Research on Clinical Applications of Iron saccharate

Introduction

Iron saccharate (Figure 1), also known as saccharated ferric oxide is an intravenous preparation indicated for patients with iron-deficiency anemia. Since its introduction into the medical market in 1961. Iron saccharate has been used widely in Japan for iron-deficiency anemia. Iron saccharate is prepared by coating ferric iron with polysaccharide to reduce the irritancy and toxicity of iron. After intravenous administration, the colloidal iron is incorporated immediately into the reticuloendothelial system of the liver and spleen, where the iron is sequestrated and stored as ferritin and hemosiderin. Some iron is released from the iron store, binds tightly to transferrin and circulates in the blood stream, and is taken up by erythroid cells in the bone marrow,leading to stimulation of erythropoiesis and improvement of iron-deficiency anemia. One vial of iron saccharate contains 40 mg iron, almost equivalent to the daily flow of iron through the periphera blood, In view of the fact that the male and female body content of iron is 50 and 37 mg/kg respectively,10 to 20 vials would be usually sufficient to treat a patient with moderate anemia.However,over 7 million vials were consumed per year 1990, suggesting excessive administration to some patients. Indeed, unexpected adverse effects developed in a few patients who received excessive iron saccharate for prolonged periods.[1]

Effect of iron saccharate and iron dextran on the metabolism of phosphorus in rats

As a means of investigating the physiologic damage to and histologic deterioration of the kidney caused by iron saccharate and iron dextran (ID), we administered these substances intraperitoneally to rats. The rats were divided into 3 groups. Group 1 rats ( n = 7) were given iron saccharate, 28 mg/kg for 9 days and 20 mg/kg for 19 days. Group 2 rats ( n = 5) were given ID, 28 mg/kg for 9 days and 20 mg/kg for 19 days. Group 3 rats (control, n = 9) were given normal saline solution. After 28 days, serum calcium, total protein, and albumin concentrations were significantly lower in the iron saccharate group than in the ID group. Serum phosphorus concentrations were significantly lower in the iron saccharate group than in the control group. Serum iron concentrations were significantly higher in the ID group than in the iron saccharate group or the control, and the fractional excretion of sodium was significantly lower in the ID group than in the control group. The percent tubular reabsorption of phosphorus was significantly greater in the ID group than in the iron saccharate group or the control group, and the theoretical threshold concentration of phosphorus was also significantly lower in the iron saccharate group than in the ID or the control group. Histologic examination of the kidney after treatment revealed neither iron in the tubules nor any structural damage to the tubules. ID was not found to induce hypophosphatemia, whereas iron saccharate did. Researchers believe that the cause of such hypophosphatemia is impaired tubular reabsorption.[2]

A study for iron deficiency anemia associated with menorrhagia

A multicenter, randomized, open-label, phase III study was conducted to compare the efficacy and safety of intravenous ferric derisomaltose (FDI) versus iron saccharate in Japanese patients with iron deficiency anemia associated with menorrhagia. FDI can be administered as a single dose up to 1000 mg, whereas iron saccharate has a maximum single dose of 120 mg. The primary endpoint, which was the maximum change in hemoglobin concentration from baseline, was noninferior for the FDI group compared with the iron saccharate group. The incidence of treatment-emergent adverse events was lower in the FDI group (66.2%) than in the iron saccharate group (90.8%). Notably, the incidence of serum phosphorus level < 2.0 mg/dL was significantly lower in the FDI group (8.4%) than in the iron saccharate group (83.2%), and severe hypophosphatemia (≤ 1.0 mg/dL) occurred in 6.7% of iron saccharatetreated patients compared with none in the FDI group. The percentage of patients who achieved the cumulative total iron dose during the 8-week treatment period was higher in the FDI group (92.8%) than in the iron saccharate group (43.2%). The study met its primary endpoint, and also demonstrated the tolerability of a high dose of FDI per infusion, with a lower incidence of hypophosphatemia.[3]

Safety of intravenous injection of iron saccharate in haemodialysis patients

The most frequent i.v. iron preparations used for haemodialysis patients are iron dextran, iron gluconate and iron saccharate. Possible side effects include anaphylactic reactions due to preformed antibodies to dextran or vascular reactions due to unbound iron during treatment with iron gluconate or iron saccharate. Four dosage regimens of i.v. iron saccharate therapy were studied: 10, 20, 40 and 100 mg, which were given over a time period of 1 min after the end of the dialysis session. Iron metabolism parameters (serum iron concentrations, transferrin saturation and serum ferritin levels) were measured at 0, 1, 5, 15 and 30 min after application and immediately prior to the next dialysis session. All 18 regular haemodialysis patients studied received recombinant human erythropoietin (rHuEpo). Serum iron levels and transferrin saturation increased significantly following i.v. injection of all doses of iron saccharate. Iron 'oversaturation' of transferrin iron binding did not occur in patients with transferrin levels > 180 mg/dl. However, in patients with transferrin levels < 180 mg/dl the injection of 100 mg iron saccharate resulted in a transferrin saturation of 102.6 +/- 39.5% (two patients with transferrin levels of 87 and 92 mg/dl had transferrin saturation of 119.8 and 149.7%, two patients with transferrin levels of 148 and 171 mg/dl had transferrin saturations of 77.9 and 63.1%, respectively). Serum ferritin levels remained unchanged during the post-injection period and increased by the next dialysis session following injection of 100 mg iron saccharate by 165%. It is concluded that intravenous iron saccharate injection (10-100 mg even within 1 min) does not result in 'oversaturation' of transferrin iron binding if serum transferrin levels are > 180 mg/dl (high-risk patients; transferrin < 100 mg/dl). This may explain, at least in part, the minimal side effects observed during the i.v. application of iron saccharate. Low-dose i.v. iron saccharate (10-40 mg) is recommended for iron supplementation of haemodialysis patients. If injection of 100 mg is necessary, serum transferrin level should exceed 180 mg/dl. There is, however, no need for fast i.v. injection during routine iron supplementation.[4] 

References

[1] Sato K, Shiraki M. Saccharated ferric oxide-induced osteomalacia in Japan: iron-induced osteopathy due to nephropathy. Endocr J. 1998;45(4):431-439. doi:10.1507/endocrj.45.431

[2] Sanai T, Oochi N, Okada M, Imamura K, Okuda S, Iida M. Effect of saccharated ferric oxide and iron dextran on the metabolism of phosphorus in rats. J Lab Clin Med. 2005;146(1):25-29. doi:10.1016/j.lab.2005.02.015

[3] Kawabata H, Tamura T, Tamai S, Fujibayashi A, Sugimura M; Study Group. Intravenous ferric derisomaltose versus saccharated ferric oxide for iron deficiency anemia associated with menorrhagia: a randomized, open-label, active-controlled, noninferiority study. Int J Hematol. 2022;116(5):647-658. doi:10.1007/s12185-022-03401-0

[4] Sunder-Plassmann G, Hörl WH. Safety of intravenous injection of iron saccharate in haemodialysis patients. Nephrol Dial Transplant. 1996;11(9):1797-1802. 

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