Safety Information

Trans-Tasman Early Warning System - Alert Communication

Gadolinium based contrast agents for MRI and retention of gadolinium in the brain

Products Affected
Information for consumers and caregivers
Information for healthcare professionals
Data Summary
What actions are Medsafe taking?
How to report adverse events
Further information

Very small amounts of gadolinium have been found in the brains of patients who have undergone multiple magnetic resonance imaging (MRI) scans with gadolinium based contrast agents (GBCAs). No harmful effects have been found from gadolinium retention (sometimes referred to as deposits) in the brain.

GBCAs are used to improve MR images. This helps healthcare professionals correctly diagnose and monitor a variety of health conditions. GBCAs are described as macrocyclic or linear, based on their chemical structure.

Medsafe and the Medicines Adverse Reactions Committee (MARC) recently conducted a safety review of GBCAs. The conclusions of this review were:

All GBCAs can enter the brain.
Administration of linear GBCAs leads to greater retention of gadolinium in the brain than use of macrocyclic GBCAs.
No harm was identified due to retention of gadolinium in the brain.
No adverse reactions have been reported to the Centre for Adverse Reactions Monitoring (CARM) due to gadolinium in the brain.

Nevertheless, the MARC considered that use of GBCAs should be restricted to situations where they are expected to provide additional information allowing the patient’s condition to be diagnosed or monitored correctly.

Products Affected

Product name	Active	Structure type
Dotarem	Gadoteric acid	macrocyclic
Gadovist	Gadobutrol	macrocyclic
Magnevist	Gadopentetic acid	linear
Primovist	Gadoxetic acid	linear
Multihance	Gadobenic acid	linear
Omniscan	Gadodiamide	linear

Information for consumers and caregivers

Gadolinium based contrast agents are used to help diagnose many health conditions and to monitor treatment. Getting the right diagnosis helps you and your doctor decide on the right treatment for you.
Some patients who have needed multiple MRI scans with some of these contrast agents have been found to have small amounts of gadolinium left behind in their brains.
No side effects from gadolinium in the brain have been reported in New Zealand, or other countries. No evidence of harm has been found in studies.
Your doctor will talk to you about why you might need a contrast agent with your MRI scan

Information for healthcare professionals

Retention of gadolinium in the brain has been found after multiple administrations of gadolinium based contrast agents (GBCAs). However no evidence of harm from gadolinium retention has been found to date.
Patients should not be denied an MRI if this is needed for diagnosis or monitoring of a health condition.
Limit the use of GBCAs where possible. Only use a GBCA when it is needed to provide the information required from the MRI scan.
Wherever possible, use the approved dose.
Depending on your patient’s individual medical history and circumstances macrocyclic agents (Dotarem and Gadovist) may be preferable to linear agents as accumulation of gadolinium in the brain is lower with macrocylic agents.
Discuss with your patients and their families what is currently known about gadolinium in the brain so that they can make an informed choice.

Data Summary

Gadolinium based contrast agents (GBCAs) are used to enhance MR images. The efficacy and need for these agents has been confirmed in numerous studies.

That gadolinium may localise in the brain was first hypothesised based on unusual signal intensities seen in parts of the brain in patients having non-contrast MRI. These patients had previously had multiple MRIs with linear GBCAs. This hypothesis was considered confirmed after autopsy studies measured gadolinium in decedents’ brains at concentrations proportional to the cumulative dose of GBCA administered.

The evidence suggests that all GBCAs enter the brain, which makes the stability of the gadolinium chelate important. Macrocyclic chelates are less likely to release gadolinium and result in lower levels in the brain than linear chelates.

MRI does not identify all the gadolinium in the brain. The autopsy studies found gadolinium in areas of the brain not associated with a signal intensity increase on MRI. MRI does not detect gadolinium directly rather the influence of gadolinium on protons (mainly from water). Therefore if there is little water surrounding the gadolinium it is not detected. However, the evidence in humans points to little to no gadolinium retention with macrocyclic GBCAs and higher levels with the linear GBCAs. The form of the gadolinium seen on MRI is generally not known as the analytical techniques do not discriminate.

The location of the retained gadolinium has also been investigated. In the human autopsy studies gadolinium was found in the capillary endothelium and neural interstitium. In rats, gadolinium was found in capillary endothelium and intercellular connective tissue in the choroid plexus.

Histopathology of brain from humans and rats containing gadolinium has not shown any abnormal findings to date.

No overt behavioural changes or neurological deficits have been noted in rats included in pre-clinical studies. Neither is there any evidence of resulting harm in humans.

What actions are Medsafe taking?

Medsafe is working with sponsors to update the data sheet with information about this concern. Medsafe will continue to monitor the safety of GBCAs and will provide more information and take further action if necessary.

How to report adverse events

Online	Submit a CARM report Prescribers can also submit a report using the online reporting tool available in patient management software.
Paper	Download a consumer reporting form (Word Document, 61KB, 1 page) Download a healthcare professional reporting form (PDF, 292 KB, 2 pages) Submit completed forms by emailing CARMreport@health.govt.nz or mail (Medsafe, Ministry of Health, 133 Molesworth Street, Thorndon, Wellington, 6011).
Email	CARMreport@health.govt.nz

Medsafe cannot give advice about an individual’s medical condition. If you have any concerns about a medicine you are taking Medsafe encourages you to talk to your healthcare professional.