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. Author manuscript; available in PMC: 2018 Jan 1.
Published in final edited form as: AJNR Am J Neuroradiol. 2017 May 11;38(7):1297–1302. doi: 10.3174/ajnr.A5188

What does the boxed warning tell us? Safe practice of using ferumoxytol as an MRI contrast agent

Csanad G Varallyay 1,2, Gerda B Toth 2, Rongwei Fu 3,4, Joao Prola Netto 1,2, Jenny Firkins 2, Prakash Ambady 2, Edward A Neuwelt 2,5,6
PMCID: PMC5509484  NIHMSID: NIHMS856447  PMID: 28495944

Abstract

Background and Purpose

Despite the label change and FDA’s boxed warning added to the Feraheme® (ferumoxytol, AMAG Pharmaceuticals, Waltham, MA) label in March 2015, radiologists have shown increasing interest in using ferumoxytol as an MRI contrast agent as a supplement or alternative to gadolinium. The goals of this study are to provide information regarding ferumoxytol safety as an imaging agent in a single center, and to assess how Feraheme® label change may affect this potential, currently off label indication.

Materials and Methods

This retrospective study evaluated the overall frequency of ferumoxytol related adverse events (AEs) when used for CNS MRI. Subjects with various CNS pathologies were enrolled in Institutional Review Board approved imaging studies. Ferumoxytol was administered as multiple rapid bolus injections. The risk of AEs was correlated with demographic data/medical history.

Results

Safety of 671 ferumoxytol enhanced MR studies in 331 subjects was analyzed. No anaphylaxis, life-threating or fatal (grade 4 or 5) AE was recorded. The overall proportion of ferumoxytol related grade 1–3 AE was 10.6% (8.6% occurring within 48h), including hypertension (2.38%), nausea (1.64%), diarrhea (1.04%) and headache (1.04%). History of one or two allergies was associated with increased risk of AE (14.61% vs. no allergies of 7.51%, p=0.0069).

Conclusion

The frequency of mild ferumoxytol related AE was comparable with literature results, and no serious AE was recorded. While the recommendations in the boxed warning should be followed, serious AE appear to be rare events and with proper precautions ferumoxytol may be a valuable MRI agent.

Introduction

Ferumoxytol, marketed as Feraheme® (AMAG Pharmaceuticals, Inc., Waltham, MA, USA), is an ultrasmall iron oxide nanoparticle approved to treat iron deficiency anemia in adults with chronic kidney disease.1 Due to its superparamagnetic properties, ferumoxytol can be used as an MRI contrast agent.2 Despite the label change and FDA’s boxed warning about possible serious hypersensitivity reactions (HSR) added to the Feraheme® label in March 2015, radiologists have shown increasing interest in using ferumoxytol as an MRI contrast agent for the following reasons: the long plasma half-life and the lack of early leakage allows imaging of the intravascular space early after injection.3–7 Delayed MRI (24h after ferumoxytol administration) shows blood-brain barrier defects similar to gadolinium agents, which makes it a potential alternative if gadolinium based contrast agents are contraindicated.8,9 Delayed ferumoxytol imaging can also take advantage of intracellular uptake of the nanoparticles to image inflammation10 or assess the lymph nodes for tumor staging.11–14

There are limited safety data of ferumoxytol as an MRI contrast agent in the literature. A recent study analyzing 65 cases of children and young adults from Institutional Review Board approved imaging studies concluded that ferumoxytol was well tolerated as an MR imaging agent.15 Another publication reported a single anaphylactoid reaction out of 2000 off label uses of ferumoxytol for MRI imaging.16 While, a recently published single center investigation with 217 patients showed no serious adverse events (AEs) with the diagnostic use of ferumoxytol.17 Our institution has over 10 years of experience using ferumoxytol as an MRI contrast agent in the CNS in subjects with or without compromised renal function; and as of December 31st 2015, had completed 671 MRI studies with ferumoxytol in eight Institutional Review Board approved imaging protocols, in which AEs were closely monitored. This is the largest single institution safety data of ferumoxytol used in imaging research protocols. Detailed demographic information was collected and subjects followed up for 6 weeks post ferumoxytol administration. The goals of this study are to provide information regarding the safety of ferumoxytol as an MRI contrast agent, and to assess how the ferumoxytol label change may affect this potential, currently off label indication.

Methods and materials

Ferumoxytol administration

This retrospective, single center study analyzes safety data of 671 ferumoxytol injections in 331 subjects between June 2004 and December 2015. The average age of the patients was 51.08 years (±16.82 years SD) and the female-male ratio was 1:1.33. All subjects signed informed consent and were enrolled in one of the eight Institutional Review Board approved ferumoxytol imaging protocols. (Table 1)

Table 1.

The characteristics of eight ferumoxytol studies at our institution.

IRB# Objective n Pathologies Fe injections and total doses ref
8097 ferumoxytol MRI enhancement time course in brain tumors 13 Primary BT: 12
Metastasis: 1		 1.: 1mg/kg
2.: 3mg/kg
Total: 4mg/kg		 8, 9
2753 vascular cerebral imaging with ferumoxytol throughout standard GBM radio/chemotherapy 12 GBM: 12 2 mg/kg
Total: 2mg/kg		 5, 33, 35–37
2864 permeability and perfusion MRI in brain tumors using ferumoxytol and gadolinium in 3T and 7T magnets. 20 High grade BT: 17
Low grade BT: 2
Meningioma: 1		 1.: 1mg/kg
2.: 3mg/kg
Total: 4 mg/kg		 33, 35– 37
1562* ferumoxytol vs. gadolinium imaging in various CNS pathologies 156 Meningioma: 12
Primary BT: 74
Metastasis: 20
Vascular: 18
Demyelination: 10
Spine: 4; Other:
18		 1.: 75mg
2.: 150mg
3.: 285mg
Total 510mg		 5, 33, 35–41
3678 changes in brain tumor vascularity after antiangiogenic therapy versus steroid therapy 5 GBM: 5 2 mg/kg
Total: 2mg/kg		 33, 42
5405 vascular properties of pediatric brain tumors using ferumoxytol 12 High grade: 8
Low grade: 4		 1.: 1mg/kg
2.: 1–3mg/kg
Total 2–4 mg/kg		 43
813 ferumoxytol and gadolinium imaging of brain tumors in a single imaging session 123 Primary BT: 105
CNS lymphoma: 5
Metastasis: 13		 1.: 1mg/kg
2.: 3mg/kg
Total: 4 mg/kg		 37, 38, 41
9846* steady state blood volume imaging throughout glioblastoma treatment 9 GBM: 7
Other: 2		 1.: 1mg/kg
2.: 2mg/kg
3.: 4mg/kg**
Total: 7 mg/kg**
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*

Ongoing trials. IRB: Institutional Review Board n: number of subjects (the same subject may have participated in more than one protocol. BT: brain tumor GBM: glioblastoma.

**

total dose 7mg/kg, but not exceeding 510mg total.

In all cases, ferumoxytol was given during MRI, using one or multiple IV bolus injections (1:1 or 1:2 diluted ferumoxytol, 3ml/s flow rate, with 20ml saline flush at the same flow rate). In most studies the first 1mg/kg (or 75mg) was used for dynamic perfusion imaging; with the remaining dose administered in one or two subsequent bolus injections. The full4–7mg/kg or 510mg was never given as a single injection. Subsequent to the label changes and boxed warning, infusion parameters were modified in all protocols as Figure 1 indicates. Subjects were evaluated for AEs after each ferumoxytol injection. Blood pressure, pulse, as well as oxygen saturation was recorded before and after each injection. Subjects were observed for at least 30 minutes after completion of ferumoxytol administration. A research nurse or physician was always present during ferumoxytol administration, the post contrast MRI acquisition and the following observation period.

Figure 1.

Figure 1

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Rate of ferumoxytol administration; for iron replacement (A) prior label allowed bolus injection of 510mg ferumoxytol not faster than 17 sec (equivalent to 30mg/s Fe). Current label recommends slow infusion of diluted ferumoxytol over 15 minutes. For imaging, which is still an off label indication, we used to administer ferumoxytol in 2 or 3 rapid bolus injections. Panel B shows ferumoxytol administration of protocol #1562, in which a full vial of 510mg was given. As a response to the boxed warning, only the initial 75mg is injected as before (3ml/s of 1:1 diluted ferumoxytol, equivalent to 45mg/s Fe), and dynamic perfusion data is acquired. The remaining doses are infused at a lower flow rate. The other ongoing protocols were adjusted accordingly with injection only the first 1mg/kg as a bolus.

Recording adverse events

Data on AEs were recorded according to Common Terminology Criteria for Adverse Events v3.0 or v4.0 (CTCAE) including the description of toxicity event, toxicity category, toxicity grade, time of occurrence after ferumoxytol injection, and toxicity attribute. Attribute describes the likelihood that the AE is caused by to ferumoxytol based on clinical judgment and has five categories: 1 unrelated, 2 unlikely, 3 possible, 4 probably, and 5 definite. We only included AE that occurred within six weeks (42 days) of each ferumoxytol injection. Subjects were contacted by phone by a research nurse or completed a clinic visit six week following administration of ferumoxytol to asses for any AEs. Patient characteristics such as age, race, gender, existence of allergies, steroid use, pathology and administered ferumoxytol dose were also recorded. Table 2 shows the potential AEs with ferumoxytol classified to CTCAE and FDA categories. Note that CTCAE grade 3 (severe) AEs may or may not be serious based on FDA classification.18–20 Serious AEs are associated with specific outcomes e.g. life threatening or hospitalization. In contrast, a “severe nosebleed” may not qualify as being categorized as serious.

Table 2.

Organ systems potentially affected by ferumoxytol related AEs, and their severity based classification using FDA and CTCAE guidelines.

FDA Adverse Events Serious Adverse Events
CTCAE Grade 1 (mild) Grade 2 (moderate) Grade 3 (severe) Grade 4 (anaphylaxis) Grade 5 (death)
Cardiac Hypertension Chest tightness, tachycardia Hypotension* Shock Cardiac arrest
Skin Injection site pain, itching erythema; Asymptomatic transient flush, rush, macular/papular eruption; Mild or localized pruritus, hyperpigmentation Injection site pain or swelling with inflammation or phlebitis; Symptomatic flush, urticaria, macular/papular eruptions covering <50% BSA; Generalized pruritus, hyperpigmentation Injection site ulceration/necrosis; Intense, widespread pruritus interfering with ADL; Severe, generalized macular/papular/vesicular eruption covering >50% BSA Generalized exfoliative, ulcerative or bullous dermatitis
Gastrointestinal Constipation, diarrhea, GERD, nausea, vomiting, taste alteration Constipation (treatment indicated), diarrhea or vomiting (IV fluids indicated)
Musculoskeletal Transient myalgia, arthralgia** Pain (treatment required)
Neurology Transient headache*** Headache (treatment required) Loss of consciousness
Constitutional Fatigue
Ocular/Visual Red eye
Respiratory Cough Cough (narcotic medication needed), dyspnea, wheezing Stridor, symptomatic bronchospasm Life-threating bronchospasm Death
Vascular Asymptomatic vein injury Symptomatic vein injury Vein injury, repair or revision indicated
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*

Systolic blood pressure of less than 90 mmHg or greater than 30% decrease from that patient’s baseline

**

Myalgias, arthralgias (e.g. back pain, chest discomfort) are called Fishbane reactions. These are transient, mild infusion reactions (not HSR) and usually they don’t require any treatment.

***

A transient, mild headache can be a normal reaction to iron infusion.

ADL=activities of daily living BSA=body surface area

Statistical methods

Descriptive statistics were used to summarize patient demographics and clinical characteristics. AEs with an attribute of 3, 4 or 5 were characterized, including at least one AE in an infusion, early AE (occurring within 48 hours of ferumoxytol administration), and AE by event type using proportions. Association between at least one AE in an infusion and patient characteristics was assessed using a logistic generalized estimating equation model while taking into account the correlation of multiple infusions within a patient. The statistical package SAS 9.4 (SAS Institute Inc., Cary, NC, USA) was used.

Results

Among the 671 ferumoxytol infusions, grade 1, 2 or 3 AE occurred in 71 infusions (10.6%) recorded within six weeks. Most AE occurred within 48h post ferumoxytol infusion (in 58 cases, 8.6% of the infusions). There was no life-threating or fatal (grade 4 or 5) AE. The most frequent mild and moderate AEs were: hypertension (2.38%), nausea (1.64%), diarrhea (1.04%) and headache (1.04%) (Figure 2). Only two grade 3 AEs were recorded (0.30%). One patient had a rapid rash on his trunk, both upper extremities and thighs after the imaging. He received IV dexamethasone and after several hours of observation all symptoms disappeared and no further treatment was needed. Another patient, who developed red sclera with burning/tingling sensation after otherwise uneventful ferumoxytol MRI, returned for a second study visit six months later. Immediately after the initial 1mg/kg ferumoxytol administration he reported severe nausea and moderate degree of shortness of breath along with lower back pain. The patient was removed from the scanner and no further ferumoxytol was given. He was treated with albuterol and diphenhydramine and symptoms completely subsided after two hours.

Figure 2.

Figure 2

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Frequency of AE potentially related to ferumoxytol. Events are displayed, which occurred in at least two cases. Note that multiple AE (symptoms, abnormal lab values) may be associated with a single injection according the CTCAE recording guidelines.

In the logistic generalized estimating equation regression model, patients with one or two pre-existing allergies were more likely to have at least an AE in one infusion compared to patients without any pre-existing allergy (14.6% vs. 7.5%, P = 0.0072). No other patient characteristics showed significant association with having at least one AE in an infusion. (Table 3)

Table 3.

Patient Characteristics

Characteristic # of infusions # of infusions with at least one event % of infusions with at least one event Odds Ratio p/value*
Age
 <70 years 634 67 10.6 Reference 0.9077
 >70 years 37 4 10.8 1.06 (0.37, 3.02)
Race
 white 645 68 10.5 Reference 0.8716
 non-white 26 3 11.5 1.10 (0.35, 3.50)
Gender
 female 272 33 12.1 Reference 0.3817
 male 399 38 9.5 0.79 (0.47, 1.33)
Number of existing allergies 0.0264**
 none 333 25 7.5 Reference
 one or two 268 39 14.6 2.13 (1.23, 3.70) 0.0072***
 >2 allergies 70 7 10 1.35 (0.58, 3.17) 0.4876
Ferumoxytol dose 0.4036**
 ≤ 2mg/kg 121 8 6.6 Reference
 2–4 mg/kg 303 34 11.2 1.77 (0.69, 4.54) 0.2340
 >4 mg/kg 247 29 11.7 1.86 (0.75, 4.58) 0.1787
Steroid use
 None 461 44 9.5 Reference 0.1263
 on decadron 183 25 13.7 1.56 (0.92, 2.67)
Pathology
 Non-tumor 5.4 5 9.3 Reference 0.7069.
 tumor 617 66 10.7 1.20 (0.47, 3.04)
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*

P-value are obtained from the logistic generalized estimating equation model.

**

Overall P-value for the number of existing allergies, or Ferumoxytol dose.

Discussion

Contrast materials are frequently used in imaging and provide valuable information, often changing the course of treatment. Contrast agents are known to be generally safe with minimal risk of HSR21. Our results of overall ferumoxytol related AE rates occurring in 10.6% infusions, most of them occurring within 48h (8.6%) are in concordance with AE rates between 10–14.6% published in the literature based on three randomized trials for iron replacement.22–24 Based on our data the frequency of AE with Feraheme® is equivalent to ionic iodinated contrast media, and about fifteen times higher than gadolinium MR contrast agents and four times higher than nonionic iodinated contrast agents,25,26 which is summarized in Table 4. Severe reactions, based on literature data, occur 6–7 times more often with ferumoxytol compared to gadolinium, or currently used non-ionic iodinated agents.

Table 4.

Frequency of adverse events using various contrast media from the literature and our data

Adverse events Severe adverse events
Gadolinium25 0.8% 0.03%
Iodinated (ionic)26 12.66% 0.22%
Iodinated (non-ionic)26 3.13% 0.04%
Ferumoxytol (Feraheme® label) 3.7% 0.2%
Ferumoxytol (our data) 10.6% 0%
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At our institution, we have not recorded any serious AE with ferumoxytol. However, we acknowledge that our sample size may not be adequate to record this rare event. It is worth mentioning that our patient population may differ from populations reported in prior studies: as most of our subjects were brain tumor patients, it has been shown that tumor patients can be anergic,27–29 as well as are often on corticosteroids, which may cause immunosuppression and in theory, help prevent HSR.30 Our results however, did not show any risk reduction in subjects with long term corticosteroid use, nor with tumor pathology. The benefit of premedication prior to IV iron products remains controversial in the literature and is generally not advised.31

While the two grade 3 reactions were possibly HSR related, most of the AEs recorded in this study are likely unrelated to HSR. Hypertension, recorded most frequently post ferumoxytol injection may be anxiety related, which normalized without intervention by the time subject left the MRI suite. No ferumoxytol related blood pressure drop has been detected. Our study found significant association between 1 or 2 existing allergies and the frequency of mild AE. The exact mechanism of iron HSR is still unclear. Bioactive, labile iron may be an important causative factor, which is present in all IV iron products. Complement activation-related pseudo-allergy, triggered by iron nanoparticles is probably a more frequent mechanism in acute reactions to current IV formulations than is an immunological IgE-mediated response.32

The boxed warning of Feraheme®, is intended to mitigate the risk and potential morbidity of HSR, thus enhancing patient safety. Recommendations are to observe patients up to 30 minutes post injection, monitor heart rate and blood pressure at baseline and after (each) ferumoxytol administration, which was re-emphasized in this warning and which we strictly adhere to in our imaging protocols. Rapid bolus injection (previously up to 30mg/sec) was eliminated from the package insert, and infusion of the diluted ferumoxytol over 15 minutes became the recommendation. Although there are currently no data using ferumoxytol to support that slow infusion is indeed safer than bolus injection, slow infusion is recommended with other iron products32 and it also allows observation of the patient during ferumoxytol administration and termination of the infusion if HSR occur.

For MR imaging, in order to best comply with FDA recommendations rapid bolus should be avoided. Our imaging protocols have eliminated rapid injection and only the first 1mg/kg is given as a bolus to gain clinically valuable dynamic imaging data. The lack of contrast agent leakage has been demonstrated as a benefit when compared to low molecular weight agents, although the latter ones may be corrected with mathematical algorithms.33 For most imaging applications, such as high resolution steady state blood volume mapping, steady state angiography, and to visualize delayed ferumoxytol enhancement/inflammation, no bolus injection is necessary, therefore high flow rate injection may be completely avoided.

The new prescribing information as of March 2015 provides additional information regarding the potential for more severe HSR in elderly patients with multiple or serious co-morbidities, and increased risk of HSR to Feraheme® in patients with a history of multiple drug allergies. This information may be useful when considering risk-benefit.

A detailed analysis and guideline has been published by an international group to minimize the risk and severity of IV iron supplement related AE. There is emphasis on observation, prompt recognition of symptoms and severity-related interventions by well-trained medical and nursing staff.32 Our recommendations in managing IV iron as an MRI contrast agent related hypersensitivity are summarized in Table 5.

Table 5.

Symptom and severity based management of ferumoxytol related hypersensitivity reactions during MR imaging – our recommendation based on Rampton et al32, UpToDate database44 and ACR Manual on Contrast Media, Version 10.245.

Severity Sign/symptom Management Medications
Potentially life threating HSR Cardiorespiratory arrest

  1. Stop iron infusion

  2. Remove patient from MRI

  3. Call fast response team

  4. Start ACLS if necessary

  5. Monitor patient

  6. Medications

  7. Transfer to ICU

 Start ACLS
Anaphylaxis, shock adrenaline (0.1 mg 1/10.000 solution over 5 min IV or 0.3–0.5 mg 1/1000 solution IM),
elevate the lower extremities,
O2 face mask (6–8 L/min),
nebulized β2 agonist (e.g. salbutamol solution 2.5 mg/3 mL or 5 mg/3mL),
rapid volume load (e.g. 1–2 L saline),
IV corticosteroid (e.g. 100–500 mg hydrocortisone IV),
Hypotension
(decrease≥30 % of SBP, or SBP drops under 90 mmHg, with repeated BP measurement)		 adrenaline (0.1 mg 1/10.000 solution over 5 min IV or 0.3–0.5 mg 1/1000 solution IM),
elevate the lower extremities, repeat BP measurement
O2 face mask (6–8 L/min),
rapid volume load (e.g. 1–2 L saline),
IV corticosteroid (e.g. 100–500 mg hydrocortisone IV),
Stridor, symptomatic bronchospasm (cyanosis) adrenaline (0.1 mg 1/10.000 solution over 5 min IV or 0.3–0.5 mg 1/1000 solution IM),
O2 face mask (6–8 L/min)
nebulized β2 agonist (e.g. salbutamol solution 2.5 mg/3 mL or 5 mg/3mL),
rapid volume load (e.g. 1–2 L saline),
IV corticosteroid (e.g. 100–500 mg hydrocortisone IV)
Mild or Moderate HSR Hypertension
(may be anxiety related)

  1. Stop iron infusion

  2. Remove patient from MRI if needed

  3. Call physician

  4. Monitor patient

  5. Medications

  6. Observation for 1–4 hours

 No therapy. Antihypertensive treatment if SBP≥180 or DBP≥120 (e.g. captopril 6.25–12.5 mg PO), repeat BP measurement
Hypotension
(decrease<30 % of SBP, 5–10% difference can be normal or measurement error)		 Wait for at least 15 min,
elevate lower extremities, repeat BP measurement
if improving consider continuing the imaging (restart iron infusion at 25–50 % reduced rate),
if not better:
isotonic fluid load (e.g. 500 mL saline),
IV corticosteroid (e.g. 100–500 mg hydrocortisone IV)
Chest tightness, tachycardia isotonic fluid load (e.g. 500 mL saline),
IV corticosteroid (e.g. 100–500 mg hydrocortisone IV)
Asymptomatic flush, rush, erythema, eruptions, edema Wait for at least 15 min,
if improving consider continuing the imaging (restart iron infusion at 25–50 % reduced rate),
if not better:
isotonic fluid load (e.g. 500 mL saline),
IV corticosteroid (e.g. 100–500 mg hydrocortisone IV)
Symptomatic flush, rush, erythema, eruptions, edema isotonic fluid load (e.g. 500 mL saline),
IV corticosteroid (e.g. 100–500 mg hydrocortisone IV)
Cough-mild Wait for at least 15 min,
if improving consider continuing the imaging (restart iron infusion at 25–50 % reduced rate),
if not better:
isotonic fluid load (e.g. 500 mL saline),
IV corticosteroid (e.g. 100–500 mg hydrocortisone IV)
Dyspnea, wheezing, severe cough, shortness of breath O2 face mask (1–2 L/min),
isotonic fluid load (e.g. 500 mL saline),
nebulized β2 agonist (e.g. salbutamol solution 2.5 mg/3 mL or 5 mg/3mL),
IV corticosteroid (e.g. 100–500 mg hydrocortisone IV)
Nausea, vomiting Antiemetic treatment (e.g. prochlorperazine 5–10 mg PO, 2.5–10 mg IV)
Dizziness Wait for at least 15 min,
if improving consider continuing the imaging (restart iron infusion at 25–50 % reduced rate),
if not better:
isotonic fluid load (e.g. 500 mL saline)
Other reactions Back pain, myalgia, arthralgia, muscle spasm (Fishbane reaction)

  1. Stop iron infusion

  2. Remove patient from MRI if needed

  3. Monitor patient

  4. Medications if needed

 No therapy needed
Headache No therapy or NSAID (e.g. ketorolac 20 mg PO, 30 mg IV)
Dysgeusia
(taste alteration)		 No therapy needed
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Contrast agent safety is a relevant clinical issue. HSR is just one of the contrast agent related AEs; in gadolinium based agents the incidence of nephrogenic systemic fibrosis has been minimized since the guidelines and boxed warning. Given the emerging safety record of macrocyclic contrast agents in patients with renal failure, remaining contraindications are rare and limited essentially to history of rare severe allergic reaction to gadolinium based agents. Gadolinium deposition in the nervous system is a recent finding, which occurs even in patients with normal renal function and its clinical impact is still unknown.34 Although at our institution no serious AE with ferumoxytol was observed out of 671 administrations, it is important to understand the potential risks, and be prepared in case a severe reaction occurs. Having trained staff and appropriate medications available would be considered good medical practice in any facility utilizing any imaging contrast agent.

The limitations of ferumoxytol imaging include potential iron overload in patients with iron metabolism disorders. The maximum administered dose (510mg) is equivalent with two units of blood, which unlikely to cause acute or chronic toxicity in patients with normal iron metabolism.15 Ferumoxytol is taken up by the liver, spleen and bone marrow, which may cause signal change on the MRI for months. In the CNS, contrast enhancement may be detectable a few days after administration. Adding another contrast agent (i.e., if used in addition to GBCA) may increase the costs, in addition to MRI time, if additional imaging is employed. Our research protocols included up to three consecutive days of scanning, and MRI times were long, between 60–90 minutes on days when contrast agent was given and 30–45 minutes to image late ferumoxytol enhancement. In clinical practice however, more focused imaging is applied to answer the clinical question. High resolution blood volume maps may be obtained with only an additional 5 minute scan time.5 Steady state angiography requires only a few minutes scan time, while late enhancement/imaging inflammation/lymph node imaging requires a separate MRI scanning session which is likely the length of a non-contrast MRI study. Multiphase contrast administration was used to test the optimal doses for various applications, but inclinical use a single infusion of the most appropriate dose is sufficient. Applications, such as visualizing the micro- and macrovasculature, visualizing inflammation, hold promise but future trials have to prove their impact on improving clinical diagnosis and clinical management.

Limitations of this study include the variable patient characteristics and ferumoxytol doses. Although our sample size of 671 was the highest reported in a single center, this number is still too low to evaluate the frequency of rare, but serious HSR.

Conclusion

Safety of 671 well documented cases of using ferumoxytol as an MR imaging agent was reported in this study. The overall rate of AE is in agreement with prior ferumoxytol safety studies, and no serious AE was observed. Although the AE rate is higher compared to gadolinium, and there may be increased costs, emerging new MRI applications may justify the use of ferumoxytol as an MRI contrast agent. The recommendations in the boxed warning should be followed to further improve the safety of imaging with ferumoxytol.

Acknowledgments

Funding:

This work was supported in part by National Institutes of Health grants NS053468, CA199111, and CA137488-15S1, in part with Federal funds from the National Cancer Institute, National Institutes of Health, under Contract No. HHSN261200800001E, and by the Walter S. and Lucienne Driskill Foundation, all to EAN.

List of abbreviations

AE

Adverse event

CTCAE

Common Terminology Criteria for Adverse Events

HSR

Hypersensitivity Reaction

Footnotes

Aspects of this manuscript were presented in part at RSNA 2015 meeting.

References

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