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    Iron Supplements

    DEA CLASS

    Rx

    DESCRIPTION

    Intravenous iron replacement product
    Used for iron deficiency anemia in adults with chronic kidney disease
    Associated with fatal and serious hypersensitivity reactions

    COMMON BRAND NAMES

    Feraheme

    HOW SUPPLIED

    Feraheme Intravenous Inj Sol

    DOSAGE & INDICATIONS

    For the treatment of iron-deficiency anemia in patients with chronic kidney disease or intolerance or unsatisfactory response to oral iron.
    Intravenous dosage
    Adults

    510 mg IV followed by a second 510 mg IV dose 3 to 8 days later. The recommended dose may be readministered to patients with persistent or recurrent iron deficiency anemia. Cumulative doses of up to 2.04 g were administered to some patients with chronic kidney disease in premarketing clinical trials.

    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.

    †Indicates off-label use

    MAXIMUM DOSAGE

    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.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    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.

    Renal Impairment

    Specific guidelines for dosage adjustments in renal impairment are not available; it appears that no dosage adjustments are needed.
     

    ADMINISTRATION

    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.

    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.

    STORAGE

    Feraheme :
    - Avoid excessive heat (above 104 degrees F)
    - Protect from freezing
    - Store between 68 to 77 degrees F, excursions permitted 59 to 86 degrees F

    CONTRAINDICATIONS / PRECAUTIONS

    Dialysis, hypotension

    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.

    Requires a specialized care setting, risk of serious hypersensitivity reactions or anaphylaxis

    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.

    Hemochromatosis, hemoglobinopathy, hemosiderosis

    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.

    Magnetic resonance imaging (MRI)

    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.

    Hepatic disease

    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.

    Geriatric

    In controlled clinical trials, no differences in safety or efficacy were noted between geriatric and younger patients; however, greater sensitivity of some elderly patients to ferumoxytol therapy cannot be ruled out. In pre-marketing clinical trials, 330 patients >= 65 years of age were included. Elderly 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

    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.

    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 post-partum 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.

    Breast-feeding

    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.

    ADVERSE REACTIONS

    Severe

    angioedema / Rapid / Incidence not known
    serious hypersensitivity reactions or anaphylaxis / Rapid / Incidence not known
    cyanosis / Early / Incidence not known

    Moderate

    wheezing / Rapid / 3.7-3.7
    hypotension / Rapid / 1.9-2.5
    constipation / Delayed / 2.1-2.1
    peripheral edema / Delayed / 2.0-2.0
    edema / Delayed / 1.5-1.5
    chest pain (unspecified) / Early / 1.3-1.3
    hypertension / Early / 1.0-1.0
    dyspnea / Early / 1.0-1.0
    sinus tachycardia / Rapid / Incidence not known

    Mild

    diarrhea / Early / 4.0-4.0
    pruritus / Rapid / 1.2-3.7
    rash / Early / 1.0-3.7
    urticaria / Rapid / 3.7-3.7
    nausea / Early / 3.1-3.1
    dizziness / Early / 2.6-2.6
    headache / Early / 1.8-1.8
    vomiting / Early / 1.5-1.5
    abdominal pain / Early / 1.3-1.3
    cough / Delayed / 1.3-1.3
    fever / Early / 1.0-1.0
    muscle cramps / Delayed / 1.0-1.0
    back pain / Delayed / 1.0-1.0
    syncope / Early / Incidence not known

    DRUG INTERACTIONS

    Darbepoetin Alfa: (Minor) It is important that iron stores be replete before beginning therapy with darbepoetin alfa due to increased iron utilization. Inadequate iron stores will interfere with the therapeutic response to these agents (e.g., red blood cell production). Supplemental iron may be needed during maintenance therapy to facilitate erythropoiesis. Iron supplementation (e.g., iron dextran; iron salts; iron sucrose, sucroferric oxyhydroxide; polysaccharide-iron complex; sodium ferric gluconate complex) may be required.
    Deferasirox: (Major) Deferasirox chelates iron and is indicated as a treatment of iron toxicity or overdose. It would be illogical for a patient to receive both iron supplementation and deferasirox simultaneously.
    Deferiprone: (Major) Deferiprone chelates iron. Therapeutically, it is typically illogical for a patient to receive both iron supplementation (e.g., iron salts, iron dextran, ferric carboxymaltose, ferric citrate, sodium ferric gluconate complex, iron sucrose, sucroferric oxyhydroxide or polysaccharide-iron complex) and deferiprone simultaneously. Concurrent use of deferiprone with iron supplements has not been studied. Since deferiprone has the potential to bind polyvalent cations (e.g., iron), allow at least a 4-hour interval between deferiprone and other oral medications or dietary supplements containing these polyvalent cations when they are used together.
    Deferoxamine: (Severe) Deferoxamine chelates iron from ferritin or hemosiderin. A stable complex is formed that prevents iron from entering into further chemical reactions. The chelate is excreted in the urine and in the feces via bile. Deferoxamine is indicated as a treatment of iron toxicity or overdose. It would be illogical for a patient to receive both iron supplementation and deferoxamine simultaneously.
    Dimercaprol: (Severe) Dimercaprol forms toxic chelates with iron. These dimercaprol-iron complexes are more toxic than the metal alone, especially to the kidneys. Do not administer iron during dimercaprol treatment. Therapy with iron should generally be delayed until 24 hours after the cessation of dimercaprol therapy.
    Epoetin Alfa: (Minor) Inadequate iron stores will interfere with the therapeutic response to epoetin alfa (e.g., red blood cell production). Most patients with chronic kidney disease will require supplemental iron (e.g., iron dextran; iron salts; iron sucrose, sucroferric oxyhydroxide; polysaccharide-iron complex; sodium ferric gluconate complex) during epoetin alfa receipt. Evaluate transferrin saturation and serum ferritin before and during epoetin alfa treatment. Administer supplemental iron therapy when serum ferritin is < 100 mcg/L or when serum transferrin saturation is < 20%. After initiation of therapy and after each dose adjustment, monitor hemoglobin weekly until the hemoglobin concentration is stable and sufficient to minimize the need for RBC transfusion.
    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.
    Methoxy polyethylene glycol-epoetin beta: (Minor) Iron stores should be replete before and during treatment with an ESA. Iron stores are utilized in erythropoiesis and can be depleted during therapy even in patients with normal pre-treatment iron concentrations. Achieving and maintaining adequate iron stores are essential to attaining an optimal response to MPG-epoetin beta. Iron supplementation may be needed before and during therapy (e.g. iron dextran; iron salts; sodium ferric gluconate complex; iron sucrose, sucroferric oxyhydroxide; and polysaccharide-iron complex.

    PREGNANCY AND LACTATION

    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 post-partum 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.

    MECHANISM OF ACTION

    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.

    PHARMACOKINETICS

    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.

    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.