Prevention of Dextran-Induced Anaphylactoid Reactions (DIAR) by Hapten Inhibition

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Prevention of Dextran-Induced Anaphylactoid
Reactions (DIAR) by Hapten Inhibition

• Laurence Landow MD, FRCPC
• Medical Officer
• Office of Blood Research and Review
• CBER, FDA

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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

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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)

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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

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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 a35-fold
  reduction as compared to previous estimates
• Warnings
• In a population of 70,000 patients, two severe
  adverse reactions were notedThe routine clinical
  use of Promit to date has involved only one fatal
  reaction in a patient with pre-existing cardiac
  disease

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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

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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

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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 200514149
Pharmacoepidemiol Drug Safety 200110211
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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/ANS0132
5.html
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Question for the Committee

• 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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DIAR

• Dextran-Induced Anaphylactoid Reactions

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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

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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

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Severity Grades of DIAR
Grade of Severity Characteristic Symptoms
I Erythema, urticaria, lumbar pain
II Hypotension (BPgt60 mmHg) responsive to fluid administration, SOB

III Severe hypotension (BPlt60 mmHg) unresponsive to fluid administration, severe bronchospasm
IV Cardiac and/or respiratory arrest
V Fatal reaction
Severe DIAR
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Incidence of Severe DIAR Before and After
Licensing of Dextran 1
Based on published articles 1982-1994
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Dextran 40 molecules
dextran 1 molecules occupy combining sites and
inhibit cross-linking
IgG cross-linking via Dextran 40 ultimately leads
to mast cell degranulation
Dextran- reactive IgG
Combining site of Dextran-reactive IgG
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