Internal Medicine Journal 36 (2006) 672–674
`
`B R I E F C O M M U N I C AT I O N
`
`Safety of iron polymaltose given as a total dose iron infusion
`E. Newnham,1 I. Ahmad,2,3 A. Thornton4 and P. R. Gibson1,4
`
`Departments of 1Gastroenterology and 3Medicine, Box Hill Hospital and 2Department of Gastroenterology, Maroondah Hospital and
`4Department of Gastroenterology, Frankston Hospital, Melbourne, Victoria, Australia
`
`Key words
`safety, anaphylaxis, total dose iron infusion,
`iron deficiency, premedication
`
`Correspondence
`Peter Gibson, Department of
`Gastroenterology, Box Hill Hospital, Box Hill,
`Vic. 3128, Australia.
`Email: peter.gibson@med.monash.edu.au
`
`Received 7 December 2005; accepted 12
`February 2006.
`
`doi:10.1111/j.1445-5994.2006.01156.x
`
`Abstract
`
`An audit of the in-hospital safety and tolerability of 401 infusions of iron
`polymaltose in 386 patients has shown no cases of anaphylaxis or other
`cardiorespiratory compromise. The infusion was terminated prematurely
`because of adverse events in six patients (1.6%). No adverse events occurred
`within the first 15 min of the infusion. Premedication (in 24%) was not
`associated with fewer adverse events. Fear of anaphylaxis should not inhibit
`the use of total dose iron infusion and the practices of premedication and of
`medical supervision during the first 15 min of the infusion should be abandoned.
`
`Iron deficiency is a common finding among hospitalized
`patients. Efficient iron replacement can result in improved
`cardiac function, reduced length of stay in the hospital and
`improved quality of life in those with congestive heart
`failure1,2 whereas oral iron replacement in deficient ado-
`lescents has resulted in improved cognitive function.3 Iron
`deficiency is both underrecognized4 and undertreated in
`patients in hospitals.5
`Current published guidelines regarding iron repletion
`strategies favour oral iron in all patients unless ‘there is
`an intolerance to at least two oral preparations or non-
`compliance’.6 However, the use of oral iron, although easy
`and convenient, is limited by such factors as absorption and
`side-effects (experienced in up to 40% of patients), which
`lead to poor adherence.7–9 Oral iron supplementation has
`been shown to be ineffectual in patients with chronic kidney
`disease10 whereas the cytokine milieu in chronic inflam-
`matory conditions results in poor iron absorption through
`mechanisms mediated by interleukin-6 and hepcidin.11
`Parenteral iron therapy enables a large dose to be given
`and obviates the need for absorption. This is particularly
`important in circumstances where there are ongoing
`
`Funding: I. Ahmad was in receipt of a Pfizer-Altana Gastroenter-
`ology Fellowship.
`Potential conflicts of interest: P. R. Gibson has participated in one
`Advisory Board meeting for Baxter Healthcare/Vifor in 2002.
`
`672
`
`gastrointestinal losses and/or there is an impaired absorp-
`tion, such as in inflammatory bowel disease.12 The reluc-
`tance to recommend parenteral iron as a primary therapy
`appears to stem at least partly from concerns regarding its
`safety. Iron polymaltose delivered i.m. is not a preferred
`option because it requires a deep injection using ‘Z tech-
`nique’ to avoid skin pigmentation, resultant disfigure-
`ment and subsequent medicolegal claims13 and may be
`complicated by sterile abscesses, pain or even sarcoma14 at
`the injection site. Furthermore, at 100 mg per 2 mL injec-
`tion, repeated injections are usually required to reach
`target iron repletion.
`Intravenous iron does not share these local complica-
`tions and, in some forms, can be given as a total dose
`infusion where iron stores can be repleted in a single
`treatment episode. Apart from the greater cost of such
`a therapy over oral iron, concerns are mainly about its
`safety, particularly anaphylaxis or anaphylactoid reactions.
`These reactions are reported to be more common in
`patients receiving therapy with angiotensin-converting
`enzyme (ACE) inhibitors.15 Because of the perceived dan-
`gers, direct supervision during the first 15 min of the
`infusion is recommended. In addition, a premedication
`of a corticosteroid with or without an antihistamine is often
`used, but this practice is not based on published evidence.
`The aims of the present study were to evaluate the safety
`and tolerability of iron polymaltose given as a total dose
`
`ª 2006 The Authors
`Journal compilation ª 2006 Royal Australasian College of Physicians
`
`Pharmacosmos A/S v. Luitpold Ex. Pharmaceuticals, Inc., IPR2015-01490
`
`Luitpold Pharmaceuticals, Inc., Ex. 2043, P. 1
`
`

`
`iron infusion across three Melbourne teaching hospitals
`and to examine the need for premedication and intensive
`medical monitoring.
`The medical records of 401 patients having total dose
`iron infusions with iron polymaltose undertaken at three
`Melbourne teaching hospitals over the same 2-year
`period (from August 2002 to August 2004) were
`reviewed. The indication, tolerance, safety and dosage
`of i.v. iron were examined in the records. The indication
`for each infusion was recorded. To provide an insight into
`the patient characteristics and the potential influence of
`concomitant medication, the referring unit and details of
`current medications were also recorded in the Box Hill
`Hospital cohort. The type and dosage of premedication (if
`used) were also recorded. Any reaction noted in the
`patient’s observation chart during or after the infusion
`while the patient remained at the hospital was defined as
`an adverse reaction. The study was carried out according
`to the National Health and Medical Research Council
`guidelines for clinical audit. Proportions were examined
`by v2 analysis (Microstat 4.1; Ecosoft, Indianapolis, IN,
`USA, 1984). A P-value less of 0.05 or less was considered
`significant.
`The protocol used for the administration of iron poly-
`maltose was similar across the three hospitals, except for
`the use of premedication. At the Maroondah and Frank-
`ston hospitals, premedication was routinely used, whereas
`it was applied at Box Hill Hospital only if requested by the
`attending physician. For each infusion, the dose was cal-
`culated from standardized charts using the patient’s
`weight and haemoglobin and infused as per hospital pro-
`tocol.16 The infusion of iron polymaltose (Baxter Health-
`care, Sydney, Australia, or Sigma Pharmaceuticals,
`Melbourne, Australia) was given in 500 mL 150 mmol/L
`NaCl, and started at 40 mL/h under the direct supervision
`of a medical practitioner for the first 15 min. If no adverse
`reactions were noted, the infusion rate was increased to
`120 mL/h after 50 mL had been given and further super-
`
`Safety of i.v. iron polymaltose
`
`vision was provided by nursing staff. The patient was
`observed for 1 h after completion of the infusion.
`In all, 401 infusions were examined in 386 patients.
`The median age was 74 years (range, 17–96 years) and
`60% were women. The mean dosage given was 1338 mg
`(range, 800–2350 mg). Iron deficiency had been biochemi-
`cally proven in all patients in the setting of known blood
`loss in 181 (45%), anaemia where the cause had yet to be
`definitively determined in 92 (23%), inflammatory bowel
`disease in 56 (14%), chronic kidney disease in 40 (10%) of
`whom none was receiving dialysis, coeliac disease in 16
`(4%) and cancer in 16 (4%). At Box Hill Hospital, 46% of
`infusions were initiated by the Gastroenterology Unit,
`26% by the General Medicine unit, 15% by the Renal
`Medicine unit, 10% by the Oncology/Haematology unit
`with the remaining 3% shared by several units. The use
`of i.v. iron varied markedly across hospitals with 27 infu-
`sions at Frankston Hospital, 77 at Maroondah Hospital and
`297 at Box Hill Hospital over the same 2-year period.
`Adverse reactions were noted in 22 (5.7%) patients.
`These are listed in Table 1. No patient receiving more than
`one infusion experienced an adverse reaction. In six
`(1.6%) patients, the reaction was significant enough to
`warrant cessation of the infusion. The most common
`adverse reaction was a rash (usually urticarial in nature).
`The most serious adverse reaction was a seizure in a patient
`with known epilepsy. No cases of anaphylaxis or anaphy-
`lactoid reactions were recorded. None of the adverse
`reactions observed occurred in the first 15 min of infusion.
`Interestingly, three patients with an urticarial rash went
`on to complete an otherwise uneventful infusion.
`In 294 (77%) patients, no premedication was used. Of
`the 92 infusions where premedication was given, three
`received hydrocortisone (100 mg) alone and 89 a combi-
`nation of hydrocortisone and promethazine (20 mg).
`Adverse events occurred in 6 (6.5%) patients who received
`premedication, compared with of 16 (5.4%) patients who
`did not (P = 0.45).
`
`Table 1 Adverse events and the need to cease the infusion of iron polymaltose according to the use of premedication or not
`
`Reaction
`
`All infusions (n = 386)
`
`With premedication (n = 92)
`
`Without premedication (n = 294)
`
`No. patients
`
`Infusion ceased
`
`No. patients
`
`Infusion ceased
`
`No. patients
`
`Infusion ceased
`
`Rash
`Nausea/light-headedness
`Chest pain
`Cannula site reaction
`Fever
`Myalgia
`Seizure
`Headache
`Total
`
`6
`5
`3
`2
`2
`2
`1
`1
`22
`
`3
`1
`1
`—
`—
`—
`1
`—
`6
`
`2
`2
`—
`—
`1
`—
`1
`—
`6
`
`—
`—
`—
`—
`—
`—
`1
`—
`1
`
`4
`3
`3
`2
`1
`2
`—
`1
`16
`
`n is the number of patients. No adverse events occurred in seven patients who received more than one infusion.
`
`3
`1
`1
`—
`—
`—
`—
`—
`5
`
`ª 2006 The Authors
`Journal compilation ª 2006 Royal Australasian College of Physicians
`
`673
`
`Pharmacosmos A/S v. Luitpold Ex. Pharmaceuticals, Inc., IPR2015-01490
`
`Luitpold Pharmaceuticals, Inc., Ex. 2043, P. 2
`
`

`
`Newnham et al.
`
`Of the 294 patients in whom medication charts were
`reviewed, 42 (14.3%) were receiving therapy with ACE
`inhibitors or angiotensin II receptor antagonists. None of
`these patients experienced an adverse reaction to i.v. iron.
`Fear of anaphylaxis or anaphylactoid reactions has been
`a significant factor against learned advice regarding treat-
`ment choices in repleting iron stores. In clinical practice,
`such fears have probably also limited the use of i.v. iron in
`the management of iron deficiency. The marked hetero-
`geneity in the use of i.v. iron within the same 2-year period
`across the three hospitals in the one city may have at least
`partly reflected this fear.
`Much of the published work regarding anaphylaxis
`centres on experience with iron dextran with rates of
`anaphylaxis reported to be as high as 0.6% with adverse
`reactions seen in up to 26%.17,18 These reactions are
`thought to be mediated by a preformed Immunoglobulin
`E antibody to the dextran moiety. Because of these reac-
`tions and unacceptable fatalities, iron dextran was with-
`drawn from the market.
`The experience of the present study indicates that total
`dose infusion of iron polymaltose is a well-tolerated and
`safe means of repleting iron. The incidence of adverse
`reactions is small (3.6%), much lower than the reported
`incidence with iron dextran. Most of the reactions seen
`were minor and resulted in cessation of the infusion in less
`than one in 60 infusions. The taking in of ACE inhibitors
`did not identify an at-risk group, although the numbers
`were small. The delayed effects of iron infusions some-
`times seen (such as myalgias and headaches) were not
`examined as the primary aim was to assess the immediate
`safety and tolerability. Although the number of infusions
`reviewed in our audit is modest and may not detect a small
`incidence of anaphylaxis, we have continued to use i.v.
`iron polymaltose because of the completion of our formal
`study without the occurrence of any serious adverse
`events in 140 infusions.
`Infusion protocols demand that medical staff be in
`attendance for the initial period (usually 15 min) of the
`infusion. This is based on the need for rapid institution of
`emergency therapy if anaphylaxis occurs. In the setting of
`a busy general hospital, such a practice is impractical,
`inconvenient and a potential source of treatment delay
`and frustration while the day procedure staff wait for the
`doctor to arrive. The findings of the present study argue
`that such a practice is no longer necessary. Furthermore,
`the use of premedication is also part of routine protocols in
`many centres. There can be no justification for continuing
`this unnecessary practice.
`In conclusion, treatment of iron deficiency with a total
`dose infusion of iron polymaltose is a safe and well-
`tolerated means of iron repletion. Fear of anaphylaxis should
`no longer limit its use. There would appear to be no justifi-
`
`674
`
`cation for the use of premedication when giving iron poly-
`maltose i.v. and the practice of intense medical monitoring
`over the first 15 min of the infusion should be abandoned.
`
`References
`
`1 Silverberg DS, Wexler D, Iaina A. The importance of anemia
`and its correction in the management of severe congestive
`cardiac failure. Eur J Heart Failure 2002; 4: 681–6.
`2 Nordyke RJ, Kim JJ, Goldberg GA, Vendiola R, Batra D,
`McCamish M et al. Impact of anemia on hospitalization time,
`charges and mortality in patients with heart failure. Value
`Health 2004; 7: 464–71.
`3 Bruner AB, Joffe A, Duggan AK, Casella JF, Brandt J.
`Randomised study of cognitive effects of iron
`supplementation in non-anaemic iron deficient adolescent
`girls. Lancet 1996; 348: 992–6.
`4 Smieja MJ, Cook DJ, Hunt DL, Ali MA, Guyatt GH. Can Med
`Assoc J 1996; 155: 691–6.
`5 Ahmad I, Gibson PR. Management of iron deficiency in
`patients admitted to hospital: time for a rethink of treatment
`principles. Intern Med J 2006; 36: 347–54.
`6 Goddard AF, McIntyre AS, Scott BB. Guidelines for the
`management of iron deficiency anaemia. Gut 2000; 46
`(Suppl. 4): S1–5.
`7 Schindler E, Scholz S, Boldt J, Zuckman B, Knothe C,
`Dietrich G et al. Effectiveness of oral vs parenteral iron
`substitution in autologous blood donors. Infusionstherapie
`und Transfusionmedizin 1994; 21: 236–41.
`8 Macdougall IC. Strategies for iron supplementation: oral vs.
`intravenous. Kidney Int 1999; 55 (Suppl. 69): S61–6.
`9 De Silva AP, Mylonaki M, Rampton DS. Oral iron therapy in
`inflammatory bowel disease: usage tolerance and efficacy.
`Inflamm Bowel Dis 2003; 9: 316–20.
`10 Wingard RL, Parker RA, Ismail N, Halim RM. Efficacy
`of oral iron therapy in patients receiving recombinant
`human erythropoietin. Am J Kidney Dis 1995; 25: 433–9.
`11 Ganz T. Hepcidin, a key regulator of iron metabolism and
`mediator of anaemia of inflammation. Blood 2003; 102:
`783–8.
`12 Gasche C. Anaemia in IBD: the overlooked villain?
`Inflamm—Bowel Dis 2000; 6: 142–50.
`13 Aders H. The stain that lasts. United J 2005; Autumn: 19–20.
`14 Greenberg G. Sarcoma after intramuscular iron injection.
`BMJ 1976; 1: 1508–9.
`15 Rolla G, Bucca C, Brussino L. Systemic reactions to
`intravenous iron therapy in patients receiving angiotensin
`converting enzyme inhibitor. J Allergy Clin Immunol 1994;
`93: 1074–5.
`16 Anon. Ferrum H injection. In: MIMS Annual. 29th edn.
`St Leonards, NSW: CMPMedica. 2005; 734–6.
`17 Hamstra RD, Block MH, Shockey AL. Intravenous iron
`dextran in clinical medicine. JAMA 1980; 243: 1726–31.
`18 Silverstein SB, Rodgers GM. Parenteral Iron therapy
`options. Am J Hematol 2004; 76: 74–8.
`
`ª 2006 The Authors
`Journal compilation ª 2006 Royal Australasian College of Physicians
`
`Pharmacosmos A/S v. Luitpold Ex. Pharmaceuticals, Inc., IPR2015-01490
`
`Luitpold Pharmaceuticals, Inc., Ex. 2043, P. 3