Canadian Adverse Reaction Newsletter

Volume 16 • Issue 4 • October 2006

Health Products and Food Branch
Marketed Health Products Directorate

In this Issue:
BioGlue: chronic inflammation and foreign-body reactions
New tool for reporting adverse reactions
Physician reporting of adverse reactions
Case presentation: Atomoxetine and tics
Summary of advisories

Scope
This quarterly publication alerts health professionals to potential signals detected through the review of case reports submitted to Health Canada. It is a useful mechanism to disseminate information on suspected adverse reactions to health products occurring in humans before comprehensive risk-benefit evaluations and regulatory decisions are undertaken. The continuous evaluation of health product safety profiles depends on the quality of your reports.

Reporting Adverse Reactions
Contact Health Canada or a Regional AR Monitoring Office free of charge
Phone: 866 234-2345
Fax: 866 678-6789

Click here for the Adverse Reaction Reporting Form

Caveat: Adverse reactions (ARs) to health products are considered to be suspicions, as a definite causal association often cannot be determined. Spontaneous reports of ARs cannot be used to estimate the incidence of ARs because ARs remain underreported and patient exposure is unknown.

BioGlue Surgical Adhesive: reported incidents of chronic inflammation and foreign-body reactions

BioGlue is the commercial name of a surgical adhesive composed of bovine serum albumin (BSA) and glutaraldehyde.¹ The glutaraldehyde molecules covalently bond the BSA molecules to each other and, upon application, to tissue proteins at the repair site.² BioGlue was originally licensed for sale in Canada in 2000 for use in the repair of acute aortic dissections and pulmonary tissues. In 2003, its indication was expanded to include the repair of most other soft tissues. BioGlue is indicated for use as an adjunct to standard methods of surgical repair (e.g., sutures, staples, electrocautery and patches) to bond, seal or reinforce soft tissue.¹ It may also be applied alone to seal or reinforce damaged parenchyma when other procedures are ineffective or impractical.¹

From Jan. 1, 2000, to June 1, 2006, Health Canada received 13 domestic reports of adverse incidents suspected of being associated with BioGlue. All reports were received in 2004 and 2005. Seven of the reports described events consistent with ongoing inflammatory processes upon reoperation at sites where BioGlue had been used months earlier. In 4 of these 7 cases, BioGlue was suspected of contributing to a sterile discharge or persistent infection. In the other 3 cases, foreign-body reactions were reported that required the removal of BioGlue-containing masses at the surgical site. A short description of these 3 cases follows:

Case 1: A patient who received BioGlue to help seal dural tissue during a spinal procedure experienced recurring clear drainage over a period of months postoperatively. Upon reoperation, a cyst-like mass alleged to contain BioGlue was removed, and the patient recovered without further complication. The surgeon described the patient's experience as a foreign-body reaction to BioGlue.

Case 2: A patient received BioGlue to help repair dural leaks. During reoperation 5 months later for removal of spinal hardware, the wound area was explored, and the surgeon found and removed a firm, green inflammatory mass. The pathologist indicated that the mass was a matrix of BioGlue containing fragments of Gelfoam and that it appeared to be the result of a histologic foreign-body reaction.

Case 3: A patient who had received BioGlue during a spinal procedure to help repair a dural defect subsequently experienced pain at the site. Upon reoperation more than 4 months later, the BioGlue was found in place and attached to the dura, but a dural leak was evident and a dark green mass was removed. The pathologist stated that the mass contained BioGlue, displayed evidence of a florid foreign-body granulomatous reaction and may have caused a mechanical pain-stimulus effect on the adjacent nerve root.

Severe, active inflammation surrounding a BioGlue remnant with multiple granulocytes and histiocytes and a massive foreign-body reaction with numerous multinucleated giant cells has been reported at 3 months after BioGlue application.³ Intense, focal acute and chronic nongranulomatous inflammation has also been observed at a site where persistent concretions of BioGlue were identified 2 years after application.⁴

Although "inflammatory and immune response" is listed among the possible complications in the device labelling, resorption times are not discussed¹ and additional long-term studies would help to evaluate these effects.² The medical literature suggests that, even when BioGlue appears to yield a clear benefit, it should be used sparingly and its toxic potential should be considered.^2,4

Andrew Gaffen, BSc, DDS; Hui Zheng, MSc; Gina Coleman, MD, Health Canada

References

1. BioGlue Surgical Adhesive [Canadian instructions for use]. Kennesaw (GA): Cryolife, Inc.; 2004.
2. Furst W, Banerjee A. Release of glutaraldehyde from an albumin-glutaraldehyde tissue adhesive causes significant in vitro and in vivo toxicity. Ann Thorac Surg 2005;79(5):1522-9. [ PubMed]
3. Erasmi AW, Sievers HH, Wolschlager C. Inflammatory response after BioGlue application. Ann Thorac Surg 2002;73(3):1025-6. [ PubMed]
4. Ngaage DL, Edwards WD, Bell MR, et al. A cautionary note regarding long-term sequelae of biologic glue. J Thorac Cardiovasc Surg 2005;129(4):937-8. [ PubMed]

New tool for reporting adverse reactions to health products

Health Canada's MedEffect Web site has been updated to accept online transmittable reports of suspected adverse reactions (ARs) to health products marketed in Canada. Now, in addition to the previous reporting methods, including mailing reports or using the toll free fax or telephone numbers, health care professionals and consumers can submit reports of ARs online. Upon the online submission of a report, the system will generate a file that can be printed and stored electronically by the reporter. Information related to the identity of the patient and the reporter of the AR will be protected as per the Access to Information Act and the Privacy Act.

Underreporting of ARs is a well-known global issue. International studies have estimated that only 1%-10% of all ARs are reported. Health professionals have identified barriers to reporting that relate to the inconvenience and lack of user-friendliness of reporting. The new user-friendly online AR reporting form will make the process more convenient and should contribute to increased AR reporting.

Visit the MedEffect Web site to submit an AR report online and to view the latest advisories, AR information and other reporting initiatives.

Physician reporting of adverse reactions: continuing medical education

Health Canada, in collaboration with the Canadian Medical Association (CMA), developed a continuing medical education (CME) course entitled "Physician Reporting of Adverse (Drug) Reactions" to improve physicians' knowledge of the program and processes for reporting adverse reactions in Canada (see Box). This CME course was posted on CMA's physician Web portal as a 1-year pilot between May 27, 2005, and May 27, 2006.

A number of reference resources were made available via hyperlinks to Health Canada's MedEffect Web site. During the pilot period, extensive marketing of the course helped to raise physicians' collective awareness of reporting ARs to Health Canada.

Because of the quality of the program and the success of the working relationship, the CMA has decided to continue to make the course available on their Web portal until Health Canada requests its removal. Future steps for the online course include posting it on Health Canada's MedEffect Web site and pilot testing the course in the medical undergraduate curriculum. The latter initiative is being achieved with CMA's help by facilitating contact between Health Canada and the National Undergraduate eLearning Committee. If successful, this initiative will result in the course being made available to all undergraduate medical programs in the country.

Outside the medical community, the development of the online AR course has generated interest and requests for similar education initiatives from other health professions and consumers. An online module for naturopathic doctors has been posted on MedEffect (with a link from the Canadian Association of Naturopathic Doctors Web site to the learning centre section of MedEffect) and will be integrated into the Canadian College of Naturopathic Medicine's curriculum this fall. Another online module and corresponding guidebook to assist consumers and patients on how to report ARs to their health care professional or Health Canada will be made available on the MedEffect Web site.

Anyone wishing to provide comments or feedback on these education initiatives may contact Health Canada's Marketed Health Products Directorate.

How to report an adverse reaction?

There are multiple ways to report an adverse reaction (AR) to Health Canada. To report an AR, go to the AR Reporting page on MedEffect.

*The Adverse Reaction Reporting Form is also available in the CPS (Canadian Compendium of Pharmaceuticals and Specialties).