1. Serious adverse events following falsely high glucose measurements resulting from administration of an IGIV product containing maltose L. Ross Pierce, M.D. Medical Officer, Clinical Review Branch, Div. of Hematology, FDA

2. Popularity and Pitfalls of Glucose Meter Testing – Adverse Drug/Device Interaction Point-of-care capillary blood glucose meters widely used in hospitals/clinics and at home. Test strips using Glucose Dehydrogenase Pyrrolo-Quinoline Quinone (GDH-PQQ) not specific for glucose – only some bear PRECAUTION in PI. Non-specific glucose test methods still inappropriately used in patients who are receiving parenteral maltose-containing products (some IGIVs)

3. Two Different Glucose Dehydrogenase Enzymes GDH-PQQ does not contain NAD – Uses EITHER glucose or maltose as substrates –Used in many test strip systems. NAD-dependent Glucose Dehydrogenase –Uses glucose but NOT maltose as substrate –Used in > 1 glucose meter test strip system.

4. BIOCHEMICAL, CHEMICAL, & ELECTROCHEMICAL REACTIONS THAT OCCUR DURING GDH-PQQ ASSAYS

5. BIOCHEMICAL, CHEMICAL, & ELECTROCHEMICAL OR COLORIMETRIC REACTIONS THAT OCCUR DURING GDH-PQQ ASSAYS

6. Relevant Redox Forms of PQQ

7. Enzyme Specificity (Maltose Interference)

8. Parenteral Maltose Causes False Hyperglycemia Results with which Test Systems? Maltose Interference –GDH-PQQ NAD-independent Point of Care Glucose Meters (Electrode) Point of Care Colorimetric systems (e.g.,”glucose-dye- oxidoreductase”) No PaO 2 effect No Maltose Interference –NAD-dependent GDH (no PaO 2 effect) –Hexokinase (low PaO 2 interferes) –Glucose Oxidase (low PaO 2 & mannitol > 5 mg/mL interfere)

9. Which IgG products contain maltose? Octagam 5% (Octapharma) Gamimune N 5% (Bayer/Talecris) WinRho SDF Liquid (Cangene) –No interference expected at labeled doses Vaccinia Immune Globulin (Cangene) –Only available through CDC –Interference expected at labeled doses

10. What recent actions has CBER taken in response to these adverse events? Formed CBER/CDRH working group Strengthen Labeling of maltose-containing IGIVs Asked sponsors to issue IMPORTANT DRUG WARNING letters to physicians, customers, and hospitals. Coordination with CDRH and CDER on Health Alerts for FDA websites and MEDWATCH Listservs. Drafting an article to be submitted widely- circulated medical journal(s).

11. Work with Sponsors Revise package inserts Re: potential for falsely elevated blood glucose results: –add a WARNING –strengthen PRECAUTIONS

12. New Class Labeling for Maltose- Containing IGIVs Labeling will indicate: –Some types of blood glucose testing systems (e.g. GDH-PQQ or “glucose-dye- oxidoreductase” methods) falsely interpret maltose as glucose. –This has resulted in inappropriate administration of insulin, resulting in life- threatening hypoglycemia.

13. Class Labeling for Maltose- Containing IGIVs (cont.) When administering maltose-containing IGIVs, use a glucose-specific method for measuring glucose. Carefully review the product information of the glucose testing system, including that of the test strips, to determine if the system is appropriate for use in patients receiving maltose-containing parenteral products. Contact the manufacturer of the test system if there is any uncertainty.

14. References (partial list): Medical Device Alert. Medicines and Healthcare Products Regulatory Agency. April 16, 2003. Kannan S et al. Intragam can interfere with blood glucose monitoring. MJA 2004;180:251-252 ISMP Medication Safety Alert! Sept 8 & 22, 2005. WWW.Octapharma.com/USA