Ferumoxytol is an intravenous iron replacement product indicated for the treatment of iron deficiency anemia in adults with chronic kidney disease. Compared to oral iron (200 mg/day for 21 days) in patients with chronic kidney disease and iron deficiency anemia, ferumoxytol use produced a significantly higher increase in hemoglobin over baseline at 35 days. Ferumoxytol was well tolerated; however, fatal and serious hypersensitivity reactions have been reported with ferumoxytol, and patients should be monitored for at least 30 minutes after ferumoxytol administration.
General Administration Information
For storage information, see specific product information within the How Supplied section.
-Monitor serum hemoglobin, ferritin, iron, and transferrin saturation at least 1 month after the second ferumoxytol dose.
Route-Specific Administration
Injectable Administration
-Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit.
-Do NOT give as an undiluted injection.
Intravenous Administration
-Allow at least 30 minutes between administration of ferumoxytol and medications that could potentially cause serious hypersensitivity reactions and/or hypotension such as chemotherapeutic agents or monoclonal antibodies.
-Administer while the patient is in a reclined or semi-reclined position.
-For patients receiving hemodialysis, administer ferumoxytol once blood pressure is stable and the patient has completed at least 1 hour of hemodialysis. Monitor for signs and symptoms of hypotension after each infusion.
-Dilute in 50 to 200 mL of 0.9% Sodium Chloride Injection or 5% Dextrose Injection for a final concentration of 2 to 8 mg elemental iron/mL.
-Administer IV over at least 15 minutes.
-Storage: Use immediately. May store at room temperature for up to 4 hours or refrigerated for up to 48 hours.
Serious hypersensitivity reactions or anaphylaxis, presenting as cardiac/cardiopulmonary arrest, clinically significant low blood pressure, angioedema, syncope, and unresponsiveness, have been reported in patients receiving ferumoxytol. Fetal adverse reactions, including fetal bradycardia, have been associated with maternal hypersensitivity reactions, especially during the second and third trimester of pregnancy. In a clinical study of iron deficiency anemia, regardless of etiology, hypersensitivity reactions were reported in 0.4% of patients receiving intravenous ferumoxytol over at least 15 minutes (n = 997). One patient experienced a severe hypersensitivity reaction, and moderate hypersensitivity reactions were reported in 3 patients. Rapid ferumoxytol injection resulted in serious hypersensitivity reactions in 0.2% of patients (n = 1,806) in premarketing clinical trials. In addition, other hypersensitivity reactions including pruritus, rash (unspecified), urticaria, and wheezing were reported in 3.5% of patients. In other premarketing evaluation, pruritus was reported in 1.2% of patients who received ferumoxytol (n = 605) compared to 0.4% of patients who received oral iron therapy (n = 280), and rash was reported in 1% of the ferumoxytol group compared to 0.4% of the oral iron group. Hypersensitivity reactions have occurred in patients in whom a previous dose was tolerated. Monitor patients for signs and symptoms of hypersensitivity reactions, including blood pressure and pulse monitoring, during administration, and for at least 30 minutes and until clinically stable following completion of each infusion.
Hypotension may occur after the administration of ferumoxytol. In pre-marketing clinical studies, hypotension was reported in 1.9% (33/1726) of the study population; 3 patients developed severe hypotensive reactions. In other pre-marketing evaluation, hypotension was reported in 2.5% of patients who received ferumoxytol (n = 605) compared to 0.4% of patients who received oral iron therapy (n = 280). Patients undergoing hemodialysis may be at particular risk for hypotension (see Contraindications/Precautions). Carefully monitor all patients for hypotension after ferumoxytol administration.
When combining the results of 3 pre-marketing clinical studies (n = 605), gastrointestinal adverse events reported for ferumoxytol compared to oral iron, respectively, include abdominal pain (1.3% vs. 1.4%), nausea (3.1% vs. 7.5%), and vomiting (1.5% vs. 5%). Diarrhea (4%) and constipation (2.1%) also have been reported in patients receiving ferumoxytol.
When combining the results of the 3 pre-marketing clinical studies (n = 605), general adverse reactions reported for ferumoxytol compared to oral iron, respectively, include dizziness (2.6% vs. 1.8%), headache (1.8% vs. 2.1%), fever (pyrexia) (1 vs. 0.7%), back pain (1% vs. 0%), and muscle cramps, reported as muscle spasms, (1% vs. 1.4%).
When combining the results of the 3 pre-marketing clinical studies (n = 605), the incidence of cardiovascular adverse reactions reported for ferumoxytol compared to oral iron, respectively, include peripheral edema (2% vs. 3.2%), edema (1.5% vs. 1.4%), and chest pain (unspecified) (1.3% vs. 0.7%). In addition, hypertension (1%) also has been reported in patients receiving ferumoxytol. Acute myocardial ischemia, with or without myocardial infarction or with in-stent thrombosis, in the setting of a hypersensitivity reaction, sinus tachycardia/rhythm abnormalities, congestive heart failure, absent pulse, and cyanosis have been reported with ferumoxytol administration in postmarketing surveillance.
When combining the results of the 3 pre-marketing clinical studies (n = 605), the incidence of pulmonary adverse reactions reported for ferumoxytol compared to oral iron, respectively, include cough (1.3% vs. 1.4%) and dyspnea (1% vs. 1.1%).
Hypotension has been reported in patients receiving intravenous iron products, including ferumoxytol. Use caution when administering ferumoxytol to patients with pre-existing hypotension or in those receiving hemodialysis. For patients receiving dialysis, administer ferumoxytol after at least one hour of hemodialysis has been completed and only when blood pressure is stable. In pre-marketing clinical trials, hypotension was reported in 1.9% (33/1726) of patients, 3 of which had serious hypotensive reactions. Blood pressure should be closely monitored after ferumoxytol administration.
Ferumoxytol is contraindicated in patients with known hypersensitivity to ferumoxytol or any of its components. Ferumoxytol is also contraindicated in patients with a history of allergic reaction to any intravenous iron product. Ferumoxytol administration requires a specialized care setting due to the risk of serious hypersensitivity reactions or anaphylaxis. Fatal and serious anaphylaxis and/or anaphylactoid reactions, presenting with cardiac or cardiopulmonary arrest, clinically significant low blood pressure, syncope, and unresponsiveness, have been reported in postmarketing surveillance. Hypersensitivity reactions have occurred in patients in whom a previous dose was tolerated. Elderly patients or patients with multiple or serious co-morbidities may be at increased risk for more severe outcomes; the potential risks and benefits of administration should be carefully considered in these patients. Only administer ferumoxytol as an intravenous infusion over at least 15 minutes. Monitor patients for signs and symptoms of hypersensitivity reactions, including blood pressure and pulse monitoring, during administration, and for at least 30 minutes and until clinically stable following completion of each infusion.
Do not administer ferumoxytol to patients with evidence of iron overload (e.g., patients with hemochromatosis). Unnecessary or prolonged administration of iron may lead to iron overload and consequently the possibility of exogenous hemosiderosis. Patients with hemoglobinopathy and other refractory anemias that might be erroneously diagnosed as iron deficiency anemias are at particular risk for such iron overload. The type of anemia and the underlying cause or causes should be determined before starting therapy with parenteral ferumoxytol. Since the anemia may be a result of a systemic disturbance, such as recurrent blood loss, the underlying cause(s) should be corrected, if possible. Patients receiving exogenous iron therapy require periodic monitoring of hematologic and hematinic parameters (i.e., hemoglobin, hematocrit, serum ferritin, and transferrin saturation) to avoid iron overload.
The administration of ferumoxytol may affect the diagnostic ability of magnetic resonance imaging (MRI) for up to 3 months; therefore, anticipated MRI studies should be conducted prior to ferumoxytol administration. If MRI studies are required within 3 months of ferumoxytol administration, use T1- or proton density-weighted magnetic resonance pulse sequences to minimize the effects of ferumoxytol. MRI using T2-weighted pulse sequences should not be performed earlier than 4 weeks after ferumoxytol administration. Maximum alteration of vascular MRI is anticipated to be evident for 1-2 days after ferumoxytol administration. Ferumoxytol will not interfere with X-ray, computed tomography (CT), positron emission tomography (PET), single photon emission computed tomography (SPECT), ultrasound, or nuclear medicine imaging.
Some patients with chronic hepatic disease may also have hemochromatosis or moderate iron overload in hepatic tissues. Use ferumoxytol with caution in patients with hepatic disease. The liver is one of the main storage sites for iron, and advanced chronic liver disease may result in excess storage of iron in the liver.
In controlled clinical trials, no differences in safety or efficacy were noted between geriatric and younger adult patients; however, greater sensitivity of some older adults to ferumoxytol therapy cannot be ruled out. Pre-marketing clinical trials included 330 patients 65 years of age and older. Geriatric patients with multiple or serious co-morbidities who experience hypersensitivity reactions and/or hypotension following ferumoxytol administration may be at increased risk for more severe outcomes; the potential risks and benefits of administration should be carefully considered in these patients.
Laboratory test interference may occur in the first 24 hours after ferumoxytol administration. Laboratory assays may overestimate serum iron and transferrin by also measuring the iron in the ferumoxytol complex.
Fetal adverse reactions, including fetal bradycardia, have been associated with maternal hypersensitivity reactions to parenteral iron products, especially during the second and third trimester of pregnancy. Data with ferumoxytol use in human pregnancy are insufficient to inform a drug-associated risk of adverse developmental outcomes. Untreated iron deficiency anemia is associated with a risk to the mother and fetus including postpartum anemia, preterm delivery, and low birth weight. In animal studies, maternal doses equivalent to 2 times the recommended human dose during organogenesis did not result in adverse maternal or fetal effects. However, maternally toxic doses of 6 times the recommended human dose administered during organogenesis did result in decreased fetal weights and fetal malformations.
There are no data on the presence of ferumoxytol in human milk, the effects on the breast-fed child, or the effects on milk production. Ferumoxytol has been detected in the milk of lactating rats; however, the clinical relevance of this finding is not clear. Consider the developmental and health benefits of breast-feeding along with the mother's clinical need for ferumoxytol and any potential adverse effects on the breast-fed child from ferumoxytol or the underlying maternal condition.
For the treatment of iron-deficiency anemia in patients who have an intolerance or unsatisfactory response to oral iron or who have chronic kidney disease:
NOTE: The dose of ferumoxytol is expressed in mg of elemental iron. Each mL contains 30 mg of elemental iron.
Intravenous dosage:
Adults: 510 mg IV every 3 to 8 days for 2 doses. Treatment may be repeated if iron deficiency persists or recurs.
For use as a magnetic resonance imaging (MRI)* contrast agent:
Intravenous dosage:
Adults: Limited data indicate that ferumoxytol may be effective as an MRI contrast agent. 1 mg/kg or 1.5 mg/kg IV undiluted or diluted depending on the MR series or 4 mg/kg IV undiluted followed immediately by a saline flush have been used in magnetic resonance angiography and perfusion studies (e.g., malignant brain tumors, aortic stent-graft endoleak). One study showed that blood pool MRI using ferumoxytol resulted in more visibility of stent-graft endoleaks at 24 hours compared to CT angiography. Another study showed more accurate brain tumor perfusion assessment, with delayed enhancement 24 to 48 hours after ferumoxytol administration, compared to gadolinium.
Maximum Dosage Limits:
-Adults
510 mg/dose IV. Cumulative doses of 2.04 grams have been administered in clinical trials.
-Elderly
510 mg/dose IV. Cumulative doses of 2.04 grams have been administered in clinical trials.
-Adolescents
Safety and efficacy have not been established.
-Children
Safety and efficacy have not been established.
Patients with Hepatic Impairment Dosing
Specific guidelines for dosage adjustments in hepatic impairment are not available; it appears that no dosage adjustments are needed. However, the liver is one of the main storage sites for iron, and some patients with chronic liver disease may have excessive iron storage. Administer ferumoxytol cautiously to patients with hepatic impairment.
Patients with Renal Impairment Dosing
Specific guidelines for dosage adjustments in renal impairment are not available; it appears that no dosage adjustments are needed.
*non-FDA-approved indication
Dimercaprol: (Major) Avoid concomitant use of dimercaprol and products containing iron. Dimercaprol forms toxic-chelates with iron which increases the risk for nephrotoxicity and other adverse effects.
Ferric Maltol: (Major) Parenteral iron formulas are generally only indicated for use in patients with documented iron deficiency in whom oral administration is either impossible or unsatisfactory. In general, do not administer parenteral iron concomitantly with other iron preparations (e.g., other parenteral iron products or oral iron supplements). Parenteral iron preparations (e.g., iron dextran; iron sucrose, sucroferric oxyhydroxide; sodium ferric gluconate complex; ferric carboxymaltose; ferumoxytol) may reduce the absorption of concomitantly administered oral iron preparations. Oral iron supplementation should be discontinued before parenteral administration of iron. Too much iron can be toxic, and iron is not easily eliminated from the body.
Iron Salts: (Major) Parenteral iron formulas are generally only indicated for use in patients with documented iron deficiency in whom oral administration is either impossible or unsatisfactory. In general, do not administer parenteral iron concomitantly with other iron preparations (e.g., other parenteral iron products or oral iron supplements). Parenteral iron preparations (e.g., iron dextran; iron sucrose, sucroferric oxyhydroxide; sodium ferric gluconate complex; ferric carboxymaltose; ferumoxytol) may reduce the absorption of concomitantly administered oral iron preparations. Oral iron supplementation should be discontinued before parenteral administration of iron. Too much iron can be toxic, and iron is not easily eliminated from the body.
Iron Salts: (Major) Parenteral iron formulas are generally only indicated for use in patients with documented iron deficiency in whom oral administration is either impossible or unsatisfactory. In general, do not administer parenteral iron concomitantly with other iron preparations (e.g., other parenteral iron products or oral iron supplements). Parenteral iron preparations (e.g., iron dextran; iron sucrose, sucroferric oxyhydroxide; sodium ferric gluconate complex; ferric carboxymaltose; ferumoxytol) may reduce the absorption of concomitantly administered oral iron preparations. Oral iron supplementation should be discontinued before parenteral administration of iron. Too much iron can be toxic, and iron is not easily eliminated from the body.
Iron: (Major) Parenteral iron formulas are generally only indicated for use in patients with documented iron deficiency in whom oral administration is either impossible or unsatisfactory. In general, do not administer parenteral iron concomitantly with other iron preparations (e.g., other parenteral iron products or oral iron supplements). Parenteral iron preparations (e.g., iron dextran; iron sucrose, sucroferric oxyhydroxide; sodium ferric gluconate complex; ferric carboxymaltose; ferumoxytol) may reduce the absorption of concomitantly administered oral iron preparations. Oral iron supplementation should be discontinued before parenteral administration of iron. Too much iron can be toxic, and iron is not easily eliminated from the body.
Levonorgestrel; Ethinyl Estradiol; Ferrous Bisglycinate: (Major) Parenteral iron formulas are generally only indicated for use in patients with documented iron deficiency in whom oral administration is either impossible or unsatisfactory. In general, do not administer parenteral iron concomitantly with other iron preparations (e.g., other parenteral iron products or oral iron supplements). Parenteral iron preparations (e.g., iron dextran; iron sucrose, sucroferric oxyhydroxide; sodium ferric gluconate complex; ferric carboxymaltose; ferumoxytol) may reduce the absorption of concomitantly administered oral iron preparations. Oral iron supplementation should be discontinued before parenteral administration of iron. Too much iron can be toxic, and iron is not easily eliminated from the body.
Levonorgestrel; Ethinyl Estradiol; Ferrous Fumarate: (Major) Parenteral iron formulas are generally only indicated for use in patients with documented iron deficiency in whom oral administration is either impossible or unsatisfactory. In general, do not administer parenteral iron concomitantly with other iron preparations (e.g., other parenteral iron products or oral iron supplements). Parenteral iron preparations (e.g., iron dextran; iron sucrose, sucroferric oxyhydroxide; sodium ferric gluconate complex; ferric carboxymaltose; ferumoxytol) may reduce the absorption of concomitantly administered oral iron preparations. Oral iron supplementation should be discontinued before parenteral administration of iron. Too much iron can be toxic, and iron is not easily eliminated from the body.
Norethindrone Acetate; Ethinyl Estradiol; Ferrous fumarate: (Major) Parenteral iron formulas are generally only indicated for use in patients with documented iron deficiency in whom oral administration is either impossible or unsatisfactory. In general, do not administer parenteral iron concomitantly with other iron preparations (e.g., other parenteral iron products or oral iron supplements). Parenteral iron preparations (e.g., iron dextran; iron sucrose, sucroferric oxyhydroxide; sodium ferric gluconate complex; ferric carboxymaltose; ferumoxytol) may reduce the absorption of concomitantly administered oral iron preparations. Oral iron supplementation should be discontinued before parenteral administration of iron. Too much iron can be toxic, and iron is not easily eliminated from the body.
Norethindrone; Ethinyl Estradiol; Ferrous fumarate: (Major) Parenteral iron formulas are generally only indicated for use in patients with documented iron deficiency in whom oral administration is either impossible or unsatisfactory. In general, do not administer parenteral iron concomitantly with other iron preparations (e.g., other parenteral iron products or oral iron supplements). Parenteral iron preparations (e.g., iron dextran; iron sucrose, sucroferric oxyhydroxide; sodium ferric gluconate complex; ferric carboxymaltose; ferumoxytol) may reduce the absorption of concomitantly administered oral iron preparations. Oral iron supplementation should be discontinued before parenteral administration of iron. Too much iron can be toxic, and iron is not easily eliminated from the body.
Sodium Ferric Gluconate Complex; ferric pyrophosphate citrate: (Major) Parenteral iron formulas are generally only indicated for use in patients with documented iron deficiency in whom oral administration is either impossible or unsatisfactory. In general, do not administer parenteral iron concomitantly with other iron preparations (e.g., other parenteral iron products or oral iron supplements). Parenteral iron preparations (e.g., iron dextran; iron sucrose, sucroferric oxyhydroxide; sodium ferric gluconate complex; ferric carboxymaltose; ferumoxytol) may reduce the absorption of concomitantly administered oral iron preparations. Oral iron supplementation should be discontinued before parenteral administration of iron. Too much iron can be toxic, and iron is not easily eliminated from the body.
Normal erythropoiesis depends on the concentration of iron and erythropoietin available in the plasma, and both are typically decreased in patients with renal failure. Exogenous administration of erythropoietin increases red blood cell production and iron utilization, contributing to iron deficiency in patients with chronic kidney disease. Ferumoxytol is a superparamagnetic iron oxide molecule coated with a polysaccharide shell. This shell aids in isolating the bioactive iron from plasma components until the iron-carbohydrate complex enters the macrophages found in the reticuloendothelial system of the liver, spleen, and bone marrow. After entering the macrophages, iron dissociates from the iron-carbohydrate complex and either enters the intracellular storage (e.g., ferritin) or is transferred to plasma transferrin for transport to erythroid precursor cells for incorporation into hemoglobin. A therapeutic response to iron therapy is dependent upon the patient's iron stores and the ability to use the iron. Use of iron is influenced by the cause of the deficiency as well as other illnesses that can affect normal erythropoiesis. Iron therapy alone does not increase red blood cell production. Administration of iron only improves anemia that is associated with iron deficiency.
Iron-containing proteins and enzymes are important in oxidation-reduction reactions, especially those of the mitochondria. Iron is a component of myoglobin and several heme-enzymes, including the cytochromes, catalase, and peroxidase. Iron is an essential component of the metalloflavoprotein enzymes and the mitochondrial enzyme alpha-glycerophosphate oxidase. Furthermore, iron is a cofactor for enzymes such as aconitase and tryptophan pyrrolase. Iron deficiency not only causes anemia and decreased oxygen delivery, it also reduces the metabolism of muscle and decreases mitochondrial activity. Iron deficiency also can lead to defects in learning or thermoregulation. Thus, iron is important to several metabolic functions in addition to erythropoiesis.
Ferumoxytol has been studied as a contrast agent for magnetic resonance imaging (MRI). Because ferumoxytol is an ultrasmall superparamagnetic iron oxide (USPIO) with a polysaccharide coating, it can be administered via intravenous bolus without mast cell degranulation, which is an attributable property for magnetic resonance angiography and perfusion imaging. Unlike gadolinium, ferumoxytol crosses the blood brain barrier slowly and is considered a 'blood pool' agent. Ferumoxytol remains in the intravascular space and provides a longer time window for data acquisition during MRI so that data can be repeatedly acquired over a period of minutes to hours with little loss of intravascular signal intensity and minimal soft tissue enhancement.
Ferumoxytol is administered intravenously. Ferumoxytol exhibits dose-dependent, capacity-limited elimination from plasma with a half-life of approximately 15 hours. The maximum plasma concentration (Cmax) and terminal half-life of ferumoxytol increase while clearance decreases with increasing ferumoxytol dose. Volume of distribution is consistent with plasma volume.
Iron therapy dosage is individualized according to patient goals for serum iron concentrations, iron storage parameters (e.g., ferritin, transferrin saturation), and serum hemoglobin concentrations. Iron toxicity may occur with excessive or unnecessary iron therapy. Systemic iron is stored in ferritin and hemosiderin, which are used for future production of hemoglobin. The absorption of iron depends upon the route of administration. The tissue that first clears parenterally administered iron from the bloodstream determines the bioavailability. If the reticuloendothelial system clears iron, only small amounts will be available over time to the bone marrow. Transferrin accepts iron from the intestinal tract or from sites of storage or hemoglobin destruction. Iron, which is bound to transferrin, is then transported in plasma and distributed to the bone marrow for hemoglobin synthesis, to the reticuloendothelial system for storage, to all cells for enzymes containing iron, and to placental cells if needed to meet fetal needs. Transferrin eventually becomes available for reuse. There is no destructive metabolism of iron because it takes place in a closed system. In normal adults, ninety percent of metabolized iron is conserved and reutilized repeatedly. Very little iron is eliminated. In normal, healthy adults, some daily loss of iron occurs through normal skin, hair, and nail loss, and GI losses. Menstruating women have an increased loss as do other persons with loss of blood.
-Route-Specific Pharmacokinetics
Intravenous Route
After two, 510 mg doses of ferumoxytol administered IV within 24 hours, ferumoxytol clearance was 69.1 ml/hr, volume of distribution was 3.16 L, and the Cmax and Tmax were 26 mcg/ml and 0.32 hr, respectively. Infusion rate did not affect pharmacokinetic parameters.
-Special Populations
Renal Impairment
Ferumoxytol is not removed by hemodialysis.
Elderly
There are no age differences in the pharmacokinetic parameters of ferumoxytol.
Gender Differences
There are no gender differences in the pharmacokinetic parameters of ferumoxytol.