Nephrol Dial Transplant 12000 15 :lditorial Comments (cid:9)
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`1743
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`Nephrol Dial Transplant r20001 15 743-1745
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`Intravenous administration of iron in epoetin-treated hae odia ysis
`patients—which drugs, which regimen?
`
`lain C. Macdougall
`
`Department of Renal Medicine, King's College Hospital, London, UK
`
`Introduction
`
`There has been a plethora of literature on iron manage-
`ment in erythropoietin ( Epo)-trea ted patients in recent
`times [1-9]. This includes published original clinical
`research [ l-3], state-of-the-art reviews [4-7], and clin-
`ical guidelines generated by advisory committees on
`both sides of the Atlantic [8,9]. If we were to summar-
`ize in one statement the main message from all this
`literature we would conclude: 'still no reliable laborat-
`ory test for iron deficiency; oral iron of limited use;
`need for regular and frequent i.v. iron in the majority
`of patients on Epo'.
`With all this published information, why then have
`the editors felt the need to commission yet another
`article'? (The request was for 'a short and snappy piece
`that can be read over a cup of coffec'! E. Ritz, personal
`communication.) Is the message recommending the
`regular use of i.v. iron not now universally accepted
`and adopted'? A recent analysis of HCFA data in the
`USA suggests otherwise [10], and data from the
`recently published European Survey on Anaemia
`Management (ESAM) are similarly pessimistic [t I ].
`The aim of this article is, however, not to report the
`benefits of i.v. iron, nor the indications for its use, but
`rather to discuss the different preparations available
`and the various treatment regimens.
`
`Are all i.v. iron preparations the same?
`
`There are at least four different i.v. iron preparations
`available worldwide: iron dextran, iron sucrose, iron
`gluconate, and iron dextrin (polymaltose). All of these
`have very different molecular weights, physico-
`chemical characteristics, degradation kinetics, and side-
`effect profiles [12]. Even within these classes, there are
`differences, e.g. the two iron dextran preparations
`marketed in the USA (Dexferrum and INFeD) have
`molecular weights of 265 and 90 kDa respectively [13].
`Iron sucrose is a smaller molecule (43 kDa), and there
`is some controversy regarding the molecular size of
`iron gluconate. Geisser et al. found it to be about
`37 kDa [14], while Nissenson ct aL reported a molecu-
`lar weight of 350 kDa [15].
`
`Correspondence and offprint requests to: Dr lain C. Macdougall,
`Renal Unit, King's College Hospital, East Dulwich Grove, London
`SE22 lIFT , UK.
`
`All the i.v. iron preparations have in common a
`central core containing elemental iron, shielded by a
`carbohydrate shell. Once injected in vivo, the iron—car-
`bohydrate complex is metabolized (probably in the
`reticulo—endothelial system), the iron is released where
`it then binds to transferrin in plasma, and the redundant
`carbohydrate moiety is then cleared via the liver. The
`degradation of the various iron complexes is, however,
`very different. In general, iron is most rapidly released
`from thc smaller molecular weight compounds, and is
`released more slowly from the iron dextran preparations
`[12]. This property therefore determines the maximum
`dose that can be administered at any one time. For
`example, up to 1000 mg or more of iron dextran may
`he given as a single dose; the maximum dose of iron
`sucrose is 500 ma, and that of iron gluconate is 125 mg.
`If too much i.v. iron is given all at once, there is a
`danger that the iron will be released from the complex
`too rapidly and overload the buffering capacity of the
`transferrin molecule to bind it. This may result in 'free
`iron' reactions [16] which are anaphylactoid in nature.
`Although the symptoms/signs are similar, they must not
`be confused with the more severe and life-threatening
`anaphylactic reactions seen in a small proportion of
`patients given i.v. iron dextran [17,18]. This latter
`complication is peculiar to iron dextran, and is due to
`an immune-mediated reaction in patients who have
`dextran antibodies. Since there have been fatalities with
`iron dextran [17], and now that there are alternative
`iron preparations available, dextran-containing iron
`compounds should be used only when absolutely neces-
`sary. For patients who have had a previous iron dextran
`reaction, it is perfectly safe to give an alternative iron
`preparation since the allergy is specific to the dextran
`portion of the molecule [19].
`
`Which i.v. iron preparation to use?
`
`The choice of i.v. iron preparation will be influenced
`by various factors. First, not all preparations are
`available in every country (although availability is
`increasina all the time). Secondly, the patient popula-
`tion will determine which i.v. iron can be used:
`although it is practical to give haemodialysis patients
`a dose once-weekly, or even thrice-weekly durina dia-
`lysis, such a regimen would be impossible in pre-
`dialysis or peritoneal dialysis patients. Thirdly, treat-
`ment regimens involving at least once-weekly dosing
`
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`1744
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`can utilize any iv. iron preparation: those involving
`once-monthly (cid:9)
`;tre lL (cid:9)
`iitahle 1)1- iron gluon-
`ate due to Ifw limitations on maximum dose. Few
`studies ha (cid:9)
`c,mq):i red the solely and efficacy of thc
`different (cid:9)
`iroa compounds. and those that have
`been done show little difference [20]. Iron dextran has
`the polenfial problem of anaphylactic reactions [17,18],
`iron glucona le may cause 'free iron' reactions [16],
`and although iron dextrin (polymaltose) is widely used
`in France and Australia it is licensed only for intramus-
`cular Ilse and not for i.v. administration. Iron sucrose
`has an excellent safety record, and mid-range doses
`(up to 500 mg ) can be given to pre-dialysis and periton-
`eal dialysis patients. Doses up to 300 mg may be safely
`given over 2 h [21], but doses of 500 mg should be
`administered as an infusion over 3.5 h or longer.
`
`Ncphrol Dial Transplant (20001 15: Editoria Comments
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`dialysate over a 6-month period. The requirements for
`i.v. iron were dramatically reduced in this group
`(10 +23 mg/week; 2 of 10 patients) compared with a
`control group continuing on i.v, iron dextran
`(56 +37 mg/week; 11 of 11 patients), and no significant
`adverse effects ere seen [29].
`For pre-dialysis and peritoneal dialysis patients, the
`preferred treatment regimen for i.v. iron is a larger
`dose given less often, e.g. once a month. This is both
`to reduce the inconvenience of frequent visits to hos-
`pital, and to preserve the veins for possible future
`vascular access. Doses of 300 mg iron sucrose infused
`over 2 h have proved to be a safc and effective treat-
`ment regimen [21].
`
`Need for a test dose?
`
`Which treatment regimen to use?
`
`There are two ways of administering i.v. iron, either
`as a 'push' (bolus) or as an infusion. Clearly the bolus
`injection has the benefit of simplicity and avoids the
`need for infusion pumps, bags of saline, and infusion
`lines. Doses of 100 mg of either iron dextran [22] or
`iron sucrose [23] may be given safely as a 'push'. Until
`further data are available, larger doses must be admin-
`istered as an infusion, usually over 2-3 h.
`For haemodialysis patients, there is greater flexibility
`with the dosing regimen. Some units use very low
`doses of iron (20-60 mg) given every dialysis session
`[24], others use doses of 100 mg given every week [23],
`while yet others administer doses of 200-300 mg every
`month [25]. Clearly the intensity of dosing will depend
`on the perceived iron deficit; in some cases aggressive
`iron administration will be required to correct absolute
`iron deficiency, while in other instances smaller doses
`may be used as maintenance iron supplementation.
`There is some debate about whether frequent low-dose
`i.v. iron administration is safer than less frequent high
`doses. In a retrospective analysis of claims data from
`Medicare dialysis patients, Collins et al. [26] found a
`significant relationship between the frequency of i.v.
`iron dosing and increased risk of death from infection.
`In a subsequent analysis, again using Medicare claims
`data, the same workers reported a significantly higher
`risk of infection-related death in patients who received
`more than 17 vials of iron during a 6-month period
`[27]. Banyai et al. [28] found higher levels of bleomy-
`cin-detectable free iron (BDI) in haemodialysis
`patients given doses of 100 mg iron sucrose, compared
`with those obtained after 10, 20, 40, and 50 mg.
`Theoretically, these higher levels of BDI could predis-
`pose the patient to reactions and infections; however,
`there is no evidence that this is relevant clinically.
`Recently, Gupta et al. [29] reported a novel means
`of supplying iron to the haemodialysis patient, namely
`by adding soluble iron pyrophosphate to the dialysate.
`This mode of administration was assessed in 10 haemo-
`dialysis patients who received increasing concentra-
`tions of iron pyrophosphate up to 121.1g/di in the
`
`One of the greatest farces in iron management is the
`usc of a test dose of i.v. iron sucrose or gluconate in
`patients receiving their first exposure to the prepara-
`tion. The Drug Regulatory Authorities have dcmandcd
`it; many doctors do not use it. Historically, this has
`dated from the recognition that iron dextran induces
`a low but significant incidence of anaphylactic reactions
`[17,18]. Thus, although a test dose is entirely appro-
`priate for iron dextran, unfortunately this practice has
`been extrapolated to other (non-dextran-containing)
`i.v. iron preparations. The anaphylactic reaction is,
`however, specific for the dextran-containing iron pre-
`parations, and there is no cross-reactivity with iron
`sucrose or gluconate. Regrettably, the habit has stuck,
`and it is clearly much harder to persuade the
`Regulatory Authorities that a test dose is not required,
`than it would be to introduce this concept in the
`first place.
`The use of a test dose for iron sucrose or gluconate
`is, however, irrational and unscientific for several
`reasons. First, there are no documented antibodies
`against sucrose or gluconate as there are for dextran.
`Secondly, despite over 40 years' experience with i.v.
`iron sucrose and gluconate, fatalities with these pre-
`parations have not been reported as they have for iron
`dextran. Thirdly, the likelihood of a patient developing
`an allergic reaction to i.v. iron sucrose or gluconate is
`much less than for certain other drugs such as i.v.
`penicillin or vancomycin, but no test dose is specified
`for these latter compounds. Fourthly, the lack of any
`reaction to a test dose does not mean the patient will
`not have a reaction in the future; dextran-induced
`anaphylaxis has been described in patients who have
`received several previous doses of i.v. iron dextran
`with no problems [30]. Finally, the practice of using a
`test dose can lull the doctor or nurse into a false sense
`of security, i.e. since the patient has been fine, the
`clinician feels more relaxed about using i.v. iron. As
`such, therefore, the use of a test dose may be more
`hazardous than not using it at all. A more sensible
`and rational approach would bc to abandon the test
`dose for iron sucrose and gluconate, while retaining
`the necessary caution in all patients receiving i.v. iron,
`
`Pharmacosmos A/S v. Luitpold Ex. Pharmaceuticals, Inc., IPR2015-01490
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`
`Nerhrcf D d Tmu (cid:9)
`
`(2000) 1 5 • Editorial Comments
`
`including lIic iced for full icsuscitation facilities being
`m.ailable on•site. Persuading the Regulatory
`Authorities or this, however, may Like some time, and
`in the meantime, test doses will continue to be used in
`some units and not others.
`
`Conclusions
`
`Intrav nous iron supplementation has quite rightly
`grown in popularity in Epo-treated patients over the
`last decade. It is etTective in correcting the commonest
`cause of a poor response to Epo, and its aggressive
`use can reduce Epo dose requirements [1,2]. There
`have, however, been few randomized controlled studies
`of i.v, iron in this setting, and much of our practice
`has been g_uided by anecdotal reports and personal
`experience.
`We need more information on whether frequent low-
`dose administration is preferable (or harmful ), and
`what the optimum ferritin is in patients on Epo. In
`addition, there is a need to investigate the maximum
`dose of iron that can be given safely as an i.v. bolus
`since, with the increasing use in pre-dialysis patients,
`prolonged infusions are costly and impractical. In the
`meantime, the most important message to get across
`in the light of the recent FICFA and ESAM data
`analyses [10,11] is the need for regular and frequent
`i.v. iron supplementation in patients receiving Epo;
`which drug and which treatment regimen are secondary
`considerations.
`
`Acknowledgement. I am grateful to my secretary, Christine Mitchell,
`for help in the preparation of this manuscript,
`
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