Association of Omniscan (Gadodiamide) and Nephrogenic Systemic Fibrosis/Nephrogenic Fibrosing Dermopathy (NSF/NFD) - For Health Professionals

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Contact MHPD

March 7, 2007

Subject: Updated safety information on OmniscanTM and Nephrogenic Systemic Fibrosis/Nephrogenic Fibrosing Dermopathy (NSF/NFD)

Dear Healthcare Professional

GE Healthcare in consultation, with Health Canada would like to inform you of important updated safety information regarding Omniscan^TM (gadodiamide), a gadolinium-based Magnetic Resonance (MR) contrast agent. New cases of Nephrogenic Systemic Fibrosis/Nephrogenic Fibrosing Dermopathy (NSF/NFD) following Omniscan^TM exposure have been identified from post-market adverse event reports and the scientific literature.

On July 12, 2006, GE Healthcare Canada Inc., in consultation with Health Canada, issued a Dear Health Care Professional communication pertaining to the occurrence of 25 cases of NSF/NFD following Omniscan^TM (gadodiamide) injection. Of these, 23 cases were assessed by Health Canada as possibly caused by Omniscan^TM exposure and two cases were deemed unassessible.

Since July 2006, GE Healthcare has received reports indicating the occurrence of seventy-one additional cases of NSF associated with Omniscan^TM injection for MRA or MRI procedure. Of these, forty four cases occurred in the US and twenty-seven cases were reported from elsewhere. The majority of cases were in patients exposed to high doses of Omniscan^TM , although a few cases have been reported with a dose as low as 0.11 mmol/kg (^5,6). A recently published study has found that patients exposed to double doses of Omniscan^TM (0.2 mmol/kg) had 12.1 fold higher risk for developing NSF/NFD than patients who were exposed to a single dose of Omniscan^TM (0.1mmol/kg).⁴

NSF was first identified in 1997. To the present date the disease has only been observed in patients with impaired renal function. NSF/NFD is a systemic disorder with the most prominent and visible effects on the skin. It is associated with significant morbidity, may run a variable clinical course and sometimes lead to death. Cutaneous lesions are caused by excessive dermal fibrosis. These lesions are usually symmetrically distributed on the limbs and trunk. Involved skin becomes thickened with a woody texture and presents an increase in dermal fibroblast-like cells associated with collagen remodelling and mucin deposition. The fibrosis associated with NFD can extend beyond dermis and involve subcutaneous tissues, striated muscles, diaphragm, pleura, pericardium, and myocardium. The disease may develop over a period of a few days to several weeks. In many cases, the skin thickening inhibits flexion and extension of joints, resulting in severe contractures. The etiology of this disease remains unknown. Various concomitant factors such as metabolic acidosis¹ or vascular injury² may be related to the precipitation of NSF/NFD². A skin biopsy is necessary to make a definitive diagnosis of NSF/NFD.

Risk management measures

GE Healthcare and Health Canada will work jointly to update the Canadian prescribing information for Omniscan^TM in order to include this new information.

Healthcare professionals need to carefully consider the risks and benefits of performing MR with Omniscan^TM in patients with moderate to severe kidney disease.

In patients with end-stage kidney disease (GFR<15 mL/min/1.73m²) who need an imaging study, unenhanced MR procedure or an alternative imaging modality should be considered.

In patients with moderate kidney disease (GFR<60mL/min/1.73m²), gadolinium enhanced imaging should be used only if clinically essential and preferably at low doses.

The utility of dialysis for preventing or treating NSF/NSD in patients with impaired renal function has not been established. Average excretory rates of gadolinium during three consecutive hemodialysis sessions were 78%, 96%, and 99%, respectively³. However, prompt dialysis was not efficient to prevent the development of NSF/NFD in some patients, as recently described in the scientific literature ⁽⁴⁾.

This Dear Health Professional Communication is posted on the Health Canada website. GE Healthcare is closely following reported cases and working with hospitals and experts in the field to conduct a thorough investigation. GE Healthcare is engaging with Health Canada and other global regulatory authorities who are making further inquiries about the occurrence of this disease after the administration of Omniscan^TM.

Adverse event reporting

Managing marketed health product-related adverse reactions depends on health care professionals and consumers reporting them. Reporting rates determined on the basis of spontaneously reported post-marketing adverse reactions are generally presumed to underestimate the risks associated with health product treatments. Any cases of serious NSF/NFD or other serious or unexpected adverse reactions should be reported to the appropriate manufacturer or Health Canada. Serious or unexpected adverse events in patients receiving Omniscan^TM should be reported to GE Healthcare or Health Canada at the following addresses:

Sincerely,

original signed by

J. Sardi
General Manager
GE Healthcare Canada

References

1. T. Grobner. Gadolinium - a Specific Trigger for the Development of Nephrogenic Fibrosing Dermopathy and Nephrogenic Systemic Fibrosis. Nephrol Dial Transplant 2006; 21: 1104-1108
2. Cowper SE. Nephrogenic fibrosing dermopathy: the first six years. Curr. Opin. Rheum. 2003, 1:785-790
3. Saitoh T, Hayasaka K, Tanaka Y, Kuno T, Nagura Y. Dialyzability of gadodiamide in hemodialysis patients.1: Radiat Med. 2006 Jul;24(6):445-51
4. Broome DR, Girguis MS, Baron PW, Cottrell AC, Kjellin I, Kirk GA. Gadodiamide-Associated Nephrogenic Systemic Fibrosis: Why Radiologists Should Be Concerned. Am J Roentgenol. 2007 Feb;188:1-7
5. Khurana A, Runge VM, Narayanan M, Greene JF Jr, Nickel AE. Nephrogenic Systemic Fibrosis: A Review of 6 Cases Temporally Related to Gadodiamide Injection (Omniscan). Invest Radiol. 2007 Feb;42(2):139-145
6. Sadowski Elizabeth A, Benneth Lindsey K, Chan Micah R, Wentland Andrew L, Garrett Andrea L, Garrett Robert W, Djamali Arjan. Nephrogenic Systemic Fibrosis: Risk Factors and Incidence Estimation. Radiology 2007, 101148