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Notice to Hospitals from the Bureau of Drug Surveillance

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Safety Warning Concerning Immune Globulin Intravenous (Human) Products (IGIV)

November 27, 1998

This is to inform you about a recent drug warning announcement made by the United States Food and Drug Administration (US FDA) on November 13, 1998 regarding safety precautions that should be taken to reduce the potential risk of ACUTE RENAL FAILURE (ARF) associated with the administration of Immune Globulin Intravenous (Human) products (IGIV). Please provide this notice to physicians who prescribe Immune Globulin Intravenous (Human) Products.

A total of 78 Canadian adverse drug reaction (ADR) reports concerning IGIV products have been received in Canada between 1965 and 1998. None of these reports implicate renal complications as an adverse effect of the IGIV products used in Canada. Several of the reports describe multiple reactions to IGIV products with the most common reactions reported as follows: fever (24); headache (16) nausea (14); vomiting (12); rigors (9); dizziness (8); rash (8); dyspnoea (7); pruritus (6); urticaria (6); anaphyactoid reaction or shock (6) and hepatitis transmission (1).

The US FDA reported having received over 114 worldwide adverse event reports of renal dysfunction and/or ARF, 17 of which resulted in death which may or may not have been caused by administration of IGIV products. Preliminary evidence suggests that IGIV products containing sucrose may present a greater risk for this complication. Hyperosmolality of certain reconstituted products, as well as differences in stabilizer sugar choice and content between different IGIV formulations may be among the factors that have contributed to different rates of renal dysfunction associated with adverse reaction reports related to the various IGIV products. The full report on this drug warning announcement can be found on the FDA website at http://www.fda.gov/medwatch/safety/1998/igiv.htm.

In the last 10 years, Health Canada has not released any lots of the IGIV products containing sucrose which were associated with the majority of the ARF associated adverse events reported in the U.S. FDA drug warning announcement (i.e. Sandoglobulin distributed by Novartis, Panglobulin distributed by the American Red Cross and Gammar, manufactured and distributed by Centeon). There may however, have been limited investigational use, or limited sale through Health Canada's Special Access Programme.

However, Health Canada supports the general recommendations made by the FDA that the following precautions be followed, regardless of the IGIV product being administered, to reduce the potential risk of ARF:

1. Assure that patients are adequately hydrated prior to the initiation of the infusion of IGIV.
2. Exercise particular caution in the administration of IGIV products in patients at increased risk for developing ARF. Such patients include, but are not limited to, those with:
   • any degree of pre-existing renal insufficiency;
   • diabetes mellitus;
   • age greater than 65;
   • volume depletion;
   • sepsis, paraproteinemia; and
   • concomitant nephrotoxic drugs
   For patients at increased risk, physicians should carefully weigh the potential benefits of administering sucrose-containing IGIV products against the risks of causing renal damage.
3. Do not exceed the manufacturers recommended dose as detailed in the Product Monograph. Reduction in dose, concentration, and/or rate of administration in patients at risk of ARF has been proposed in order to reduce the risk of ARF. Because no prospective data are presently available to identify a maximal safe dose, concentration, or rate of infusion for IGIV products for patients at risk of ARF, FDA recommends that, for such patients, prescribers reconstitute/dilute the product in such a manner as to produce both the minimum concentration and rate of infusion practicable. For sucrose-containing IGIV, a maximum infusion rate of 3 mg sucrose/kg/minute (2 mg Ig/kg/min for Sandoglobulin and Panglobulin; 3 mg Ig/kg/min for Gammar-P I.V) should not be exceeded.
4. Renal function, including urine output, blood urea nitrogen and serum creatinine, should be assessed prior to infusion of IGIV, particularly in patients judged to have a potential increased risk for developing ARF, and again at appropriate intervals. If renal function deteriorates, discontinuation of the product should be considered.

As with all therapeutic products, health care professionals are strongly encouraged to report all serious or unexpected adverse events that are associated with the use of IGIV's, including cases of ARF, to Health Canada. ADR reports may be sent to any of the Regional ADR Centres listed on the back of the Health Canada ADR report form or directly to Health Canada's Adverse Drug Reaction Monitoring Program either by FAX (1-613- 957-0335) or by mail to the following address: National ADR Reporting Unit, Continuing Assessment Division, Bureau of Drug Surveillance, Therapeutic Products Programme, AL 0201C2, Ottawa, Ontario. K1A 1B9.

Questions regarding this message can be directed to the ADR Reporting Unit, Bureau of Drug Surveillance, Therapeutic Products Programme at (613-957-0337).