Summary Safety Review - Gadolinium based contrast agents - Assessing the risk of gadolinium build-up in the brain and potential brain and nervous system (neurological) side effects

May 1, 2018

Product

Gadolinium based contrast agents

Potential Safety Issue

Gadolinium build-up in the brain and potential brain and nervous system (neurological) side effects

Key Messages

• Gadolinium based contrast agents (GBCAs) are authorized for sale in Canada to make it easier to view certain body tissues on magnetic resonance imaging (MRI) scans. There are two structurally distinct categories of commercially available GCBAs in Canada: linear and macrocyclic. Both types are marketed in Canada.
• In 2016, Health Canada reviewed the risk of gadolinium build-up in the brain and the unknown potential neurological side effects because some published studies showed that gadolinium may stay in the brain when GBCAs are given repeatedly. Health Canada’s review concluded that the risk of gadolinium build-up in the brain is higher with repeated doses of both types of GBCAs, and with the use of linear GBCAs compared to macrocyclic GBCAs; however, no neurological side effects were found in either of these situations. The product information for all GBCAs was updated in June 2017 to include warnings about the potential for gadolinium build-up in the brain, and advice to use the lowest dose needed and to carefully consider whether repeated doses are required.
• Health Canada carried out a second review in 2017 because new information was emerging, including: a review from the European Medicines Agency; reports from the manufacturers; and scientific publications. Health Canada’s second review concluded that children and pregnant women may be at greater risk of gadolinium build-up in the brain.
• Health Canada is working with the manufacturers to make additional changes to the product information to include warnings that the use of macrocyclic GBCAs may be preferable to linear GBCAs in patients who may need repeated GBCA doses, as well as in children and pregnant women. Patients having an MRI scan using GBCAs should contact their healthcare provider if they have any questions or concerns.

Overview

In 2016, Health Canada reviewed the risk of gadolinium build-up in the brain and potential neurological side effects in light of published studies showing that gadolinium may accumulate in the brain when GBCAs are given repeatedly. The neurological effects of these build-ups are not known.

Following this review, Health Canada published an Information Update in January of 2017. The product information for GBCAs was updated in June 2017 to include warnings about the potential for gadolinium build-up in the brain, and advice to use the lowest dose needed and to carefully consider whether repeated doses are required. Because new information was becoming available, including from the European Medicines Agency, manufacturers and published literature, a second review was initiated in 2017. Health Canada reviewed the additional information to see if there was any evidence to support taking further action.

Use in Canada

• GBCAs are authorized for sale in Canada to make it easier to view certain body tissues on MRI scans. Gadolinium is a chemical element found in GBCAs.
• GBCAs are either of the linear or macrocyclic type, based on their differing chemical structures. Both types are presently marketed in Canada. In 2016, the majority of GBCAs used in Canada were of the macrocyclic type. There are currently 8 GBCAs authorized for sale in Canada:
  • linear agents: Magnevist (gadopentetate dimeglumine), MultiHance (gadobenate dimeglumine), Omniscan (gadodiamide), Optimark (gadoversetamide), Primovist (gadoxetate disodium);
  • macrocyclic agents: Dotarem (gadoterate meglumine), Gadovist (gadobutrol), ProHance (gadoteridol).
• GBCAs are given through the veins (intravenous injection).

Safety Review Findings

• At the time of both reviews, Health Canada had not received any Canadian reports related to gadolinium build-up in the brain linked to the use of GBCAs.
• This safety review looked at published and unpublished studies (57 in humans and 12 in animals) and 7 international case reports of gadolinium build-up in the brain linked to the use of GBCAs. The human studies and case reports found evidence of gadolinium build-up in the brain, in most cases this occurred many months after the use of GBCAs. Similar findings were seen in the animal studies.
• Evidence from these studies suggests that the risk of gadolinium build-up in the brain is higher with repeated use of GBCAs and with linear GBCAs. However, gadolinium build-ups were seen with both types of GBCAs.
• The review did not find any neurological side effects linked to gadolinium build-up in the brain based on the information available at the time. However, it is difficult to identify potential effects because they could take some time to appear and some patients may have similar symptoms because of their condition.
• Factors that may increase the risk of gadolinium build-up in the brain following the use of GBCAs are not yet completely understood. However, patients who may need repeated GBCA use and vulnerable populations (e.g. children, pregnant women) may be more at risk of gadolinium build-up in the brain.

Conclusions and Actions

• Health Canada’s review of the available information has found a link between repeated GBCA administration and the risk of gadolinium build-up in the brain. This risk was considered to be potentially greater in children, pregnant women, and in people receiving multiple doses of GBCAs. At the time of the review, no neurological side effects were linked to gadolinium build-up in the brain.
• In January 2017, Health Canada issued an Information Update to raise awareness about this safety issue after its first review of gadolinium build-up in the brain. As of June 2017, the product information for all GBCAs has been updated to include warnings about the potential for gadolinium build-up in the brain, advice to use the lowest dose needed and to carefully consider whether repeated doses are required.
• Health Canada is working with the manufacturers to make additional changes to the product information to include warnings that the use of macrocyclic GBCAs instead of linear GBCAs may be preferable in certain patients, such as those who may need repeated GBCA doses and vulnerable populations (e.g. children, pregnant women).
• Health Canada will continue to monitor safety information involving GBCAs, as it does for all health products on the Canadian market, to identify and assess potential harms. Health Canada will take appropriate and timely action if and when any new health risks are identified.

Additional Information

The analysis that contributed to this safety review included scientific and medical literature, international adverse reaction reports and what is known about the use of these products both in Canada and internationally.

For additional information, contact the Marketed Health Products Directorate