On May 23, 2007, the FDA issued an Alert indicating that the FDA has requested the addition of a boxed warning and new warnings about risk of Nephrogenic Systemic Fibrosis (NSF) to the prescribing information (package inserts) for all gadolinium-based contrast agents (GBCAs), including Magnevist. The new Boxed Warning and new Warnings section describe NSF, populations at risk for NSF, and advise on screening procedures, dosing and other considerations.

Below is the text of the boxed warning.

In addition, the Warnings and Precautions section on Nephrogenic Systemic Fibrosis in the package inserts will now include the following:

WARNINGS AND PRECAUTIONS: NEPHROGENIC SYSTEMIC FIBROSIS (NSF)

• Gadolinium-based contrast agents increase the risk for nephrogenic systemic fibrosis (NSF) in patients with acute or chronic severe renal insufficiency (glomerular filtration rate < 30 mL/min/1.73m2) and in patients with acute renal insufficiency of any severity due to the hepato-renal syndrome or in the perioperative liver transplantation period. In these patients, avoid use of gadolinium-based contrast agents unless the diagnostic information is essential and not available with noncontrast enhanced MRI. For patients receiving hemodialysis, physicians may consider the prompt initiation of hemodialysis following the administration of a gadolinium-based contrast agent in order to enhance the contrast agent's elimination. The usefulness of hemodialysis in the prevention of NSF is unknown.
• Among the factors that may increase the risk for NSF are repeated or higher than recommended doses of a gadolinium-based contrast agent and the degree of renal function impairment at the time of exposure.
• Post-marketing reports have identified the development of NSF following single and multiple administrations of gadolinium-based contrast agents. These reports have not always identified a specific agent. Where a specific agent was identified, the most commonly reported agent was gadodiamide (Omniscan™), followed by gadopentetate dimeglumine (Magnevist^®) and gadoversetamide (OptiMARK^®). NSF has also developed following sequential administrations of gadodiamide with gadobenate dimeglumine (MultiHance^®) or gadoteridol (ProHance^®). The number of post-marketing reports is subject to change over time and may not reflect the true proportion of cases associated with any specific gadolinium-based contrast agent¹.
• The extent of risk for NSF following exposure to any specific gadolinium-based contrast agent is unknown and may vary among the agents. Published reports are limited and predominantly estimate NSF risks with gadodiamide. In one retrospective study of 370 patients with severe renal insufficiency who received gadodiamide, the estimated risk for development of NSF was 4% (J Am Soc Nephrol 2006; 17:2359). The risk, if any, for the development of NSF among patients with mild to moderate renal insufficiency or normal renal function is unknown.
• Screen all patients for renal dysfunction by obtaining a history and/or laboratory tests. When administering a gadolinium-based contrast agent, do not exceed the recommended dose and allow a sufficient period of time for elimination of the agent prior to any readministration.

Additionally, the FDA has requested that all manufacturers prospectively collect data on patients with varying degrees of renal insufficiency who are exposed to GBCAs to more accurately estimate the magnitude of the risk for NSF for patients with kidney disease. FDA will continue to evaluate new reports of NSF and may request additional studies and/or labeling changes.

The full text of the FDA Alert can be accessed at: http://www.fda.gov/cder/drug/InfoSheets/
HCP/gcca_200705.htm

¹ Omniscan is a trademark of GE Healthcare; OptiMARK is a registered trademark of Mallincrodt, Inc, a division of Tyco Healthcare; MultiHance and ProHance are registered trademarks of Bracco Diagnostics, Inc.

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