Ferumoxytol: A New Intravenous Iron Preparation
Ferumoxytol: A New Intravenous Iron Preparation
Ferumoxytol is an intravenous iron preparation for treatment of the anemia of chronic kidney disease (CKD). It is a carbohydrate-coated, superparamagnetic iron oxide nanoparticle. Because little free iron is present in the preparation, doses of 510 mg have been administered safely in as little as 17 seconds. Two prospective, randomized studies compared two doses of ferumoxytol 510 mg given in 5 ± 3 days with 3 weeks of oral iron 200 mg/day (as ferrous fumarate) in anemic patients with CKD. One study enrolled 304 patients with stages 1–5 CKD (predialysis), and the other study enrolled 230 patients with stage 5D CKD (undergoing hemodialysis). In both studies, a greater increase in hemoglobin level from baseline to end of study (day 35) was noted in patients who received ferumoxytol compared with those who received oral iron (mean ± SD 0.82 ± 1.24 vs 0.16 ± 1.02 g/dl in patients with stages 1–5 CKD and 1.02 ± 1.13 vs 0.46 ± 1.06 g/dl in patients with stage 5D CKD, p<0.001). A greater proportion of both predialysis and hemodialysis patients who received ferumoxytol had hemoglobin level increases from baseline of 1 g/dl or more compared with those who received oral iron (p<0.001). In a prospective, double-blind, crossover study of more than 700 patients with CKD stages 1–5D that compared the safety of ferumoxytol with normal saline injection, the rates of treatment-related adverse events were 5.2% and 4.5%, respectively. Serious treatment-related adverse events were seen in one patient in each treatment group. The most common adverse events with ferumoxytol occurred at the injection site (bruising, pain, swelling, erythema). Dizziness, nausea, pruritus, headache, and fatigue occurred in less than 2% of patients receiving ferumoxytol, with a similar frequency noted after administration of normal saline. In short-term studies, intravenous ferumoxytol was safely and rapidly administered, and was more effective than oral iron therapy in increasing hemoglobin levels in anemic patients with CKD. Long-term clinical trials with clinical outcomes and studies comparing ferumoxytol with other parenteral iron agents will help define the role of ferumoxytol in treating the anemia of CKD.
Anemia is a common feature of all stages of chronic kidney disease (CKD) and is associated with a lack of production of erythropoietin by the kidneys, often in association with iron deficiency. In patients treated with erythropoiesis-stimulating agents (e.g., epoetin alfa, darbepoetin alfa), iron deficiency may develop when available iron is used for hemoglobin synthesis. Intravenous iron therapy can decrease the required dosage of epoetin alfa in anemic patients who require hemodialysis.
As CKD is an inflammatory condition, there is often a sequestration and impaired release of iron from macrophages of the reticuloendothelial system in the liver, spleen, and bone marrow. This situation is referred to as reticuloendothelial blockade and causes a functional iron deficiency in which iron is present but not usable for hemoglobin synthesis. The provision of adequate amounts of bioavailable iron to correct deficits, replace ongoing losses (including those induced by erythropoiesis-stimulating agent therapy, blood loss during the hemodialysis procedure, gastrointestinal bleeding, and frequent phleboto-mies for blood tests), and overcome reticulo-endothelial blockade is critical to successfully treat anemia of CKD.
The prevalence of iron deficiency in patients with CKD is 25–70%, even in recently performed analyses. Iron therapy may be inadequate or impractical for a number of reasons. Oral iron products often have intolerable gastrointestinal toxicity, and patients my not adhere to prescribed treatments. Hepcidin, a compound produced by the liver during inflammation (such as during CKD), inhibits oral iron absorption in the small intestine, limiting bioavailability. Thus, intravenous iron treatments may be used to overcome reticuloendothelial blockade and guarantee delivery of a sufficient quantity of iron to support hemoglobin synthesis and erythropoiesis.
The currently available intravenous iron products—low-molecular-weight iron dextran, high-molecular-weight iron dextran, sodium ferric gluconate, and iron sucrose—have problems associated with their use, including toxicity (e.g. arthralgias, hypotension, dyspnea) and rate-of-administration constraints, that make their use inconvenient and/or time consuming. Ferumoxytol is a new treatment that may represent a safer and more convenient source of iron in the treatment of the anemia of CKD.
Ferumoxytol was approved for clinical use by the United States Food and Drug Administration on June 30, 2009. The professional labeling states that ferumoxytol is indicated for the treatment of iron deficiency anemia in adults with CKD. The approved dosage regimen is an intravenous dose of 510 mg, followed by a second dose 3–8 days later. The drug is given undiluted at a rate of up to 1 ml/second (30 mg/sec). This regimen may be repeated after 1 month if the hematologic response is deemed inadequate. Monitoring parameters include hemoglobin level, ferritin level, transferrin saturation, and blood pressure. Ferumoxytol has been studied only in adults (aged ≥ 18 yrs) with CKD or in healthy subjects. Patients aged 65 years or older had similar efficacy and safety responses compared with younger patients. To my knowledge, no human data are available regarding ferumoxytol use during pregnancy or nursing.
Ferumoxytol is contraindicated in patients with evidence of iron overload, known sensitivity to ferumoxytol or any of its components, or anemia not caused by iron deficiency. Drug interactions with ferumoxytol have not been studied, although it may reduce the absorption of concomitantly administered oral iron preparations.
Abstract and Introduction
Abstract
Ferumoxytol is an intravenous iron preparation for treatment of the anemia of chronic kidney disease (CKD). It is a carbohydrate-coated, superparamagnetic iron oxide nanoparticle. Because little free iron is present in the preparation, doses of 510 mg have been administered safely in as little as 17 seconds. Two prospective, randomized studies compared two doses of ferumoxytol 510 mg given in 5 ± 3 days with 3 weeks of oral iron 200 mg/day (as ferrous fumarate) in anemic patients with CKD. One study enrolled 304 patients with stages 1–5 CKD (predialysis), and the other study enrolled 230 patients with stage 5D CKD (undergoing hemodialysis). In both studies, a greater increase in hemoglobin level from baseline to end of study (day 35) was noted in patients who received ferumoxytol compared with those who received oral iron (mean ± SD 0.82 ± 1.24 vs 0.16 ± 1.02 g/dl in patients with stages 1–5 CKD and 1.02 ± 1.13 vs 0.46 ± 1.06 g/dl in patients with stage 5D CKD, p<0.001). A greater proportion of both predialysis and hemodialysis patients who received ferumoxytol had hemoglobin level increases from baseline of 1 g/dl or more compared with those who received oral iron (p<0.001). In a prospective, double-blind, crossover study of more than 700 patients with CKD stages 1–5D that compared the safety of ferumoxytol with normal saline injection, the rates of treatment-related adverse events were 5.2% and 4.5%, respectively. Serious treatment-related adverse events were seen in one patient in each treatment group. The most common adverse events with ferumoxytol occurred at the injection site (bruising, pain, swelling, erythema). Dizziness, nausea, pruritus, headache, and fatigue occurred in less than 2% of patients receiving ferumoxytol, with a similar frequency noted after administration of normal saline. In short-term studies, intravenous ferumoxytol was safely and rapidly administered, and was more effective than oral iron therapy in increasing hemoglobin levels in anemic patients with CKD. Long-term clinical trials with clinical outcomes and studies comparing ferumoxytol with other parenteral iron agents will help define the role of ferumoxytol in treating the anemia of CKD.
Introduction
Anemia is a common feature of all stages of chronic kidney disease (CKD) and is associated with a lack of production of erythropoietin by the kidneys, often in association with iron deficiency. In patients treated with erythropoiesis-stimulating agents (e.g., epoetin alfa, darbepoetin alfa), iron deficiency may develop when available iron is used for hemoglobin synthesis. Intravenous iron therapy can decrease the required dosage of epoetin alfa in anemic patients who require hemodialysis.
As CKD is an inflammatory condition, there is often a sequestration and impaired release of iron from macrophages of the reticuloendothelial system in the liver, spleen, and bone marrow. This situation is referred to as reticuloendothelial blockade and causes a functional iron deficiency in which iron is present but not usable for hemoglobin synthesis. The provision of adequate amounts of bioavailable iron to correct deficits, replace ongoing losses (including those induced by erythropoiesis-stimulating agent therapy, blood loss during the hemodialysis procedure, gastrointestinal bleeding, and frequent phleboto-mies for blood tests), and overcome reticulo-endothelial blockade is critical to successfully treat anemia of CKD.
The prevalence of iron deficiency in patients with CKD is 25–70%, even in recently performed analyses. Iron therapy may be inadequate or impractical for a number of reasons. Oral iron products often have intolerable gastrointestinal toxicity, and patients my not adhere to prescribed treatments. Hepcidin, a compound produced by the liver during inflammation (such as during CKD), inhibits oral iron absorption in the small intestine, limiting bioavailability. Thus, intravenous iron treatments may be used to overcome reticuloendothelial blockade and guarantee delivery of a sufficient quantity of iron to support hemoglobin synthesis and erythropoiesis.
The currently available intravenous iron products—low-molecular-weight iron dextran, high-molecular-weight iron dextran, sodium ferric gluconate, and iron sucrose—have problems associated with their use, including toxicity (e.g. arthralgias, hypotension, dyspnea) and rate-of-administration constraints, that make their use inconvenient and/or time consuming. Ferumoxytol is a new treatment that may represent a safer and more convenient source of iron in the treatment of the anemia of CKD.
Ferumoxytol was approved for clinical use by the United States Food and Drug Administration on June 30, 2009. The professional labeling states that ferumoxytol is indicated for the treatment of iron deficiency anemia in adults with CKD. The approved dosage regimen is an intravenous dose of 510 mg, followed by a second dose 3–8 days later. The drug is given undiluted at a rate of up to 1 ml/second (30 mg/sec). This regimen may be repeated after 1 month if the hematologic response is deemed inadequate. Monitoring parameters include hemoglobin level, ferritin level, transferrin saturation, and blood pressure. Ferumoxytol has been studied only in adults (aged ≥ 18 yrs) with CKD or in healthy subjects. Patients aged 65 years or older had similar efficacy and safety responses compared with younger patients. To my knowledge, no human data are available regarding ferumoxytol use during pregnancy or nursing.
Ferumoxytol is contraindicated in patients with evidence of iron overload, known sensitivity to ferumoxytol or any of its components, or anemia not caused by iron deficiency. Drug interactions with ferumoxytol have not been studied, although it may reduce the absorption of concomitantly administered oral iron preparations.
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