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  1. Drug Safety and Availability

FDA Drug Safety Communication: FDA evaluating the risk of brain deposits with repeated use of gadolinium-based contrast agents for magnetic resonance imaging (MRI)

The FDA has issued new information about this safety issue, see the FDA Drug Safety Communication issued on 5-22-2017.

[7-27-2015] The U.S. Food and Drug Administration (FDA) is investigating the risk of brain deposits following repeated use of gadolinium-based contrast agents (GBCAs) for magnetic resonance imaging (MRI). MRIs help detect abnormalities of body organs, blood vessels, and other tissues. Recent publications in the medical literature have reported that deposits of GBCAs (See Table 1) remain in the brains of some patients who undergo four or more contrast MRI scans, long after the last administration.1-21 It is unknown whether these gadolinium deposits are harmful or can lead to adverse health effects.

FDA, including its National Center for Toxicological Research (NCTR), will study this possible safety risk further. We are working with the research community and industry to understand the mechanism of gadolinium retention and to determine if there are any potential adverse health effects. Based on the need for additional information, at this time, we are not requiring manufacturers to make changes to the labels of GBCA products.

To reduce the potential for gadolinium accumulation, health care professionals should consider limiting GBCA use to clinical circumstances in which the additional information provided by the contrast is necessary. Health care professionals are also urged to reassess the necessity of repetitive GBCA MRIs in established treatment protocols. 

Patients, parents, and caregivers should talk to their health care professionals if they have any questions about the use of GBCAs with MRIs. This issue affects only GBCAs; it does not apply to other types of scanning agents used for other imaging procedures, such as those that are iodine-based or radioisotopes.

After being administered, GBCAs are mostly eliminated from the body through the kidneys. However, trace amounts of gadolinium may stay in the body long-term. Recent studies conducted in people and animals have confirmed that gadolinium can remain in the brain, even in individuals with normal kidney function.1-21 Available information does not identify any adverse health effects. 

We urge health care professionals, patients, and parents/caregivers to report possible side effects involving GBCAs to the FDA MedWatch program, using the information in the “Contact FDA” box at the bottom of the page.

Table 1. FDA Approved GBCAs

Brand name
Generic name
Ablavar
gadofosveset trisodium
Dotarem
gadoterate meglumine
Eovist
gadoxetate disodium
Gadavist
gadobutrol
Magnevist
gadopentetate dimeglumine
MultiHance
gadobenate dimeglumine
Omniscan
gadodiamide
OptiMARK
gadoversetamide injection
ProHance
gadoteridol

In published studies, investigators reviewed noncontrast magnetic resonance imaging (MRI) scans of patients who had received several gadolinium-based contrast agent (GBCA) MRIs as part of management for cancer, multiple sclerosis, or other illnesses.1-21 The noncontrast MRIs demonstrated findings highly suggestive that gadolinium contrast was retained in various structures in the brain. To date, no signs or symptoms of adverse health effects and no pathological changes have been associated with these gadolinium deposits in the brain. In some of these studies, examination of brain tissue at autopsy confirmed the presence of gadolinium deposits. In these studies, researchers found that GBCAs more prone to dissociation into free gadolinium, which is when gadolinium separates from the molecule it is bound to, demonstrated greater brain deposition than GBCAs less prone to dissociation. A study in rats performed by a GBCA manufacturer showed greater gadolinium deposition throughout the brain in rats given a linear GBCA that is known to have greater dissociation of gadolinium, compared to a macrocyclic GBCA. No histopathological changes were observed in the animal brains. Gadolinium may also deposit in other body structures such as bone and skin.
 
We have also received reports submitted to the FDA Adverse Event Reporting System (FAERS) database and other reports from patients describing pain and other symptoms following either single or multiple administrations of GBCAs. To date, we have been unable to discern a commonality of features among these reports or reasonably link the reported symptoms to gadolinium. 

1.      Absinta M, Rocca MA, Filippi M. Dentate nucleus T1 hyperintensity in multiple sclerosis. AJNR Am J Neuroradiol 2011;32:E120-1.
2.      Adin ME, Yousem DM, Kleinberg L. Hyperintense dentate nuclei on T1 weighted MRI. Neuroradiol 2014;56:247.
3.      Caruso RD, Postel GC, McDonald CS, Sherry RG. High signal on T1-weighted MR images of the head: a pictorial essay. Clin Imaging 2001;25:312-9.
4.      Errante Y, Cirimele V, Mallio CA, Di Lazzaro V, Zobel BB, Quattrocchi CC. Progressive increase of T1 signal intensity of the dentate nucleus on unenhanced magnetic resonance images is associated with cumulative doses of intravenously administered gadodiamide in patients with normal renal function, suggesting dechelation. Invest Radiol 2014;49:685-90.
5.      Ginat DT, Meyers SP. Intracranial lesions with high signal intensity on T1-weighted MR images: differential diagnosis. Radiographics 2012;32:499-516.
6.      Kanal E, Tweedle MF. Residual or retained gadolinium: practical implications for radiologists and our patients. Radiology 2015;275:630-4.
7.      Kanda T, Kawaguchi H. Hyperintense dentate nucleus and globus pallidus on unenhanced T1-weighted MR images are associated with gadolinium-based contrast media. Neuroradiol 2013;55:1268-9.
8.      Kanda T, Ishii K, Kawaguchi H, Kitajima K, Takenaka D. High signal intensity in the dentate nucleus and globus pallidus on unenhanced T1-weighted MR images: relationship with increasing cumulative dose of a gadolinium-based contrast material. Radiology 2014;270:834-41.
9.      Kanda T, Osawa M, Oba H, Toyoda K, Kotoku J, Haruyama T, et al. High signal intensity in dentate nucleus on unenhanced T1-weighted MR images: association with linear versus macrocyclic gadolinium chelate administration. Radiology 2015;275:803-9.
10.      Kanda T, Fukusato T, Matsuda M, Toyoda K, Oba H, Kotoku J, et al. Gadolinium-based contrast agent accumulates in the brain even in subjects without severe renal dysfunction: evaluation of autopsy brain specimens with inductively coupled plasma mass spectroscopy. Radiology 2015:142690. [Epub ahead of print].
11.      Kasahara S, Miki Y, Kanagaki M, Yamamoto A, Mori N, Sawada T, et al. Hyperintense dentate nucleus on unenhanced T1-weighted MR images is associated with a history of brain irradiation. Radiology 2011;258:222-8.
12.      Maschke M, Weber J, Dimitrova A, Bonnet U, Bohrenkämper J, Sturm S, et al. Age-related changes of the dentate nuclei in normal adults as revealed by 3D fast low angle shot (FLASH) echo sequence magnetic resonance imaging. J Neurol 2004;251:740-6.
13.      McDonald RJ, McDonald JS, Kallmes DF, Jentoft ME, Murray DL, Thielen KR, et al. Intracranial gadolinium deposition after contrast-enhanced MR imaging. Radiology 2015;275:772-82.
14.      Neruda A, Prayer D, Slavc I, Weber M. Is there any relationship between radiotherapy and MRI-signal changes in the basal ganglia and/or dentate nucleus? Neuroradiol J 2010;23:285-6.
15.      Quattrocchi CC, Mallio CA, Errante Y, Cirimele V, Carideo L, Ax A, et al. Gadodiamide and dentate nucleus T1 hyperintensity in patients with meningioma evaluated by multiple follow-up contrast-enhanced magnetic resonance examinations with no systemic interval therapy. Invest Radiol 2015;50:470-2.
16.      Radbruch A, Weberling LD, Kieslich PJ, Eidel O, Burth S, Kickingereder P, et al. Gadolinium retention in the dentate nucleus and globus pallidus is dependent on the class of contrast agent. Radiology 2015;275:783-91.
17.      Ramalho J, Castillo M, AlObaidy M, Nunes RH, Ramalho M, Dale BM, et al. High signal intensity in globus pallidus and dentate nucleus on unenhanced T1-weighted MR images: evaluation of two linear gadolinium-based contrast agents. Radiology 2015 Jun 16:150872 [Epub ahead of print].
18.      Robert P, Lehericy S, Grand S, Violas X, Fretellier N, Idée JM, et al. T1-weighted hypersignal in the deep cerebellar nuclei after repeated administrations of gadolinium-based contrast agents in healthy rats: difference between linear and macrocyclic agents. Invest Radiol 2015 Jun 22 [Epub ahead of print].
19.      Roccatagliata L, Vuolo L, Bonzano L, Pichiecchio A, Mancardi GL. Multiple sclerosis: hyperintense dentate nucleus on unenhanced T1-weighted MR images is associated with the secondary progressive subtype. Radiology 2009;251:503-10.
20.      Sanyal S, Marckmann P, Scherer S, Abraham JL. Multiorgan gadolinium (Gd) deposition and fibrosis in a patient with nephrogenic systemic fibrosis--an autopsy-based review. Nephrol Dial Transplant 2011;26:3616-26.
21.      Warakaulle DR, Anslow P. Differential diagnosis of intracranial lesions with high signal on T1 or low signal on T2-weighted MRI. Clin Radiol 2003;58:922-33.

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Drug Safety Communication (PDF-43KB)

 

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