FDA requests boxed warning for contrast agents used to improve MRI images.

The requested warning would state that patients with severe kidney insufficiency who receive gadolinium-based agents are at risk for developing a debilitating, and a potentially fatal disease known as nephrogenic systemic fibrosis (NSF). In addition, it would state that patients just before or just after liver transplant, or those with chronic liver disease, are also at risk for developing NSF if they are experiencing kidney insufficiency of any severity.

"FDA has been carefully monitoring potential safety signals related to these contrast agents after receiving reports about the risk of this potentially life-threatening disease," said Steven Galson, M.D., M.P.H., director of FDA's Center for Drug Evaluation and Research. "This latest action demonstrates FDA's continuing vigilance about ensuring the safety of drug products once they enter the marketplace."

Patients with NSF 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 NSF is not known and there is no consistently effective treatment of this condition.

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

Gadolinium-based contrast agents are commonly used to improve the visibility of internal structures when patients undergo an MRI. Five gadolinium-based contrast agents have been approved for use in the United States: Magnevist (gadopentetate dimeglumine), Ominiscan (gadodiamide); OptiMARK (gadoversetamide); MultiHance; (gadobenate dimeglumine); and Prohance (gadoteridol).

Reports have identified the development of NSF following single and multiple administrations of the gadolinium-based contrast agents.

The reports have not always identified a specific agent. Omniscan was the most commonly reported agent, when a specific agent was identified, followed by Magnevist and OptiMARK.

NSF also has developed after the sequential administration of Omniscan and MultiHance and Omniscan and ProHance. Because reports incompletely describe exposure to gadolinium-based contrast agents, it is not possible to know if the extent of risks for developing NSF is the same for all agents.

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 NSF among patients with normal kidney function or those with mild-to-moderate kidney insufficiency.

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.

What is gadolinium and what is its use in clinical medicine?
Gadolinium is a paramagnetic metal ion. Paramagnetic ions, such as gadolinium, move differently within a magnetic field. This trait makes gadolinium useful for magnetic resonance imaging (MRI).

GBCAs are manufactured by a chelating process, a procedure in which large organic molecules form a stable complex around the gadolinium. The chelate reduces the chances of toxicity that could result from exposure to gadolinium. This stable complex is eliminated predominantly via the kidneys.

What is the difference between MRA and MRI?
MRA is a special type of MRI used to study blood vessels. MRA aids the detection of heart disorders, stroke, and vascular diseases.

Can an MRI and MRA be performed without gadolinium-based contrast?
Yes, MRI and MRA can be performed without contrast.

Are there other approved MRI contrast agents that do not contain gadolinium?
Yes. However, the two other approved MRI contrast agents, Feridex, I.V. (an iron-containing injectable solution) and Teslascan (a manganese-containing injectable solution) are FDA-approved only for the evaluation of lesions of the liver.

Imaging contrast agents, such as iodinated contrast agents are used in Computed Tomography, plain X-ray and X-ray angiography. However, these iodinated contrast agents require X-ray imaging rather than MRI. These agents also have serious risks such as anaphylaxis (a severe and life-threatening allergic reaction) and kidney damage.

What is the treatment for NSF?
There is no known treatment for NSF.

Do the gadolinium-based contrast agents cause NSF?
Whether the GBCAs are the only agents or conditions that may be associated with NSF in patients with renal disease is unknown. The conclusions that can be drawn from the NSF reports are limited. However, the reports FDA has received of gadolinium deposits in the skin of patients with NSF/NFD, suggest that GBCAs play a role in the development of NSF in patients with acute or chronic severe kidney insufficiency or kidney dysfunction due to the hepato-renal syndrome or in the perioperative liver transplantation period.