IMPROVING OUTCOMES IN DIALYSIS PATIENTS
`
`The Comparative Safety of Intravenous Iron Dextran, Iron
`Saccharate, and Sodium Ferric Gluconate
`
`Steven Fishbane and Edward A. Kowalski
`Division of Nephrology, Department of Medicine, Winthrop-University Hospital, Mineola, New York
`
`ABSTRACT
`
`Intravenous iron treatment is an important component of anemia
`therapy for patients on dialysis. Until recently iron dextran was
`the only parenteral form of iron available in the United States.
`This drug has been associated with occasional serious adverse
`reactions, including full-blown anaphylaxis. In 1999 the Food
`
`and Drug Administration approved a second form of iron for
`intravenous administration, sodium ferric gluconate in sucrose.
`It is expected that by the time of this publication, a third agent,
`iron saccharate will also be approved. In this review the com-
`parative safety of these three agents is critically evaluated.
`
`Intravenous (IV) iron therapy is an important tool uti-
`lized by nephrologists to improve the response of hemo-
`dialysis patients to recombinant human erythropoietin
`therapy (rHuEPO). A large body of literature supports
`the efficacy of this treatment (1–9), and it is accepted that
`most hemodialysis patients require regular dosing with
`IV iron to achieve a target hematocrit value of 33–36%
`(10). In contrast to the efficacy of IV iron therapy, which
`has been clearly demonstrated, the safety of such therapy
`has been incompletely studied. The purpose of this ar-
`ticle is to compare the relative safety of three forms of IV
`iron—iron dextran, sodium ferric gluconate, and iron
`saccharate. To do so requires a clear definition of the
`aspects of safety that will be reviewed. We intend to
`narrow the scope of this discussion to adverse reactions
`occurring within the first 24–72 hr after treatment. The
`literature is best able to objectively define the risk for
`such reactions. We will avoid analyzing the risk for po-
`tential longer-term safety issues such as iron overload,
`infection, cardiovascular risk, and oxidative vascular
`properties. The literature in general remains sparse on
`these subjects, and is especially weak on the relative
`risks of the individual drugs.
`Before discussing the risks associated with IV iron
`therapy it is necessary to briefly conceptualize the ben-
`efits of such therapy and the resulting risk-reward equa-
`tion. Most of the benefit of iron repletion derives from
`the ability to consistently achieve higher hematocrit and
`hemoglobin levels. The National Kidney Foundation Di-
`alysis Outcomes Quality Initiative (NKF-DOQI) guide-
`lines state that, “To achieve and maintain a Hct of 33%–
`36%. . .most hemodialysis patients will require intrave-
`
`Addresscorrespondenceto:Steven Fishbane, MD, 222 Sta-
`tion Plaza North, Suite 510, Mineola, NY 11501.
`Seminars in Dialysis—Vol 13, No 6 (November/December)
`2000 pp. 381–384
`
`nous iron on a regular basis” (10). Hematocrit values in
`that range have been associated with a lower risk of
`mortality and hospitalization (11–13). The potential to
`achieve these improved outcomes, and the greater quality
`of life associated with higher hematocrits has led expert
`panels to place far greater weight on the benefits of IV
`iron therapy, in relation to the risks (10,14).
`
`Iron Dextran
`
`Much of our knowledge relating to safety issues with
`IV iron treatment comes from clinical experience and
`research studies utilizing iron dextran. Most nephrolo-
`gists who frequently prescribe this drug can vividly re-
`call the occasional severe reactions they have witnessed.
`The stereotypical reaction occurs rapidly, often while
`syringe and needle are still engaged with the dialysis
`tubing. The patient describes flushing, lightheadedness,
`backache, and a feeling of impending doom. There is
`often a decrease in blood pressure, which can be severe,
`and rarely respiratory failure may develop.
`The dramatic nature of the reactions probably leads
`clinicians to overestimate the reaction risk. Two studies
`have attempted to quantitate the actual frequency. Ham-
`stra et al. (15) studied 481 subjects including nonuremic
`patients and normal volunteers. There were three life-
`threatening anaphylactoid reactions, representing a rate
`of 0.6% of the patients treated. Our group retrospectively
`studied 573 consecutive hemodialysis patients treated
`with IV iron dextran at four geographically dispersed
`dialysis units. The methodology employed, chart abstrac-
`tion, would tend to underestimate minor reactions, while
`offering a reasonably accurate estimation of severe reac-
`tions. We found that 10 patients (1.7%) experienced re-
`actions that had features suggestive of anaphylaxis. Only
`4 patients, or 0.7%, had reactions that were potentially
`life threatening. Of interest, a history of multiple drug
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`382
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`Fishbane and Kowalski
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`allergies was a strong predictor of subsequent reactions
`to iron dextran. However, the negative predictive value
`of an absent history of drug allergies was not strong
`enough to be very useful clinically (16).
`It appears consistent from the two studies that the per
`patient risk of a life-threatening reaction is on the order
`of 0.6–0.7%. If 100,000 hemodialysis patients were
`treated with IV iron dextran per year in the United States,
`then the number of such severe reactions would be on the
`order of 600–700. Faich and Strobos (17) recently re-
`ported that during the period 1976–1996 there were 31
`deaths reported in the United States due to iron dextran.
`Clearly one could speculate that this problematic safety
`profile might hinder the ability to achieve the targets set
`forth by the NKF-DOQI anemia guidelines.
`The cause of these immediate severe reactions with
`iron dextran is incompletely understood. Many of the
`signs and symptoms are consistent with, if not charac-
`teristic, anaphylaxis. Yet immunologic studies have not
`definitively proven this to be true. In fact, several mecha-
`nisms have been found, including direct release of me-
`diators by mast cells, without stimulation by IgE or im-
`mune complexes (18). This may be analogous to the
`types of reactions seen with contrast media or opiates.
`Is it the iron or the dextran component that causes the
`reactions? Dextran was first used as a volume expander
`in the 1950s, and anaphylaxis was a rare but dreaded
`complication (19). Allergy occurs even on first exposure
`to the drug, suggesting the importance of preformed an-
`tidextran antibodies (20). Dextran chains are glucose
`polymers of varying sizes. Both increasing polymer size
`and variability of size have been hypothesized as stimu-
`lants of anaphylaxis. Supporting this notion is the obser-
`vation that administration of dextran-1, a small-chain
`polymer with molecular weight of 1000 Da, can greatly
`reduce the risk of dextran-induced anaphylaxis (21).
`The above discussion would suggest that iron com-
`pounds free of dextran would be preferred, and indeed
`this should be true. The following sections discuss the
`safety profiles of sodium ferric gluconate and iron sac-
`charate, two dextran-free compounds that appear to be
`safer than iron dextran. First a note of caution: the lit-
`erature on the use of these drugs is not quite as rich as
`that for iron dextran. As such, the conclusions cannot be
`very firm. Second, although dextran does appear to be
`the primary culprit in iron dextran reactions, patients
`treated with dextran-free iron agents are not totally free
`of immediate reactions. In fact, as described below, some
`of the reactions are quite similar to those seen with iron
`dextran, although less severe and less frequent. It is
`likely that iron itself may cause some of the observed
`reactions.
`
`Sodium Ferric Gluconate (Sodium Ferric
`Gluconate Complex in Sucrose)
`
`This agent contains the same iron hydroxide core as
`iron dextran, but utilizes sucrose and gluconate to stabi-
`lize and solubilize the compound. These simple carbo-
`hydrates should have little anaphylactic potential. In fact,
`the drug has been used in Europe for 40 years with
`
`anecdotal reports of excellent safety. It was introduced in
`the United States in 1999 under the brand name Ferrlecit
`(Schein Pharmaceutical, Inc., Florham Park, NJ). In con-
`trast to the literature on iron dextran, there are no rigor-
`ous studies that have sought to define the risk of imme-
`diate severe reactions with sodium ferric gluconate. Fa-
`ich and Strobos (17), in the work discussed above,
`focused on the population safety of this agent. In the
`years 1992–1996 they found that there were approxi-
`mately 2.7 million annual administrations of this drug in
`Germany and Italy. During the period 1976–1996 there
`were a total of 74 reports of allergy or anaphylaxis, but
`of importance, there were no deaths reported. This stands
`in stark contrast to the 31 deaths reported in this time
`period with iron dextran (17).
`There are a number of prospective studies published in
`which the clinical response to sodium ferric gluconate
`was analyzed. Very few of the studies, however, were
`designed and powered to look critically at safety. In a
`letter published in 1992, Pascual et al. reported on three
`reactions observed in 82 patients treated. One patient
`experienced malaise, heat, vomiting, and loin pain after a
`slow injection. A second patient developed anaphylac-
`toid symptoms during an infusion, with severe hypoten-
`sion that resolved after an hour. A third patient experi-
`enced epigastric pain. All three patients were subse-
`quently treated with an infusion over 30 min without any
`side effects (22). Nissenson et al. (23) recently studied 83
`patients treated with a standard eight-dose course with
`sodium ferric gluconate and found no allergic or anaphy-
`lactic reactions. As part of their study, nine patients al-
`lergic to iron dextran were included, and none reacted to
`the sodium ferric gluconate.
`Zanen et al. (24), in 1996, published a report that
`raised concern over excessively rapid release of iron by
`sodium ferric gluconate. The stimulus for the study was
`the observation of two patients who had experienced
`flushing and a drop in blood pressure after treatment with
`the drug. Both patients had serum iron concentrations
`that rose sharply after treatment, leading to a calculated
`transferrin saturation of more than 100%. Twenty addi-
`tional patients were subsequently treated with 30- or
`240-min IV infusion of the drug. The primary finding
`was that transferrin saturations rapidly rose to high lev-
`els, exceeding 100% in all but patients treated with 62.5
`mg infused over 240 min. In all patients the transferrin
`saturation normalized within 48 hr (24). Recently the
`results of this study have been called into question. Se-
`ligman and Schleicher (25) demonstrated that the tech-
`nique Zanen et al. (24) used to measure transferrin satu-
`ration yields falsely elevated levels during IV iron treat-
`ment. This method uses ascorbic acid and guanidine to
`liberate iron from transferrin so that it may be quanti-
`tated. Unfortunately iron present in sodium ferric glu-
`conate is also liberated, making it appear that the trans-
`ferrin saturation is far greater than it actually is (25).
`Therefore the results of Zanen et al. (24) are likely er-
`roneous.
`In summary, the anecdotal record of safe use of so-
`dium ferric gluconate for several decades in Europe
`seems to be supported by the results of clinical studies. In
`particular the Faich and Strobos (17) study documents
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`COMPARATIVE SAFETY OF IV IRON
`
`383
`
`the safer risk profile compared to iron dextran. It appears
`that reactions can certainly occur, but they seem to be of
`a milder intensity and lesser frequency than with iron
`dextran. The catastrophic iron dextran anaphylactic re-
`actions probably do not occur with sodium ferric glu-
`conate.
`
`scribing IV iron treatment. With both agents the risk of
`the “catastrophic” type of iron dextran anaphylactic
`event appears minimal. Given the existing literature, no
`rational differentiation can be made between these drugs
`based on safety. Both appear to be safer than iron dex-
`tran, and it is unlikely that either one is substantially
`safer than the other.
`
`Iron Sucrose (Iron Saccharate)
`
`This agent, soon to marketed in the United States un-
`der the brand name Venofer (American Regent Labora-
`tories, Inc., Shirley, NY), has been used for decades in
`Europe. In the treatment of iron deficiency in hemodi-
`alysis patients there has been an anecdotal impression of
`excellent safety. Like sodium ferric gluconate, however,
`iron saccharate has not been rigorously studied with re-
`spect to adverse events. Much of the published literature
`is studies intended to evaluate efficacy, and the informa-
`tion provided on safety tends to be sparse.
`A useful study was a report by Hoigne et al. (26) in
`1998. In a group of 400 obstetric patients treated with
`iron saccharate, 7 generalized reactions occurred, 4 with
`flushing and 3 with rash. In the same report, a retrospec-
`tive analysis of hemodialysis patients was conducted by
`surveying dialysis unit medical directors. There were no
`life-threatening reactions reported from an estimated ex-
`posure of 8100 patient-years, with 160,000 administra-
`tions of a 100 mg dose. There were 5–7 episodes of
`transient hypotension, and 10 patients experienced flush-
`ing (26). In a report by Nyvad et al. (27) of 34 hemodi-
`alysis patients treated with iron saccharate, only one had
`a significant reaction. This patient experienced perioral
`swelling and urticaria, which abated after stopping the
`drug. Of note, the patient was concurrently being treated
`with an oral antibiotic (27). A recent report by Vychytil
`and Haag-Weber (28) evaluated iron saccharate treat-
`ment in peritoneal dialysis patients. The method of ad-
`ministration was by 10-min IV injection. They found that
`0.9% of patients receiving 100 mg and 5.9% receiving
`200 mg experienced events such as hypotension and
`back pain. The authors concluded that a slower rate of
`infusion might be warranted. Similarly, Sunder-
`Plassmann and Horl (29) recently recommended a maxi-
`mum dose for iron saccharate of 100–200 mg.
`Like sodium ferric gluconate, the anecdotal history of
`decades of safe use of iron saccharate seems to be sup-
`ported by the existing literature. Both of these drugs
`appear to be a meaningful step forward compared to iron
`dextran with regard to safety. With both drugs, reactions
`may be similar to those with iron dextran, but of a lesser
`intensity. Since these two drugs are free of dextran, it
`may be that the reactions characterized by hypotension
`and flushing are due to their iron component. By exten-
`sion, it is likely that some iron dextran reactions are also
`caused not by dextran, but by the iron itself.
`
`Conclusion
`
`Sodium ferric gluconate and iron saccharate are drugs
`that should increase the comfort level of clinicians pre-
`
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