FDA Requests Boxed Warning for Contrast Agents Used to Improve MRI Images

The U.S. Food and Drug Administration (FDA) has asked manufacturers to include a new boxed warning on the product labeling of all gadolinium-based contrast agents which are used to enhance the quality of magnetic resonance imaging (MRI).

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 transplantation, 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:

1. Magnevist (gadopentetate dimeglumine)
2. Ominiscan (gadodiamide)
3. OptiMARK (gadoversetamide)
4. MultiHance (gadobenate dimeglumine)
5. 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.

Gadolinium is an FDA-approved contrast agent for magnetic resonance imaging (MRI). Gadolinium is also called gadolinium-DPTA and gadodiamide, and it goes by various brand names. Gadolinium is non-radioactive and resembles plain water.

Reports have identified a possible link between NSF/NFD and exposure to gadolinium containing contrast agents used at high doses for a procedure called Magnetic Resonance Angiography (MRA). An MRA test uses magnetic resonance imaging to take pictures of blood vessels. The gadolinium contrast agent is injected into a patient's vein in order to distinguish blood vessels from other nearby tissues.

The 25 cases of NSF/NFD were reported on May 29, 2006, by the Danish Medicines Agency. Among these, 20 cases occurred in Denmark and five cases occurred in Austria. The patients developed NSF/NFD within 3 months (range 2 weeks to 3 months) after receiving the gadolinium-containing contrast agent.

As of April 3, 2007, the Food and Drug Administration has received another 65 cases of Nephrogenic Systemic Fibrosis/Nephrogenic Fibrosing Dermopathy (NSF/NFD).

NSF/NFD is typically characterized by swelling and tightening of the skin, usually limited to the extremities. but sometimes involving the trunk. The condition may develop over a period of days to several weeks. In many cases, skin thickening inhibits the flexion and extension of joints, resulting in painful contractures. In the most severe of cases, affected patients may be unable to walk, or fully extend the joints of their arms, hands, legs, and feet. Complaints of muscle weakness are common.

Once a patient contracts NSF/NFD, the skin changes may start as reddened or darkened patches, papules, or plaques. In time, the skin surface may distort to resemble the texture of the peel of an orange. Some patients may experience burning, itching, or severe sharp pains in areas of involvement. Radiography may reveal calcifications of the soft tissue. NSF/NFD patients can report "bone ache" described in the hips and in the ribs.

Topically, the skin lesions are commonly symmetrical, with zones between the ankles and thighs most commonly involved, followed by involvement between the wrist and upper arms. Hand and foot swelling with blister-like lesions has also been reported in patient with NSF/NFD. Some patients have reported yellow papules or plaques on or near the eyes.