ABSORPTION Bioavailability studies were not conducted as ferumoxytol has been developed for IV administration only [L2179].; ; Iron therapy dosage is individualized according to specific goals for blood iron concentrations, iron storage parameters (e.g., ferritin, transferrin saturation), and serum hemoglobin concentrations. Iron toxicity is possible with excessive or unnecessary iron therapy. Systemic iron is stored in ferritin and hemosiderin, which are utilized for future production of hemoglobin. The absorption of iron depends on the route of administration. The tissue that first clears parenterally ingested iron from the plasma determines its bioavailability. If the reticuloendothelial system clears iron effectively, only small amounts will become available over time to the bone marrow. Transferrin accepts iron from the intestinal tract and also from sites of hemoglobin storage and destruction [L2190].

PHARMACODYNAMICS The pharmacodynamic effect of ferumoxytol on hematologic indexes such as Hgb (hemoglobin), serum ferritin, and TSAT (transferrin saturation) were studied and measured as primary and secondary endpoints in clinical efficacy studies [L2187]. ; ; Feraheme (ferumoxytol) reached the primary endpoint with statistical significance (p<0.001) in all three trials versus oral iron [L2187].; ; Ferumoxytol has been examined as a contrast agent for magnetic resonance imaging (MRI) studies. Because ferumoxytol is a very small superparamagnetic iron oxide (USPIO) with a polysaccharide coating, it may be administered via the intravenous bolus route without mast cell degranulation, which is an attributable property for magnetic resonance angiography and perfusion imaging. Unlike gadolinium, ferumoxytol crosses the blood-brain barrier at a slow pace and is considered a 'blood pool' agent. Ferumoxytol stays in the intravascular space and offers a longer time period for data acquisition during an MRI study so that data can be repeatedly obtained over a period of several minutes to hours with only small losses of intravascular signal intensity and minimal soft tissue enhancement [L2190].; ; Iron-containing proteins and enzymes are important in oxidation-reduction reactions, particularly those in the mitochondria. Iron is a part of myoglobin and several heme-enzymes, including the cytochromes, _catalase_, and _peroxidase_. Iron is an essential component of the m_etalloflavoprotein_ enzymes and the mitochondrial enzyme _alpha-glycerophosphate oxidase_. In addition, iron is a cofactor for enzymes such as _aconitase_ and _tryptophan pyrrolase_. Iron deficiency cause anemia and decreased oxygen delivery. This also reduces the metabolism of muscle and decreases mitochondrial activity. Iron deficiency may also cause defects in both learning or thermoregulation. Therefore, iron is important to several metabolic functions in addition to erythropoiesis [L2190].;

MOA Feraheme (ferumoxytol) is comprised of a superparamagnetic iron oxide that is coated with a carbohydrate shell, aiding in the isolation the bioactive iron from plasma components until the iron-carbohydrate complex enters the reticuloendothelial system macrophages of the liver, spleen and the bone marrow [L2190]. ; ; The iron is then released from the iron-carbohydrate complex within vesicles located in the macrophages. Iron then either enters the intracellular storage of iron (e.g., ferritin) or can be transferred to plasma transferrin for its transport to erythroid precursor cells for incorporation into hemoglobin [FDA label].; ; A therapeutic response to iron therapy depends upon the individual's iron stores and ability to utilize the iron. The systemic use of iron is influenced by the cause of the deficiency in addition to the illnesses/conditions that may affect erythropoiesis. Iron therapy by itself does not increase red blood cell (RBC) production. Administration of iron improves only the anemia associated with iron deficiency [L2190].; ; Iron-containing proteins and enzymes are essential in oxidation-reduction reactions, particularly those in the mitochondria. Iron is a part of myoglobin and various heme-enzymes, including the cytochromes, catalase, and peroxidase. Iron is an important component of the _metalloflavoprotein _enzymes as well as the mitochondrial enzyme _alpha-glycerophosphate oxidase_. In addition, iron serves as a cofactor for enzymes such as _aconitase _and tryptophan _pyrrolase_. Iron deficiency leads anemia and decreased oxygen delivery, but also reduces muscle metabolism and decreases mitochondrial activity [L2190]. ; ; Iron deficiency may also lead to defects in both learning and body thermoregulation. Therefore, iron is imperative to several metabolic functions in addition to erythropoiesis [L2190].; ; After intravenous administration, ferumoxytol replaces iron stores with less frequent side effects compared to the use of oral iron therapy. In addition, this agent generates T1 relaxation, producing a magnetic field and enhancing T2 relaxation, thereby darkening contrast media-containing structures in magnetic resonance imaging (MRI). Due to small particle size, ferumoxytol remains in the intravascular space for a prolonged period and so may be used as a blood pool agent [L2182]. ; ; T1 and T2, in radiology, refer to the timing of radiofrequency pulse sequences used to make images. The timing used to create T1 images results in images which emphasize fat tissue. The timing of radiofrequency pulse sequences utilized to create T2 images results in images which emphasize fat AND water within the body [L2189].; ;

INDICATION This drug is indicated for the treatment of iron deficiency anemia in adult patients who have experienced intolerance to oral iron or have experienced an unsatisfactory response to oral iron or; who have chronic kidney disease (CKD) [FDA label].

ROE Iron can either become a component of intracellular ferritin or be transferred to erythroid precursor cells [L2185].;

HALF-LIFE The pharmacokinetic (PK) behavior of Feraheme has been studied in healthy subjects and in patients with stage 5D of chronic kidney disease, on hemodialysis [L2182].; ; Feraheme showed dose-dependent, capacity-limited elimination from the plasma with a half-life of **approximately 15 hours** in humans [L2182].

METABOLISM Ferumoxytol metabolism is not dependent on renal function. It is removed from the circulation by the reticuloendothelial system of the liver, spleen, and bone marrow [L2186].; ; Iron, bound to transferrin, is then transported in the plasma and distributed to the bone marrow for the synthesis of hemoglobin, to the reticuloendothelial system for storage, and to all cells for enzymes containing iron, and to placental cells if needed to meet fetal needs. Transferrin eventually becomes available for recycling. In normal adults, 90% of metabolized iron is conserved and reutilized repeatedly [L2190].

TOXICITY **Hypersensitivity**; ; The FDA has ; Feraheme (ferumoxytol) may cause serious hypersensitivity reactions, including anaphylaxis and/or anaphylactoid reactions. Serious hypersensitivity reactions were reported in 0.2% (3/1,726) of subjects administered Feraheme. Some other reactions potentially associated with hypersensitivity (e.g., pruritus, rash, urticaria or wheezing) were reported in 3.7% (63/1,726) of these subjects. It is necessary to monitor patients for signs and symptoms of hypersensitivity for at least 30 minutes following Feraheme injection and limit administration of the drug only to when personnel and therapies are readily available for the treatment of hypersensitivity reactions [FDA label]. ; ; Ferumoxytol was not tested for carcinogenic effects. In general genotoxicity tests, ferumoxytol showed no evidence of mutagenic activity in an in vitro Ames test or clastogenic activity in either an in vitro chromosomal aberration assay or an in vivo micronucleus assay. No adverse effects on fertility were observed in animal studies. Ferumoxytol had no effect on male or female fertility or general reproductive function in rats [FDA label].; ; **Hypotension**; ; Feraheme may cause significant hypotension.; In a clinical study with Feraheme in patients with IDA, regardless of etiology, moderate hypotension was reported in 0.2% of subjects receiving Feraheme administered as intravenous infusion for at least 15 minutes [FDA label].; ; **Iron overload**; ; Excessive therapy with parenteral iron may lead to excess storage of iron with a possibility of iatrogenic hemosiderosis. Frequently monitor the hematologic response during parenteral iron therapy. It is advised not to administer Feraheme to patients with iron overload [FDA label].; ; **A note on MRI studies**; ; Administration of Feraheme may transiently affect the diagnostic ability of MR imaging. Anticipated MR imaging studies should be done before the administration of Feraheme. Alteration of MRI imaging studies may persist for up to 12 weeks after the last Feraheme dose [FDA label].;