Sodium ferric gluconate complex maintenance therapy in children on hemodialysis

Intravenous iron therapy is recommended for children and adults who receive hemodialysis (HD) and recombinant human erythropoietin (rHuEPO). However, limited information exists on the use of any maintenance IV iron regimen in children. Therefore, we conducted a prospective, multicenter, open-label trial of maintenance therapy with sodium ferric gluconate complex (SFGC) in iron-replete pediatric HD patients receiving rHuEPO. Patients received SFGC weekly at an initial dose of 1.0 mg kg⁻¹ week⁻¹, not to exceed 125 mg. Doses could be adjusted based on iron indices. Twenty-three patients (mean age: 13.2±2.39 years) were enrolled and received at least one dose of SFGC, while twelve patients completed the study. After 12 weeks of treatment, the mean SFGC dose delivered was 1.0 mg/kg. Mean TSAT and serum ferritin levels remained within NKF-K/DOQI target ranges and the mean Hgb level remained unchanged from baseline. No unexpected or unusual safety risks were associated with SFGC use. In summary, this experience provides evidence for the safety and efficacy of intravenous SFGC and supports the recommendation that the maintenance SFGC starting dose should be 1.0 mg/kg, not to exceed 125 mg, with subsequent adjustments made according to TSAT and/or serum ferritin levels.     

Anaphylactoid reaction to intravenous sodium ferric gluconate complex during pregnancy

We report the first case of a severe anaphylactic or anaphylactoid reaction to sodium ferric gluconate complex in a pregnant patient. Sodium ferric gluconate complex is felt to be one of the safest forms of iron therapy during pregnancy. This case highlights the need for extreme caution and vigilance in pregnant patients receiving any type of parenteral iron therapy.     

Drug insight: Safety of intravenous iron supplementation with sodium ferric gluconate complex

Intravenous iron is necessary for optimal management of anemia in patients receiving hemodialysis and is utilized in the majority of these patients in the US. The availability of nondextran formulations of intravenous iron has significantly improved the safety of its use. The nondextran iron formulation sodium ferric gluconate complex (SFGC) has been extensively studied in the hemodialysis population, with two large phase IV trials documenting its safety. SFGC is efficacious and, at recommended doses, is associated with a low incidence of adverse events. There have been few comparative studies of the nondextran intravenous iron preparations; however, they are known to have different pharmacokinetic characteristics. There is also evidence to indicate that these compounds differ in terms of their cytotoxic and proinflammatory properties, and their propensity to induce oxidative stress. This paper reviews the current literature on the safety of SFGC and examines the emerging safety issues surrounding the use of intravenous iron.     

达依泊汀α在维持性血液透析患者中单次静脉给药的安全性和耐受性

目的 评估长效红细胞生成素达依泊汀α在维持性血液透析（MHD）患者中单次静脉给药的安全性和耐受性。 方法 采用单中心、开放性临床试验方法。选择MHD 3个月以上,病情稳定的患者43例,其中男26例,女17例,分为5个剂量组,分别给予达依泊汀α 0.225、0.45、0.9、1.8、3.6 μg/kg单次静脉注射,观察给药前后患者的生命体征、临床症状、心电图（ECG）和生化指标等变化,评价其安全性和耐受性。 结果 达依泊汀α的最大耐受剂量达3.6 μg/kg。与达依泊汀α可能有关的不良反应为高血压加重（7％）。1例出现严重不良事件（患者死亡）,但与达依泊汀α无关。观察期间未发现与达依泊汀α相关的严重不良反应。 结论 达依泊汀α的安全性和耐受性良好。     

Effect of frequency of intravenous iron administration on hemoglobin variability in maintenance hemodialysis patients

Target

To observe the effect on hemoglobin (Hb) variability with different treatment frequencies of intravenous iron in maintenance hemodialysis (MHD) patients.

Methods

There were 41 MHD patients enrolled in the cohort. The patients were separated into two groups randomly. The baseline data were collected after oral iron agents for 1 month (wash out). There were two methods of intravenous iron administration, either continuous or intermittent. For continuous administration (CA), 100 mg sucrose iron agents were given during every HD session with total dose of 1000 mg. For intermittent administration (IA), 100 mg sucrose iron agents were given once every week with the same total dose of 1000 mg. The protocol were designed to do a follow-up of 7 months, which included two to three-month steps of different administrations of intravenous iron and 1 month of wash-out period by oral iron agents between two steps, respectively. Patients in Group one (G1) administrated iron agents by CA at the first step and IA at the second step. Patients in Group two (G2) did IA and then transfer to CA. The clinical parameters including Hb, serum ferritin (SF), transferrin saturation (TAST), and doses of recombined human erythropoietin (rHuEPO) were detected and recorded during follow-up period. The standard deviation of Hb (Hb-SD) and coefficient variation of Hb (Hb-CV) were calculated. The baseline data were compared between two groups. The parameters on month 3 and 7 were compared with those on month 0 in two groups, respectively. The effects of both CA and IA on Hb-SD and Hb-CV were compared by two-stage cross-comparison general linear model (GLM) method.

Results

There were 34 patients (82.9%) completed the trail. The amounts of cases, rates of gender and primary diseases, the mean value of age, Hb, SF, TSAT, and doses of rHuEPO on baseline in two groups were similar (p?>?0.05). The SF levels in two groups increased significantly during follow-up period, which were 235.4?±?51.8 ng/ml on month 0, 362.4?±?140.2 ng/ml on month 3, and 315.0?±?97.73 ng/ml on month 7 in G1 (p?<?0.01), and 250.5?±?37.8 ng/ml, 332.2?±?118.9 ng/ml, and 347.4?±?124.3 ng/ml in G2 (p?<?0.01), respectively. Compared to CA, IA could decline the Hb-SD (5.93?±?3.97 g/l vs. 7.36?±?3.81 g/l, F?=?4.377, p?=?0.044) and Hb-CV (0.054?±?0.035 vs. 0.069?±?0.030, F?=?7.042, p?=?0.012) significantly. The mean levels of Hb and doses of rHuEPO were similar between CA and IA.

Conclusion

The administration of intravenous iron by CA or IA has the similar effects on iron supplement and anemia treatment. However, IA may be more benefit to Hb variability than CA in MHD patients.

     

Intravenous iron gluconate administration increases circulating PAPP-A in hemodialysis patients

BACKGROUND: Pregnancy-associated plasma protein-A (PAPP-A) is a proatherosclerotic molecule, interrelated with oxidative stress in hemodialysis (HD) patients. As intravenous (IV) iron might enhance oxidative stress in HD patients, this study investigates circulating PAPP-A during HD session and after IV iron administration. METHODS: In 20 HD patients, plasma PAPP-A concentration was assessed immunochemically during 2 HD sessions (prior to HD and at 60, 130, and 240 min of HD session). Sodium ferric gluconate (62.5 mg) was given IV to all patients 65 min after the start of the second HD. RESULTS: Sixty-five min after IV iron application, there was a significant increase in plasma PAPP-A (from 36.0+/-9.9 to 79.6+/-28.9 mU/L, p<0.0001). At the end of this HD session, PAPP-A decreased significantly (p<0.0001), but still remained 1.5-fold greater compared with predialysis levels (p<0.0005). CONCLUSION: IV iron increases circulating PAPP-A, and in this way, it might contribute to more pronounced cardiovascular complications in HD patients.     

'Oversaturation' of transferrin after intravenous ferric gluconate (FerrlecitR) in haemodialysis patients

BACKGROUND: Chronic haemodialysis causes blood loss and iron-deficiency.This can be corrected with intravenous preparations, e.g. sodiumferric-gluconate (FeGl). In two patients complaints of hypotensionand malaise during FeGl infusion coincided with high levelsof serum iron and a calculated transferrin iron saturation above100%. Iron toxicity could be the cause of these complaints.Free iron is known to aggravate the toxicity of free radicalsand other reactive oxygen products that are constantly formedin the body. We compared four rates of FeGl infusion with regardto iron parameters. METHODS: 20 dialysis patients received a total of 36 infusions of FeGl.A rapid infusion of 125 mg (Protocol A (n=10)) or 62.5 mg (ProtocolB (n=7)) of FeGl was given during the last 30 min of dialysis.A slow infusion of 125 mg (Protocol C (n=9)) or 62.5 mg (ProtocolD (n=10)) was given during 4 or 4.5 h of dialysis. Blood wastaken at regular intervals before, during, and after dialysisfor determination of serum iron, transferrin, ferritin, haematocrit,total protein, albumin, and lactate dehydrogenase (LDH). Transferrinsaturation was calculated from transferrin and serum iron. RESULTS: With rapid infusion A (125mg) the highest levels of serum iron(median 120 (range 40–159) micromol/l) and transferrinsaturation (207 (84–331)%) were seen at the end of theinfusion. These were significantly higher than the peak levelswith B, C, and D (P0.03). With rapid infusion B (62.5 mg), peaklevels were intermediately high (serum iron 61 (50–96)µmol/l; transferrin saturation 118 (91–174)%). Withslow infusion C (125 mg) similar peak levels were seen (serumiron 83 (43–106) µmol/l; transferrin saturation141 (88–172)%). With slow infusion D (62.5 mg), the lowestpeak levels were seen (serum iron 38 (31–55) µmol/l;transferrin saturation 78 (43–92)%). These levels weresignificantly lower than those with A, B and C (p0.002). Onlywith D all patients showed a transferrin saturation lower than100%. Ferritin was increased before the next dialysis in allpatients. LDH was not significantly elevated during any infusion. CONCLUSIONS: The commonly used rapid infusion rate (A) of FeGl causes ‘oversaturation’of transferrin. This is compatible with iron toxicity due tofree iron which may explain our patients' complaints. Free ironcannot be measured directly. LDH as a crude measure of celldamage was not elevated. Better measurements to prove free irontoxicity, like lipid peroxides, are not yet readily available.Infusion during a longer period at a lower dose (D) is effectiveand eliminates ‘oversaturation’ of transferrin andprobably the danger of iron toxicity.     

The comparative safety of intravenous iron dextran, iron saccharate, and sodium ferric gluconate

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 comparative safety of these three agents is critically evaluated.     

Sodium ferric gluconate complex therapy in anemic children on hemodialysis

Pediatric patients with end-stage renal disease undergoing hemodialysis (HD) frequently develop anemia. Administration of recombinant human erythropoietin (rHuEPO) is effective in managing this anemia, although the additional demand for iron often results in iron deficiency. In adult patients undergoing HD, intravenous (IV) iron administration is known to replenish iron stores more effectively than oral iron administration. Nevertheless, IV iron supplementation is underutilized in pediatric patients, possibly because of unproved safety in this population. This international, multicenter study investigated the safety and efficacy of two dosing regimens (1.5 mg kg^–1 and 3.0 mg kg^–1) of sodium ferric gluconate complex (SFGC) therapy, during eight consecutive HD sessions, in iron-deficient pediatric HD patients receiving concomitant rHuEPO therapy. Safety was evaluated in 66 patients and efficacy was evaluated in 56 patients. Significant increases from baseline were observed in both treatment groups 2 and 4 weeks after cessation of SFGC dosing for mean hemoglobin, hematocrit, transferrin saturation, serum ferritin, and reticulocyte hemoglobin content. Efficacy and safety profiles were comparable for 1.5 mg kg^–1 and 3.0 mg kg^–1 SFGC with no unexpected adverse events with either dose. Administration of SFGC was safe and efficacious in the pediatric HD population. Given the equivalent efficacy of the two doses, an initial dosing regimen of 1.5 mg kg^–1 is recommended for pediatric HD patients.An erratum to this article can be found at The Ferrlecit Pediatric Study Group is a co-author of this paper     

The safety of sodium ferric gluconate complex in haemodialysis patients has been extensively evaluated

Sir, This letter is a response to the letter from Bhowmik and Tiwari[1] concerning the safety of sodium ferric gluconate complex(SFGC). Of all the formulations of intravenous iron, SFGC hasbeen prospectively studied     

Comparison of the therapeutic efficacy of epoetin beta and epoetin alfa in maintenance phase hemodialysis patients

In May 2009 for financial reasons, the epoetin product used for hemoglobin (Hb) maintenance in our renal dialysis unit was changed from epoetin beta to epoetin alfa. Although widely believed that the dosage requirements are the same, we undertook a retrospective analysis to investigate whether the dosage requirements in chronic renal failure patients were comparable for both preparations. We studied 128 stable end-stage renal failure patients on hemodialysis (three times per week) receiving erythropoietin therapy to maintain their Hb at 11-12.5 g/dL. Patients were excluded if within the study period they developed signs of infection, bleeding, required blood transfusion, were under-dialyzed, or required hospital admission. Regular monthly Hb concentrations and hematocrit (Hct) levels were measured for each patient. The weekly EPO index (defined as weekly epoetin dose/mean monthly Hct) was derived for each patient, before and after regime change. Of the 128 patients in end-stage renal failure, 79 were included in the study. There was no significant difference between the two preparations in terms of Hct level achieved (p = 0.15). However, the median weekly epoetin dose requirement increased from 6733 (range 750-30,000) IU/week to 9000 (250-30,667) IU/week (p < 0.001). EPO index similarly increased from 20,465 (2500-130,846) IU/week/% to 27,073 (729-98,937) IU/week/% (p < 0.001). Our study showed that a higher dose of epoetin alfa was needed to maintain target Hb concentration.     

Anticoagulant efficacy of PEG-Hirudin in patients on maintenance hemodialysis

BACKGROUND: Heparins are currently the anticoagulants of choice in long-term hemodialysis (HD). Because of their shortcomings, including the increasing incidence of heparin-induced thrombocytopenia (HIT II), alternative anticoagulation is necessary. The study objectives were to provide safe and effective HD by investigating an appropriate PEG (polyethylene glycol)-Hirudin dosage regimen in patients on HD, as well as to compare the safety, tolerability, and efficacy of PEG-Hirudin with that of unfractionated heparin (UFH). METHODS: Twenty patients (12 males, 8 females, mean age 57.8 years) with end-stage renal disease (ESRD) took part in the study. Dialysis sessions lasting a mean of 4.3 hours (QB 250 to 300 mL/min, QD 500 mL/min) were performed 3 times a week with a Gambro GFS plus 16 dialyzer. Ten patients (group I) received UFH at 3 regular dialysis sessions (HD1-3) followed by 5 dialysis sessions using PEG-Hirudin (HD4-8). Another 10 patients (group II) received UFH at 3 regular dialysis sessions (HD1-3) followed by 10 sessions on PEG-Hirudin (HD4-13). The starting dose of PEG-Hirudin was a single bolus injection of 80 microg/kg BW (HD4), except for the first patient, who received 50 microg/kg BW followed by a 12 microg/kg bolus. Before each of the following sessions (HD5-13), an individualized PEG-Hirudin dose of between 26 to 65 microg/kg body weight (BW) (mean dose 41 microg/kg BW) was injected. PEG-Hirudin plasma and blood concentrations derived from anti-Iia activity and ecarin clotting time (ECT), respectively, activated partial thromboplastin time (aPTT), bleeding time, and arteriovenous (AV) fistula compression time were investigated to calculate the pharmacokinetic parameters or to assess anticoagulant efficacy. RESULTS: Mean predialysis PEG-Hirudin plasma concentrations increased up to a maximum of 488 ng/mL in group I (HD8) and up to 536 ng/mL in group II (HD8). Mean plasma concentrations measured at 5 minutes after the 1st (HD4), 5th (HD8), and 10th (HD13) PEG-Hirudin injection ranged from 1076 to 1298 ng/mL. Mean post-dialysis plasma levels ranged from 818 to 995 ng/mL. Mean predialysis aPTT was not affected by UFH, but was prolonged by 46 to 56 seconds by PEG-Hirudin. Five minutes after injecting PEG-Hirudin or UFH, mean aPTT was prolonged to a maximum of 85 and 188 seconds, respectively. Mean post-dialysis aPTT values ranged from 60 to 68 seconds after PEG-Hirudin and 34 to 46 seconds after UFH. PEG-Hirudin was well tolerated; no serious adverse events or bleeding complications were observed. Safety assessments yielded no significant difference between the two anticoagulants. CONCLUSION: This pilot study confirmed the usefulness and tolerability of a PEG-Hirudin dose regimen consisting of a single, fixed bolus dose of 80 microg/kg BW injected before starting the first dialysis session (HD4) and followed by a dose titration period over at least 4 sessions (HD5-8), which again was followed by a fixed maintenance dose period (HD9-13). On the basis of PEG-Hirudin data from patients with various degrees of renal insufficiency but not undergoing hemodialysis and prior recombinant-hirudin (r-hirudin) experience, patients were titrated into an EC-controlled dose range that proved to be efficacious enough to prevent clotting and safe enough to prevent bleeding. Due to the favorable pharmacokinetic properties of PEG-Hirudin, a residual anticoagulant effect is maintained in the intervals between dialysis sessions, and this permanent state of anticoagulation may prevent vascular access complications as well as other vascular events.     

Sodium ferric gluconate complex in hemodialysis patients. II. Adverse reactions in iron dextran-sensitive and dextran-tolerant patients

BACKGROUND: Iron dextran administration is associated with a high incidence of adverse reactions including anaphylaxis and death. Although dextran, rather than iron, is believed to be the cause of these reactions, it is not known whether iron dextran-sensitive patients can be safely administered another form of parenteral iron, sodium ferric gluconate in sucrose (SFGC). METHODS: In a 69 center, prospective, double-blind, controlled trial of safety and tolerability of SFGC, the rate of reactions to SFGC and placebo in 144 iron dextran-sensitive patients was compared with 2194 patients who were previously tolerant to iron dextran preparations. Serum tryptase levels, a marker of mast cell degranulation, also were measured. RESULTS: Among 143 iron dextran-sensitive patients exposed to SFGC, three (2.1%) were intolerant. All three had suspected allergic events to SFGC, including one patient with a serious reaction (0.7%). One dextran-sensitive patient (0.7%) had a suspected allergic reaction after placebo. In contrast, among 2194 iron dextran-tolerant patients, reactions to SFGC were significantly less common, with SFGC intolerance seen in seven patients (0.3%; P = 0.020), including five (0.2%) who had suspected allergic events (P = 0.010), but none who had serious events (0.0%; P = 0.061). Two iron dextran-tolerant patients (0.09%) had allergic-like reactions following placebo injections. Two of the three suspected allergic events in the iron dextran-sensitive group were confirmed as mast cell dependent by a 100% increase in serum tryptase, while there were no confirmed allergic events in the iron dextran-tolerant group. Long-term exposure to SFGC in iron dextran-sensitive patients resulted in intolerance in only one additional patient and no serious adverse events. CONCLUSIONS: Patients with a history of iron dextran sensitivity had approximately sevenfold higher rates of reaction to both placebo and SFGC compared to iron dextran tolerant patients. However, logistic regression analysis, performed to account for the higher reaction rate to placebo, suggests that this increased reactivity was not drug-specific nor immunologically mediated, but represented host idiosyncrasy. These results support the conclusions that reactions to SFGC can be attributed to pseudoallergy, and that SFGC is not a true allergen.     

Sodium ferric gluconate complex in hemodialysis patients: adverse reactions compared to placebo and iron dextran

BACKGROUND: Parenteral iron is often required by hemodialysis patients to maintain adequate iron stores. Until recently, the only available form of intravenous iron was iron dextran, which is associated with significant adverse reactions, including anaphylaxis and death. Sodium ferric gluconate complex (SFGC) was recently approved for use in the U.S. under FDA's priority drug review. This Phase IV study was designed to evaluate the safety of a single dose of intravenous SFGC as compared to placebo and a historical iron dextran control. METHODS: This multicenter, crossover, randomized, double blind, placebo-controlled prospective comparative study was performed in hemodialysis patients requiring at least 125 mg of elemental iron. The historical control was obtained from a meta-analysis of four publications examining outcomes in patients exposed to iron dextran. SFGC na?ve patients were administered SFGC without a test dose, undiluted, at a rate of 125 mg over 10 minutes, and compared to placebo comprising bacteriostatic saline. RESULTS: A total of 2534 patients were enrolled. The incidence of drug intolerance (an adverse event precluding re-exposure) was significantly less [0.44%, confidence interval (CI) 0.21 to 0.71%] after SFGC as compared to the iron dextran control (2.47%, CI 1.87 to 3.07%, P < 0.0001), but higher than after placebo (0.1%, P = 0.02). There was no difference found between SFGC and placebo in serious adverse events. A single life-threatening event occurred after SFGC (0.04%, CI 0.00 to 0.22%), which was significantly less than following iron dextran (0.61%, CI 0.36 to 0.86%), P = 0.0001. CONCLUSION: SFGC is well tolerated when given by intravenous push without a test dose. SFGC has a significantly lower incidence of drug intolerance and life-threatening events as compared to previous studies using iron dextran. The routine use of iron dextran in hemodialysis patients should be discontinued.     

Do we need to change our administration practice with regard to sodium ferric gluconate complex in glucose?

Sir, We read with considerable interest the original article by Chertowet al. [1] on the relative safety of parenteral iron