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Quick Test posted on 6.18.13:
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Parenteral Iron for Treatment of Anemia of Chronic Kidney Disease
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Pharmacologic Therapy
Pharmacologic therapy for anemia of CKD is based upon a foundation of ESA therapy to correct erythropoietin deficiency and iron supplementation to correct and prevent iron deficiency caused by ongoing blood loss and increased iron demands associated with the initiation of erythropoietic therapy (Figs. 53–3 and 53–4). Iron therapy is first-line therapy for anemia of CKD if iron deficiency is diagnosed, and for some patients the target Hb may be achieved without concomitant ESA therapy. For most individuals with advanced CKD, however, combined therapy with iron and an ESA is often required to effectively stimulate erythropoiesis.
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| Figure 53–3. Algorithm for iron therapy in the management of the anemia of CKD. (ESA, erythropoietic-stimulating agent; Hb, hemoglobin; TSat, transferrin saturation; ND-CKD, nondialysis CKD patients; PD-CKD, peritoneal dialysis patients; HD-CKD, hemodialysis patients.) |
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Iron Supplementation
Options for iron supplementation include oral and IV therapy (Tables 53–6 and 53–7). Oral iron preparations differ in their content of elemental iron: ferrous salts (ferrous sulfate, ferrous fumarate, and ferrous gluconate), polysaccharide iron complex, and a heme iron polypeptide formulation. Five IV iron products are currently available in the United States (see Table 53–7): two composed of iron dextran (INFeD, molecular weight [MW] 96 kDa; and Dexferrum, MW 265 kDa), sodium ferric gluconate (Ferrlecit, MW 350 kDa), iron sucrose (Venofer, MW 43 kDa), and ferumoxytol (Feraheme, MW 750 kDa).
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Table 53-7 Intravenous Iron Preparations
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| Iron Compounds |
FDA-Approved Indications |
FDA-Approved Dosing |
Warnings |
Dose Ranges
a
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| Iron Dextran (INFeD, Watson Pharma Inc., Morrisontown, NJ, and DexFerrum, American Regent, Inc.. Shirley, NY)
b
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Patients with iron deficiency in whom oral iron is unsatisfactory |
IV push: 100 mg over 2 min (25-mg test dose required) |
Black box (risk of anaphylactic reactions) |
25–1,000 mg |
| Sodium ferric gluconate (Ferrlecit, Sanofi-Aventis, Dagenham, Essex, England)
c
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Adult and pediatric HD patients age 6 years and older receiving ESA therapy |
IV push (adult): 125 mg over 10 min
IV infusion (adult): 125 mg in 100 mL of 0.9% NaCl over 60 min
IV infusion (pediatric): 1.5 mg/kg in 25 mL of 0.9% NaCl over 60 min; maximum dose 125 mg |
General |
62.5–1,000 mg |
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Iron sucrose (Venofer, American Regent, Inc., Shirley, NY)
d
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HD patients with CKD receiving ESA therapy |
IV push: 100 mg over 2–5 min
IV infusion: 100 mg in maximum of 100 mL of 0.9% NaCl over 15 min |
General |
25–1,000 mg |
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Nondialysis-CKD patients receiving or not receiving ESA therapy |
IV push: 200 mg over 2–5 min on 5 different occasions within 14-day period |
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PD patients receiving ESA therapy |
IV infusion: 2 infusions, 14 days apart, of 300 mg in a maximum of 250 mL of 0.9% NaCl over 1.5 h, followed by 1 infusion, 14 days later, of 400 mg in a maximum of 250 mL of 0.9% NaCl over 2.5 h |
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| Ferumoxytol (Feraheme, AMAG Pharmaceuticals, Lexington, MA)
e
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Adult patients with iron-deficiency anemia associated with chronic kidney disease
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IV: 510 mg (17 mL) as a single dose, followed by a second 510 mg dose 3–8 days after the initial dose (rate of 1 mL or 30 mg/second) |
General |
510 mg |
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CKD, chronic kidney disease; ESA, erythropoietin-stimulating agent; HD, hemodialysis; PD, peritoneal dialysis.
a
Small dosing ranges (e.g., 25–150 mg per week) generally used for maintenance regimens. Larger doses (e.g., 1 g) should be administered in divided doses.
b
Supplied in 2-mL single-dose vials containing 50 mg of elemental iron per mL.
c
Available in colorless glass ampules containing 62.5 mg elemental iron (12.5 mg/mL).
d
Supplied in 5-mL single-dose vials containing 100 mg elemental iron (20 mg/mL).
e
Supplied as a 17-mL single-use vial containing 510 mg elemental iron (30 mg/mL).
Source: DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey LM:
Pharmacotherapy: A Pathophysiologic Approach, 8th Edition: http://www.accesspharmacy.com
Copyright © The McGraw-Hill Companies, Inc. All rights reserved.
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Pharmacology and Mechanism of Action
Iron supplements provide the elemental iron required for production of hemoglobin and its subsequent incorporation in red blood cells, the net result of which is an increase in the transportation of oxygen to tissues.
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Bioavailability
Approximately 10% of orally administered iron is absorbed in the duodenum and upper jejunum. Absorption of iron is decreased by food and achlorhydria. The heme form of oral iron binds to a different receptor in the GI tract than nonheme iron, is absorbed to a greater extent, and may be better tolerated. Some oral iron formulations also include ascorbic acid to enhance iron absorption.
Intravenous iron preparations are colloids that consist of an iron-containing core that is surrounded by a carbohydrate shell to stabilize the iron complex. Available agents differ in the size of the core and the composition of the surrounding carbohydrate. These differences affect the rate of dissociation of iron from the complex to phagocytes within the reticuloendothelial system where iron is either stored or released to the extracellular carrier protein transferrin, which transports iron to the bone marrow for red blood cell production. The half-lives of the available IV iron formulations differ: ferric gluconate (1 hour), iron sucrose (6 hours), ferumoxytol (15 hours), and iron dextran (40 to 60 hours).
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Efficacy, Dosage, and Administration
Although supplementation using oral preparations may seem more practical than IV administration, oral iron therapy is limited by poor absorption and nonadherence with therapy primarily due to adverse effects and, thus, it is a challenge to achieve goal iron indices. If oral therapy is initiated, the recommended dose is 200 mg of elemental iron per day (see Table 53–6). Either oral or IV administration of iron is recommended in early-stage CKD and the peritoneal dialysis population. Oral iron supplementation is more convenient for these patients, who do not have regular IV access; however, at some point they are likely to require IV iron supplementation to meet iron needs and correct absolute iron deficiency, especially if receiving an ESA.
In patients with ESRD, GI absorption of iron is often inadequate to meet the increase in iron demand from ESA therapy and chronic blood loss in the hemodialysis population. K/DOQI guidelines recommend IV iron as the preferred route of administration in the hemodialysis population. Parenteral iron improves the responsiveness to ESA therapy and reduces the dose required to achieve and maintain the target Hb in hemodialysis patients. For the hemodialysis population typical repletion dosing regimens are 100 mg as iron sucrose or iron dextran over 10 dialysis sessions, or 125 mg of sodium ferric gluconate over 8 dialysis sessions (see Table 53–7). Ferumoxytol is administered as 510 mg at a rate not to exceed 30 mg per second (1 mL per second) with a second dose given within 3 to 8 days. Administration of 1 g of IV iron is recommended to initially replete hemodialysis patients with an absolute iron deficiency; however, without ongoing iron supplementation, many patients quickly become iron deficient. To prevent iron deficiency maintenance doses of IV iron are administered in hemodialysis patients (e.g., iron sucrose or iron dextran 25 to 100 mg/wk; sodium ferric gluconate 62.5 to 125 mg/wk) based on evidence of improved Hb and lower ESA doses with these regimens.
Iron administration in patients with what is known as iron restricted erythropoiesis (also referred to as functional iron deficiency) is more questionable. Under these conditions a trial of IV iron therapy may be warranted if the Hb is less than the target of 11 g/dL (110 g/L; 6.83 mmol/L). A recent study conducted in ESA-treated anemic hemodialysis patients with a low TSat (<25% [<0.25]) and an elevated serum ferritin (>500 ng/mL [>500 μg/L]) showed a significantly greater Hb response rate in patients who received a 1 g course of IV iron as sodium ferric gluconate in conjunction with a 25% increase in ESA dose than in those who only received an increase in the ESA dose.
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Adverse Effects
Adverse effects of oral iron are primarily GI in nature and include constipation, nausea, and abdominal cramping. These adverse effects are more likely as the dose is escalated and may be present in more than 50% of patients receiving 200 mg of elemental iron per day. These unfavorable effects often discourage patients from taking these medications on a chronic basis. Some of these GI side effects can be minimized if oral iron products are taken with food; however, food decreases absorption of oral iron. Patients should initially be instructed to take oral iron on an empty stomach; however, if side effects lead to intolerance and nonadherence these agents can be administered with food, or an alternative agent may be prescribed.
Adverse effects of IV iron include allergic reactions, hypotension, dizziness, dyspnea, headaches, lower back pain, arthralgia, syncope, and arthritis. Some of these reactions, in particular hypotension, can be minimized by decreasing the dose or rate of infusion of iron. The most concerning potential consequence of IV iron administration is anaphylaxis. Anaphylactoid reactions to iron dextran have been reported in up to 1.8% of patients, with serious reactions including respiratory complications and cardiovascular collapse occurring in approximately 0.6%. Such reactions are believed to be partly a response to antibody formation to the dextran component. Adverse reactions have been reported two to eight times more frequently in those receiving Dexferrum compared with INFeD. Based on the labeling for all iron dextran products clinicians should (a) administer a test dose of 25 mg prior to the first therapeutic dose; if there are no signs or symptoms of an anaphylactic-type reaction then administer the full therapeutic dose; (b) observe for signs or symptoms of anaphylactic-type reactions during and after every administration; and (c) note that patients with a history of drug allergies may be at increased risk of anaphylactic-type reactions. The potential for increased risk of reactions with concomitant use of angiotensin-converting enzyme inhibitors and iron dextran is also highlighted in the labeling for iron dextran, and a statement is included to clarify that there are differences in the chemical characteristics and clinical effects of available iron dextran products (e.g., Dexferrum and INFeD) since these agents are often erroneously considered interchangeable.
The risk of adverse events with iron dextrans was particularly influential in product selection prior to the availability of sodium ferric gluconate, iron sucrose, and ferumoxytol. These IV iron formulations have a better safety record than either of the iron dextran products, based on their history of use in Europe over the last 4 decades (sodium ferric gluconate and iron sucrose) and data in the United States since these products were approved. These newer agents do not require administration of a test dose prior to administration of the full dose. As a precaution with all IV preparations, patients should be observed during and immediately following administration for any adverse reactions.
Administration of IV iron also introduces a risk of iron overload. Deposition of excess iron may affect several organ systems, leading to hepatic, pancreatic, and cardiac dysfunction. Bone marrow biopsy provides the most definitive diagnosis of iron overload, but because it is an extremely invasive procedure, it is not widely employed in most clinical settings. Maintaining serum ferritin and TSat values that demonstrate efficacy in preventing iron deficiency yet are safe is the most reasonable approach to minimize the risk of iron toxicity. The challenge is in defining these upper limits, particularly for serum ferritin, which may be elevated in inflammatory conditions and not reflective of true iron stores in such situations. If symptomatic overload does occur, deferoxamine (Desferal) or phlebotomy may be necessary.
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Dosage Considerations
The safety and efficacy of high-dose IV iron regimens have been evaluated to determine the most cost-effective and efficacious dosing strategies. Iron dextran has been safely administered to dialysis patients in total-dose infusions ranging from 400 mg to 2 g. Similar high-dose regimens of 500 mg have also been safely administered to patients with stage 3 or 4 CKD. Sodium ferric gluconate has been safely administered at doses of 250 mg infused over 1 hour (4.2 mg/min). In this same evaluation, 19 doses greater than 250 mg were administered; 1 dose of 312.5 mg, 14 doses of 375 mg, and 4 doses of 500 mg, with infusion rates varying from 1.22 mg/min to 25 mg/min. No serious adverse events were reported, although nonserious events, such as pruritus, did occur in 4 of the 144 patients who received the 250 mg dose. If doses higher than those currently approved are used in practice, they should be administered over a prolonged time period (e.g., at least 2–3 hours). Iron sucrose at doses of up to 500 mg administered over 3 hours on consecutive days has been successful in maintaining iron stores without causing serious adverse events. When administered over a shorter time period this same dose was associated with dizziness, hypotension, and nausea. In this same evaluation the administration of lower doses of 200 to 300 mg given over 2 hours resulted in fewer adverse events. Higher-dose regimens for iron sucrose have been approved in patients with early-stage CKD and peritoneal dialysis patients (see Table 53–7), populations in whom administration of higher doses are more convenient as these patients are seen less frequently by healthcare providers than the hemodialysis population. Ferumoxytol was approved in 2009 for use in the adult CKD population, including dialysis and nondialysis patients. The approved dose is 510 mg administered at a rate of up to 30 mg per second, a higher dose and administration rate compared with other available IV iron formulations.
Although there are conflicting reports, most clinicians believe that exposure to iron may contribute to the risk of bacterial infection because iron is used by microorganisms for metabolic functions. The association of IV iron with oxidative stress, acceleration of atherosclerosis, and other cardiovascular conditions has also been suggested. These potential long-term risks of IV iron therapy are not clearly defined, and there are no data confirming unequivocally that aggressive use of IV iron in CKD patients treated with ESA therapy increases patient morbidity or mortality.
As a superparamagnetic oxide, ferumoxytol may affect the diagnostic ability of magnetic resonance imaging studies; therefore, these imaging studies should be done prior to administration of ferumoxytol when possible. These effects may persist for up to 3 months following administration of ferumoxytol. Ferumoxytol will not interfere with x-ray, computed tomography, positron emission tomography, single photon emission computed tomography, ultrasonography, or nuclear medicine imaging.
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Quick Test Questions QUESTION 1: According to the K/DOQI guidelines
for anemia management which of the following is the preferred route
of iron administration in the nondialysis CKD population?
QUESTION 2: Which of the following is a typical repletion
dose of IV iron recommended in the hemodialysis population with
absolute iron deficiency?
QUESTION 3: Which of the following iron preparations
requires a test dose because of the association with anaphylactic
reactions?
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