Nephrogenic systemic fibrosis or nephrogenic fibrosing dermopathy (NSF/NFD)

Nephrogenic systemic fibrosis (NSF), previously known as nephrogenic fibrosing dermopathy (NFD) was first described in the medical literature in 2000, with the first reported case going back to 1997⁽¹⁾. NSF has only been reported in patients with severe renal impairment (glomerular filtration rate <30 mL/min/1.73 m²) and in patients with acute renal insufficiency of any severity, due to the hepato-renal syndrome or in the perioperative liver transplantation period. Signs and symptoms may include progressive thickening and induration of the skin with or without pigment alterations; contractures around the joints that may impair mobility; swelling (mostly of the lower extremities); redness; pruritus; and a burning sensation. Systemic involvement of organs such as the lung and the heart may also occur. In approximately 5% of patients the course of the disease is rapidly progressive and may potentially lead to a fatal outcome.

Based on current information, it appears that males and females are affected in approximately equal numbers, with onset generally during middle age although pediatric cases have also been reported. Currently, there is no known cure for NSF. Improving renal function seems to slow or arrest NSF and may even result in a gradual reversal.

The etiology of NSF is still unknown but is likely to be multifactorial. Specific triggers under scientific evaluation have included surgery and/or the occurrence of thrombosis or other vascular injury⁽²⁾, proinflammatory state⁽³⁾, the administration of high doses of erythropoietin⁽⁴⁾, and more recently the use of gadolinium-based contrast agents^(5,6,7,8).

On June 8, 2006, the FDA issued a Public Health Advisory titled "Gadolinium-containing Contrast Agents for Magnetic Resonance Imaging (MRI): Omniscan^®, OptiMARK^®, Magnevist^®, ProHance^®, and MultiHance^®", including the demand to report all adverse events via MedWatch to FDA on the occurrence of NSF/NFD in patients with severe renal impairment following CE-MRI with gadolinium-containing contrast agents. On December 22, 2006, the FDA issued updates to its Public Health Advisory on MRI Contrast Agents Containing Gadolinium and Nephrogenic Fibrosing Dermopathy, its Questions and Answers on Gadolinium-Containing Contrast Agents, and its Information for Healthcare Professionals on Gadolinium-Based Contrast Agents for Magnetic Resonance Imaging Scans.

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 NSF to the prescribing information for all gadolinium-based contrast agents marketed in the US, Omniscan^®, Magnevist^®, MultiHance^®, ProHance^® and OptiMARK^® (for detailed information see: http://www.fda.gov/cder/drug/InfoSheets/
HCP/gcca_200705.htm).

Bayer HealthCare submitted to FDA a revised Magnevist^® package insert with a boxed warning referring to the potential risk of Nephrogenic Systemic Fibrosis (NSF) in association with Gd contrast media in patients with:

• acute or chronic severe renal insufficiency (glomerular filtration rate <30 mL/min/1.73m²), or
• acute renal insufficiency of any severity due to the hepato-renal syndrome or in the perioperative liver transplantation period.

Since its approval in 1988 Magnevist^® has established a record as a safe and reliable contrast agent with over 90 million applications worldwide, in more than 100 countries, and has more than 14,000 citations in scientific publications.

As of April 1, 2008, Bayer HealthCare and its affiliates had received and evaluated 163 reports of patients who had reportedly developed NSF following Magnevist^® administration. For 92 of these reports, the currently available information is insufficient to establish a temporal association to Magnevist injection and/or confirm the diagnosis of NSF via skin biopsy and/or confirm that Magnevist was specifically administered. Consequently these 92 reports are currently considered as not assessable.

In approximately 27% of the reports of NSF in which Magnevist is identified either as the GBCA or as one of the GBCAs that the patient received, the time of the onset of signs and symptoms is unknown. In many of the remaining reports the time of onset dates back as much as several years. (See table 1)

The time span between the latest reported administration of MR contrast medium and the earliest reported occurrence of signs and symptoms suggestive of NSF ranged between several days and several years.

In 64 of the remaining 71 assessable reports, a possible association with Magnevist could not be excluded, based primarily on a temporal relationship between documented Magnevist administration and onset of signs and symptoms, lack of known alternative explanations, and confirmation of a diagnosis of NSF via skin biopsy. In 7 of the 71 assessable reports, an association with Magnevist is currently excluded.

Table 1: Onset of NSF signs and symptoms for all reports of patients who reportedly developed NSF following Magnevist^® administration, as of Apr 1, 2008

In the 64 reports of NSF in which a possible relationship to Magnevist^® could not be excluded, patient ages ranged from 27 to 81 years (median age = 59.5 years); 52 patients were on dialysis at the time of Magnevist^® administration (45 on hemodialysis and 7 on peritoneal dialysis; time on dialysis ranging from less than one year to 20 years); one patient had chronic kidney disease (CKD) with GFR < 30 ml/minute and initiated dialysis after Magnevist^® administration and one patient had end stage renal disease with failing kidney transplant. Eight patients had renal impairment/insufficiency not otherwise explained, and in two cases, the renal impairment status was not discussed.

The onset of NSF signs and symptoms of NSF reflected in these reports dates back to 2001 and earlier (See table 2).

Table 2: Onset of NSF signs and symptoms for reports of NSF in which a possible relationship to Magnevist^® could not be excluded, as of Apr 1, 2008

Investigations into these reports is ongoing, and new information will be presented to the Health Authorities as it becomes available.

Preclinical studies and interdisciplinary discussions with NSF experts are ongoing to investigate the possible relationship of NSF and Gd-containing contrast agents and to evaluate in more detail the pathogenesis of this disease entity and potential differences in risk among the various Gd-based MR contrast agents.

April 17, 2008

(1) Cowper SE, Robins HS, Steinberg HM, Su LD, Gupta S, Leboit PE; Scleromyxedema-like cutaneous diseases in renal-dialysis patients. Lancet 2000; 356: 1000-1001

(2) Cowper SE; Nephrogenic fibrosing dermopathy: the first 6 years. Curr Opin Rheumatol 15:785-790, 2003

(3) Sadowski EA, Bennett LK, Chan MR, Wentland AL, Garrett AL, Garrett RW, Djamali A. Nephrogenic Systemic Fibrosis: Risk Factors and Incidence Estimation. Radiology 2007, Published online before print January 31, 2007

(4) Swaminathan S, Ahmed I, Mc Carthy JT, Albright RC, Pittelkow MR, Caplice NM; Nephrogenic fibrosing dermopathy and high-dose erythropoietin therapy. Annals of Internal Medicine Vol. 145 No. 3, August 2004, 234-235

(5) Marckmann P, Skov L, Dupont A, Damholt MB, Heaf JG, Thomsen HS; Nephrogenic systemic fibrosis: suspected causative role of gadodiamide used for contrast- enhanced magnetic resonance imaging. J Am Soc Nephrol, August 2, 2006

(6) Thomsen HS. Nephrogenic systemic fibrosis: a serious late adverse reaction to gadodiamide. Eur Radiol. Epub 24 Oct 2006

(7) Broome DR, Girguis MS, Baron PW, Cottrell AC, Kjellin I, Kirk GA. Gadodiamide-associated nephrogenic systemic fibrosis: why radiologists should be concerned. AJR Am J Roentgenol. 2007 Feb;188(2):586-592

(8) 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

MAGNEVIST FAIR BALANCE STATEMENT:

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