A Comprehensive Monograph on Ferumoxytol (DB06215): A Dual-Use Nanoparticle for Iron Deficiency Anemia and Magnetic Resonance Imaging

Executive Summary

Ferumoxytol is an intravenously administered iron replacement product and diagnostic agent with a unique nanoparticle structure that defines its clinical profile. Identified by DrugBank ID DB06215 and CAS Number 722492-56-0, it is marketed primarily under the brand name Feraheme. Structurally, Ferumoxytol is a superparamagnetic iron oxide (SPION) nanoparticle with a non-stoichiometric magnetite core encapsulated by a semi-synthetic carbohydrate shell. This core-shell design is fundamental to its mechanism, providing stability, controlling iron release, and dictating its pharmacokinetic behavior.

The primary therapeutic indication for Ferumoxytol is the treatment of iron deficiency anemia (IDA) in adult patients. Initially approved by the U.S. Food and Drug Administration (FDA) in 2009 for IDA in the context of chronic kidney disease (CKD), its label was expanded in 2018 to include all adult IDA patients who have an intolerance or an unsatisfactory response to oral iron therapy. Its mechanism involves uptake of the nanoparticle by the reticuloendothelial system (RES), followed by controlled intracellular iron release, which then enters the body's iron transport and storage pathways for hemoglobin synthesis. This RES-mediated clearance makes it a suitable option for patients with renal impairment, as it is not dependent on kidney function and is not removed by hemodialysis.

Clinically, Ferumoxytol offers a significant convenience advantage over older intravenous iron formulations, such as iron sucrose, allowing for a full 1.02 g therapeutic course to be administered in just two slow infusions over 3 to 8 days. Head-to-head clinical trials have demonstrated its non-inferiority in efficacy to both iron sucrose and ferric carboxymaltose. A pivotal finding from comparative studies is the markedly lower incidence of severe hypophosphatemia with Ferumoxytol compared to ferric carboxymaltose, a key safety differentiator.

The most significant risk associated with Ferumoxytol is the potential for serious, life-threatening hypersensitivity reactions, including anaphylaxis. This risk prompted an FDA BOXED WARNING and a shift in administration from a rapid intravenous injection to a mandatory slow infusion over at least 15 minutes. The drug is contraindicated in patients with a history of allergy to any intravenous iron product, and strict monitoring during and after infusion is required. Other notable risks include hypotension, the potential for iron overload with excessive use, and prolonged interference with magnetic resonance imaging (MRI) studies.

Beyond its therapeutic role, Ferumoxytol's superparamagnetic properties enable its off-label use as a biodegradable, gadolinium-sparing MRI contrast agent. Its long intravascular half-life makes it an effective blood pool agent for high-resolution magnetic resonance angiography. This dual functionality as both a therapeutic and a diagnostic agent underscores its unique position in modern medicine. In conclusion, Ferumoxytol is a potent and convenient treatment for IDA, whose benefits, particularly its efficacy, dosing schedule, and favorable hypophosphatemia profile, must be carefully weighed against the serious risk of hypersensitivity reactions.

Product Identification and Physicochemical Properties

2.1. Nomenclature and Identifiers

Ferumoxytol is recognized by a variety of names and identifiers across scientific, regulatory, and commercial domains, reflecting its complex nature as both a chemical entity and a pharmaceutical product.

• Generic Name: The United States Adopted Name (USAN) for the drug is Ferumoxytol.[1]
• Brand Names: In the United States and Canada, it is marketed under the brand name Feraheme.[3] In the European Union and Switzerland, it has been marketed as Rienso.[2] Other trade names mentioned in association with the product include Feridex.[3]
• DrugBank ID: The unique identifier in the DrugBank database is DB06215.[3]
• CAS Number: The Chemical Abstracts Service registry number is 722492-56-0.[1] Other associated CAS numbers, including deprecated ones, have been noted, such as 119683-68-0 and 1309-38-2.[6]
• Synonyms and Codes: During its development and in various contexts, Ferumoxytol has been referred to by several synonyms and codes. These include Ferumoxytol non-stoichiometric magnetite, AMI-7228, CODE 7228, C 7228, and Cytogen.[1]

2.2. Molecular Structure and Formulation

Ferumoxytol is not a conventional small molecule but a complex, engineered nanoparticle. Its structure and formulation are intricately linked to its function and clinical profile.

• Core-Shell Nanoparticle Structure: Ferumoxytol is classified as an ultrasmall superparamagnetic iron oxide (USPIO) nanoparticle.[3] The core of the nanoparticle consists of non-stoichiometric magnetite, a form of iron oxide.[11] The chemical formula for the iron oxide core is sometimes represented simply as Fe3​O4​ or more complexly as Fe5​874O8​752, reflecting the non-stoichiometric nature of the crystalline structure.[1] This inorganic core is encapsulated by a hydrophilic, semi-synthetic carbohydrate shell identified as polyglucose sorbitol carboxymethylether or carboxymethyl-dextran.[1] The complete complex has an estimated molecular weight of approximately 750 kDa and a complex empirical formula of Fe5​874O8​752⋅C11719​H18682​O9933​Na414​.[2]
• Physical Characteristics: The overall hydrodynamic diameter of the colloidal particle ranges from 17 to 31 nm.[10] It is supplied as a sterile, aqueous colloidal solution that appears black to reddish-brown.[11] The formulation is made isotonic through the inclusion of mannitol (44 mg/mL) and is buffered to a neutral pH between 6 and 8.[11] The final product has an osmolality of 270-330 mOsm/kg and contains no preservatives.[11] Each single-dose vial provides 510 mg of elemental iron in a 17 mL volume, resulting in a concentration of 30 mg of elemental iron per mL.[11]

The specific core-shell architecture of Ferumoxytol is the central determinant of its entire clinical profile, a concept that underpins its utility and safety. The carbohydrate shell is not merely a passive delivery vehicle but an active component critical to the drug's function. Firstly, it serves to isolate the bioactive iron core from direct exposure to plasma components upon injection.[3] This sequestration prevents the uncontrolled release of labile, non-transferrin-bound iron, which can catalyze the formation of reactive oxygen species and induce significant toxicity.[15] Secondly, the size and surface characteristics conferred by the shell dictate the nanoparticle's pharmacokinetic behavior, leading to a long intravascular half-life and targeting the complex for clearance by the macrophages of the reticuloendothelial system (RES).[3] This RES-mediated uptake is the required first step for the drug's therapeutic mechanism, as the iron is subsequently released within these specific cells.[3] Therefore, the nanoparticle's physical structure directly governs its unique metabolic pathway, which is distinct from simpler iron salts, independent of renal function, and fundamental to both its therapeutic action and its safety considerations.[3]

Clinical Pharmacology

3.1. Mechanism of Action (Pharmacodynamics)

Ferumoxytol exhibits a dual mechanism of action, functioning both as a therapeutic iron replacement product and as a diagnostic magnetic resonance imaging (MRI) contrast agent. These distinct functions are derived from the unique physicochemical properties of its nanoparticle structure.

3.1.1. As an Iron Replacement Product (Therapeutic Use)

The therapeutic action of Ferumoxytol is to replenish depleted iron stores in the body, thereby enabling the production of functional red blood cells and correcting anemia.[16] The process begins after intravenous administration, where the intact Ferumoxytol nanoparticles circulate in the bloodstream. Due to their size and carbohydrate coating, they are specifically targeted for uptake by phagocytic cells of the reticuloendothelial system (RES), located primarily in the liver, spleen, and bone marrow.[3]

Once inside intracellular vesicles within these macrophages, the iron-carbohydrate complex is metabolized. The carbohydrate shell is degraded, leading to the controlled release of iron from the magnetite core.[3] This liberated iron then enters the body's normal iron-handling pathways. It can either be incorporated into ferritin for intracellular storage within the macrophage or be transported out of the cell via the protein ferroportin.[3] Once in the plasma, the iron binds to the transport protein transferrin.[3] Transferrin-bound iron is then delivered to erythroid precursor cells in the bone marrow, where it is incorporated into hemoglobin, the oxygen-carrying molecule in red blood cells.[3] This restoration of hemoglobin synthesis addresses the fundamental deficit in iron deficiency anemia. Beyond erythropoiesis, the replenished iron is also distributed to all other cells for incorporation into essential iron-containing proteins and enzymes, such as myoglobin, cytochromes, and catalase, which are vital for cellular respiration and metabolism.[3]

3.1.2. As a Diagnostic Agent (MRI Contrast)

The diagnostic utility of Ferumoxytol stems from the superparamagnetic nature of its iron oxide core.[1] When subjected to the strong external magnetic field of an MRI scanner, these nanoparticles generate their own powerful local magnetic fields. This property dramatically alters the relaxation times of adjacent water protons, which is the basis of MRI signal generation.

Specifically, Ferumoxytol causes a profound shortening of the T2 and T2* relaxation times, a phenomenon known as high T2 relaxivity.[3] This T2/T2* shortening effect is the dominant magnetic property and manifests as a significant signal loss, or darkening (hypointensity), on T2- and T2*-weighted MRI sequences. This effect is most pronounced in tissues where the agent accumulates, such as the RES organs (liver, spleen, bone marrow).[10] The agent also shortens T1 relaxation time, but the T2 effect is much stronger.[3]

A critical feature for its diagnostic use is its behavior as a "blood pool" agent. The large size of the nanoparticle (17-31 nm) and the stability of its carbohydrate shell prevent it from easily leaking out of blood vessels into the surrounding interstitial space.[3] Consequently, Ferumoxytol remains confined to the intravascular compartment for a prolonged period. This long intravascular residence time is highly advantageous for magnetic resonance angiography (MRA), as it provides an extended window for acquiring high-resolution images of the vasculature. It also enables advanced imaging techniques like perfusion imaging to assess tissue blood flow and volume.[3]

3.2. Pharmacokinetics (ADME Profile)

The pharmacokinetic profile of Ferumoxytol is dictated by its nanoparticle structure and is distinct from that of traditional drugs.

• Administration and Absorption: Ferumoxytol is formulated exclusively for intravenous administration, and as such, traditional absorption studies are not applicable.[3] The entire dose is delivered directly into the systemic circulation.
• Distribution: Following administration, Ferumoxytol exhibits a small volume of distribution. Population pharmacokinetic modeling estimated the volume of the central compartment (V(1)) to be approximately 2.71 L, and the overall volume of distribution (Vd) to be approximately 3.16 L.[11] This small Vd is consistent with the volume of plasma and confirms that the drug is largely retained within the intravascular space, a key property for its function as a blood pool imaging agent.[3] After a standard 510 mg dose, the mean maximum observed plasma concentration (Cmax) is approximately 206 mcg/mL, reached at a tmax of 0.32 hours.[11]
• Metabolism: Ferumoxytol does not undergo metabolism by the cytochrome P450 enzyme system. Its clearance and "metabolism" are one and the same process: the uptake of the intact nanoparticle from the circulation by the macrophages of the RES.[3] This process is not dependent on renal or hepatic function in the conventional sense, making the drug suitable for patients with kidney disease.[3] Within the RES, the iron is dissociated from the carbohydrate shell and enters the body's iron metabolic pathways.[3]
• Elimination: The elimination of Ferumoxytol from the plasma is a capacity-limited, dose-dependent process that is best described by Michaelis-Menten kinetics rather than simple first-order kinetics.[3] A study in healthy volunteers estimated the maximal elimination rate (Vmax) to be 14.3 mg/h.[20] The terminal elimination half-life is approximately 15 hours in humans.[3] Due to its large size, Ferumoxytol is not cleared by the kidneys and is not removed by hemodialysis, a critical consideration for its use in patients with end-stage renal disease.[11]

The pharmacokinetic profile of Ferumoxytol creates a direct link between its clinical utility and its principal risks. The long 15-hour half-life and RES-mediated clearance pathway are the very properties that enable its convenient dosing regimen and its use in patients with CKD. A full therapeutic course can be delivered in just two visits, a significant advantage over older agents like iron sucrose which may require five to ten separate infusions.[22] This same RES clearance mechanism makes it a safe option for CKD patients, which was the basis for its initial approval.[3] However, this slow, RES-based processing means the iron persists in the body for an extended time. This creates a direct and foreseeable risk of iatrogenic hemosiderosis (iron overload) if therapy is not appropriately monitored, necessitating regular assessment of hematologic parameters like ferritin and transferrin saturation.[13] Furthermore, the persistence of the superparamagnetic iron particles for weeks to months is the direct cause of the drug's prolonged interference with T2-weighted MRI scans, a key warning and precaution for clinicians planning diagnostic imaging.[4] Thus, the very pharmacokinetic properties that are advantageous for dosing and specific patient populations are inextricably and causally linked to the drug's most significant non-hypersensitivity safety warnings.

Clinical Efficacy and Therapeutic Applications

4.1. Approved Indications and Regulatory History

The regulatory journey of Ferumoxytol reflects an expanding understanding of its clinical utility, moving from a niche indication to a broader patient population.

• Initial FDA Approval (June 2009): The U.S. Food and Drug Administration (FDA) first approved Ferumoxytol on June 30, 2009.[5] The initial indication was specifically for the treatment of iron deficiency anemia (IDA) in adult patients with chronic kidney disease (CKD).[3] This approval was based on data from three pivotal clinical trials that demonstrated Ferumoxytol's superiority over oral iron in this patient population, showing a mean hemoglobin increase of approximately 1.0 g/dL over 35 days.[26]
• Expanded FDA Approval (February 2018): Following the submission of a supplemental New Drug Application (sNDA), the FDA expanded the approved indication for Ferumoxytol on February 5, 2018.[5] The label was broadened to include the treatment of IDA in all adult patients who have an intolerance to oral iron or have had an unsatisfactory response to oral iron, regardless of the presence of CKD.[3] This decision was supported by results from two key Phase 3 trials (IDA-1 and IDA-2) and a large head-to-head safety trial comparing Ferumoxytol to ferric carboxymaltose (the FIRM study).[22]
• European Status: Ferumoxytol has been marketed in the European Union under the brand name Rienso for the intravenous treatment of IDA in adult patients with CKD.[2] However, on March 9, 2023, the marketing authorisation applicant, Covis Pharma Europe B.V., withdrew its application for a marketing authorisation of Feraheme from the European Medicines Agency (EMA).[30]
• Drug Class: Ferumoxytol is classified therapeutically as an iron replacement product and pharmacologically as a hematinic.[8] It is also categorized as a paramagnetic contrast agent for diagnostic purposes.[3]

4.2. Review of Clinical Trial Data

The clinical development program for Ferumoxytol has been extensive, encompassing studies across different phases and patient populations to establish its safety and efficacy profile.

• Phase 1-2 Trials: Early-phase studies focused on establishing the fundamental safety, tolerability, and pharmacokinetic profile of Ferumoxytol. A completed Phase 1 trial (NCT00360425) specifically evaluated the electrocardiogram effects and pharmacokinetics in healthy volunteers, demonstrating no clinically meaningful effect on the QT interval or heart rate at supratherapeutic doses.[11] Phase 2 trials, such as NCT01052779, began to explore its efficacy in treating IDA in specific populations like those with glomerulonephritis and CKD, often using active comparators like iron sucrose.[33]
• Phase 3/4 Trials in CKD: Several large-scale trials solidified Ferumoxytol's role in the CKD population. The FIRST trial (NCT01052779) was a Phase 3 study comparing Ferumoxytol to iron sucrose for IDA in adult subjects with CKD.[33] Another Phase 4 study (NCT01227616) compared the efficacy and safety of repeat doses of Ferumoxytol with iron sucrose in hemodialysis-dependent CKD patients with IDA.[35] These trials consistently demonstrated that Ferumoxytol effectively increased hemoglobin and replenished iron stores, with efficacy and safety comparable to iron sucrose, but with a more convenient dosing schedule.[22]
• Phase 3 Trials in General IDA: The label expansion beyond CKD was primarily supported by two pivotal trials. IDA Trial 1 (NCT01114139) was a randomized, double-blind, placebo-controlled study which showed that a significantly greater proportion of Ferumoxytol-treated patients achieved a hemoglobin increase of ≥20 g/L compared to placebo (81.1% vs 5.5%).[22] IDA Trial 2 (NCT01114204) was a randomized, open-label, active-controlled trial comparing Ferumoxytol to iron sucrose.[38] In this trial, Ferumoxytol was found to be non-inferior to iron sucrose in raising hemoglobin levels and was well-tolerated.[23] These trials established its benefit in the broader population of patients who cannot use or have not responded to oral iron, including those with underlying gastrointestinal disorders or abnormal uterine bleeding.[22]
• Off-Label Dosing Studies: While the FDA-approved regimen is two 510 mg doses, clinical practice and research have explored a more convenient single-dose administration. A retrospective study of 140 patients evaluated a total dose infusion (TDI) of 1020 mg over 15 minutes. This off-label approach was found to be as effective as the standard two-dose regimen (mean hemoglobin change of 2.00 g/dL vs. 1.96 g/dL) and did not increase the rate of infusion reactions (1.04% vs 0.57%). The primary benefit was a significant reduction in the number of required infusion clinic visits, improving patient convenience and resource utilization.[39]

4.3. Comparative Clinical Landscape

The selection of an intravenous iron product is often guided by head-to-head comparative data on efficacy, safety, and convenience. Ferumoxytol has been directly compared to the most commonly used IV iron agents. A summary of these pivotal comparisons is essential for evidence-based clinical decision-making.

Table 1: Head-to-Head Clinical Trial Summary: Ferumoxytol vs. Other IV Irons
Trial Name/Identifier	Comparator Drug	Patient Population	Ferumoxytol Dose	Comparator Dose	Primary Efficacy Endpoint Result	Primary Safety Endpoint Result	Key Secondary Finding
IDA Trial 2 (NCT01114204) 23	Iron Sucrose	General IDA, intolerant/unresponsive to oral iron	2 x 510 mg	5 x 200 mg	Non-inferiority met for proportion of patients with Hb increase ≥2 g/dL (84% vs 81.4%). Superiority met for mean change in Hb at Week 5 (2.7 g/dL vs 2.4 g/dL).	Safety outcomes were similar.	Similar improvements in quality-of-life scores.
FIRST Trial (NCT01052779) 34	Iron Sucrose	IDA in CKD patients	2 x 510 mg	5-10 doses totaling 1.0 g	Mean change in Hb was similar (0.8 g/dL vs 0.7 g/dL).	Overall adverse event rates were similar (48% vs 65%).	Fewer administrations required for Ferumoxytol.
FIRM Trial (IDA-304) 28	Ferric Carboxymaltose (FCM)	General IDA, intolerant/unresponsive to oral iron	2 x 510 mg (1.02 g total)	2 x 750 mg (1.5 g total)	Non-inferiority met for mean change in Hb at Week 5 (1.4 g/dL vs 1.6 g/dL).	Non-inferiority met for composite of moderate-to-severe HSR or hypotension (0.6% vs 0.7%).	Markedly lower rate of severe hypophosphatemia (0.4% vs 38.7%).

4.3.1. Ferumoxytol vs. Iron Sucrose (Venofer®)

Comparisons between Ferumoxytol and iron sucrose have been central to establishing its place in therapy, particularly as iron sucrose was a well-established standard of care.

• Efficacy: In both the general IDA population (IDA Trial 2) and the CKD population (FIRST trial), Ferumoxytol demonstrated at least non-inferior efficacy to iron sucrose in raising hemoglobin levels.[23] The IDA Trial 2 went further, showing that Ferumoxytol was statistically superior to iron sucrose based on the mean change in hemoglobin from baseline to week 5 (2.7 g/dL vs. 2.4 g/dL, p=0.0124).[23]
• Safety: The overall safety profiles were found to be comparable. In one study, the overall incidence of adverse events was numerically lower for Ferumoxytol (48%) compared to iron sucrose (65%).[36] A post-hoc analysis suggested that rates of adverse events of special interest, namely hypotension and hypersensitivity, were lower with Ferumoxytol (2.5%) than with iron sucrose (5.3%).[41]
• Convenience: The most significant advantage of Ferumoxytol over iron sucrose is the administration schedule. A full 1-gram therapeutic course of Ferumoxytol can be completed in two infusions, whereas the same dose of iron sucrose typically requires five (for non-dialysis patients) to ten (for dialysis patients) separate administrations.[22] This reduction in clinic visits improves patient convenience and adherence while also decreasing the burden on healthcare resources.[23]

4.3.2. Ferumoxytol vs. Ferric Carboxymaltose (Injectafer®)

The comparison with ferric carboxymaltose (FCM) is particularly relevant as FCM is another newer-generation IV iron that allows for high-dose administration. The FIRM trial (IDA-304) was a large, double-blind, head-to-head study designed specifically to compare the safety profiles of these two agents at the request of the FDA.[28]

• Safety (Primary Endpoint): The primary objective of the FIRM trial was to assess non-inferiority for a composite safety endpoint of moderate-to-severe hypersensitivity reactions (including anaphylaxis) or moderate-to-severe hypotension. Ferumoxytol met this endpoint, with an event rate of 0.6% compared to 0.7% for FCM, confirming that the risk of these serious infusion-related reactions was not different between the two drugs.[28]
• Efficacy: In terms of absolute hemoglobin increase, Ferumoxytol (1.02 g total dose) was non-inferior to a higher dose of FCM (1.5 g total dose), with mean hemoglobin increases of 1.38 g/dL and 1.63 g/dL, respectively, at week 5.[40] However, when normalized for the amount of iron administered, Ferumoxytol demonstrated a superior hemoglobin increase per gram of iron (1.35 g/dL per gram for Ferumoxytol vs. 1.10 g/dL per gram for FCM).[28]
• Key Differentiator - Hypophosphatemia: The most striking difference identified in the FIRM trial was the incidence of severe hypophosphatemia (defined as serum phosphate <0.6 mmol/L). This adverse event occurred in only 0.4% of patients treated with Ferumoxytol, compared to a staggering 38.7% of patients treated with FCM.[28] This highly statistically significant difference highlights a major safety and tolerability advantage for Ferumoxytol over FCM.

4.4. Investigational and Off-Label Uses

Beyond its approved indications for IDA, Ferumoxytol's unique properties have led to significant investigational and off-label use, particularly in diagnostic imaging.

• MRI Contrast Agent: Ferumoxytol is widely used off-label as a gadolinium-sparing MRI contrast agent.[3] This is especially valuable in patients with impaired renal function, for whom gadolinium-based contrast agents (GBCAs) carry a risk of nephrogenic systemic fibrosis, a devastating condition that Ferumoxytol does not cause.[10] It is also frequently used in the pediatric population.[10] Its excellent blood pool properties provide long-lasting vascular enhancement, facilitating high-quality MRA.[3] Active clinical trials, such as NCT03270059, are currently recruiting patients to formally evaluate its diagnostic utility in comparison to gadolinium for central nervous system abnormalities.[45]
• Other Research: Preclinical and emerging clinical research is exploring the broader biomedical applications of Ferumoxytol. Its inherent biocatalytic and immunomodulatory properties are being investigated for use in treating microbial biofilms (e.g., in dental applications), as an anti-inflammatory agent, and in cancer immunotherapy and drug delivery systems.[12]

Safety Profile and Risk Management

The safety profile of Ferumoxytol is well-characterized, dominated by the risk of hypersensitivity reactions, which has led to stringent risk management protocols.

5.1. BOXED WARNING: Risk for Serious Hypersensitivity/Anaphylaxis Reactions

The FDA prescribing information for Ferumoxytol carries a boxed warning, the agency's strongest safety alert, regarding the risk of severe allergic reactions.

• Nature of Risk: Fatal and serious hypersensitivity reactions, including anaphylaxis, have been reported in patients receiving Ferumoxytol.[13] These reactions can be life-threatening and may present with symptoms such as cardiac or cardiorespiratory arrest, clinically significant hypotension, syncope, and unresponsiveness.[13] These events can occur during the infusion or within the immediate post-infusion monitoring period.
• Incidence: In clinical studies using the currently recommended slow infusion method, serious hypersensitivity reactions were reported in 0.2% of subjects, with any hypersensitivity reaction (including less severe events like pruritus, rash, urticaria, or wheezing) reported in 0.4% of subjects.[13] The risk was noted to be higher with the previously approved method of rapid intravenous injection.[13]
• Risk Mitigation Strategies: A comprehensive set of measures is mandated to mitigate this risk:
• Contraindication: Ferumoxytol is absolutely contraindicated in patients with a known hypersensitivity to Ferumoxytol or any of its components, and critically, in patients with a history of any allergic reaction to any intravenous iron product.[11]
• Administration Protocol: The drug must be administered as a slow intravenous infusion over a period of at least 15 minutes.[10] The previous administration method of a rapid IV bolus or injection is no longer approved and should not be used.[10]
• Patient Monitoring: Patients must be closely observed for signs and symptoms of hypersensitivity during the infusion and for at least 30 minutes following completion of the infusion. This includes monitoring of blood pressure and pulse.[13]
• Clinical Setting and Preparedness: Ferumoxytol should only be administered in a setting where personnel and therapies (including epinephrine) are immediately available for the treatment of anaphylaxis and other serious hypersensitivity reactions.[13]
• Patient History: A higher risk may be present in patients with a history of multiple drug allergies. It is crucial to note that hypersensitivity reactions have occurred in patients in whom a previous dose of Ferumoxytol was tolerated, meaning a safe initial dose does not preclude a reaction to a subsequent dose.[13]

5.2. Other Warnings and Precautions

Beyond the boxed warning, several other important safety considerations are outlined in the prescribing information.

• Hypotension: Ferumoxytol may cause clinically significant hypotension that can occur independently of a hypersensitivity reaction.[1] Patients should be monitored for signs and symptoms of hypotension (e.g., dizziness, lightheadedness, feeling faint) following each administration.[13]
• Iron Overload: As with any parenteral iron therapy, excessive or prolonged treatment with Ferumoxytol can lead to excess storage of iron and the possibility of iatrogenic hemosiderosis.[13] It is contraindicated in patients with evidence of iron overload.[4] Regular monitoring of hematologic parameters, including hemoglobin, ferritin, and transferrin saturation, is essential to guide therapy and prevent overload.[13] It is also important to note that for 24 hours following administration, standard laboratory assays may overestimate serum iron and transferrin-bound iron by measuring the iron still contained within the circulating Ferumoxytol complex.[13]
• Magnetic Resonance (MR) Imaging Interference: The superparamagnetic properties of Ferumoxytol significantly interfere with MRI studies.[4] This alteration of diagnostic imaging can persist for up to 3 months following the last dose. The maximum interference with vascular MR imaging is expected 1-2 days post-administration. T2-weighted pulse sequences are most affected and should not be performed earlier than 4 weeks after the last dose. If an MRI is necessary within this window, T1- or proton density-weighted sequences should be used to minimize the interference. Therefore, any anticipated MRI studies should ideally be conducted prior to starting Ferumoxytol therapy.[10]

5.3. Adverse Reactions

The tolerability profile of Ferumoxytol has been defined through extensive clinical trials and postmarketing surveillance.

Table 2: Incidence of Common Adverse Reactions (≥2%) from Clinical Trials
Adverse Reaction	Incidence Rate (%)
Diarrhea	≥ 2%
Headache	≥ 2%
Nausea	≥ 2%
Dizziness	≥ 2%
Hypotension	≥ 2%
Constipation	≥ 2%
Peripheral Edema	≥ 2%
Source: 13

• Common Reactions (≥2%): As detailed in Table 2, the most frequently reported adverse reactions in clinical trials are primarily gastrointestinal or neurological in nature, including diarrhea, headache, nausea, dizziness, hypotension, constipation, and peripheral edema.[13]
• Other Reported Reactions: Other adverse events reported in clinical trials at lower frequencies include flushing, back pain, joint pain, muscle pain or spasms, pain or irritation at the injection site, rash, cough, fever, fatigue, and chest pain or discomfort.[4]
• Postmarketing Experience: The most serious adverse events have been identified through postmarketing reports. These include the fatal and life-threatening anaphylactic-type reactions described in the boxed warning. Additionally, there have been reports of acute myocardial ischemia, with or without myocardial infarction, occurring in the context of a hypersensitivity reaction.[13]

5.4. Drug and Disease Interactions

• Drug Interactions: Ferumoxytol is known to interact with at least 28 other drugs.[51] There is one major interaction listed with dimercaprol, and combinations should be avoided. The 27 moderate interactions include concurrent use of oral iron preparations, which can reduce the absorption of the oral iron and should be discontinued prior to IV iron therapy. Interactions with ACE inhibitors have also been noted.[51] Additionally, Ferumoxytol may decrease the absorption of other orally administered drugs, such as calcium phosphate.[3]
• Disease Interactions: The most critical disease-state considerations are a history of significant allergies or hypersensitivity reactions, which is a contraindication to use, and a predisposition to hypotension.[49] Ferumoxytol is also contraindicated in patients with anemias not caused by iron deficiency (e.g., hemolytic anemia) and in patients with evidence of iron overload (e.g., hemochromatosis).[4]

The evolution of Ferumoxytol's safety profile and administration guidelines provides a clear example of how post-marketing surveillance informs clinical practice. The drug was initially approved with an administration protocol that allowed for a rapid intravenous injection, sometimes as fast as 30 mg/sec.[14] Early clinical trials also utilized this rapid injection method.[23] However, post-marketing experience began to reveal a concerning pattern of "fatal and serious anaphylactic type reactions".[13] This led to a direct regulatory and clinical response. The FDA issued cautions against bolus injections, noting that rapid injection speed is a potential risk factor for complement activation-related pseudoallergies.[10] Consequently, the prescribing information was updated to mandate the current, more cautious approach: a slow intravenous infusion over a minimum of 15 minutes.[13] This historical progression from rapid push to slow infusion is a direct causal chain, where severe adverse event signals led to a fundamental change in the administration protocol to enhance patient safety. This context is critical for understanding the stringency of the current guidelines and the continued presence of the boxed warning.

Dosage, Administration, and Special Populations

6.1. Recommended Dosing and Administration

The administration of Ferumoxytol follows a specific protocol designed to maximize efficacy while mitigating the risks of infusion reactions.

• Standard Regimen: The FDA-approved recommended dose of Ferumoxytol is a total therapeutic course of 1.02 g of elemental iron, administered as two separate doses. An initial 510 mg dose is given, followed by a second 510 mg dose administered 3 to 8 days later.[13] The hematologic response should be evaluated at least one month after the second infusion.[11]
• Administration: Each 510 mg dose must be diluted in 50-200 mL of either 0.9% Sodium Chloride Injection, USP, or 5% Dextrose Injection, USP. The diluted solution must be administered as an intravenous infusion over a period of at least 15 minutes.[10] During the infusion, the patient should be in a reclined or semi-reclined position to help manage potential hypotensive effects.[13] For patients on hemodialysis, the dose should be administered after the patient has completed at least one hour of dialysis and their blood pressure is stable.[13]
• Off-Label Regimen: Clinical research and practice have explored the use of a single total dose infusion (TDI) of 1020 mg administered over 15 minutes. This off-label regimen has been shown in retrospective studies to be as safe and effective as the standard two-dose regimen while significantly reducing the number of required clinic visits for patients.[39]

6.2. Use in Specific Populations

The use of Ferumoxytol requires special consideration in certain patient populations.

• Geriatric: Appropriate studies have not demonstrated any geriatric-specific problems that would limit the usefulness of Ferumoxytol in the elderly. However, caution is advised. Elderly patients are more likely to have age-related decline in renal, hepatic, or cardiac function, as well as a higher burden of concomitant diseases and polypharmacy.[14] Furthermore, elderly patients with multiple serious co-morbidities may experience more severe outcomes if they have a hypersensitivity reaction or hypotensive event following administration.[13]
• Pediatric: The safety and efficacy of Ferumoxytol in the pediatric population (patients under 18 years of age) have not been established.[13] The planned Phase 3 clinical trials designed to evaluate Ferumoxytol in pediatric patients with CKD (NCT01155388 and NCT01155375) were terminated prematurely due to significant challenges with patient enrollment. As a result, definitive data on dosing, efficacy, and safety in children are not available.[54]
• Pregnancy and Lactation:
• Pregnancy: There are no adequate and well-controlled studies of Ferumoxytol in pregnant women.[14] The former FDA Pregnancy Category was C.[14] Animal reproduction studies in rats showed decreased fetal weights and malformations, but only at maternally toxic doses that were 13-15 times the recommended human dose.[14] Despite the lack of specific data, treating IDA during pregnancy is important, as it is associated with risks of premature birth and low birth weight.[50] General guidelines for managing IDA in pregnancy suggest that intravenous iron, such as Ferumoxytol, can be considered from the second trimester onward for women who are intolerant of, or do not respond to, oral iron.[18] The potential benefits of treating the maternal condition must be weighed against the potential risks to the fetus.[52]
• Lactation: There is no information available on the presence of Ferumoxytol in human milk, the effects on the breastfed infant, or the effects on milk production.[8] However, it has been administered safely to neonates as an MRI contrast agent, suggesting that exposure and risk to a breastfed infant may be low.[8] Given the lack of data, alternative IV iron products with more established lactation safety profiles, such as ferric carboxymaltose or iron sucrose, are often considered.[8] A risk-benefit assessment is recommended before using Ferumoxytol in a breastfeeding woman.[48]

Manufacturer and Commercial Landscape

7.1. Manufacturers and Marketers

The development and commercialization of Ferumoxytol have involved several pharmaceutical companies over time.

• Originator and US Marketer: Ferumoxytol was originally developed by a company called Advanced Magnetics Inc., which later changed its name to AMAG Pharmaceuticals to focus on the drug's clinical development as an iron therapeutic.[27] AMAG Pharmaceuticals, Inc. was the originator and held the initial marketing authorization in the United States.[2] In November 2020, AMAG Pharmaceuticals was acquired by Covis Pharma.[57] The product continues to be distributed in the US under the AMAG/Covis Pharma umbrella.[11]
• Generic Availability: A generic version of Ferumoxytol injection is marketed by Sandoz Inc., providing an alternative to the brand-name product, Feraheme.[2]
• International Marketers: Outside of the United States, Ferumoxytol has been marketed by Takeda Pharmaceutical Company. Takeda has marketed the drug in Canada under the name Feraheme and in the European Union and Switzerland as Rienso.[7]

7.2. Economic Considerations

The cost and cost-effectiveness of Ferumoxytol are important factors in its placement within the therapeutic landscape, particularly in comparison to other available IV and oral iron therapies.

• Relative Cost: Ferumoxytol is generally considered a higher-cost intravenous iron formulation compared to older agents like generic iron sucrose or low-molecular-weight iron dextran. Its cost is more in line with other newer, high-dose formulations like ferric carboxymaltose.[59] Payer policies, such as those from Aetna, may note the higher cost and lack of evidence for superiority over lower-cost alternatives for certain indications, which can influence formulary placement and coverage decisions.[59]
• Cost-Effectiveness: Economic evaluations have been conducted to assess the value of Ferumoxytol. A cost-effectiveness analysis comparing Ferumoxytol to oral iron (with or without erythropoietin-stimulating agents) in non-dialysis-dependent CKD patients found that Ferumoxytol was a cost-effective treatment over a 5-week period.[61] This was largely driven by its superior efficacy in raising hemoglobin levels, which offset its higher drug acquisition cost.[61] When comparing different IV iron therapies, the economic calculation is complex. It involves not only the drug acquisition cost but also administration costs (which may be lower for high-dose agents like Ferumoxytol that require fewer infusions) and the costs associated with managing adverse events. For instance, while ferric carboxymaltose may have a different acquisition cost, the potential need for monitoring and treating the high rate of hypophosphatemia associated with it adds another layer to its overall cost-utility consideration when compared to Ferumoxytol.[60]

Conclusion and Clinical Perspective

Ferumoxytol represents a significant advancement in the management of iron deficiency anemia, embodying the progress of nanomedicine from the laboratory to the clinic. Its sophisticated core-shell nanoparticle structure is not merely a novelty but the fundamental driver of its entire clinical profile, granting it a dual identity as both a potent therapeutic and a valuable diagnostic tool.

As a therapeutic agent, Ferumoxytol's primary contribution is providing a highly effective and convenient option for iron repletion. Its pharmacokinetic profile, characterized by a long half-life and a renal-independent, RES-mediated clearance pathway, allows for a full 1.02 g course to be delivered in just two high-dose infusions. This is a marked improvement in patient convenience and healthcare resource utilization compared to older formulations like iron sucrose, which require multiple, smaller, more frequent doses. Head-to-head trials have confirmed its non-inferior efficacy against its main competitors, iron sucrose and ferric carboxymaltose.

However, the clinical utility of Ferumoxytol is inseparably linked to its safety profile. The paramount concern is the risk of serious, life-threatening hypersensitivity reactions, a liability significant enough to warrant an FDA boxed warning. This risk has fundamentally shaped its use, mandating a transition from a rapid injection to a slow, monitored infusion and establishing an absolute contraindication in patients with a history of allergy to any IV iron product. While the incidence of these reactions is low, their potential severity demands unwavering vigilance, strict adherence to administration protocols, and careful patient selection.

In the contemporary clinical landscape, the choice between Ferumoxytol and its closest competitor, ferric carboxymaltose, often hinges on a nuanced assessment of their respective safety profiles. While both carry a similar risk of hypersensitivity reactions, the FIRM trial revealed a critical differentiator: Ferumoxytol is associated with a markedly and significantly lower incidence of severe hypophosphatemia. This finding positions Ferumoxytol as a potentially safer option in patients for whom phosphate homeostasis is a concern.

Looking forward, the expanding off-label use of Ferumoxytol as a gadolinium-sparing MRI contrast agent highlights its versatility. As concerns about gadolinium deposition grow, the role of biodegradable, effective alternatives like Ferumoxytol in diagnostic imaging is likely to expand, particularly in vulnerable populations such as children and patients with renal failure.

In conclusion, Ferumoxytol is a valuable second-generation intravenous iron therapy. It offers a compelling combination of efficacy and convenience for adult patients with IDA who have failed or cannot tolerate oral iron. Its selection for a given patient requires a thorough risk-benefit analysis, weighing its clear advantages in dosing and its favorable hypophosphatemia profile against the rare but serious risk of anaphylaxis. For the appropriately chosen patient, treated within the strict confines of its risk management plan, Ferumoxytol remains a cornerstone of modern parenteral iron therapy.

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