Internal Medicine Journal 39 (2009) 252–255
`
`B R I E F C O M M U N I C AT I O N
`Delayed adverse reactions to total-dose intravenous
`iron polymaltose
`M. L. Haines1,2 and P. R. Gibson1,2
`
`1Department of Gastroenterology and Hepatology, Monash University, Melbourne, and 2Department of Medicine, Box Hill Hospital, Melbourne,
`Victoria, Australia
`
`Key words
`iron deficiency, adverse effects, intravenous
`iron.
`
`Correspondence
`Peter Gibson, Department of Medicine, Box Hill
`Hospital, Box Hill, Victoria 3128, Australia.
`Email: peter.gibson@med.monash.edu.au
`
`Received 4 February 2008; accepted 12 July
`2008.
`
`doi:10.1111/j.1445-5994.2009.01898.x
`
`Abstract
`
`The rate of infusion reactions to total-dose intravenous iron polymaltose is
`very low, but the frequency and severity of adverse reactions following the
`infusion are unknown. In 50 consecutive patients, adverse reactions devel-
`oped up to 2 days after the infusion in 26% and lasted 1–8 days (median 4).
`Severe systemic reactions occurred in 8%. Patients should be warned of the
`chance of delayed reactions and an alternative iron preparation should be
`considered if parenteral iron is again indicated.
`
`Iron deficiency is a common clinical finding in gastroen-
`terology patients, as a result of occult or overt gastrointes-
`tinal bleeding and/or impaired iron absorption secondary
`to coeliac disease or systemic inflammation.
`Iron is
`an essential element involved in oxygen transport and
`storage, growth, immune defence, energy metabolism
`and DNA synthesis. Chronic fatigue, frequently caused by
`anaemia, has a significant effect of the quality of life of
`patients with inflammatory bowel disease (IBD) and
`may debilitate patients as much as abdominal pain and
`diarrhoea.1
`There are several strategies for iron repletion with both
`oral and parenteral routes of administration. Despite
`relative ease of administration, oral iron is limited by
`poor absorption, intolerance and induction of oxidative
`inflammation.2,3 Common
`stress at the site of bowel
`gastrointestinal side-effects include nausea, bloating,
`diarrhoea, constipation and abdominal pain,4,5 which
`may lead to poor compliance.
`
`Funding: ML Haines was in receipt of a Pharmatel-Fresenius-
`Kabi Fellowship.
`Potential conflicts of interest: PR Gibson has consulted for
`Aspen Pharmacare Pty Ltd.
`
`252
`
`Intravenous iron replacement therapy can be used to
`replenish iron stores in iron deficient patients with or
`without coexisting anaemia. Parenteral
`iron obviates
`the need for absorption, can be given in large doses
`and it may reduce inflammation through inhibition
`interferon-g activity and reduction of circulating levels of
`tumour necrosis factor-a and peroxides.6 The types of
`parenteral
`iron preparations available vary across the
`world, but, in Australia, only iron polymaltose and iron
`sucrose are available, the latter being used in the event of
`intolerance to iron polymaltose.
`Iron polymaltose is very similar to iron dextran in terms
`of stability and structure, but is rarely associated with the
`problem of anaphylaxis that led to the withdrawal of iron
`dextran from the market. A major advantage of iron
`polymaltose is that it can be administered at high single
`doses (total-dose therapy). Administration requires long
`infusion times of up to 4–5 h, but adverse reactions asso-
`ciated with the infusion itself are very uncommon, occur-
`ring in 3.6% and necessitating cessation of the infusion in
`less than one in 60.7 Furthermore, there is no apparent
`need for premedication with corticosteroids and antihis-
`tamines as was routine with the use of iron dextran.
`Product information on iron polymaltose describes
`possible adverse effects of its use, but states that they are
`reported infrequently. Anecdotal experience suggests
`
`© 2009 The Authors
`Journal compilation © 2009 Royal Australasian College of Physicians
`
`Pharmacosmos A/S v. Luitpold Ex. Pharmaceuticals, Inc., IPR2015-01490
`
`Luitpold Pharmaceuticals, Inc., Ex. 2042, P. 1
`
`

`
`Table 1 Adverse reactions reported in the 8 days following a total-dose iron polymaltose infusion
`
`Adverse reaction
`
`n (% reactions)
`
`Headache
`Nausea and/or vomiting
`Chills and fevers
`Arthralgia
`Faintness
`Rash
`Dizziness
`Total
`
`10 (31)
`7 (22)
`6 (19)
`4 (13)
`2 (6)
`2 (6)
`1 (3)
`32
`
`Mild
`
`3
`2
`2
`2
`2
`2
`1
`14 (44%)
`
`Safety of intravenous iron polymaltose
`
`Severity
`
`Moderate
`
`4
`3
`2
`1
`0
`0
`0
`10 (31%)
`
`Severe
`
`3
`2
`2
`1
`0
`0
`0
`8 (25%)
`
`that, delayed systemic reactions, such as headaches,
`dizziness, syncope, arthralgia, chills, fever and myalgia,
`may occur, but their frequency and severity of such reac-
`tions have not been determined.
`The aim of this study was to evaluate prospectively the
`post-infusion safety and tolerability of intravenous iron
`polymaltose administered as a total-dose infusion in
`gastroenterology patients with iron deficiency.
`Consecutive gastroenterology patients who received
`iron polymaltose as a total-dose infusion in the period
`from March 2007 to February 2008 were included in this
`prospective audit. Medical records were reviewed and
`patient characteristics recorded including age, sex, cause
`of iron deficiency, concomitant medications and dose of
`iron polymaltose administered. Previous adverse reac-
`tions to iron polymaltose were noted. Laboratory values
`pre-infusion were recorded: haemoglobin, mean cell
`volume, platelets, iron, transferrin, transferrin saturation,
`ferritin and C-reactive protein.
`The treating physician (M. L. H.) contacted all patients
`by telephone 8 days following the iron infusion and
`enquired about adverse events, including time of onset
`after the infusion, duration and severity. Severity was
`graded as mild, moderate and severe according to the
`following criteria: (i) mild reactions resulted in no limi-
`tation of daily activities, (ii) moderate reactions caused
`limitation of daily activities, including ability to work,
`and (iii) severe reactions were those in which patients
`were confined to bed and/or medical attention sought.
`Fifty patients received iron polymaltose as a total-dose
`infusion during the study period. The dose administered
`was weight-based and no pre-medications were used.
`The median age was 43 years (range 18–87) and 60%
`were women. Iron deficiency was confirmed biochemi-
`cally in all patients and was due to Crohn’s disease in 21
`(42%), ulcerative colitis in 8 (16%), coeliac disease in 3
`(6%), gastric ulceration in 4 (8%) and a gastric angio-
`dysplasia in 1 (2%). The cause of iron deficiency was yet
`to be determined in 13 (26%).
`
`© 2009 The Authors
`Journal compilation © 2009 Royal Australasian College of Physicians
`
`There were two minor infusion-related reactions,
`neither requiring discontinuation of the infusion. There
`was a total of 32 adverse reactions by 13/50 (26%)
`patients during the week following intravenous iron
`polymaltose and these are shown in Table 1. Eight reac-
`tions (25%) were classified as severe, 10 (31%) moderate
`and 14 (44%) mild. Six adverse events started 2 days and
`12 started 1 day after the infusion, while 12 started on
`the same day of the infusion. The median duration of
`adverse events was 4 days (range 1–8) and all reactions
`completely resolved.
`Baseline characteristics and laboratory values of those
`who did and did not have an adverse reaction are shown
`in Table 2. A significantly higher number of patients who
`had a reaction were female (85%). The dose of iron
`received and previous iron infusion had no impact on the
`rate of adverse events. Previous experience of iron poly-
`maltose infusion was not necessarily predictive of the
`presence or absence of adverse reactions as shown in
`Table 2. Current steroid use offered little protection
`against the development of side-effects.
`
`Table 2 Comparison of demographics and laboratory values between
`patients who did and did not report an adverse reaction to total-dose iron
`polymaltose infusion
`
`No reaction
`
`Reaction
`
`Number of patients (%)
`Male (%)
`Mean age (range), years
`Mean dose iron polymaltose (range), g
`Previous iron polymaltose (%)
`Without reaction
`With reaction
`Current prednisolone use (%)
`Mean haemoglobin (g/L)
`Mean platelet count
`C-reactive protein > 5 mg/L (%)
`
`37 (74)
`18 (49)
`49 (23–87)
`1.6 (1–2)
`12 (32)
`11
`1
`9 (24)
`120
`316 ¥ 109/L
`11 (30)
`
`*P = 0.034 compared with no reaction (Fisher’s exact test).
`
`13 (26)
`2 (15)*
`36 (18–70)
`1.6 (0.8–2)
`5 (38)
`3
`2
`2 (15)
`123
`359 ¥ 109/L
`2 (15)
`
`253
`
`Pharmacosmos A/S v. Luitpold Ex. Pharmaceuticals, Inc., IPR2015-01490
`
`Luitpold Pharmaceuticals, Inc., Ex. 2042, P. 2
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`

`
`Haines & Gibson
`
`Four patients (8%) had severe adverse reactions
`following parenteral iron. Patient 1 was an 18-year-old
`woman with coeliac disease who had not had a pre-
`vious infusion. She developed a headache, nausea and
`vomiting and fevers 2 days after her iron infusion,
`which persisted for 5 days. She saw her general practi-
`tioner and was unable to attend university. Patient 2
`was a 36-year-old woman with iron deficiency of
`unknown cause. The day of her iron infusion she devel-
`oped a headache, chills, arthralgia, faintness and a slight
`rash. She was confined to bed for 8 days. Patient 3 was
`a 48-year-old woman with Crohn’s disease who had
`had several iron polymaltose infusions in the past with
`no previous adverse reaction. Two days after the infu-
`sion she developed a headache, nausea, vomiting, faint-
`ness, dizziness and a rash, which persisted for 1 week.
`She contacted the hospital several times during that
`week and saw her general practitioner. She was con-
`fined to bed for 3 days. She has subsequently had two
`infusions with iron sucrose without side-effects. Simi-
`larly, patient 4 was a 19-year-old man with Crohn’s
`disease who had no reaction to previous parenteral
`iron. Shortly after his infusion, he developed a severe
`headache and arthralgia, which lasted 1 day only. He
`was kept an extra several hours in hospital for obser-
`vation because of these reactions.
`Total-dose intravenous iron polymaltose is used widely
`throughout Australia, and locally the rate of infusion
`reactions is low.7 This is the first series to document the
`incidence of post-infusion reactions, which was high at
`26%. Four patients (8%) had severe reactions, which
`resulted in incapacity and/or the need to seek medical
`attention. Many of the reactions started as late as 2 days
`after the iron infusion and lasted up to 8 days.
`The nature and timing of the symptoms experienced
`indicated that they were likely to be caused by the infu-
`sion and not be associated with the underlying or inter-
`current illness. Over half of the patients had IBD, which
`potentially might make the patients more susceptible to
`systemic inflammatory reactions from the intravenous
`iron, but the rate of adverse effects was similar in patients
`with non-inflammatory disease. The relatively small
`number of patients audited might also lead to error in the
`frequency of adverse events, but it was a 1-year experi-
`ence and the frequency of events was sufficiently high to
`raise concern.
`There are four implications of these findings:
`1. In advising the use of parenteral iron, patients should
`be warned of the possibility of transient adverse events in
`the week after the infusion and they should be encour-
`aged to report them to the attending clinician.
`2. Previous uneventful iron infusions do not guarantee
`freedom from adverse effects on subsequent infusions.
`
`254
`
`iron should be
`3. Alternative sources of parenteral
`considered if iron deficiency recurs. Iron sucrose has an
`excellent safety record and post-marketing surveillance
`safety reports show that it is the safest parenteral iron
`complex available.8 However, total-dose infusions are not
`possible as only up to 300 mg or 7 mg/kg are considered
`safe and tolerable.9,10 In patients with IBD-associated
`anaemia more than 1000 infusions have been given in
`trials without major side-effects.11–13
`4. This unexpected frequency of adverse events should
`not deter clinicians from the use of intravenous iron, as
`the problems associated with oral
`iron replacement
`therapy, including poor compliance, high rate of side-
`effects and slow and inadequate iron repletion, far out-
`weigh the chance of transient, albeit occasionally severe
`adverse effects from a therapy that ensures iron repletion.
`
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`© 2009 The Authors
`Journal compilation © 2009 Royal Australasian College of Physicians
`
`Pharmacosmos A/S v. Luitpold Ex. Pharmaceuticals, Inc., IPR2015-01490
`
`Luitpold Pharmaceuticals, Inc., Ex. 2042, P. 3
`
`

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`© 2009 The Authors
`Journal compilation © 2009 Royal Australasian College of Physicians
`
`255
`
`Pharmacosmos A/S v. Luitpold Ex. Pharmaceuticals, Inc., IPR2015-01490
`
`Luitpold Pharmaceuticals, Inc., Ex. 2042, P. 4