PRAC Review Finds Evidence of Gadolinium Deposits in the Brain After MRI But No Signs of Harm

The European Medicines Agency's Pharmacovigilance and Risk Assessment Committee (PRAC) has recommended the suspension of the marketing authorizations 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 MRI body scans.

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 months after the last injection of a gadolinium contrast agent.

The companies concerned by this review have the right to request the PRAC to re-examine its recommendations.

The PRAC's final recommendations will be sent to the Committee for Medicinal Products for Human Use (CHMP) for its opinion. Further details will be published at the time of the CHMP opinion.

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. Per the Europeans Medicines Agency's 2010 review of gadolinium contrast agents, deposition of gadolinium in other organs and tissues has been associated with rare side effects of skin plaques and nephrogenic systemic fibrosis, a scarring condition in patients with kidney impairment. Furthermore, nonclinical laboratory studies have shown that gadolinium can be harmful to tissues.

The four agents recommended for suspension are referred to as linear agents. Linear agents have a structure more likely to release gadolinium, which can build up in body tissues. Other agents, known as macrocyclic agents, are more stable and have a much lower propensity to release gadolinium. The 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.

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 a diagnosis and only if unenhanced scans are not suitable.

For those marketing authorizations 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, show that their product—modified or not—does not release gadolinium significantly, or lead to its retention in tissues.

More About the Medicine

Gadolinium contrast agents are used as contrast enhancers to improve image quality with MRI scans.

MRI 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.

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 authorized nationally in the European Union (EU). OptiMARK is the only gadolinium contrast agent that was authorized centrally in the EU.

More About the Procedure

The review of gadolinium contrast agents was initiated on March 17, 2016 at the request of the European Commission, under Article 31 of Directive 2001/83/EC.

The review has been carried out by the PRAC, the committee responsible for the evaluation of safety issues for human medicines, which made a set of recommendations. The PRAC's final recommendations will be sent to the CHMP, responsible for questions concerning medicines for human use, which will adopt the Agency's 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.

Source: European Medicines Agency

GE Healthcare Statement on PRAC Recommendation Regarding GBCAs

As a result of the European Medicines Agency (EMA) Article 31 procedure, the Pharmacovigilance Risk Assessment Committee (PRAC) of the EMA recommended that the use of linear gadolinium-based contrast agents (GBCAs), including GE's commonly used product Omniscan, be suspended within the European Union. GE Healthcare is disappointed by this recommendation and has begun the process of formally requesting a re-examination based on the strong safety profile and clinical utility of Omniscan, which has been used routinely as part of MRI diagnostic scans for 24 years and in more than 80 million administrations.

As a market leader, GE Healthcare has, in partnership with world-leading clinical experts, demonstrated that while all GBCAs, ­both linear and macrocyclic, may result in trace amounts of gadolinium in the brain, there exists no clinical evidence that this leads to an increase in risk or harm for patients. Further, a recently conducted meta-analysis presented to the PRAC confirmed that the safety profile of Omniscan is favorable in comparison with other agents in its class, including macrocyclic agents. Additionally, Omniscan is approved in several member states for the evaluation of coronary artery disease (CAD) by myocardial perfusion imaging MRI for the detection and localization of CAD and differentiation between areas of ischemia and infarction. Making only macrocyclic agents available on the market would mean that physicians have no option for an approved method of providing this critical cardiac diagnostic information to patients in certain regions.

The safety of individual patients continues to be the most important priority for GE Healthcare. The company looks forward to extending its close collaboration with the EMA on this issue and continuing to conduct further research and employ all available pharmacovigilance measures to identify any potential clinical implications of trace amounts of brain gadolinium that are detected after exposure to all types of linear and macrocyclic agents.

Source: GE Healthcare