FDA Orders Black Box Warning for Gadolinium-Based Contrast Agents

ROCKVILLE, Md., May 23 -- The FDA today ordered black-box warnings for all gadolinium-based contrast agents for magnetic resonance imaging, detailing an increased risk for nephrogenic systemic fibrosis with kidney-disease patients.

The warning alerts clinicians of possible severe kidney insufficiency in patients at risk for nephrogenic systemic fibrosis, a potentially fatal disease, who receive gadolinium-based agents. The boxed message also warns that the nephrogenic systemic fibrosis risk extends to patients with chronic liver disease including those just before or after liver transplantation.

The warning is to be added to the labels of the five gadolinium-based contrast agents that are FDA-approved. Those products are gadopentetate dimeglumine (Magnevist), gadodiamide (Ominiscan), gadoversetamide (OptiMARK), gadobenate dimeglumine (MultiHance), and gadoteridol (ProHance).

Steven Galson, M.D., M.P.H., director of FDA's Center for Drug Evaluation and Research, said the FDA has been monitoring safety reports concerning the gadolinium-based products.

Patients should be screened for kidney problems prior to receiving one of these imaging agents. The recommended dose should not be exceeded and enough time should elapse to ensure that a dose has been eliminated from the body before the agent is used again.

There have been no reports of nephrogenic systemic fibrosis among patients with normal kidney function or those with mild-to-moderate kidney insufficiency.

Reports have identified the development of nephrogenic systemic fibrosis following single and multiple administrations of the gadolinium-based contrast agents. The reports have not always identified a specific agent. Gadodiamide was the most commonly reported agent, when a specific agent was identified, followed by gadopentetate dimeglumine and gadoversetamide.

Nephrogenic systemic fibrosis also has developed after the sequential administration of gadodiamide, and gadobenate dimeglumine and gadomiamide and gadoteridol. Because several reports incompletely described exposure to gadolinium-based contrast agents, it is not possible to know whether the extent of risks for developing nephrogenic systemic fibrosis is the same for all agents.

Patients with nephrogenic systemic fibrosis develop thickening of the skin and connective tissues that inhibits their ability to move and may result in broken bones. Other organs are at risk of thickening as well. The cause of nephrogenic systemic fibrosis is not known and there is no consistently effective treatment.

The FDA first notified health care professionals and the public about the gadolinium-related risks for nephrogenic systemic fibrosis in June 2006. Information on the risks was updated in December.

Bayer Schering Pharma, Berlin, Germany, manufactures Magnevist; GE Healthcare, Chalfont St. Giles, U.K., is the maker of Omniscan; OptiMARK is manufactured by Mallinckrodt, Inc., Hazelwood, Mo.; and ProHance and Multihance are made by Bracco Diagnostics Inc., Princeton, N.J.