Kim-Lien Nguyen1, Rola Saouaf2, Cynthia K. Rigsby3, Lindsay M. Griffin4, Mark L. Fogel5, Kevin K. Whitehead5, Mark L. Schiebler4, David E. Newby6, and J. Paul Finn1
1Department of Radiological Sciences and Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA, United States, 2Department of Radiology, Cedars-Sinai Medical Center, Los Angeles, CA, United States, 3Department of Medical Imaging, Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, IL, United States, 4Department of Radiology, University of Wisconsin-Madison, Madison, WI, United States, 5Division of Cardiology, Children's Hospital of Philadelphia, Philadelphia, PA, United States, 6British Heart Foundation Centre for Cardiovascular Science, University of Edinburgh, Edinburgh, United Kingdom
Synopsis
Ferumoxytol is approved in the United States (U.S.) for treatment of
iron deficiency anemia in chronic kidney disease. However, its
superparamagnetic properties can be leveraged for off-label use in MRI. In
2015, the U.S. Food and Drug Administration (FDA) issued a “black-box” warning
regarding risk of rare but serious hypersensitivity reactions based on
post-marketing surveillance therapeutic use data. Preliminary experience from
the FeraSafe Multi-Center RegistryTM suggests a low incidence of
adverse events with the off-label diagnostic use of ferumoxytol. To date, these
preliminary results suggest that with appropriate clinical use and monitoring, there is an acceptable benefit /risk profile.
INTRODUCTION:
Controversies about the use of gadolinium-based
contrast agents (GBCAs) in MRI and their unintended consequences have led to
rising interest in ferumoxytol as a contrast agent for magnetic resonance
imaging (MRI). Ferumoxytol is a superparamagnetic iron oxide nanoparticle approved
for treatment of iron deficiency anemia in chronic kidney disease and is also used
off-label to treat iron deficiency anemia in other settings (pregnancy, cancer,
gastrointestinal bleeding). Because of
its long intravascular half-life, unique MR relaxivity, and safety profile in
patients with kidney impairment, the off-label use of ferumoxytol enables MR
applications well beyond those possible with current GBCAs1, 2.
Although the U.S. Food and Drug Administration (FDA) issued a “black-box”
warning in 2015 based on post-marketing surveillance data of therapeutic use, there
have been reports documenting single-center diagnostic safety experience3-6.
The FeraSafe Multi-Center RegistryTM was established to foster the
safe and appropriate use of ferumoxytol and to facilitate collaborations among
users exploring the theranostic applications of ferumoxytol. We aim to
summarize our early multi-center registry safety experience. METHODS:
The FeraSafe Multi-Center MRI RegistryTM
was created using the REDCap platform7. In this HIPAA-compliant and
IRB-approved study, safety data for ferumoxytol-enhanced (FE) MRI exams between
2011-2017 from five academic medical centers across the U.S. and three in the
United Kingdom (U.K.) were pooled and analyzed. Feraheme® (AMAG
Pharmaceuticals, Waltham, MA) was used at centers in the U.S. and Rienso®
(Takeda Italia, Italy) was used in the U.K. Ferumoxytol was diluted and
administered as boluses (prior to FDA warning in 2015) and subsequently as slow
infusions over 15 minutes at a maximum dose of 4mg/kg. Both first-pass and steady
state image acquisitions were performed. Severity of adverse events were
categorized as mild, moderate, severe, life-threatening, or death. Adverse
events were classified as unrelated, possibly related, or definitely related to
ferumoxytol administration. Mean arterial blood pressure, heart rate, and pulse
oximetry were reviewed. Renal function was determined from plasma creatinine
levels. RESULTS:
Between
2011-2017, a total of 1195 ferumoxytol injections were administered for
diagnostic purposes in 1130 human patients (age range: 1 day-96 years, 768 male)
at five academic centers in the U.S. (n=628) and three academic centers in the
U.K. (n=502). Forty-one patients received multiple administrations of
ferumoxytol. More adults (904/1130, 80%) than children (226/1130,
20%) received ferumoxytol. A total of 117 (10%) patients had immature renal function (age < 3.5
years); 53 (5%) patients had end-stage renal disease and were on dialysis. No ferumoxytol-related severe or
life-threatening adverse events occurred. There were six mild adverse
events (n=2 hypotension, n=2 nausea, n=1 nose pruritus and dry cough, n=1
hypertension and headache) that were either possibly related or definitely
related to ferumoxytol administration; five occurred at U.S. sites. Two patients
received supportive care: intravenous fluid (hypotension, n=1) and
diphenhydramine (dry cough, n=1). Anesthesia or sedation was used in 212 (19%)
patients. The predominant indication for the off-label use
of ferumoxytol was for MRA (vascular assessment) in patients with renal
insufficiency. In those with documented vital signs at the time of this
analysis (n=128), changes in mean arterial blood pressure, heart rate, or pulse
oximetry were not statistically significant (p>0.05).DISCUSSION:
Recent
findings of gadolinium accumulation in soft tissues such as brain and bone of
patients with normal renal function who had multiple contrast-enhanced MRI
exams have caused further unrest among clinicians and scientists8. The European Medicine
Association suspended the use of linear agents in July of 2017 while the U.S. FDA
in September of 2017 recommended that gadolinium retention be added to warning
labels and required GBCA manufacturers to conduct additional research into gadolinium
retention. Although the FeraSafe Multi-Center RegistryTM was
established to foster the safe and appropriate use of ferumoxytol rather than
to directly address an unmet clinical need, our early multi-center safety
experience suggests that in cases where there are clear benefits, and with careful
monitoring, ferumoxytol can serve as a safe alternative to GBCA for
contrast-enhanced MRI /MRA. A larger databank will be necessary for convergence
towards a confident and precise assessment of short- and long-term adverse
event rates in diagnostic clinical practice. CONCLUSION:
Early
experience from the FeraSafe Multi-Center RegistryTM suggests that
the off-label use of ferumoxytol for MRI /MRA has a very low incidence of
adverse events. More extensive experience and investigation will be needed to
better define the risk /benefit profile across a spectrum of clinical
applications and disease states and establish best practices. Where there are
clear benefits, ferumoxytol has the potential to extend MR applications beyond
the current capabilities of extracellular GBCAs.Acknowledgements
The
authors are grateful for support from the ISMRM attendees who were at the ISMRM
Ferumoxytol Working Group meeting in Toronto, Canada (2015). We also thank Dr.
Takegawa Yoshida, Ms. Nikhita Kathuria, and Ms. Fiona Wee for their assistance.
The
FeraSafe Multi-Center RegistryTM is currently hosted and supported
by resources from the Department of Radiological Sciences, David Geffen School
of Medicine at UCLA, Los Angeles, CA, USA.References
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