The Pharmacovigilance and Risk Assessment Committee (PRAC) of the European Medicines Agency (EMA) has recommended the suspension of the marketing authorisations for four linear gadolinium contrast agents because of evidence that small amounts of the gadolinium they contain are deposited in the brain. The agents concerned are intravenous injections of gadobenic acid, gadodiamide, gadopentetic acid and gadoversetamide, which are given to patients to enhance images from magnetic resonance imaging (MRI) body scans.
Gadolinium-based contrast agents (GBCAs) are used as contrast enhancers to improve image quality with MRI scans. MRI is an imaging method that relies on the magnetic fields produced by water molecules in the body. Once injected, gadolinium
interacts with the water molecules. As a result of this interaction, the water molecules give a stronger signal, helping to obtain a brighter image. Since the free Gadolinium ion is very toxic, the contrast agents contain the gadolinium in complexed form
. The different GBCA's on the market differ in the structure and composition of these complexing ligands. Two types of complexing ligands can be differentiated: linear chelates and macrocyclic chelates. In theory, the bonds between the gadolinium and ligand are strong and enable the contrast agent to be expelled from the body unchanged. However, when retained in the body for prolonged time, some reactions either exchanging the Gadolinium against another metal such as iron (called transmetallation) or degrading the chelating ligands leading to the release of gadolinium seem to be possible (see the EVISA News from 29 October 2012
). The fact, that linear agents have a structure more likely to release gadolinium, is accepted since US FDA announced a warning for patients with advanced chronic kidney disease or acute renal failure in 2010 (see the EVISA News from September 15, 2010
). Since 2013, studies looking at the contrast in brain images have indicated that traces of gadolinium remaining in the brains of patients who had received MRI scans -- years after the studies took place (see the EVISA News from August 13, 2015
). The form in which gadolinium is retained has not yet been identified, however the studies seem to indicate that linear agents are more susceptible to deposition than macrocyclic agents.
The review of gadolinium contrast agents was initiated on 17 March 2016 at the request of the European Commission, under Article 31 of Directive 2001/83/EC
. Most gadolinium-containing contrast agents have been authorised nationally in the European Union (EU). OptiMARK (gadoversetamide) is the only gadolinium contrast agent that was authorised centrally in the EU.
The four agents covered by the PRAC's ruling this week are all linear gadolinium agents:
- Gadobenic acid, marketed under the trade name MultiHance by Bracco
- Gadodiamide, sold under the trade name Omniscan by GE Healthcare
- Gadopentetic acid, marketed as Magnevist by Bayer HealthCare Pharmaceuticals
- Gadoversetamide, sold as Optimark by Guerbet
"The PRAC's review of gadolinium agents found convincing evidence of accumulation of gadolinium in the brain from studies directly measuring gadolinium in brain tissues and areas of increased signal intensity seen on MRI scan images many months after the last injection of a gadolinium contrast agent," the committee wrote in a press release on the ruling.
Although no symptoms or diseases linked to gadolinium in the brain have been reported, the PRAC took a precautionary approach, noting that data on the long-term effects in the brain are limited. Deposition of gadolinium in other organs and tissues has been associated with rare side effects of skin plaques and nephrogenic systemic fibrosis (see EVISA news below), a scarring condition in patients with kidney impairment.
Some linear agents will remain available: gadoxetic acid, a linear agent used at a low dose for liver scans, can remain on the market as it meets an important diagnostic need in patients with few alternatives. In addition, a formulation of gadopentetic acid injected directly into joints is to remain available because its gadolinium concentration is very low – around 200 times lower than those of intravenous products. Both agents should be used at the lowest dose that enhances images sufficiently to make diagnoses and only if unenhanced scans are not suitable.
PRAC also pointed out, that for those marketing authorisations recommended for suspension, the suspensions can be lifted if the respective companies provide evidence of new benefits in an identified patient group that outweigh its risks or show that their product (modified or not) does not release gadolinium significantly (dechelation) or lead to its retention in tissues.
PRAC recommends that macrocyclic agents (Gadobutrol, gadoteric acid and gadoteridol) be used at the lowest dose that enhances images sufficiently to make diagnoses and only when unenhanced body scans are not suitable. Macrocyclic agents, are more stable and have a much lower propensity to release gadolinium.
Source: EMA press release from March 10 Related information
EMA: March 10, 2017: PRAC concludes assessment of gadolinium agents used in body scans and recommends regulatory actions, including suspension for some marketing authorisations EMA: March 8, 2016: PRAC reviews gadolinium contrast agents used in MRI scans FDA:
July 27, 2015: FDA evaluating the risk of brain deposits with repeated
use of gadolinium-based contrast agents for magnetic resonance imaging
(MRI) Related EVISA Resources
Brief summary: Speciation analysis for the study of metallodrugs and their biomolecular interactions Link Database: Toxicity of Gadolinium compounds
Link database: Use of Gadolinium in pharmaceuticals
Materials Database: Gadolinium Materials
Link page: All about Mass Spectrometry: Resources related to Mass Spectrometry Related EVISA News
April 10, 2016: New Studies Question Safety of MRI Contrast Agents August 13, 2015: FDA investigating risk of gadolinium contrast agent brain deposits March 4, 2015: Detection of Gd-based contrast agent in the skin of a patient eight years after administration October 29, 2012: Identification and quantification of potential metabolites of Gd-based contrast agents September 15, 2010: US FDA Announces Gadolinium-Based MRI Contrast Agent Warning March 25, 2010: Publication on the separation of Gd-based contrast agents awarded May 4, 2009: Gadolinium speciation analysis in search for the cause of nephrogenic systemic fibrosis (NSF)
last time modified: March 11, 2017