The CHMP1 Pharmacovigilance Working Party has considered the safety of gadolinium-containing MRI contrast agents. The Committee has concluded that recommendations on the use of these contrast agents should be amended for patients with impaired renal function.
The recommendations have been amended as a consequence of a confirmed suspicion that the use of these MRI contrast agents may result in a rare but severe adverse reaction: nephrogenic systemic fibrosis (more details below). The suspicion is primarily associated with the MRI contrast agent named Omniscan®, but it is possible that one or more of the other gadolinium-containing contrast agents may also cause this adverse reaction.
Gadolinium-containing MRI contrast agents licenced in the EU
Magnevist® (gadopentetic acid)
Multihance® (gadobenic acid)
Dotarem® (gadoteric acid)
Primovist® (gadoxetic acid)
Amended recommendations - Omniscan ®
The MRI contrast agent Omniscan ® should not be used (is contraindicated) in patients with severe kidney failure (GFR <30 ml/min/1.73 m2) and in patients who have had, or who are awaiting, liver transplantation. Neonates and infants up to 1 year should be treated with Omniscan ® only after careful consideration because their kidneys are not fully developed.
Amended recommendations – other gadolinium-containing MRI contrast agents
The other 7 gadolinium-containing MRI contrast agents should be administered only after careful consideration to patients with kidney failure.
Nephrogenic systemic fibrosis
Nephrogenic systemic fibrosis (nephrogenic fibrosing dermopathy) is a rare condition which leads to increased formation of fibrous tissue in the skin. The skin is thickened and becomes coarse and hard. The formation of fibrous tissue may affect the joints and the walking function, and it may also occur in the lungs, heart, liver and muscles.
Nephrogenic systemic fibrosis is seen only in patients with kidney impairment. In most of the cases the patients suffered from severe kidney dysfunction while only few patients suffered from moderate kidney impairment.
Approximately 200 cases of nephrogenic systemic fibrosis have been registered worldwide. The majority of patients had received Omniscan®2. Only few reports have been registered on nephrogenic systemic fibrosis following Magnevist® administration. The European Competent Authorities have not received any reports on nephrogenic systemic fibrosis regarding the other gadolinium-containing MRI contrast agents.
It is not quite clear to the experts, how administration of gadolinium-containing MRI contrast agents can lead to the development of nephrogenic systemic fibrosis in patients with kidney impairment. Free gadolinium is toxic and must not be in direct contact with human tissue. In the MRI contrast media, gadolinium is consequently encapsulated. Theoretically gadolinium can be released into the tissue and thereby provoke the formation of fibrous tissue. In patients with impaired renal function there is greater risk for adverse reactions due to their slower excretion of gadolinium-containing MRI contrast agents.
Differences in the gadolinium-containing MRI contrast agents’ physico-chemical properties may explain why nephrogenic systemic fibrosis is seen primarily in association with Omniscan® administration. This may result from the fact that the gadolinium bond in Omniscan® is weaker than in the other contrast agents.
Continuous monitoring of adverse reactions
In coordination with the other competent authorities in the EU and the marketing authorisation holders, the Danish Medicines Agency will continue to monitor adverse reactions associated with gadolinium-containing MRI contrast agents. The Danish Medicines Agency urges doctors or patients to report suspected adverse reactions occurring after administration of MRI contrast agents.
For further information, please contact Doris I. Stenver, tel +45 4488 9247.
The Danish Medicines Agency, 7 February 2007
1: Committee for Human Medicinal Products.
2: or Optimark which is not licenced in the EU, but in the US
Grobner T. Gadolinium – a specific trigger for the development of nephrogenic fibrosing dermatopathy and nephrogenic systemic fibrosis? Nephrol Dial Transplant 2006 April; 21(4):1104-8.
Marckmann P, Skov L, Rossen K, Dupont A et al. Nephrogenic systemic fibrosis: suspected causative role of gadodiamide used for contrast-enhanced magnetic resonance imaging. J Am Soc Nephrol. 2006 September; 17(9):2359-62.
Idee JM, Port M, Schaefer M, Le Greneuer S, Corot C. Clinical and biological consequences of transmetallation induced by contrast agents for magnetic resonance imaging: e review. Fundam Clin Pharmacol. 2006 December; 20(6):563-76.
Thomsen HS, Morcos SK , Dawson P. Is there a causal relation between the administration of gadolinium based contrast media and the development of nephrogenic systemic fibrosis (NSF)? Clin Radiol. 2006 November; 61(11):905-6.
Morcos SK. Nephrogenic systemic fibrosis following the administration of extracellular gadolinium based contrast agents: Is the stability of the contrast agent molecule an important factor in the pathogenesis of this condition? (In press).
Joffe P, Thomsen HS, Meusel M. Pharmacokinetics of gadodiamide injection in patients with severe renal insufficiency and patients undergoing hemodialysis of continuous ambulatory peritoneal dialysis. Acad Radiol 1998;5:491-502.