Iron deficiency is considered to be the most frequent cause of an initial or subsequent poor response to recombinant human erythropoietin (rHuEPO). 1,2 However, the iron requirement of these patients generally exceeds the amount of iron that oral iron preparations can provide. 3–7 Recent guidelines proposed by the National Kidney Foundation-Dialysis Outcomes Quality Initiative (NKF-DOQI) indicate that most patients receiving hemodialysis (HD) require parenteral iron to maintain their iron status. 8 Until recently, only one form of parenteral iron (iron dextran) was available in the United States, and, although it is generally safe, it has been reported to cause severe allergic reaction and even death. 9–12 Up to 26% of patients receiving parenteral iron dextran therapy experience side effects, the majority of which are self-limited and mild. Approximately 3% of patients develop more severe symptoms, and ≥0.6% of patients develop life-threatening anaphylaxis. 13 Most of these reactions occur immediately after the administration of the test dose and may include headache, dyspnea, flushing, chest pain, abdominal or back pain, nausea, vomiting, broncho- spasm, hypotension, seizure, fever, urticaria, and anaphylaxis. Delayed reactions, occurring 1-3 days after infusion, are due to deposition of iron in tissues and include arthralgia, myalgia, phlebitis, and lymphadenopathy. The anaphylactic reactions are not dose-dependent and may occur after the test dose or after many doses. 9 The mechanism of hypersensitivity reaction to iron dextran remains unclear and is probably multifactorial. It may involve mast cell degranulation or formation of a specific immunoglobulin G to iron dextran, without immune complex involvement. 14
Ferric gluconate complex in sucrose is a high molecular weight complex (350,000 d) that has been in clinical use since 1959 in more than 20 countries outside of the United States. It was recently approved by the Food and Drug Administration for use in the United States and has been shown to be quite safe and effective for HD patients. 15 The safety profile of nondextran iron preparations is believed to be somewhat superior to that of iron dextran. In one study, the overall adverse event rates for iron dextran and ferric gluconate were 8.7 and 3.3 allergic episodes per million doses per year, respectively (p = ns). 12 However, when case fatalities for ferric gluconate and iron dextran were compared, there were no reports of death over the entire period of 1976 to 1996, during which ferric gluconate had been used extensively in Europe, whereas 31 fatalities were reported in the United States from the same time period, from 196 allergy/anaphylaxis cases (a case fatality rate of 15.8%) taking iron dextran. 12 Nevertheless, one should note that the types of iron dextran preparation differed during this time period and that the monitoring of reporting for iron gluconate might have been less complete than for iron dextran. In this report, we present five patients with a history of severe reaction to iron dextran (INFeD, Watson Pharmaceutical, Inc., Corona, CA) who tolerated subsequent doses of iron gluconate (Ferrlecit, R & D Laboratories, Marina del Rey, CA; distributed by Schein Pharmaceutical) without any adverse effects.
A 36 year old African-American woman, with end-stage renal disease (ESRD) secondary to chronic glomerulonephritis, on HD since 1982, required intravenous iron dextran therapy in December 1996 for treatment of iron deficiency. Symptoms of severe wheezing, hypotension, and respiratory stridor complicated treatment. In May 2000, she was treated with 30 injections of ferric gluconate, 62.5 mg each, administered during HD sessions, which were not complicated by any adverse effects.
A 21 year old African-American man, on HD since September 1999, required parenteral iron dextran therapy in October 1999. Immediately after a test dose of 25 mg, he developed severe hypotension and unresponsiveness followed by severe hypertension (230/120 mm Hg). In March 2000, he had no reaction to a test dose of 25 mg of ferric gluconate, followed by 10 doses, 62.5 mg each, of ferric gluconate administered during HD sessions.
A 49 year old African-American woman, with ESRD secondary to focal segmental glomerulosclerosis, on maintenance HD since October 1999, required parenteral iron therapy at the initiation of HD. She developed severe shortness of breath, back pain, and hypertension immediately after receiving a 25 mg test dose of iron dextran. In February 2000, she received 10 injections of ferric gluconate, 62.5 mg each, which were not complicated by any adverse effects.
A 28 year old African-American man, with ESRD secondary to chronic pyelonephritis and reflux nephropathy, on maintenance HD since August 1998, required parenteral iron therapy in October 1998. He developed severe “heart racing,” wheezing, and angioedema in his throat immediately after a test dose of 25 mg of iron dextran. In March 2000, he received 10 injections, 62.5 mg each, of ferric gluconate administered during HD sessions, which were not complicated by adverse effects.
A 34 year old African-American man, with ESRD secondary to hypertension, on chronic HD since December 1998, required parenteral iron administration in January 1999. He developed severe chest pain, shortness of breath, and wheezing immediately after a 25 mg test dose of iron dextran. In May 2000, he received 10 injections, 62.5 mg each, of ferric gluconate administered during HD sessions, which were not complicated by any adverse effects.
We did not know whether case 1 had received angiotensin converting enzyme inhibitors (ACEI) during the iron dextran infusion that was complicated by allergic reaction; however, cases 2, 3, and 4 were not receiving any ACEI, and case 5 was receiving an ACEI during both the iron dextran and ferric gluconate infusions. Moreover, none of the patients had received any medications, such as steroids or diphenhydramine HCl (Benadryl, Warner-Lambert Company, New York, NY), which might have blunted the occurrence of allergic reactions to ferric gluconate.
In a preliminary report on nine patients with a history of reaction to iron dextran (anaphylaxis in five, chest tightness in one, shortness of breath in two, and joint pain in one patient), all patients were successfully treated with ferric gluconate complex in sucrose without any allergic reaction. 16 The present report adds five additional cases of patients with a history of serious reactions to iron dextran, i.e., bronchospasm, severe hypotension or hypertension, respiratory stridor, unresponsiveness, back pain, chest pain, shortness of breath, or angioedema of the throat. These patients tolerated ferric gluconate with no adverse effects. In four of our five patients, the reaction happened immediately after the test dose. We were unsure whether a test dose had been administered to the remaining patient (case 1).
In view of the studies showing poor oral iron absorption in patients on dialysis, 17,18 our finding and the preliminary report by Nissenson et al.16 suggest that, in patients with a known history of severe allergic reactions to iron dextran, ferric gluconate is a safer mode of parenteral iron administration. A similar safety profile has been reported with iron sucrose (also referred to as iron saccharate or iron [III] hydroxide sucrose complex). In two North American clinical trials, a total of 980 doses of iron sucrose were administered to 100 patients, including 33 patients who were sensitive to iron dextran and 27 patients with concomitant ACEI therapy, without any serious adverse drug reactions. 19,20 Finally, at least four different intravenous iron preparations are available worldwide—iron dextran, iron sucrose, iron gluconate, and iron dextrin (polymaltose)—each with different molecular weights, physiochemical characteristics, degradation kinetics, and side effect profiles. Because of this, we have referred clinicians to two recent reports that nicely summarize the different iron preparations and their side effect profiles. 21,22
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