Ferumoxytol

Identification

Name
Ferumoxytol
Accession Number
DB06215
Description

Ferumoxytol is an intravenously administered iron preparation indicated in the EU and the US for the treatment of iron deficiency anemia in adult patients with chronic kidney disease (CKD) 4.

It is comprised of superparamagnetic iron oxide nanoparticles which are coated by a semi-synthetic carbohydrate shell in an isotonic, neutral pH solution that may be administered at relatively high dose by rapid intravenous injection 8.

Type
Small Molecule
Groups
Approved, Investigational
Structure
Thumb
Weight
Average: 231.531
Monoisotopic: 231.784466
Chemical Formula
Fe3O4
Synonyms
  • Ferumoxytol non-stoichiometric magnetite
External IDs
  • AMI-7228
  • CODE 7228
  • CODE-7228

Pharmacology

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) Label.

Associated Conditions
Contraindications & Blackbox Warnings
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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 14.

Feraheme (ferumoxytol) reached the primary endpoint with statistical significance (p<0.001) in all three trials versus oral iron 14.

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 17.

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 metalloflavoprotein 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 17.

Mechanism of action

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 17.

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 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 17.

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 17.

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 17.

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 9.

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 16.

Absorption

Bioavailability studies were not conducted as ferumoxytol has been developed for IV administration only 7.

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 17.

Volume of distribution

The population mean estimates for volume of distribution of the central compartment (V(1)), maximum elimination rate (V(max)), and ferumoxytol concentration at which rate of metabolism would be one-half of V(max) (K(m)) were 2.71 l, 14.3 mg/hr, and 77.5 mg/L, respectively 9.

Protein binding
Not Available
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 13.

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 17.

Route of elimination

Iron can either become a component of intracellular ferritin or be transferred to erythroid precursor cells 12.

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 9.

Feraheme showed dose-dependent, capacity-limited elimination from the plasma with a half-life of approximately 15 hours in humans 9.

Clearance

Since there is no renal clearance, ferumoxytol is safe in renal failure patients 11. One study estimated the clearance to be 0.0221 L/h 7.

Adverse Effects
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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 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 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 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 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 Label.

Affected organisms
  • Humans and other mammals
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
This information should not be interpreted without the help of a healthcare provider. If you believe you are experiencing an interaction, contact a healthcare provider immediately. The absence of an interaction does not necessarily mean no interactions exist.
DrugInteraction
Calcium PhosphateFerumoxytol can cause a decrease in the absorption of Calcium Phosphate resulting in a reduced serum concentration and potentially a decrease in efficacy.
Calcium phosphate dihydrateFerumoxytol can cause a decrease in the absorption of Calcium phosphate dihydrate resulting in a reduced serum concentration and potentially a decrease in efficacy.
CarbidopaFerumoxytol can cause a decrease in the absorption of Carbidopa resulting in a reduced serum concentration and potentially a decrease in efficacy.
CinoxacinFerumoxytol can cause a decrease in the absorption of Cinoxacin resulting in a reduced serum concentration and potentially a decrease in efficacy.
CiprofloxacinFerumoxytol can cause a decrease in the absorption of Ciprofloxacin resulting in a reduced serum concentration and potentially a decrease in efficacy.
DeferiproneThe serum concentration of Deferiprone can be decreased when it is combined with Ferumoxytol.
DelafloxacinFerumoxytol can cause a decrease in the absorption of Delafloxacin resulting in a reduced serum concentration and potentially a decrease in efficacy.
DimercaprolDimercaprol may increase the nephrotoxic activities of Ferumoxytol.
Dipotassium phosphateFerumoxytol can cause a decrease in the absorption of Dipotassium phosphate resulting in a reduced serum concentration and potentially a decrease in efficacy.
EnoxacinFerumoxytol can cause a decrease in the absorption of Enoxacin resulting in a reduced serum concentration and potentially a decrease in efficacy.
Additional Data Available
  • Extended Description
    Extended Description

    Extended description of the mechanism of action and particular properties of each drug interaction.

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  • Severity
    Severity

    A severity rating for each drug interaction, from minor to major.

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  • Evidence Level
    Evidence Level

    A rating for the strength of the evidence supporting each drug interaction.

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  • Action
    Action

    An effect category for each drug interaction. Know how this interaction affects the subject drug.

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Food Interactions
No interactions found.

Products

Active Moieties
NameKindUNIICASInChI Key
IronunknownE1UOL152H77439-89-6XEEYBQQBJWHFJM-UHFFFAOYSA-N
International/Other Brands
Rienso
Brand Name Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
FerahemeInjection510 mg/17mLIntravenousAMAG Pharmaceuticals, Inc.2009-07-13Not applicableUS flag
FerahemeSolution30 mgIntravenousAmag Pharmaceuticals Inc2012-05-012016-09-26Canada flag
FeridexSolution11.2 mg/1mLIntravenousBayer2008-03-10Not applicableUS flag
Additional Data Available
  • Application Number
    Application Number

    A unique ID assigned by the FDA when a product is submitted for approval by the labeller.

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  • Product Code
    Product Code

    A governmentally-recognized ID which uniquely identifies the product within its regulatory market.

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Categories

Drug Categories
Classification
Not classified

Chemical Identifiers

UNII
G6N3J05W84
CAS number
722492-56-0
InChI Key
WTFXARWRTYJXII-UHFFFAOYSA-N
InChI
InChI=1S/3Fe.4O/q+2;2*+3;4*-2
IUPAC Name
diiron(3+) lambda2-iron(2+) tetraoxidandiide
SMILES
[O--].[O--].[O--].[O--].[Fe++].[Fe+3].[Fe+3]

References

General References
  1. Neuwelt EA, Varallyay CG, Manninger S, Solymosi D, Haluska M, Hunt MA, Nesbit G, Stevens A, Jerosch-Herold M, Jacobs PM, Hoffman JM: The potential of ferumoxytol nanoparticle magnetic resonance imaging, perfusion, and angiography in central nervous system malignancy: a pilot study. Neurosurgery. 2007 Apr;60(4):601-11; discussion 611-2. [PubMed:17415196]
  2. Landry R, Jacobs PM, Davis R, Shenouda M, Bolton WK: Pharmacokinetic study of ferumoxytol: a new iron replacement therapy in normal subjects and hemodialysis patients. Am J Nephrol. 2005 Jul-Aug;25(4):400-10. Epub 2005 Jul 28. [PubMed:16088081]
  3. Schwenk MH: Ferumoxytol: a new intravenous iron preparation for the treatment of iron deficiency anemia in patients with chronic kidney disease. Pharmacotherapy. 2010 Jan;30(1):70-9. doi: 10.1592/phco.30.1.70. [PubMed:20030475]
  4. McCormack PL: Ferumoxytol: in iron deficiency anaemia in adults with chronic kidney disease. Drugs. 2012 Oct 22;72(15):2013-22. doi: 10.2165/11209880-000000000-00000. [PubMed:22994536]
  5. Feraheme Product Info [Link]
  6. FDA Orders Stricter Warnings for Ferumoxytol (Feraheme ) [Link]
  7. EMA label [Link]
  8. Ferumoxytol [Link]
  9. Ferumoxytol pubChem [Link]
  10. Plasma Pharmacokinetics of Two Consecutive Doses of Ferumoxytol in Healthy Subjects [Link]
  11. Comparative analysis of ferumoxytol and gadoteridol enhancement using T1- and T2-weighted MRI in neuroimaging [Link]
  12. Ferumoxytol, Davisplus [Link]
  13. Ferumoxytol-Enhanced Magnetic Resonance Imaging in Late-Stage CKD [Link]
  14. Feraheme-ferumoxytol [Link]
  15. Cardiovascular magnetic resonance T2* for tissue iron assessment in the heart [Link]
  16. T1 and T2 images, Radiology Masterclass [Link]
  17. Feraheme PDR [Link]
KEGG Drug
D04177
PubChem Compound
16211978
PubChem Substance
347827764
ChemSpider
4937312
RxNav
473387
ChEBI
50821
Wikipedia
Iron(II,III)_oxide
FDA label
Download (97.6 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
4CompletedBasic ScienceIron Deficiency Anemia (IDA)1
4CompletedTreatmentChronic Kidney Disease (CKD) / Iron Deficiency Anemia Treatment1
4CompletedTreatmentInflammatory Reaction / Iron Deficiency Anemia (IDA) / Iron-Deficiency Anemias / Oxidative Stress1
4Not Yet RecruitingTreatmentAnemia1
4Not Yet RecruitingTreatmentAnemia of Pregnancy / Iron Deficiency Anemia (IDA) / Pregnancy Related1
4Not Yet RecruitingTreatmentHeavy Menstrual Bleeding / Iron Deficiency Anemia (IDA)1
4RecruitingDiagnosticOsteonecrosis1
4RecruitingDiagnosticPediatric Congenital Heart Disease1
3CompletedTreatmentAnemia3
3CompletedTreatmentIron Deficiency Anemia (IDA)4

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage Forms
FormRouteStrength
InjectionIntravenous510 mg/17mL
SolutionIntravenous30 mg
SolutionIntravenous11.2 mg/1mL
Prices
Not Available
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)Region
US8501158No2013-08-062020-03-08US flag
US8591864No2013-11-262020-03-08US flag
US6599498No2003-07-292023-06-30US flag
US7553479No2009-06-302020-03-08US flag
US7871597No2011-01-182020-03-08US flag
US8926947No2015-01-062020-03-08US flag
Additional Data Available
  • Filed On
    Filed On

    The date on which a patent was filed with the relevant government.

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Properties

State
Solid
Experimental Properties
Not Available
Predicted Properties
PropertyValueSource
logP-0.77ChemAxon
pKa (Strongest Acidic)4.58ChemAxon
Physiological Charge2ChemAxon
Hydrogen Acceptor Count0ChemAxon
Hydrogen Donor Count0ChemAxon
Polar Surface Area0 Å2ChemAxon
Rotatable Bond Count0ChemAxon
Refractivity0 m3·mol-1ChemAxon
Polarizability1.78 Å3ChemAxon
Number of Rings0ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterNoChemAxon
Veber's RuleYesChemAxon
MDDR-like RuleNoChemAxon
Predicted ADMET Features
PropertyValueProbability
Human Intestinal Absorption+0.893
Blood Brain Barrier+0.9831
Caco-2 permeable-0.5852
P-glycoprotein substrateNon-substrate0.8626
P-glycoprotein inhibitor INon-inhibitor0.9243
P-glycoprotein inhibitor IINon-inhibitor0.979
Renal organic cation transporterNon-inhibitor0.9406
CYP450 2C9 substrateNon-substrate0.8648
CYP450 2D6 substrateNon-substrate0.8885
CYP450 3A4 substrateNon-substrate0.7664
CYP450 1A2 substrateNon-inhibitor0.8662
CYP450 2C9 inhibitorNon-inhibitor0.8859
CYP450 2D6 inhibitorNon-inhibitor0.9369
CYP450 2C19 inhibitorNon-inhibitor0.8911
CYP450 3A4 inhibitorNon-inhibitor0.9708
CYP450 inhibitory promiscuityLow CYP Inhibitory Promiscuity0.9446
Ames testNon AMES toxic0.5943
CarcinogenicityCarcinogens 0.6372
BiodegradationReady biodegradable0.7981
Rat acute toxicity2.4005 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Weak inhibitor0.9107
hERG inhibition (predictor II)Non-inhibitor0.9799
ADMET data is predicted using admetSAR, a free tool for evaluating chemical ADMET properties. (23092397)

Spectra

Mass Spec (NIST)
Not Available
Spectra
Not Available

Transporters

Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Transporter
General Function
Transferrin receptor binding
Specific Function
Transferrins are iron binding transport proteins which can bind two Fe(3+) ions in association with the binding of an anion, usually bicarbonate. It is responsible for the transport of iron from si...
Gene Name
TF
Uniprot ID
P02787
Uniprot Name
Serotransferrin
Molecular Weight
77063.195 Da
References
  1. Ferumoxytol, Davisplus [Link]
Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Storage
General Function
Iron ion binding
Specific Function
Stores iron in a soluble, non-toxic, readily available form. Important for iron homeostasis. Iron is taken up in the ferrous form and deposited as ferric hydroxides after oxidation. Also plays a ro...
Gene Name
FTL
Uniprot ID
P02792
Uniprot Name
Ferritin light chain
Molecular Weight
20019.49 Da
References
  1. Ferumoxytol, Davisplus [Link]
Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Storage
General Function
Iron ion binding
Specific Function
Stores iron in a soluble, non-toxic, readily available form. Important for iron homeostasis. Has ferroxidase activity. Iron is taken up in the ferrous form and deposited as ferric hydroxides after ...
Gene Name
FTH1
Uniprot ID
P02794
Uniprot Name
Ferritin heavy chain
Molecular Weight
21225.47 Da
References
  1. Ferumoxytol, Davisplus [Link]

Drug created on March 19, 2008 10:17 / Updated on June 12, 2020 11:41

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