European Medicines Agency recommends to pull linear Gadolinium-based MRI contrast agents from market

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 PRAC's review of gadolinium agents found convincing evidence of accumulation of gadolinium in the brain from studies directly measuring gadolinium in brain tissue 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.