Gadolinium-based contrast agents (GBCA) are complexes of gadolinium (III) with different types of organic chelators. They are used for contrast enhancement in magnetic resonance imaging (MRI) and magnetic resonance angiography (MRA). Intra-articular GBCA formulations are also used in arthrography for magnetic resonance of joints. Within the class, they can be divided into linear or macrocyclic compounds1.
Background of Safety Issue
The European Medicines Agency (EMA) took action to suspend the authorisation of some linear GBCAs and restrict the use of others due to evidence of gadolinium deposition in brain tissues following use of GBCAs. Although no symptoms or diseases linked to gadolinium accumulation in the brain have been identified, EMA took a precautionary approach, noting that data on the long-term effects in the brain are limited.
The suspended linear GBCAs are gadobenic acid, gadodiamide, gadopentetic acid (intravenous use) and gadoversetamide. Linear agents which will remain available include gadoxetic acid and gadopentetic acid (intra-articular use). Gadoxetic acid remains on the market as it meets an important diagnostic need in patients with few alternatives. Gadopentetic acid (intra-articular use) remains available as the dose of gadolinium required for these scans is very low.
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. EMA recommends that these may 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 suitable2.
There are currently 11 GBCA products registered in Malaysia. The linear agents registered include gadodiamide, gadobenic acid, gadopentetic acid (intravenous) and gadoxetic acid, whereas the macrocyclic agents registered are gadoteric acid and gadobutrol.
In January 2018, the Drug Control Authority (DCA) decided to suspend gadodiamide and gadopentetic acid (intravenous), and restrict the indication of gadobenic acid to liver scans.
As for gadoxetic acid and macrocyclic agents, the package inserts will be updated to include information regarding the risk of gadolinium deposition in the brain.
Adverse Drug Reaction Reports
Since year 2000, NPRA has received a total of 73 reports with 122 adverse events suspected to be related to GBCA. Majority (58, 79.5%) of the reports involve linear agents. The number of ADR reports for the GBCA which have been suspended are six (6) for gadodiamide and four (4) for gadopentetic acid. The common adverse events reported were nausea, rash, itching and erythema.
Advice for Healthcare Professionals
- Healthcare professionals should use GBCA only when essential diagnostic information cannot be obtained with unenhanced scans.
- Healthcare professionals should always use the lowest dose that provides sufficient enhancement for diagnosis.
- European Medicine Agency (2017). Assessment Report – Gadolinium containing contrast agents.
- European Medicine Agency (2017). EMA’s final opinion confirms restrictions on use of linear gadolinium agents in body scans.
This publication is aimed at health professionals. The information is meant to provide updates on medication safety issues, and not as a substitute for clinical judgement. While reasonable care has been taken to verify the accuracy of the information at the time of publication, the NPRA shall not be held liable for any loss whatsoever arising from the use of or reliance on this publication.