The FDA is asking health care professionals and patients to report possible cases of nephrogenic systemic fibrosis and nephrogenic fibrosing dermopathy through the MedWatch program by phone (800-FDA-1088) or by the Internet at www.fda.gov/medwatch/index.html.
Gadolinium-based contrast agents, when given to patients with renal disease, have been associated with a rare, potentially fatal, sclerodermalike skin disease called nephrogenic systemic fibrosis or nephrogenic fibrosing dermopathy.
On Dec. 22, the Food and Drug Administration issued a public health advisory stating that the agency has received reports of 90 patients with moderate to end-stage kidney disease who developed the new disease within 2 days to 18 months after they had magnetic resonance imaging (MRI) or magnetic resonance angiography (MRA) with a gadolinium-based contrast agent. Many—but not all—of these patients received a high dose of the contrast agent; some received only one dose, according to the FDA.
Nephrogenic fibrosing dermopathy (NFD) is marked by areas of tight, rigid skin and may progress to nephrogenic systemic fibrosis (NSF), which is associated with scarring of internal organs. Symptoms may include burning; itching; swelling; hardening and tightening of the skin; red or dark patches on the skin; yellow spots on the whites of the eyes; stiffness in joints, with trouble moving or straightening the arms, hands, legs, or feet; pain deep in the hip bones or ribs; and muscle weakness.
Worldwide, about 215 cases of NSF/NFD have been reported. The medical histories of 75 of these patients have been reviewed in detail, and all had received a gadolinium-based contrast agent. Gadolinium has been found in skin biopsies of affected patients, but the specific cause for the disease is not yet known.
The advisory recommends alternative imaging studies for patients with renal disease. When patients with renal disease must receive a gadolinium-based contrast agent, prompt dialysis following the MRI or MRA should be considered, the FDA statement said.
Reports of the new disease have been steadily increasing since April 2006, when two European hospitals reported 25 cases following Omniscan injection. These cases had accumulated over a period of 4 years. In June 2006, the FDA issued an initial advisory about the disorder. In its December advisory, the FDA said that cases have been associated with three of the five approved gadolinium-based contrast agents, but there is reason to believe that any of the approved agents could cause the disease. Dr. Emanuel Kanal, professor of radiology and neuroradiology at the University of Pittsburgh Medical Center, was one of several radiologists who reviewed concerns about the emerging disease at the annual meeting of the Radiological Society of North America in Chicago.
“Nearly 100% of the patients with known NSF were confirmed to have received a gadolinium-based MR contrast agent prior to the diagnosis being made. Of those, over 90% had received Omniscan, which is way out of proportion to Omniscan's market share,” said Dr. Kanal, who also is director of MR services at the medical center.
It has been estimated that 3%–5% of patients with renal disease who receive Omniscan injections develop NSF, he added. Fewer cases of NSF have been reported in patients who had been scanned using OptiMARK or Magnevist, and no cases have been linked to the remaining licensed agents, ProHance and MultiHance.
Dr. Henrick S. Thomsen stated: “It is striking that many radiologists were unaware that nephrogenic systemic fibrosis may be a serious late adverse reaction to gadolinium-based contrast media despite the fact that the Food and Drug Administration issued a warning on June 8” (Eur. Radiol. 2006;16:2619–21).
“Furthermore, the warning from the vendor of gadodiamide [GE Healthcare], … issued on June 6, 2006, had not been distributed in several countries [and] no other vendors have issued a warning,” said Dr. Thomsen, professor of radiology at Copenhagen University.
In a statement, GE Healthcare said the company is “concerned by this trend of a higher incidence of NSF concurrent with gadodiamide use, and we continue to urge caution in using Omniscan in renally compromised patients, consistent with our prescribing information. We are closely following reported cases and working with hospitals and experts in the field to conduct a thorough investigation. We are engaging with global regulatory authorities that are making further inquiries about the occurrence of this disease.”
The University of Pittsburgh has mandated that gadolinium contrast media not be used without a written prescription. “Even though this is a prescription drug, radiologists have not been doing this. If a referring physician requests a contrast-enhanced study on a patient with severe renal disease, we the radiologists have to decide whether that contrast administration is warranted on that patient after performing an appropriate risk-benefit assessment,” Dr. Kanal said.
Until more information becomes available, the association between gadolinium contrast media and NSF should be kept in perspective, cautioned Dr. Michael Brant-Zawadzki, noting that only a tiny percentage of patients undergoing contrast MRI have developed NSF. “The vast majority of gadolinium-enhanced studies are safe, and patients need not worry,” said Dr. Brant-Zawadzki, medical director of radiology at Hoag Memorial Hospital Presbyterian in Newport Beach, Calif.
A revised guidance document for safe MRI practices, written by Dr. Kanal and including a new section on NSF, is slated for publication in the American Journal of Roentgenology and on the American College of Radiology Web site early this year.
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