1. 1 Prevention of Dextran-Induced Anaphylactoid Reactions (DIAR) by Hapten Inhibition Laurence Landow MD, FRCPC Medical Officer Office of Blood Research and Review CBER, FDA

2. 2 Summary Slide Dextran 40 and Dextran 70 –Developed, manufactured, and marketed in Sweden since the late 1940s and licensed in the US since the 1950s –Rarely associated with life-threatening anaphylactoid reactions when given without hapten pre-administration Dextran 1 –Administration of the hapten, dextran 1 (Promit ® ), immediately before dextran 40 or 70 administration results in a 35-fold reduction in the incidence of anaphylactoid reactions and a 90-fold reduction in mortality

3. 3 Regulatory Background Dextran 40 –Approved 18-JAN-1967 –Thromboembolic prophylaxis –Volume resuscitation –CPB pump prime Dextran 70 –Approved 19-SEP-1952 –Volume resuscitation Anecdotal experience indicates that in the U.S., dextran is used primarily for thromboembolic prophylaxis by –Plastic surgeons (skin flaps) –Vascular surgeons (e.g., carotid endarterectomy)

4. 4 Chronology of Events 1950s and 1960s –Rare reports of severe hypotension, bronchospasm, and cardiac arrest 1970s –DIAR discovered to be triggered by pre-formed, circulating dextran- reactive IgG antibodies Occur naturally or by digestion of polysaccharide component of bacterial cell walls –In a canine model, pre-administration — but not simultaneous administration — of a small hapten, dextran 1, blocked IgG cross- linking and prevented DIAR 30-OCT-1984 –Promit® (dextran 1) approved for prophylaxis of DIAR

5. 5 Dextran 1 Labeling Indication –“Promit (dextran 1) is indicated for the prophylaxis of serious reactions in connection with the IV infusion of clinical dextran solutions” Clinical Pharmacology –“A retrospective 10 year review of severe reactions to dextran after the prophylactic use of hapten inhibition demonstrated a…35-fold reduction as compared to previous estimates” Warnings –“In a population of 70,000 patients, two severe adverse reactions were noted…The routine clinical use of Promit to date has involved only one fatal reaction… in a patient with pre-existing cardiac disease”

6. 6 The Issue at Hand Dextran 1 (Promit, Meda AB) was approved decades after Dextran 40/70 products were approved Current labeling for dextran products do NOT mention use of dextran 1 preinjection “…for the prophylaxis of serious reactions in connection with the IV infusion of clinical dextran solutions”

7. 7 FDA Adverse Event Reporting System (AERS) 1969-2005 –92 cases worldwide of DIAR (2 in 2005) 15 fatalities –66 cases in US of DIAR 10 fatalities

8. 8 Ways of Communicating Heightened Risk Dear Healthcare Professional Letters –Mailed warnings alone do not affect prescribing patterns –A letter accompanied by substantial internet and media coverage, and a campaign to inform pharmacy dispensing organizations of the warning resulted in a change in prescribing patterns Pharmacoepidemiol Drug Safety 2005;14:149 Pharmacoepidemiol Drug Safety 2001;10:211

9. 9 Ways of Communicating Heightened Risk Black Box Warning –“Designed to highlight special problems, particularly those that are serious… –Provide physicians with important insights as to how to prescribe a drug that may be associated with serious side effects in a way that maximizes its benefits and minimizes its risks.” FDA talk paper for Depo-Provera http://www.fda.gov/bbs/topics/ANSWERS/2004/ANS01325.html

10. 10 Question for the Committee 1.What revisions to the product labeling for Dextran 40 and Dextran 70 would be most appropriate to address the risk of DIAR and the relevance of pre-treatment with Dextran 1. In particular, please comment a. Whether a class labeling change is warranted b. What other forms of risk communication FDA should consider to alert the medical community about the risk of DIAR

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12. 12 DIAR Dextran-Induced Anaphylactoid Reactions

13. 13 Should DIAR be Classified as an Anaphylactoid or an Anaphylactic Event? 2 events clinically indistinguishable –Both are “explosive” in onset –Circulatory shock, malignant arrhythmias, severe bronchospasm, upper airway obstruction Caused by sudden and complete depletion of pre-formed mediators contained within mast cells/basophils Not dose-response phenomena

14. 14 Should DIAR be Classified as Anaphylactoid or Anaphylactic Event? Anaphylactic reactions –Initial antigen exposure, production of antigen-specific IgE, and binding of this IgE to mast cells/basophils –Upon re-exposure, IgE molecules become cross-linked –Cross-linking initiates a signal- transduction cascade and the release of cytotoxic mediators Anaphylactoid reactions –No prior antigen exposure –Mediator release and complement activation caused by “direct” antigen exposure to mast cells/basophils –May be antibody mediated (e.g., IgG), but not by IgE

15. 15 Severity Grades of DIAR Grade of SeverityCharacteristic Symptoms IErythema, urticaria, lumbar pain IIHypotension (BP>60 mmHg) responsive to fluid administration, SOB IIISevere hypotension (BP<60 mmHg) unresponsive to fluid administration, severe bronchospasm IVCardiac and/or respiratory arrest VFatal reaction Severe DIAR

16. 16 Incidence of Severe DIAR Before and After Licensing of Dextran 1* *Based on published articles 1982-1994

17. 17 Left panel: Without dextran 1, Dextran 40 cross-links dextran-reactive IgG molecules Right panel: With dextran 1, combining sites on IgG molecules are blocked Dextran 40 molecules dextran 1 molecules occupy combining sites and inhibit cross-linking Combining site of Dextran-reactive IgG IgG cross- linking via Dextran 40 ultimately leads to mast cell degranulation Dextran- reactive IgG