March 10, 2017 – A committee of the European Medicines Agency (EMA) has recommended the suspension of the marketing authorizations for four linear gadolinium-based contrast agents (GBCAs) used for MRI scans because of concerns about small amounts of gadolinium from administered GBCAs being deposited in the brain.
At the completion of its year-long review of GBCAs, the EMA’s Pharmacovigilance and Risk Assessment Committee (PRAC) “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”.
Linear agents recommended for suspension by the PRAC are:
Gadobenic acid, marketed as MultiHance by Bracco Diagnostics Inc.
Gadodiamide, marketed as Omniscan by GE Healthcare
Gadopentetic acid, marketed as Magnevist by Bayer HealthCare Pharmaceuticals
Gadoversetamide, marketed as OptiMARK by Mallinckrodt Inc.
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 when CHMP renders its opinion regarding the removal of the four linear agents from the market.
In its press release, the PRAC noted that deposition of gadolinium in other organs and tissues has been associated with rare side effects of skin plaques and Nephrogenic Systemic Fibrosis (NSF). It also noted that “non-clinical laboratory studies have shown that gadolinium can be harmful to tissues”.
The PRAC said that two linear agents will remain available: gadoxetic acid (brand name Eovist), used at a low dose for liver scans, since it meets an important diagnostic need in patients with few alternatives, and a formulation of gadopentetic acid injected directly into joints because its gadolinium concentration is very low. The PRAC indicated that both agents should be used at “the lowest dose that enhances images sufficiently to make diagnoses and only if unenhanced scans are not suitable”.
On July 27, 2015, the FDA issued its first, and so far only, Safety Announcement regarding gadolinium retention in the brain following repeated use of a GBCA for MRIs. It acknowledged that trace amounts of gadolinium may stay in the body long-term, and noted that “recent studies conducted in people and animals have confirmed that gadolinium can remain in the brain, even in individuals with normal kidney function”.
The 2015 announcement said that the FDA, including its National Center for Toxicological Research (NCTR), “will study this possible safety risk further”. As of this writing, the FDA has made no further public safety announcements regarding the use of gadolinium-based contrast agents.
It remains to be seen if the FDA will follow the lead of the EMA and suspend the use of the linear GBCAs. Three of the four suspended agents are linked to the most unconfounded cases of NSF, and they are among the most widely used GBCAs for magnetic resonance imaging (MRI) procedures.
PRAC concludes assessment of gadolinium agents used in body scans and recommends regulatory actions, including suspension for some marketing authorisations. EMA/157486/2017. http://www.ema.europa.eu/docs/en_GB/document_library/Press_release/2017/03/WC500223209.pdf