Gadolinium-based contrast agents and risk of gadolinium brain deposits

HSA has recently completed its benefit-risk assessment on the potential risk of gadolinium deposition in the brain following repeated administration of gadolinium-based contrast agents (GBCAs). This assessment was triggered by recent findings from scientific publications suggesting that gadolinium is retained in the brain after use of GBCAs in magnetic resonance imaging (MRI) scans, as well as the European Medicines Agency’s (EMA) decision to suspend the marketing authorisations of selected intravenous (IV) linear GBCAs and restrict the use of another IV linear GBCA in July 2017.¹ HSA’s review concluded that while there is currently no definite evidence of clinical harm of gadolinium brain deposition following GBCA administration, healthcare professionals are advised to use the lowest effective dose of GBCA whenever possible as a precautionary measure.

About GBCAs

GBCAs are used to enhance the quality of magnetic resonance (MR) images to improve the diagnostic accuracy of the MRI. GBCAs may be categorised according to their chemical structures i.e. linear or macrocyclic. Scientific evidence suggests that when compared to macrocyclic agents, the linear agents are more susceptible to dissociation of the chelate and subsequent deposition of free gadolinium in the brain.^2-5 There are six GBCAs registered in Singapore (Table 1) and all of them are indicated for the enhancement of MRI scans of several anatomical structures (e.g. cranial and spinal regions and liver), with the exception of Primovist (gadoxetate disodium), which is approved only for liver MRI scans.

Table 1. Registered GBCAs in Singapore

Literature findings

Initial brain imaging studies documented hyperintensities in brain MRI scans of patients who had received multiple GBCAs administrations, leading to the hypothesis that gadolinium is deposited in the brain after repeated GBCA use.⁶ This hypothesis was confirmed by post-mortem studies documenting the presence of gadolinium in harvested brain tissues of deceased individuals who had been exposed to repeated GBCAs during their lifetime.^7-8 In addition, the evidence for gadolinium deposition had been found to be much stronger with the less stable linear GBCAs as compared to the macrocyclic agents, suggesting that the propensity of a GBCA to cause brain deposition could be related to the chemical structure and stability of the GBCA chelate.^3-5 Based on the current available scientific evidence, the presence of gadolinium brain deposits has not been shown to result in clinical adverse effects and the long-term effects are still being studied.

International regulatory actions

International regulatory health authorities, namely the EMA, United States Food and Drug Administration (US FDA), Health Canada, Australia Therapeutic Goods Administration (TGA) and New Zealand Medsafe had conducted safety reviews on the potential risk of gadolinium brain deposition following administration of GBCAs. While all the reviews of these agencies concluded that there was no clinical harm that could be directly attributed to gadolinium brain deposition, EMA recommended the suspension of the marketing authorisations of three IV linear GBCAs (gadopentetic acid, gadodiamide and gadoversetamide) while restricting the use of the IV formulation of the linear agent gadobenic acid to liver scans only as a precautionary measure.¹ No additional restrictions were instituted for macrocyclic GBCAs but EMA advised that they should be used at the lowest doses that enhanced images sufficiently and only when unenhanced body scans were not suitable. The other agencies did not suspend the use of linear GBCAs but strengthened the package inserts (PIs) of the approved GBCAs (both linear and macrocyclic) in their jurisdictions to include information on this potential risk.^9-12

HSA’s benefit-risk assessment and advisory

HSA’s assessment took into consideration findings from scientific literature, information provided by the drug companies, local usage of GBCAs, expert opinions of the local radiologists, and actions taken by the international regulatory health authorities. An advisory issued by the College of Radiologists Singapore in 2017 had shared that there was no definitive evidence of Parkinson’s disease or other neurological diseases linked to GBCAs. It also stated that GBCAs had a long history of use with clear benefits to patients without major long-term side effects.¹³

HSA has assessed that linear GBCAs still have a place in local clinical practice, particularly in specialised MRIs such as liver and cardiac imaging. Scientific evidence has shown that gadolinium accumulates in brain tissues following multiple GBCA administrations, with a tendency towards higher gadolinium deposition with the linear agents as compared to macrocyclic agents. However, no adverse clinical consequences have been identified and the long-term clinical significance of gadolinium deposition is presently unknown.

To date, HSA has not received any reports of adverse events arising from the accumulation of gadolinium in brain tissues. A Dear Healthcare Professional Letter was issued in March 2018 to enhance healthcare professionals’ awareness to this safety issue.¹⁴ HSA is working with the companies to strengthen the local PIs of GBCAs to warn of the potential risk of gadolinium brain deposits.

While the benefit-risk profile of linear GBCAs remains favourable, HSA would like to advise healthcare professionals, in particular radiologists, of the following as a precautionary measure:

• Consider the retention characteristics of each GBCA when choosing GBCAs for patients

• Use the lowest effective dose of GBCA whenever possible and repeated doses of GBCAs should be administered only after careful benefit-risk assessment

• Closely monitor patients who have been administered GBCAs and to report any serious adverse events suspected to be associated with GBCA use

HSA will continue to monitor the international and local developments regarding this safety issue and update healthcare professionals of any new significant findings. Healthcare professionals are encouraged to report any serious adverse events suspected to be related to GBCAs to the Vigilance and Compliance Branch.

References

1. http://www.ema.europa.eu/docs/en_GB/document_library/Referrals_
   document/gadolinium_contrast_agents_31/Opinion_provided_by_
   Committee_for_Medicinal_Products_for_Human_Use/WC500231824.pdf

2. J Magn Reson Imaging. 2017;46:338-53

3. Radiology. 2015;3:803-9

4. Eur Radiol. 2017;27(8):3353-61

5. Radiology. 2015;275(3):783-91

6. Radiology. 2014;270(3):834-41

7. Radiology. 2015;275(3):772-82

8. Radiology. 2015;276(1):228-32

9. https://www.fda.gov/Drugs/DrugSafety/ucm589213.htm

10. http://healthycanadians.gc.ca/recall-alert-rappel-avis/hc-sc/2017/61676a-eng.php

11. https://www.tga.gov.au/alert/gadolinium-based-contrast-agents-mri-scans

12. http://www.medsafe.govt.nz/safety/EWS/2017/
    GadoliniumContrastAgents.asp

13. http://ams.edu.sg/view-pdf.aspx?file=media%5c4087_fi_750.pdf&ofile=Advisory+on+Linear+Gadolinium-Based+Contrast+Agents_FINAL.pdf

14. https://www.hsa.gov.sg/announcements/Dear-Healthcare-Professional-Letters