FDA requests "black box" warning on gadolinium contrast packaging

May 31, 2007

All five gadolinium-based MR agents on the U.S. market will carry a "black box" warning describing the risk of developing nephrogenic systemic fibrosis for patients with severe renal disease.

All five gadolinium-based MR agents on the U.S. market will carry a "black box" warning describing the risk of developing nephrogenic systemic fibrosis for patients with severe renal disease.

The FDA asked manufacturers May 23 to carry the warning and to prospectively collect data on patients exposed to these contrast agents to find out if they had any renal insufficiency. The goal is to estimate more accurately the magnitude of the risk of developing NSF for patients with kidney disease, according to the agency. The manufacturers and their agents are Bayer Schering Pharma (Magnevist), Bracco (MultiHance and ProHance), GE Healthcare (Omniscan), and Mallinckrodt (OptiMark).

As of May 22, 239 cases of NSF had been reported worldwide. All documented cases have so far been limited to people with severe renal disorders who were administered a gadolinium-based contrast agent before undergoing MRI, according to Dr. Shawn Cowper, a Yale University dermatopathologist who maintains an NSF patient registry.

About 85% of the NSF cases have been linked with gadodiamide (Omniscan). Magnevist, which accounts for about half of all clinical MR contrast sales, has been involved in about 10% of the documented fibrosis incidents, according to panelists at an NSF symposium last week at the International Society for Magnetic Resonance in Medicine meeting in Berlin.

The European Union introduced a strict contraindication for the use of Omniscan in patients with severe renal failure and ordered a warning for all gadolinium products in February.

Cases of NSF have been reported following the administration of each of the five agents that are subject to the FDA black box requirement, but agency investigators are not certain whether all of the agents are directly linked to the condition. Some adverse event reports have incomplete patient histories of agent exposure, and other reports indicate that patients received more than one type of agent prior to an NSF diagnosis.

The FDA stated that only patients who have severe renal insufficiency appear to be at increased risk for developing the disease, which causes an often debilitating, sometimes fatal fibrosis of the skin and connective tissues. This is a change from December 2006, when the agency issued a warning that patients with moderate renal insufficiency were at risk for developing NSF. Since then, the FDA has learned that those patients thought to have moderately insufficient kidney function actually were in acute renal failure at the time they received a gadolinium agent.

The agency now recommends that patients should be screened for kidney problems before receiving a gadolinium-based MR agent. 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, it said in a release.

Gadolinium-based agents are manufactured by a chelation process in which large organic molecules form a stable complex around the metal, reducing its toxicity potential. This stable complex is eliminated predominantly via the kidneys.

The May 23 requests demonstrated the FDA's "continuing vigilance about ensuring the safety of drug products once they enter the marketplace," according to Steven Galson, director of the FDA's Center for Drug Evaluation and Research.

The FDA said its investigators will continue to evaluate new reports of NSF and may request additional studies and/or labeling changes.

For more information, refer to these articles from the Diagnostic Imaging archives:

Panel recommends caution in administration of contrast in the wake of gadolinium-related NSF cases

Europeans urge caution with all gadolinium agents

Skin disease linked to gadolinium prompts warning

Report from ECR: Scottish researchers probe link between gadolinium and nephrogenic systemic fibrosis