Response to the FDA's May 23, 2007, Nephrogenic Systemic Fibrosis Update

Abstract

Emanuel Kanal, MD Dale R. Broome, MD Diego R. Martin, MD, PhD Henrik S. Thomsen, MD On May 23, 2007, the Food and Drug Administration (FDA) requested that a “black box” warning (one of the more extreme mechanisms that the FDA may invoke for calling attention to observed serious adverse reactions) regarding the potential risk of nephrogenic systemic fibrosis (NSF) in patients with renal failure be added to the product descriptions of all five FDAapproved gadolinium-based magnetic resonance (MR) contrast agents marketed in the United States: Magnevist (gadopentetate dimeglumine; Bayer Healthcare, Wayne, NJ), MultiHance (gadobenate dimeglumine; Bracco Diagnostics,Princeton,NJ),Omniscan(gadodiamide; GE Healthcare, Oslo, Norway), OptiMARK (gadoversetamide; Tyco-Mallinckrodt, St Louis, Mo), and ProHance (gadoteridol; Bracco Diagnostics). All five agents were treated equally, in this regard, despite data suggesting that certain agents possessed a seemingly greater risk for precipitating NSF than did others. The authors of this commentary believe this implied equality among the five gadolinium-based agents available in the United States to be imprudent in light of present information. We are concerned as to how the implicationof equivalent risk amonggadolinium-based contrast agents may impact agent selection for renally impaired patients. As such, we provide the following points of information so that all health care providers may make a more fully informed decision regarding the selection of contrast agents for use in patients with renal impairment. 1. Dr Shawn Cowper, who first described NSF in 2000, maintains the Yale NSF Registry, which contains nearly 250 patients. A retrospective review of this database has shown that among patients in whom an exposure could be verified within 2–3 months of NSF onset, approximately 85% of these patients had been administered Omniscan prior to receiving a diagnosis of NSF; the rest had been administered Magnevist (unpublished data, July 16, 2007). Similarly, Thomsen reported, “More than 150 patients have developed NSF after exposure to a Gd-based contrast medium. The overwhelming majority ( 90%) had had gadodiamide with certainty” (1). 2. As of March 12, 2007, a review of the peer-reviewed literature (2) revealed a total of 74 cases of NSF, 72 of which were associated with prior Omniscan administration; one, with prior Magnevist administration; and one, with no gadolinium-based agent identified. There is also one case reported in the peer-reviewed literature (3) of NSF developing in a patient who had received MultiHance and who subsequently received Omniscan before developing NSF. 3. Although the FDA MedWatch database is an unmonitored and largely unverified reporting system, as of April 17, 2007, there were 160 Omniscan-associated cases of NSF, 73 Magnevist-associated cases, and three OptiMARK-associated cases. There were also several known confounded cases reported in which more than one gadolinium-based agent had been administered. There were no reports of NSF after isolated MultiHance or ProHance administration. 4. The UK Commission on Human Medicines in conjunction with the European Pharmacovigilance Party (4) published that, as of June 26, 2007, 180 cases of NSF worldwide had been reported with Omniscan and 78, with Magnevist (with one case in a patient who had received MultiHance and Omniscan.) Several cases have also been reported with OptiMARK in the United States. 5. The June 26, 2007, public assessment report issued by the Commission Published online before print 10.1148/radiol.2461071267