Gadolinium-containing contrast agents: removal of Omniscan and iv Magnevist, restrictions to the use of other linear agents
A review has found that low levels of gadolinium can be retained in the brain and other tissues after administration of gadolinium-containing contrast agents (GdCAs). There is currently no evidence that gadolinium deposition in the brain has caused adverse neurological effects in patients; however, licences for gadodiamide (Omniscan) and intravenous gadopentetic acid (also known as gadopentetate dimegulumine; Magnevist) will be suspended from 1 February 2018 and these products will be recalled. The use of gadobenic acid (also known as gadobenate dimeglumine; MultiHance) and gadoxetic acid (Primovist) will be limited to delayed phase liver imaging only*.
Post-publication note:
As of 1 February 2018, Omniscan and intravenous Magnevist are now no longer authorised for use and a product recall of any existing unexpired stock is underway. See Drug Safety Update February 2018.
Advice for healthcare professionals:
- linear gadolinium-containing contrast agents (GdCAs) are associated with higher retention of gadolinium in the brain than macrocyclic GdCAs
- licences will be suspended for linear agents gadodiamide (Omniscan) and intravenous gadopentetic acid (Magnevist)
- suspended products will be recalled from 1 February 2018, by which time healthcare professionals are expected to have switched over to alternative GdCAs
- the authorised indication of the linear agents gadobenic acid (also known as gadobenate dimeglumine; MultiHance) and gadoxetic acid (Primovist) will be limited to delayed phase liver imaging*
- macrocyclic agents gadoteridol (Prohance), gadobutrol (Gadovist), and gadoteric acid (Dotarem) will remain authorised, as will gadopentetic acid for intra-articular use
- use GdCAs only when diagnostic information is essential and not available with unenhanced magnetic resonance imaging (MRI); do not exceed the recommended dose per kilogram of body weight and use the lowest dose that is effective for diagnosis
Background and 2007 European review
Gadolinium-containing contrast agents (GdCAs) are indicated for the enhancement of magnetic resonance imaging (MRI). GdCAs contain gadolinium bound to a ligand molecule and can be divided into two groups based on their chemical structure — linear and macrocyclic.
A 2007 European-level review identified a risk of nephrogenic systemic fibrosis (NSF) following use of GdCAs in patients with severely impaired renal function. Linear GdCAs were categorised as having a higher risk of causing NSF than macrocyclic GdCAs. In 2010, we published advice aiming to minimise the risk of NSF. Since 2006, the use of linear GdCAs has decreased markedly in the UK, and most patients now receive macrocyclic GdCAs.
Gadolinium retention in the brain and other tissues
A European-level scientific review to investigate gadolinium retention in brain and other tissues has now completed. Low levels of gadolinium deposition in the brain, particularly in the dentate nucleus of the cerebellum and in the sub-cortical structure the globus pallidus, have been confirmed by mass spectrometry and studies of MRI data. Data on stability, as well as in-vitro and non-clinical studies, show that macrocyclic agents have a significantly lower potential to cause retention of gadolinium in the body. This is because they are more stable and do not release gadolinium to any significant extent from the ligand molecule.
In view of the evidence of retention of gadolinium in brain and other tissues following exposure to these agents, the risks of gadodiamide and intravenous gadopentetic acid are considered to outweigh their benefits.
There is currently no evidence that gadolinium deposition in the brain has caused adverse neurological effects in patients; however, data on long-term effects of gadolinium deposition in the brain or other tissues are very limited. The European Medicines Agency has issued information to patients about the review.
When using one of the linear GdCAs that will remain on the market, weigh the possible diagnostic advantages in patients who will require repeated scans against the potential for deposition of gadolinium in the brain and other tissues.
Status of gadolinium-containing contrast agents after the review
| Brand leader product name | Active substance | Structure | Recommendation from EU review |
| Omniscan | gadodiamide | Linear | Suspension |
| Magnevist | gadopentetic acid (USAN[footnote 1] gadopentetate dimeglumine) | Linear | Suspension |
| Magnevist (intra-articular product) | gadopentetic acid, dimeglumine salt | Linear | Updates to product information |
| MultiHance | gadobenic acid (USAN[footnote 1] gadobenate dimeglumine) | Linear | Indication revised to delayed phase liver imaging only; updates to product information |
| Primovist | gadoxetic acid | Linear | Indication revised to delayed phase liver imaging only; updates to product information |
| ProHance | gadoteridol | Macrocyclic | Updates to product information |
| Gadovist | gadobutrol | Macrocyclic | Updates to product information |
| Dotarem[footnote 2] | gadoteric acid | Macrocyclic | Updates to product information |
| One linear agent, gadoversetamide (OptiMARK), has been withdrawn by the Marketing Authorisation Holder and is not available in the UK |
Reporting of suspected adverse reactions
Gadolinium-containing contrast agents are authorised as medicines. Suspected adverse reactions should be reported to us on a Yellow Card.
Further information
EMA’s final opinion confirms restrictions on use of linear gadolinium agents in body scans.
Central Alerting System message to healthcare professionals. 13 December 2017.
*Post-publication note
Following queries from healthcare professionals, the description of the new indication for linear agents gadobenic acid and gadoxetic acid in a follow-up article was amended to “for liver imaging and when imaging in the delayed phase is required” to more precisely reflect the current indication. This is not a change in the regulatory position. Full indications for all medicines can be found in Summaries of Product Characteristics.
Article citation: Drug Safety Update volume 11 issue 5; December 2017: 1.