Gadolinium-based contrast dyes will now bear new warnings on their labels regarding their association with nephrogenic systemic fibrosis (NSF), according to the Food & Drug Administration (FDA). Gadolinium-based contrast dyes are intravenous drugs approved by the FDA for use with magnetic resonance imaging (MRI) or magnetic resonance angiography (MRA) to help detect abnormalities of body organs, blood vessels, and other tissues.

Three of the dyes, Bayer Healthcare’s Magnevist, GE Healthcare’s Omniscan, and Covidien’s Optimark, will be described as inappropriate for use among patients with acute kidney injury or chronic severe kidney disease. All gadolinium contrast dye labels will emphasize the need to screen patients to detect these types of kidney dysfunction before administration, the FDA said.

In a statement, the FDA said these label changes are intended to help ensure these drugs are used appropriately, and that patients at risk for NSF who receive these agents are actively monitored for the development of the disease.

In its announcement, the agency said its safety review of the most widely used gadolinium agents determined that Magnevist, Omniscan, and Optimark are associated with a greater risk than other gadolinium contrast dyes for NSF in certain patients with kidney disease.

To further enhance the safe use of the imaging agents, the FDA further recommends that health care professionals:

• Estimate kidney function through laboratory testing for patients at risk for chronically reduced kidney function.
• Avoid use of gadolinium contrast agents in patients suspected or known to have impaired drug elimination unless the imaging is essential and not available without contrast.
• Monitor for signs and symptoms of NSF if a gadolinium is administered to a patient with acute kidney injury or chronic, severe kidney disease.
• Administer a gadolinium contrast agent only once during an imaging session.

NSF leads to excessive formation of connective tissue in the skin and internal organs. It is characterized by high blood pressure, burning, itching, swelling and hardening of the skin. Other symptoms include red or dark patches on the skin; pain deep in the hip bones or ribs and muscle weakness. There are no effective treatments for NSF, and the disease can progress to the point of causing severe stiffness in joints, and it can lead to death.

While not much is known about the disease, a growing mountain of evidence indicates that NSF is most likely to occur in people with severe kidney disease who have been exposed to a gadolinium contrast dyes. Since 2007, all gadolinium agents sold in the U.S. have carried the same black box warning – the FDA’s strongest safety notice – regarding the risk of NSF.

GE Healthcare and the other makers of gadolinium agents are named in approximately 500 lawsuits filed by NSF patients, most of which have been consolidated in the U.S. District Court for the Northern District of Ohio as part of a multidistrict litigation (MDL) before Judge Dan Polster.

The panel’s findings are no surprise to the NSF lawyers at our firm. More than 500 lawsuits over NSF, a debilitating and often fatal disease that appears only in people with severe kidney disease who have been exposed to gadolinium, have been filed in U.S. courts against makers of these drugs. The majority of these lawsuits involve Omniscan.

Omniscan has also been the gadolinium contrast dye most cited in NSF reports filed with the FDA and European regulators. In November 2009, Europe’s health regulatory agency said Omniscan, Magnevist and Optimark shouldn’t be used in patients with severe kidney problems.

The FDA advisory panel was convened to comment on the agency’s latest risk assessment of gadolinium agents, and on filings submitted by the manufacturers. That assessment found that Omniscan, Optimark and Magnevist appeared to carry the highest risk of NSF. The lowest risk was associated with Bracco Diagnotics’ Prohance and Multihance, though the danger could not be ruled out for any of the agents.

The FDA staffers who conducted the assessment also recommended that the drug labels note the varying levels of risks with each product. They did not recommend removing any gadolinium agent from the market.

The release of that risk assessment in November 2009 did prompt one company, Covidien, to add a new warning to its OptiMark product. At the time, a spokesperson for the company told Reuters that ?it was prudent to act now, rather than wait for a causal link? to be established? between the imaging drugs and NSF.

All gadolinium contrast dyes already bear a black box warning – the FDA’s strongest safety warning – about the risk of NSF. That black box was mandated in September 2007. But according to Reuters, at the advisory panel meeting, most members felt prescribing instructions for Omniscan and Optimark should clearly warn they should not be used in severe kidney disease patients.

Dr. Sidney Wolfe, a panel member and head of Public Citizen?s Health Research Group, was among those pushing for stronger warnings on Omniscan and Optimark. According to Reuters, Dr. Wolfe expressed concerns that leaving the same warning on all the drugs ?may cause more problems than if you distinguish between the drugs as best as you can.”

Other members expressed concerns that labeling for gadolinium agents needed to reflect their real world use. Radiologists speaking at the meeting noted that gadolinium contrast dyes are, for the most part, no longer used in people with severe kidney disease.

No actual vote was taken at the advisory panel meeting, but the recommendation represented the overall opinion of the panel. The FDA will now determine what, if any, label modifications Omniscan, Optimark and the other agents will undergo. The FDA does not have to follow recommendations of advisory panels, but it usually does so.

Though the FDA’s drug safety unit said the NSF risk associated with the gadolinium contrast dyes ?does not compel removal of specific (imaging agents) from the U.S. market?, it recommended that the drug labels note the varying levels of risks with each product. While the lowest NSF risk was associated with Prohance and Multihance, the agency said ?the data do not appear to rule out an NSF risk for each of the agents.?