GM, Mason PD, Vaage-Nilsen O, Ahlmen J (2004). On the relative safety of parenteral
`iron formulations. Nephrol. Dial. Transplant, 19, 1571-1575.
`
`Eichbaum Q, Foran S, Dzik S (2003). Is iron gluconate really safer than iron dextran? Blood,
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`Faich G, Strobos J (1999). Sodium ferric gluconate complex in sucrose: safer intravenous
`therapy than iron dextrans. Am. J. Kidney Dis., 33, 464-470.
`
`Fishbane S (2003). Safety in iron management. Am. J. Kidney Dis., 41(5), 18-26.
`
`Fletes R, Lazarus JM, Gage J, Chertow GM (2001). Suspected iron dextran-related adverse drug
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`
`Hoigne R, Breymann C, Kunzi UP, Brunner F (1998). Parenteral iron therapy: problems and
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`
`Hudson JQ, Comstaock TJ (2001). Considerations for optimal iron use for anemia due to chronic
`kidney disease. Clin. Ther., 23, 1637-1671.
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`Nissenson AR, Charytan C (2003). Controversies in iron management. Kidney Int. Suppl.,
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`Van Wyck DB, Cavallo G, Spinowitz BS, Adhikaria R, Gagnon S et al (2000). Safety and efficacy
`in patients sensitive to iron dextran: North American clinical trial. Am. J. Kidney Dis., 36, 88-97.
`
`Zager RA, Johnson AC, Hanson SY, Wasse H (2002) Parenteral iron formulations: a comparative
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