Notice to Hospitals - Association of gadolinium-containing contrast agents and Nephrogenic Systemic Fibrosis /Nephrogenic Fibrosing Dermopathy (NSF/NFD)

Starting date:

March 9, 2007

Posting date:

March 13, 2007

Type of communication:

Notice to Hospitals

Subcategory:

Drugs

Source of recall:

Health Canada

Audience:

Healthcare Professionals

Identification number:

RA-170001605

Notice about Health Canada advisories

Notice to Hospitals - Health Canada Issued Important Safety Information on Gadolinium-Containing Contrast Agents

March 9, 2007

To: Hospital Chief of Medical Staff

Please distribute to Departments of Radiology, Nephrology, Emergency Medicine, Internal Medicine, Nursing, Intensive Care and other involved professional staff and post this NOTICE in your institution.

Subject: Association of Nephrogenic Systemic Fibrosis/Nephrogenic Fibrosing Dermopathy (NSF/NFD) with the Use of Gadolinium-Containing Contrast Agents

Health Canada is informing you of international post-market case reports of Nephrogenic Systemic Fibrosis/Nephrogenic Fibrosing Dermopathy (NSF/NFD) associated with the use of Gadolinium (Gd)-Containing Contrast Agents for Magnetic Resonance (MR) procedures.

The NSF/NFD cases have been reported in association with three Gd-containing contrast agents, gadodiamide (Omniscan™), gadopentetate dimeglumine (Magnevist^®) and gadoversetamide (Optimark^®). The majority of cases have been reported following an exposure to Omniscan™ (96 cases). Eleven reported cases were from patients possibly exposed to Magnevist^® and two cases following exposure to Optimark^®. To date, no cases have been reported for other Gd-containing contrast agents.

This notice applies to the following contrast agents authorized for sale in Canada:

NSF was first identified in 1997 and has so far, been observed only in patients with renal disease. This is a systemic disorder with the most prominent and visible effects on the skin. Cutaneous lesions associated with this disorder are caused by excessive fibrosis and are usually symmetrically distributed on the limbs and trunk. Involved skin becomes thickened which may inhibit flexion and extension of joints and result in severe contractures. The fibrosis associated with NSF can extend beyond dermis and involve subcutaneous tissues, striated muscles, diaphragm, pleura, pericardium, and myocardium. NSF/NFD may be fatal by restricting effective ventilation, or by restricting mobility to the point of causing a fall¹. The diagnosis of NSF/NFD is difficult, mainly due to a lack of familiarity of the health professionals with respect to this relatively new clinical entity. A skin biopsy is necessary in order to exclude the diagnosis of similarly presenting skin disorders (e.g scleromyxedema).

• To date, a total of 109 cases of NSF/NFD have been reported worldwide in association with the use of three Gd-containing contrast agents: Omniscan™, Magnevist^® and Optimark^®.
• NSF/NFD development is considered a potential class-related effect of all Gd-containing contrast agents.
• All patients with NSF/NFD had moderate to advanced renal disease. Patients with end-stage renal disease (GFR<15 mL min 1.73m^{2) constitute the vast majority of patients who developed NSF/NFD following the administration of Gd-containing contrast agents.}
• There are no reported cases of NSF/NFD in Canada at this time.
• In patients with end-stage kidney disease (GFR<15 mL min 1.73m^{2) who need an imaging study, unenhanced MR procedure or an alternative imaging modality should be used.}
• In patients with moderate kidney disease (GFR<60ml min 1.73m^{2), Gd-enhanced imaging should be used only if clinically essential and preferably at lowest approved dosage.}
• Dialysis did not prevent the development of NSF/NFD in some patients, as recently described in the scientific literature⁵.

To date, all patients with NSF/NFD had compromised renal function with the underlying renal disease varying among patients. The majority of patients were receiving dialysis. In many of the observed NSF/NFD cases, renal impairment was accompanied by various concomitant diseases such as vascular and/or liver disease, both of which have been suggested to contribute towards the development of NSF/NFD. A high percentage of patients who have developed NSF/NFD have been exposed to high doses of Gd-containing contrast agents (doses 2-3 fold higher than the currently labelled dose). However, cases of NSF/NFD have also been reported in association with the currently labelled dose of Gd-containing contrast agents².

Although a causative relationship between Gd chelates and NSF has not been definitively established, the following constitutes evidence suggesting that such a relationship may exist:

• There is a plausible temporal relationship between the development of NSF/NFD and the use of Gd -containing contrast agents^2-5;
• A strong association between the use of Gd-containing contrast agents and NSF/NFD development was reported in two observational studies (odds ratio of 32.5 and 22.3 respectively)^{4, 5};
• There is evidence of a dose-response relationship. A recently published study has found that patients exposed to 0.2 mmol/kg of gadodiamide had 12.1 fold higher odds of developing NSF/NFD than patients exposed to 0.1mmol/kg of gadodiamide⁴.
• Detection of gadolinium in the skin, soft tissue and blood vessel walls of NSF/NFD patients^{6, 7};
• A biologically plausible mechanism whereby Gd-based contrast agents may be contributing to the development of NSF/NFD in patients with renal disease is described in the scientific literature^8-10.

Health Canada will be working with the marketing authorization holders of the Gd-containing contrast agents to update the Canadian prescribing information for these agents.

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-market adverse reactions are generally presumed to underestimate the risks associated with health product treatments. Any case of NSF/NFD should be reported to Health Canada at the following addresses:

Any suspected adverse incident can be reported to:
Canadian Adverse Drug Reaction Monitoring Program (CADRMP)
Marketed Health Products Directorate
HEALTH CANADA
Address Locator: 0701C
OTTAWA, Ontario, K1A 0K9
Tel: (613) 957-0337 or Fax: (613) 957-0335
To report an Adverse Reaction, consumers and health professionals may call toll free:
Tel: 866 234-2345
Fax: 866 678-6789
cadrmp@hc-sc.gc.ca

The AR Reporting Form and the AR Guidelines can be found on the Health Canada web site or in The Canadian Compendium of Pharmaceuticals and Specialties.

For other inquiries related to this communication, please contact Health Canada at:
Marketed Health Products Directorate (MHPD)
Email: mhpd_dpsc@hc.gc.ca
Tel: (613) 954-6522
Fax: (613) 952-7738