FDA calls for ‘black box’ warning on gadolinium agents

May 24, 2007

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

The FDA yesterday asked the manufacturers 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, according to the agency, is to more accurately estimate the magnitude of the risk of developing NSF for patients with kidney disease. The manufacturers and their agents are Bayer Schering Pharma (Magnevist), Bracco (MultiHance and ProHance), GE Healthcare (Omniscan), and Mallinckrodt (OptiMark).

Cases of NSF have been reported following the administration of each of these agents, but FDA investigators are not certain whether all 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 fibrosis of the skin and connective tissues, and can often be fatal. 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.

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 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.