Ferumoxytol

Identification

Summary

Ferumoxytol is an intravenous iron replacement product used to treat iron deficiency anemia (IDA) in patients with chronic kidney disease (CKD), or in patients who are unable to tolerate or who have not responded adequately to oral iron supplementation.

Brand Names

Feraheme

Generic Name

Ferumoxytol

DrugBank Accession Number

DB06215

Background

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

Similar Structures

Weight: Average: 231.531
Monoisotopic: 231.784466
Chemical Formula: Fe₃O₄

Synonyms

Ferumoxytol
Ferumoxytol non-stoichiometric magnetite

External IDs

AMI-7228
CODE 7228
CODE-7228

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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.

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Associated Conditions

Indication Type	Indication	Combined Product Details	Approval Level	Age Group	Patient Characteristics	Dose Form
Treatment of	Iron deficiency anemia		••••••••••••	•••••

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.

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.

Drug	Interaction
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Calcium Phosphate	Ferumoxytol can cause a decrease in the absorption of Calcium Phosphate resulting in a reduced serum concentration and potentially a decrease in efficacy.
Calcium phosphate dihydrate	Ferumoxytol can cause a decrease in the absorption of Calcium phosphate dihydrate resulting in a reduced serum concentration and potentially a decrease in efficacy.
Carbidopa	Ferumoxytol can cause a decrease in the absorption of Carbidopa resulting in a reduced serum concentration and potentially a decrease in efficacy.
Cinoxacin	Ferumoxytol can cause a decrease in the absorption of Cinoxacin resulting in a reduced serum concentration and potentially a decrease in efficacy.
Ciprofloxacin	Ferumoxytol can cause a decrease in the absorption of Ciprofloxacin resulting in a reduced serum concentration and potentially a decrease in efficacy.

Food Interactions

No interactions found.

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Active Moieties

Name	Kind	UNII	CAS	InChI Key
Iron	unknown	E1UOL152H7	7439-89-6	XEEYBQQBJWHFJM-UHFFFAOYSA-N

International/Other Brands

Rienso

Brand Name Prescription Products

Name	Dosage	Strength	Route	Labeller	Marketing Start	Marketing End
Feraheme	Solution	30 mg / mL	Intravenous	Amag Pharmaceuticals Inc	2012-05-01	2016-09-26
Feraheme	Injection	510 mg/17mL	Intravenous	AMAG Pharmaceuticals, Inc.	2009-07-13	Not applicable
Feridex	Solution	11.2 mg/1mL	Intravenous	Bayer	2008-03-10	Not applicable

Generic Prescription Products

Name	Dosage	Strength	Route	Labeller	Marketing Start	Marketing End	Region	Image
Ferumoxytol	Injection	510 mg/17mL	Intravenous	Sandoz Inc	2021-07-15	Not applicable

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

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. [Article]
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. [Article]
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. [Article]
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. [Article]
Feraheme Product Info [Link]
FDA Orders Stricter Warnings for Ferumoxytol (Feraheme ) [Link]
EMA label [Link]
Ferumoxytol [Link]
Ferumoxytol pubChem [Link]
Plasma Pharmacokinetics of Two Consecutive Doses of Ferumoxytol in Healthy Subjects [Link]
Comparative analysis of ferumoxytol and gadoteridol enhancement using T1- and T2-weighted MRI in neuroimaging [Link]
Ferumoxytol, Davisplus [Link]
Ferumoxytol-Enhanced Magnetic Resonance Imaging in Late-Stage CKD [Link]
Feraheme-ferumoxytol [Link]
Cardiovascular magnetic resonance T2* for tissue iron assessment in the heart [Link]
T1 and T2 images, Radiology Masterclass [Link]
Feraheme PDR [Link]

External Links

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

Phase	Status	Purpose	Conditions	Count
4	Completed	Basic Science	Iron Deficiency Anemia (IDA)	1
4	Completed	Other	Pediatric Congenital Heart Disease	1
4	Completed	Treatment	Chronic Kidney Disease (CKD) / Iron Deficiency Anemia Treatment	1
4	Completed	Treatment	Inflammation / Iron Deficiency Anemia (IDA) / Stress Oxidative	1
4	Completed	Treatment	Periodontitis, Apical / Pulp Disease, Dental	1

Pharmacoeconomics

Manufacturers

Not Available

Packagers

Not Available

Dosage Forms

Form	Route	Strength
Injection	Intravenous	510 mg/17mL
Solution	Intravenous	30 mg / mL
Solution	Intravenous	11.2 mg/1mL
Injection, solution	Intravenous	30 MG/ML

Prices

Not Available

Patents

Patent Number	Pediatric Extension	Approved	Expires (estimated)
US8501158	No	2013-08-06	2020-03-08
US8591864	No	2013-11-26	2020-03-08
US6599498	No	2003-07-29	2023-06-30
US7553479	No	2009-06-30	2020-03-08
US7871597	No	2011-01-18	2020-03-08
US8926947	No	2015-01-06	2020-03-08

Properties

State

Solid

Experimental Properties

Not Available

Predicted Properties

Property	Value	Source
logP	-0.77	Chemaxon
pKa (Strongest Acidic)	4.58	Chemaxon
Physiological Charge	2	Chemaxon
Hydrogen Acceptor Count	0	Chemaxon
Hydrogen Donor Count	0	Chemaxon
Polar Surface Area	0 Å²	Chemaxon
Rotatable Bond Count	0	Chemaxon
Refractivity	0 m³·mol^-1	Chemaxon
Polarizability	1.78 Å³	Chemaxon
Number of Rings	0	Chemaxon
Bioavailability	1	Chemaxon
Rule of Five	Yes	Chemaxon
Ghose Filter	No	Chemaxon
Veber's Rule	Yes	Chemaxon
MDDR-like Rule	No	Chemaxon

Predicted ADMET Features

Property	Value	Probability
Human Intestinal Absorption	+	0.893
Blood Brain Barrier	+	0.9831
Caco-2 permeable	-	0.5852
P-glycoprotein substrate	Non-substrate	0.8626
P-glycoprotein inhibitor I	Non-inhibitor	0.9243
P-glycoprotein inhibitor II	Non-inhibitor	0.979
Renal organic cation transporter	Non-inhibitor	0.9406
CYP450 2C9 substrate	Non-substrate	0.8648
CYP450 2D6 substrate	Non-substrate	0.8885
CYP450 3A4 substrate	Non-substrate	0.7664
CYP450 1A2 substrate	Non-inhibitor	0.8662
CYP450 2C9 inhibitor	Non-inhibitor	0.8859
CYP450 2D6 inhibitor	Non-inhibitor	0.9369
CYP450 2C19 inhibitor	Non-inhibitor	0.8911
CYP450 3A4 inhibitor	Non-inhibitor	0.9708
CYP450 inhibitory promiscuity	Low CYP Inhibitory Promiscuity	0.9446
Ames test	Non AMES toxic	0.5943
Carcinogenicity	Carcinogens	0.6372
Biodegradation	Ready biodegradable	0.7981
Rat acute toxicity	2.4005 LD50, mol/kg	Not applicable
hERG inhibition (predictor I)	Weak inhibitor	0.9107
hERG inhibition (predictor II)	Non-inhibitor	0.9799

ADMET data is predicted using admetSAR, a free tool for evaluating chemical ADMET properties. (23092397)

Spectra

Mass Spec (NIST): Not Available
Spectra: Not Available
Chromatographic Properties: Collision Cross Sections (CCS)
Not Available

Carriers

Details1. Serotransferrin

Kind: Protein
Organism: Humans
Pharmacological action: No
Actions: Binder

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

EMA label [Link]

Drug created at March 19, 2008 16:17 / Updated at October 07, 2021 12:08

Ferumoxytol

Identification

Structure for Ferumoxytol (DB06215)

Pharmacology

Interactions

Products

Categories

Chemical Identifiers

References

Clinical Trials

Pharmacoeconomics

Properties

Spectra

Collision Cross Sections (CCS)

Carriers

References