Summary Safety Review - Immunoglobulins - Risk of Blood Clots (Thrombosis)
Review decision
A Summary Safety Review complements other safety related information to help Canadians make informed decisions about their use of health products. Each summary outlines what was assessed in Health Canada’s review, what was found and what action was taken by Health Canada, if any.
Issued: 2014-10-09
issue
A safety review was initiated to examine the information in the Canadian product monograph on the risk of blood clots (thrombotic events) for all non-hyperimmune immunoglobulin products (referred to as immunoglobulins for the purpose of this summary). The review was prompted by the ongoing assessment of information regarding these products and this adverse event, including data provided by manufacturers, two scientific and medical publications as well as regulatory actions by the United States Food and Drug Administration (US-FDA).
Background
Approved use of Immunoglobulins in Canada
Immunoglobulin products contain human antibodies which are also present in blood. Antibodies help the body to fight infections. While there are different strengths and ways to administer them, immunoglobulins are generally used in patients who do not have enough antibodies in their blood and tend to get frequent infections (called Primary and Secondary Immune Deficiency). In addition, some products are used to treat specific conditions that affect the nervous system, conditions that can cause the immune system to attack the body (autoimmunity), blood cancers (leukemia), and a severe decline in the number of blood clotting cells (platelets) called immune thrombocytopenic purpura (ITP).
Thrombosis Risk in Immunoglobulins
Thrombosis (or blood clot) is a condition that results in a partial or complete blockage of blood flow, and can arise in a wide variety of ways and in any location in the body, including in the legs (deep vein thrombosis), the lungs (pulmonary embolism), the heart (myocardial infarction), and the brain (stroke). In many cases, thrombotic events may be life threatening.
The risk of thrombosis has been a known issue with some immunoglobulin products, and can occur regardless of immunoglobulin dose or route of administration (injection into a muscle, vein, or under the skin).
Objective
To assess available information regarding the risk of thrombosis (blood clots) for all immunoglobulin products, and to determine the need for updating the Canadian product information for all immunoglobulin products. The evidence considered Canadian and international adverse reaction reports, scientific and medical literature, as well as what is known about the use of these products both in Canada and internationally.
Key findings
Use of Immunoglobulins in Canada
The immunoglobulins are a large and diverse group of products derived from human blood and their use in clinical settings varies widely from region to region. Immunoglobulins are issued to hospitals in Canada by the Canadian Blood Services and Héma-Québec.
The following immunoglobulins are authorized for sale in Canada: Gammagard Liquid and Gammagard S/D; GamaSTAN; Gamunex; Hizentra; IGIVnex; Immune Serum Globulin (human); Octagam (5% and 10%); and Privigen.
Canadian reports of Thrombosis associated with the Immunoglobulins
At the time of this review, 19 cases in Canada were reported, all involving intravenous (injected into the vein) immunoglobulin products. Various thrombotic events were reported but there was no pattern in the type of thrombotic event.
Scientific reports
Two separate publications in 2012 and 2013 detailed the findings of the review of a large database. In both studies, it was found that the risk of thrombosis appeared to span all products and routes of administration. Although both studies had limitations, there was enough evidence to suggest the need for a closer examination of the Canadian product information for all immunoglobulin products.
Furthermore, additional data submitted by the manufacturers in Canada, as part of regular periodic review, was analyzed and also justified the need for updating the product information, for consistency.
In addition, as part of Health Canada's monitoring of international events, it was learned that in 2013, the US-FDA issued a Safety Communication that was based on the emergence of post-marketing reports as well as the review of the database. The US-FDA stated that thrombosis risks applied to all routes of administration. The proposed new labelling for these products would include strong warnings and specific information regarding the types of events that could occur and risk factors.
Conclusions and actions
Based on information reviewed, it was determined that there is enough evidence for updating the information for all immunoglobulin products.
The following actions have been undertaken by Health Canada:
- The Canadian product information for all immunoglobulin products has been updated to include a Boxed Warning and an updated Warnings and Precautions section with information regarding the risk of thrombosis, by describing the type of events that may occur as well as risk factors.
- A risk communication will be issued to inform Canadians about the risk of thrombosis with immunoglobulin products.
- Monitoring of thrombosis cases for all immunoglobulin products will continue, with a particular focus on the intramuscular and subcutaneous immunoglobulin products.
Health Canada will keep Canadians informed and take action, as appropriate, if any new safety information is identified.
References
- FDA Drug Safety Communication: FDA Safety Communication: New boxed warning for thrombosis related to human immune globulin products. Silver Spring (MD): US Food and Drug Administration; 2013 Nov 14. (accessed 2013 Nov 14).
- Daniel GW, Menis M, Sridhar G, et al. Immune globulins and thrombotic adverse events as recorded in a large administrative database in 2008 through 2010. Transfusion 2012;52(10):2113-21.
- Menis M, Sridhar G, Selvam N, et al. Hyperimmune globulins and same-day thrombotic adverse events as recorded in a large healthcare database during 2008-2011. Am J Hematol 2013;88(12):1035-40.
Footnotes
- This list of references is not intended to be exhaustive. References have been selected as suggestions for further reading and reflect the most current information at the time of the safety review.