EMA reviewing gadolinium contrast agents used in MRI scans
Review to consider evidence on gadolinium accumulation in brain tissue
The European Medicines Agency (EMA) has started a review of the risk of gadolinium deposition in brain tissue following the use of gadolinium contrast agents in patients having magnetic resonance imaging (MRI) scans.
Gadolinium contrast agents are diagnostic products that may be given to patients before or during MRI scans to help doctors obtain better images of organs and tissues. After administration, gadolinium agents are mostly eliminated via the kidneys but studies indicate that deposits can build up in some body tissues, including in the liver, kidney, muscle, skin and bone.
Recently, a number of publications have reported that gadolinium contrast agents also accumulate in brain tissue1-7. In January 2016, EMA’s Pharmacovigilance Risk Assessment Committee (PRAC) reviewed these publications. Although no adverse effects relating to gadolinium brain deposition have been reported to date, the PRAC will carry out an in-depth review of the risk of brain deposits and of the overall safety of these products.
The PRAC’s recommendations will be sent to Committee for Medicinal Products for Human Use (CHMP), which will issue the Agency’s final opinion.
1. 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. Investigative radiology 2014;49(10):685-90.
2. 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;276(1):228-32.
3. 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(3):834-41.
4. 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(3):803-9.
5. 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(3):772-82.
6. 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. Investigative radiology 2015;50(7):470-2.
7. 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(3):783-91.
- More about the medicine
Gadolinium contrast agents contain gadolinium, which is used as a ‘contrast enhancer’ to help make body tissues more visible on the scan.
This review covers agents containing the following active substances: gadobenic acid, gadobutrol, gadodiamide, gadopentetic acid, gadoteric acid, gadoteridol, gadoversetamide and gadoxetic acid.
Most gadolinium-containing contrast agents have been authorised nationally in the European Union (EU). OptiMARK (gadoversetamide) is currently the only centrally authorised gadolinium contrast agent in the EU.
- More about the procedure
The review of gadolinium contrast agents has been initiated at the request of the European Commission, under Article 31 of Directive 2001/83/EC.
The review is being carried out by the Pharmacovigilance Risk Assessment Committee (PRAC), the Committee responsible for the evaluation of safety issues for human medicines, which will make a set of recommendations.
The PRAC recommendations will then be forwarded to the Committee for Medicinal Products for Human Use (CHMP), responsible for questions concerning medicines for human use, which will adopt a final opinion. The final stage of the review procedure is the adoption by the European Commission of a legally binding decision applicable in all EU Member States.
A previous EMA review of gadolinium contrast agents in 2010 evaluated the risk of nephrogenic systemic fibrosis (NSF).
|Name||Language||First published||Last updated|
|Gadolinium Article-31 referral - Review started||(English only)||18/03/2016|
About this medicine
|Approved name||Gadolinium-containing contrast agents|
|International non-proprietary name (INN) or common name|
gadobenic acid / gadobutrol / gadodiamide / gadopentetic acid / gadoteric acid / gadoteridol / gadoversetamide / gadoxetic acid
About this procedure
|Current status||Under evaluation|
|Type||Article 31 referrals|
This type of referral is triggered when the interest of the Community is involved, following concerns relating to the quality, safety or efficacy of a medicine or a class of medicines.
|Decision making model||PRAC-CHMP-EC|
|Authorisation model||Centrally and nationally authorised products (mixed)|
Key dates and outcomes
|Procedure start date||17/03/2016|
|Name||Language||First published||Last updated|
|Gadolinium Article-31 referral – Notification||EN = English||18/03/2016|
|Gadolinium Article-31 referral - Annex I||EN = English||18/03/2016||26/04/2016|
|Gadolinium Article-31 referral - Review started||EN = English||18/03/2016|
|Gadolinium Article-31 referral – Timetable for the procedure||EN = English||18/03/2016||14/06/2016|
|Gadolinium Article-31 referral – PRAC list of questions||EN = English||18/03/2016|
- Annex I - List of the medicines affected by the referral
- Annex II - Scientific conclusions of the Committee for Medicinal Products for Human Use (CHMP) or Coordination Group for Mutual Recognition and Decentralised Procedures - Human (CMDh)
- Annex III - Changes to the summary of product characteristics, labelling or package leaflet - available when the CHMP or CMDh recommends changes to the product information. Also includes conditions for lifting of suspensions, if applicable
- Annex IV - Conditions of the marketing authorisation - available when the CHMP or CMDh recommends other measures to be taken for the marketing authorisation such as safety measures or additional studies
- Notification - A letter from a Member State, the European Commission or a marketing-authorisation holder requesting the initiation of a referral procedure
- Rationale for triggering - Background provided by the party triggering the referral explaining the issues leading to the initiation of the procedure
- PRAC list of questions - Questions agreed by the PRAC requesting further information to evaluate the issues identified
- PRAC timetable - Timeframe agreed by the PRAC to receive information, assess the issues and adopt a recommendation
- PRAC / CHMP / CMDh assessment report - The assessment and conclusions of the PRAC and CHMP or CMDh on the issues investigated