1. 1 Serious Adverse Events Following Falsely Elevated Glucose Measurements Resulting from Administration of an IGIV Product Containing Maltose BPAC Meeting, Gaithersburg, MD, November 4, 2005

2. 2 Adverse Event Case Report Summary Ann Gaines, PhD, MT(ASCP) Division of Epidemiology Office of Biostatistics and Epidemiology Center for Biologics Evaluation and Research BPAC Meeting, Gaithersburg, MD, November 4, 2005

3. 3 Artifactual Hyperglycemia Falsely increased glucose results may occur in patients:  Who receive parenteral maltose-, parenteral galactose-, or oral d-xylose-containing biologic and drug products.  When blood glucose levels are measured by methodologies that are non-specific for glucose in presence of maltose-, galactose-, or d-xylose- containing products.

4. 4 Clinical Consequence Falsely elevated glucose results due to maltose, galactose, or d-xylose may result in life-threatening or fatal hypoglycemia when:  Insulin is inappropriately administered for artifactual hyperglycemia, e.g.,  glucose-non-specific methodology = 231 mg/dL, yet  glucose-specific methodology = 84 mg/dL.  Treatment is not provided for actual hypoglycemia, e.g.,  glucose-non-specific methodology = 167 mg/dL, yet  glucose-specific methodology = 41 mg/dL.

5. 5 Case Reports CBER is aware of 6 case reports involving maltose- containing intravenous immune globulin products and falsely elevated blood glucose measurements. Case Location Year Outcome 1 U.S. 2005Fatal 2 U.K. 2002Fatal 3 France 2003Resolved 4 France 2003Resolved 5 Australia 2004Resolved 6 Australia 2004Resolved

6. 6 Case Report 1 + 86-year-old male patient with complicated medical history, including diabetes. + Admitted with 4-day history of cellulitis of foot. + Received OCTAGAM* for treatment of septic shock. + Experienced complicated hospital course. + Monitored blood glucose levels [and adjusted insulin doses] primarily with glucose non-specific methodology. +Became hypoglycemic then comatose. +Expired. * IGIV manufactured by Octapharma; contains 10% maltose.

7. 7 Case Report 1 (continued) Blood glucose levels in conjunction with OCTAGAM administration

8. 8 Case Report 1 (continued) Blood glucose levels in conjunction with insulin administration

9. 9 Case Report 2 Reported to the Medicines and Healthcare Products Regulatory Agency (U.K.) in 2002: + 50-year-old diabetic male with failing pancreas-renal transplant received OCTAGAM as anti-rejection agent. + Based on artifactual hyperglycemia, inappropriate insulin administered. + Developed severe hypoglycemia, became comatose, expired.

10. 10 Case Reports 3 and 4 Reported to the French Health Products Safety Agency in 2003; both cases involved 3-week-old non-diabetic males: + Received OCTAGAM for unknown indications. + Developed artifactual hyperglycemia. + Recognized or resolved without intervention.

11. 11 Case Reports 5 and 6 Reported in Medical Journal of Australia in 2004: + 64-year-old diabetic female on dialysis received Intragam P* for ITP:  developed artifactual hyperglycemia.  increased insulin administered.  developed actual hypoglycemia.  resolved without apparent sequelae. + 35-year-old non-diabetic female on parenteral nutrition received Intragam P* for ITP:  developed artifactual hyperglycemia.  recognized and resolved without intervention. * IGIV manufactured by CSL Limited; contains 10% maltose

12. 12 Unknown Frequency of Adverse Event +FDA’s adverse event surveillance for licensed products uses primarily passive surveillance. +Limitations of passive surveillance systems, such as FDA’s MedWatch (e.g., voluntary reporting). +Actual incidence rate of artifactual hyperglycemia adverse event (e.g., occurrences per 100,000 patients) unknown. +Estimated reporting rate of artifactual hyperglycemia adverse event (e.g., reports per 1,000,000 prescriptions) unknown.

13. 13 Adverse Event Reporting Physicians, other health care professionals, and patients encouraged to submit serious adverse event reports for any FDA-approved product:  Directly to FDA:  by Internet at http://www.fda.gov/medwatch.http://www.fda.gov/medwatch  by telephone at 1-800-FDA-1088.  by fax at 1-800-FDA-0178.  by mail at MedWatch, HF-2, 5600 Fishers Lane, Rockville, MD 20852-9787. + To FDA through manufacturers or distributors: contact information generally available in professional package inserts or on web sites.