FDA Panel Agrees With Kidney Warning on Certain Gadolinium Contrast Dyes

Emma Hitt, PhD

December 09, 2009

December 9, 2009 — A US Food and Drug Administration (FDA) advisory panel is generally in agreement that at least 2 gadolinium contrast dyes, gadodiamide (Omniscan, GE Healthcare) and gadoversetamide (Optimark, Covidien), may carry a higher risk in patients with severe kidney disease but that other products are not necessarily safer. Gadolinium contrast dyes are frequently used in brain magnetic resonance imaging.

All 7 gadolinium contrast dyes currently on the market already carry boxed warnings about the risk for nephrogenic systemic fibrosis (NSF), saying that use should be avoided in patients with severe kidney disease. Other products currently on the market include gadobenate dimeglumine (Multihance, Bracco Diagnostics), gadodiamide (Omniscan, GE Healthcare), gadopentetate dimeglumine (Magnevist, Bayer Healthcare), gadoteridol (Prohance, Bracco Diagnostics), gadoversetamide (Optimark, Covidien), gadoxetate disodium (Eovist, Bayer Healthcare), and gadofosveset trisodium (Ablavar, previously known as Vasovist, Lantheus Medical Imaging).

The aim of yesterday's meeting of the FDA’s Cardiovascular and Renal Drugs Advisory Committee and Drug Safety and Risk Management Advisory Committee was to review data from gadolinium contrast manufacturers regarding risk for NSF among gadolinium agents and to provide the FDA guidance on labeling.

In the session, the panel was not asked to vote on whether to recommend any new warnings but rather to weigh the risks and ascertain differences between the products. Panel chair Robert A. Harrington, MD, Duke University Medical Center, Durham, North Carolina, summarized the 8-hour session by noting that most of the group felt that "at least 2 of the agents do appear to be different than the other agents. ... There seemed to be less consensus about the risks associated with a third agent."

Dr. Harrington also pointed out that there was "no clear evidence that any single agent was safe in this population." Other suggestions from the panel included highlighting the importance of using the lowest possible dose of these agents and considering the effects of cumulative dosing.

In September 2007, manufacturers were asked to add a black box warning to the product labels about the association with NSF. The FDA also warned that patients with kidney disease should avoid these products or receive a minimal dose if use of the dyes could not be avoided.

According to FDA data released in November and collected since the initiation of the black box warning, the highest risk for NSF was associated with Omniscan, Magnevist, and Optimark, whereas the lowest risk was associated with Prohance and Multihance. The risk of developing NSF has been estimated as being between 1% and 6% in patients with severe end-stage renal disease.

Although the agency has stated that the risk for NSF does not “compel removal of specific (imaging agents) from the US market,” it has recommended that the drug labels note the varying levels of risks with each product.

NSF is a potentially fatal disorder associated with excessive formation of connective tissue in the skin and internal organs and is characterized by high blood pressure and burning, itching, swelling, and hardening of the skin. Other symptoms include red or dark patches on the skin, pain, and muscle weakness. NSF appears to develop only in patients with preexisting kidney disease.

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