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
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Abstract |
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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
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Introduction |
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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.
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Subjects and methods |
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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.
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Results |
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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 250500 mg of SFGC have been published separately [8].
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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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Discussion |
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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 250500 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.
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Acknowledgments |
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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.
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References |
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