Sodium ferric gluconate complex in haemodialysis patients: a prospective evaluation of long-term safety

Beckie Michael1, Daniel W. Coyne2, Vaughn W. Folkert3, Naomi V. Dahl4 and David G. Warnock5 for the Ferrlecit® Publication Committee

1Jefferson Medical College, Philadelphia, PA, 2Washington University School of Medicine, St Louis, MO, 3Albert Einstein College of Medicine/Montefiore Medical Center, Bronx, NY, 4Watson Laboratories, Morristown, NJ and 5University of Alabama at Birmingham, Birmingham, AL, USA

Correspondence and offprint requests to: Beckie Michael, DO, Clinical Associate Professor of Medicine, Jefferson Medical College, Director, Dialysis Services, Thomas Jefferson University Hospital, 834 Walnut Street, Philadelphia, PA 19107, USA. Email: Beckie.Michael{at}jefferson.edu



   Abstract
 Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
Background. A previous single dose placebo-controlled double-blinded trial showed an extremely low (0.4%) intolerance rate of sodium ferric gluconate complex (SFGC) in SFGC-naive haemodialysis patients. No large prospective trials have assessed the safety of SFGC during repeated exposure in the outpatient haemodialysis setting.

Methods. Chronic haemodialysis patients completing the single-dose trial of SFGC were eligible to participate in this prospective, multicentre, open-label, long-term evaluation of SFGC, designed to record adverse events occurring up to 72 h post-dose. Patients received as many as 20 ampules (1250 mg total) of SFGC at an investigator-determined dose and rate over a 9 month evaluation period.

Results. Among 1412 enrolled patients at 54 centres, 1321 received 13 151 infusions of SFGC. Most doses (94.8%) were <=125 mg and the majority were given over 10 min. Infusion rates ranged from <5 to 125 mg/min. There were no life-threatening events. Fifty-one patients (3.9%) experienced an adverse event, possibly related to SFGC. Of these, one experienced a serious event (hypotension). Five patients (0.4%) experienced an event that precluded SFGC readministration: pruritus (three), vasodilatation (one) and loss of taste (one). Among 372 patients (28.2%) receiving angiotensin-converting enzyme inhibitor (ACEI) therapy, adverse events were neither more common nor more severe than in the other patients.

Conclusions. Repeated doses of SFGC are very well tolerated in haemodialysis patients. No life-threatening events were observed in over 13 000 doses administered. Administration of SFGC to patients using ACEI is safe and does not increase the incidence or severity of adverse events to SFGC.

Keywords: haemodialysis; intravenous iron; iron deficiency; iron dextran sensitivity; sodium ferric gluconate complex



   Introduction
 Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
A major factor limiting achievement of target haemoglobin in haemodialysis patients is undiagnosed or untreated iron deficiency [1]. Several studies have shown that oral iron cannot adequately maintain iron stores in haemodialysis patients [24]. As a result, the use of intravenous iron is necessary to optimally care for these patients [1]. Until recently, iron dextran was the only form of parenteral iron available in the United States. This drug is associated with a significant incidence of anaphylactoid reactions [5], limiting its utility in treating iron deficiency anaemia. Allergy is believed to relate to the dextran moiety of the drug. In 1999, sodium ferric gluconate complex in sucrose solution (SFGC) was approved by expedited review by the US Food and Drug Administration. This drug has no dextran component and has an extended history of safe use in Europe. Recently, we completed a large prospective, double-blinded study that documented the safety of a single exposure of SFGC compared with concurrent placebo and historical iron dextran controls in SFGC-naive haemodialysis patients [6]. Severe adverse events with SFGC were reduced by 93% compared with iron dextran and were not significantly different from the incidence or severity of events observed with placebo [6].

Thus, it appears that the safety profile of a single exposure to SFGC is excellent. However, it is possible that with repeated exposure sensitivity could develop, as has been observed with iron dextran preparations. In addition, a brief case report raised the possibility of an interaction between angiotensin-converting enzyme inhibitors (ACEI) and intravenous iron, resulting in hypotension [7]. Therefore, the purpose of the present study is to evaluate the safety of repeated exposure to SFGC during its routine clinical use. This paper presents the results of a long-term open-label study of SFGC in haemodialysis patients.



   Subjects and methods
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 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
This study was a prospective, open-label, multicentre surveillance study of the safety of repeated doses of SFGC administered to iron-deficient adult haemodialysis patients. Two subsets of this study have been reported previously: 144 patients receiving 250–500 mg of SFGC as single infusions [8] and 92 patients with prior iron dextran sensitivity [9]. These patients are included here for clarity. The primary objectives of the study were (i) to evaluate protocol events defined as outcome adverse events, life-threatening adverse events or allergic adverse events following repeated exposure to SFGC in SFGC-tolerant patients and (ii) to compare the incidence of adverse events in SFGC-treated patients who were receiving ACEI therapy with those patients who were not.

Patients who completed the preceding single-dose SFGC safety study [6] and provided informed consent were invited to participate in this study. All centres received approval from their respective Institutional Review Boards. Patients were enrolled at 54 centres in the United States between August 1999 and February 2001 and assigned 20 ampules of SFGC, each containing 62.5 mg elemental iron. SFGC dose, rate of infusion and frequency were at the local investigator's discretion to mimic routine clinical use of SFGC in the outpatient haemodialysis setting.

Individual patient participation ended when all 20 ampules were administered or 9 months had elapsed. Patients were assessed by the Study Coordinator for adverse events (an unfavourable sign or symptom temporally related to SFGC administration) during the dialysis session in which they received SFGC and at the dialysis session following. An outcome adverse event was any reaction that required permanent cessation of SFGC therapy. A life-threatening adverse event was any immediate reaction following SFGC administration that required the institution of resuscitative measures other than those usually used during dialysis to treat common intradialytic complications. A serious adverse event was any hospitalization or life-threatening event. An allergic adverse event was any event the investigator felt, based on the patient's symptoms, to be allergic in nature. Hypotension was defined clinically. Patients with symptoms of hypotension were to have their blood pressure checked immediately and reassessed within 10 min. Events were classified as instantaneous if they occurred during SFGC infusion, immediate if after infusion but before dialysis was completed and delayed if the event occurred after dialysis was completed and before the next dialysis session.

Statistical methods
The percentage of patients experiencing adverse events was tabulated by body system and the individual Coding System for a Thesaurus of Adverse Reaction Terms (COSTART) preferred term. The primary and safety analysis was conducted on all patients who entered the study and received at least one dose of SFGC (evaluable population). Categorical data were analysed with a two-sided Fisher's exact test. All computations were performed using the Statistical Analysis System (SAS) v. 6.12.



   Results
 Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
Demographics
A total of 1412 patients were enrolled at 54 centres and 91 (6.4%) did not receive SFGC. The demographics and baseline characteristics of the remaining 1321 patients (evaluable population) are shown in Table 1 and compared with the demographics of the entire US haemodialysis population in 1999 [10]. Due to the locations of the study sites, blacks and Hispanics are over-represented in the study.


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Table 1. Summary of demographic and baseline patient characteristics

 
Of the 1321 patients, 129 (9.8%) stopped the study prematurely and 119 of these discontinuations were unrelated to SFGC. The reasons for withdrawal unrelated to SFGC were (a) logistical reasons (83, 6.3%), including kidney transplantation, transfer to another dialysis unit and change to peritoneal dialysis, (b) withdrawn consent without an adverse event (28, 2.1%) and (c) withdrawn consent with an unrelated adverse event (8, 0.6%).

Ten (0.8%) patients discontinued the study due to adverse events considered possibly or probably related to SFGC: pruritus (three), nausea/vomiting (two), diarrhoea, nausea and vomiting (one), vasodilatation (one), back pain and nausea (one), abdominal pain (one) and loss of taste (one). Four of these reactions [pruritus (three) and vasodilatation (one)] were classified as intolerance and allergic events. One event (loss of taste) was considered an intolerance event, while the remaining five patients had non-serious events that were felt not to preclude readministration.

SFGC administration
A total of 13 151 doses of SFGC were administered (Table 2). Most SFGC doses (94.7%) were given as <=125 mg per dialysis session. The majority of patients (75.5%) received >=1000 mg SFGC during the study. The majority of doses were administered as 125 mg intravenous over 10 min. Rates of administration ranged from <5 mg/min (33.5%) to 125 mg/min (3.7%), though 94% were <15 mg/min. The details of the 144 patients receiving 250–500 mg of SFGC have been published separately [8].


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Table 2. Summary of SFGC administration and related adverse events

 
All adverse events
A total of 260 patients (19.7%) experienced at least one adverse event (related and unrelated to SFGC) during the study (Table 3). Most events (88%) were of mild or moderate intensity and represent events commonly seen in haemodialysis patients. Adverse events occurred with greatest frequency in the following body systems: body as a whole (8.6%); cardiovascular (8.1%); and digestive (6.1%). Adverse events reported by >=1% of patients were hypotension (4.0%), pain (2.3%), nausea (2.0%), headache (2.0%), diarrhoea (1.9%), hypertension (1.2%) and vomiting (1.1%). Pruritus was reported in 1.1% of patients.


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Table 3. Overall incidence of adverse events

 

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Table 4. Summary of drug intolerance and suspected allergic events

 
A total of 56 (4.2%) patients experienced at least one serious adverse event and none of these precluded readministration of SFGC. One serious event (hypotension) was considered to be SFGC-related: a 37-year-old male receiving an ACEI developed hypotension, abdominal pain and vomiting immediately following 125 mg SFGC given over 2–3 min. He was treated with 1950 ml saline and the dialysis session was terminated. His blood pressure improved and he was sent home from the dialysis unit. The patient received six more doses of SFGC (125 mg over 12–17 min) without incident. Of the 19 patients who died during the study, all died >72 h after SFGC infusion and none had adverse events felt to be related to the study drug.

Fifty-one patients (3.9%) experienced a total of 78 adverse events considered by the investigator to be related (probably, possibly or unknown) to SFGC and all were classified as mild to moderate in severity. There was no correlation between these events and SFGC dose, rate of infusion or total exposure to SFGC (Table 2). Gastrointestinal complaints were the most common events (34), followed by hypotension (10), pruritus (seven), nervous system disorders (six), vasodilatation (three), dyspnoea (three), asthenia (two), chest pain (two), pain (two), palpitations/tachycardia (two), peripheral oedema (two), taste loss/perversion (two), non-specified allergic reaction (one), back pain (one) and headache (one).

SFGC drug intolerance and allergic events
SFGC drug intolerance and allergic events are summarized in Table 4. No life-threatening events were observed. Four patients had events characterized as both a drug intolerance and an allergic event [pruritus (three) and vasodilatation (one)], one patient had a non-allergic drug intolerance event only (loss of taste) and one patient had an allergic reaction (pruritus) after the second dose of SFGC, but received eight additional doses without recurrence of symptoms. The four patients with pruritus were treated with diphenhydramine (two intravenously and two orally), with resolution of symptoms. The patient with symptoms characterized as vasodilatation experienced shortness of breath and a hot flush around the neck, which resolved after 50 mg intravenous diphenhydramine.

Lack of relationship of concomitant ACEI therapy or other drugs to adverse events
A total of 372 patients (28.2%) were receiving concomitant ACEI therapy and 949 (71.8%) were not. Table 5 shows the incidence of adverse events in the two groups. There was no significant difference in the incidence of adverse events, drug intolerance, allergic reactions or serious adverse events between the groups. The most commonly reported adverse event in the study was hypotension. Twelve patients (3.2%) receiving an ACEI experienced hypotension as compared with 4.3% of patients who were not (P = 0.437).


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Table 5. Overall incidence of adverse events (related and unrelated to SFGC) in relation to ACEI therapy in patients who experienced at least one adverse event during the study

 
Concomitant medication information was collected on all 260 patients who had any adverse event (related or unrelated) during the study. Among these patients, 205 (78.8%) were receiving antihypertensive agents, 50 (19.2%) were receiving antilipaemic agents and 75 (28.8%) were on antidiabetic therapy. The rates of occurrence of drug-related adverse events and outcome events were not different among patients receiving these concomitant medications and those who were not.



   Discussion
 Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
Iron deficiency has been shown to be present in 25–37.5% of haemodialysis patients [1]. Oral iron therapy is usually ineffective in repleting or maintaining adequate iron stores in haemodialysis patients receiving epoetin [24]. Consequently, the National Kidney Foundation's Kidney Disease Outcomes Quality Initiative guidelines emphasize that the majority of haemodialysis patients will require intravenous iron on a regular basis [1].

Parenteral iron therapy can result in a number of adverse reactions [5,11,12]. Some, such as nausea, are unlikely to be immune-mediated, while others, including rash, dyspnoea and wheezing, appear to represent true allergic reactions. Serious allergic (anaphylactic) reactions are rare, but can be life-threatening [11]. The majority of life-threatening reactions have been associated with iron dextran, with at least 30 deaths attributed to its use [13]. These adverse events appear to be related to the dextran moiety of this preparation. In contrast to iron dextran, SFGC has one gluconate and four sucrose ligands at the five iron oxide coordinating positions, resulting in an iron oxide polymer rather than iron oxide crystals. Additionally, SFGC does not contain any dextran. Our previous reports of a double-blinded prospective study of the adverse events and safety of a single dose of SFGC also demonstrated a low incidence of adverse reactions [6,9]. Although there was a statistically greater incidence of drug intolerance following SFGC as compared with placebo, there was no difference in serious adverse events or hypotension [6].

While most serious iron dextran reactions occur upon initial exposure to the drug (and even to the test dose), reactions can occur after multiple uneventful exposures [14]. Fletes et al. [15] found that 30% of iron dextran-associated serious adverse reactions occurred after repeated administration. Although SFGC has been used extensively in Europe for decades with an excellent safety record, large prospective clinical studies addressing outcomes with repeated exposure have been lacking.

The present study demonstrates repeated administration of SFGC is very well tolerated, with 0.4% of haemodialysis patients experiencing an adverse event that precluded readministration. These reactions were generally mild to moderate in severity. There were no life-threatening events observed with over 13 000 doses administered. The most common adverse events were gastrointestinal symptoms, hypotension and headache, events commonly seen in haemodialysis patients regardless of drug therapy. There was no evidence that the incidence of adverse events increased with repeated administration. These results are similar to the findings of the single exposure Ferrlecit® safety study, where the incidence of drug intolerance in SFGC-naive haemodialysis patients was 0.4% [6].

Rolla et al. [7] suggested concomitant use of ACEI might increase the number or severity of reactions to intravenous iron products. The use of ACEI has been associated with an increased risk of anaphylactoid reactions in patients dialysed with certain dialysis membranes or sterilizing agents [16,17] and might be mediated by increases in bradykinin. The results of this study found no increase in the frequency or severity of adverse events following repeated SFGC infusion in ACEI-treated patients and these results are consistent with the previous safety study [6].

This study allowed investigators to determine the dose and rate of infusion of SFGC to assess safety during routine clinical practice. Although infusion rates were >=15 mg/min in 5.9% of infusions and doses exceeded 125 mg in 5.3% of infusions, the frequency and severity of reactions were not increased in these subgroups. The 144 patients receiving SFGC at doses of 250–500 mg have been discussed in depth previously [8]. However, it is suggested that the current infusion recommendation (125 mg intravenously over 10 min) continues to be followed.

Repeated administration of SFGC in haemodialysis patients is associated with a low incidence of adverse events, which does not increase with repeated exposure. These reactions are also not influenced by ACEI or other common concomitant medications. SFGC was demonstrated to have a wide margin of safety in this open-label study of routine clinical practice.



   Acknowledgments
 
The additional participating investigators were Rajiv Agarwal, MD, Indiana University, Indianapolis, IN; Raul Balagtas, MD, Tampa, FL; Daniel C. Batlle, MD, Northwestern University Medical School, Chicago, IL; Jeffrey Berns, MD, University of Pennsylvania; Jose Cangiano, MD, San Juan Bautista School of Medicine, San Juan, Puerto Rico; Laura Dember, MD, Boston University Medical Center; Devasmita Dev, MD, Veterans Administration North Texas Health Care; Jorge Diego, MD, University of Miami, Miami, FL; Joseph W. Eschbach, MD, Northwest Kidney Center, Seattle, WA; Stephen Z. Fadem, MD, Houston Kidney Center, Houston, TX; Steven Fishbane, MD, Winthrop University Hospital, Mineola, NY; Mary Gellens, MD, St Louis University Medical College; Michael Germain, MD, West Springfield, MA; Charles Graeber, MD, Newington, CT; Mandeep Grewal, MD, Chattanooga, TN; Louisa Ho, MD, Evanston, IL; Onyekachi Ifudu, MD, State University of New York; Dennis Imperio, MD, Sarasota, FL; Sam James, MD, University of Arizona Medical Center; Mark Kaplan, MD, Nashville, TN; Ellie Kelepouris, MD, Temple University School of Medicine; Ken Kleinman, MD, University of California at Los Angeles; David Leehey, MD, Loyola University Medical Center; Jill Lindberg, MD, New Orleans, LA; Robert Lynn, MD, Bronx Dialysis Center, New York City, NY; Thomas Marbury, MD, Orlando, FL; Ronald Mars, MD, University of Florida; Allen R. Nissenson, MD, UCLA School of Medicine, Los Angeles, CA; Chamberlain Obialo, MD, Morehouse School of Medicine, Atlanta, GA; Chika Oguagha, MD, Nephrology Foundation of Brooklyn, New York City, NY; Walter Piering, MD, Medical College of Wisconsin; Rasib Raja, MD, Albert Einstein Medical Center, Philadelphia, PA; Steven Rosenblatt, MD, San Antonio Kidney Diseases Center, San Antonio, TX; Jeff Sands, MD, Emory University; Steve Schwab, MD, Duke University Medical Center South; Allan Schwartz, MD, Hahnemann University Hospital; Andrea J. Shaer, MD, Medical University of South Carolina, Charleston, SC; Warren Shapiro, MD, Brookdale, NY; Anupkumar Shetty, MD, Henry Ford Health Systems; Jerald Sigala, MD, Orange, CA; David Spiegel, MD, University of Colorado Health Sciences Center; Richard Swartz, MD, University of Michigan; Nosratola Vaziri, MD, University of California Irvine Medical Center; Sergio Vega, MD, West Palm Beach, FL; Kevin Vitting, MD, St Joseph's Hospital and Medical Center; Michael Walczyk, MD, Portland, OR; Robert Weiss, DO, Temple University; Duane Wombolt, MD, Norfolk, VA; Elizabeth Wrone, MD, Palo Alto, CA. This paper was supported by a grant from Watson Pharmaceuticals, Inc., to each of the participating centres.

Conflict of interest statement. B.M., D.C., V.F. and D.W. have conducted research sponsored by Watson Pharmaceuticals, Inc., the manufacturer of Ferrlecit®, and/or served on its speakers’ bureau. N.D. is Director, Clinical Affairs at Watson Laboratories.



   References
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 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 

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Received for publication: 3.10.03
Accepted in revised form: 18. 2.04