Europe Reaffirms Gadolinium Restriction in Scans

Pauline Anderson

July 07, 2017

The Pharmacovigilance Risk Assessment Committee (PRAC) of the European Medicines Agency (EMA) has reaffirmed its conclusion that there is convincing evidence of gadolinium deposition in brain tissues following use of gadolinium contrast agents.

Following its earlier recommendation in March of this year, some marketing authorization holders had requested a reexamination, according to a press release from the EMA.

Gadolinium is a heavy metal that can be retained not only in the brain but also in bone and skin. Gadolinium-based contrast agents (GBCAs) have either linear or macrocyclic chemical structures.

As a result of the review, the PRAC recommends that the intravenous linear agents gadoxetic acid and gadobenic acid should be used only for liver scans in the situations where they meet an important diagnostic need. In addition, gadopentetic acid should be used only for joint scans because the gadolinium concentration in the formulation used for joint injections is very low.

All other intravenous linear agents (gadodiamide, gadopentetic acid, and gadoversetamide) should be suspended in line with the PRAC’s March 2017 recommendation.

Another class of gadolinium agents known as macrocyclic agents (gadobutrol, gadoteric acid, and gadoteridol) are more stable and have a lower propensity to release gadolinium than linear agents. These can continue to be used in their current indications but in the lowest doses that enhance images sufficiently and only when unenhanced body scans are not suitable.

The PRAC's initial review had recommended suspension of 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 intravenously administered gadobenic acid, gadodiamide, gadopentetic acid, and gadoversetamide. These agents are given to patients to enhance images from MRI body scans.

According to the press release, the PRAC's review 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 many months after the last injection of a gadolinium contrast agent.

The PRAC's final recommendations will be sent to the Committee for Medicinal Products for Human Use for its opinion.

Although there have been no reports of symptoms or diseases linked to gadolinium in the brain, the PRAC took a precautionary approach, noting that data on the long-term effects in the brain are limited, said the press release.

No Restriction by FDA

As reported by Medscape Medical News in May of this year, the US Food and Drug Administration (FDA) has taken a different stance.

After a 2-year study, it found no evidence of adverse events from the brain's retention of gadolinium after MRI that employs GBCAs.

Accordingly, the FDA will not restrict the use of GBCAs, it said in a press release at the time. However, it said it will continue to study their safety.

In the meantime, clinicians should continue to use GBCAs sparingly. As the FDA recommended in July 2015, clinicians should limit their use to cases in which additional information yielded by the contrast agent is necessary and reassess the need for repetitive MRIs with GBCAs.

The agency's caution about these contrast agents was prompted by reports of gadolinium retention in the brains of patients undergoing four or more contrast MRI scans during the management of conditions such as multiple sclerosis or cancer, even when those patients had normal kidney function. GBCAs are mostly eliminated through the kidneys.

The FDA's review of scientific literature and adverse events reported to the agency showed that use of linear GBCAs results in more gadolinium retention in the brain than macrocyclic GBCAS. "However, our review did not identify adverse health events related to this brain retention," the agency said in its press release.

The FDA's ongoing review of GBCAs will investigate a rare skin condition called nephrogenic systemic fibrosis (NSF), which is the only known adverse event related to gadolinium retention.

Characterized by thickening and hardening of the skin, NSF can involve the joints and significantly limit motion.

The disorder occurs in a small group of patients with preexisting kidney failure, although the FDA has come across recent reports of patients with normal kidneys who developed NSF after receiving GBCAs for an MRI.

Some of these patients had retained gadolinium in their brains as well. The FDA said it will try to determine whether these fibrotic reactions are indeed linked to retained gadolinium.

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