Disseminated Intravascular Coagulation Associated with Acute Hemoglobinemia andor Hemoglobinuria fol

1
Disseminated Intravascular Coagulation Associated
with Acute Hemoglobinemia and/or Hemoglobinuria
following Rho(D) Immune Globulin Intravenous
Administration for Immune Thrombocytopenic
Purpura

• Ann Gaines, PhD, MT(ASCP)
• Division of Epidemiology
• Office of Biostatistics and Epidemiology
• Center for Biologics Evaluation and Research

BPAC Meeting, Gaithersburg, MD, July 21, 2005
2

• Licensure
• Rho(D) Immune Globulin Intravenous (Human)
• (anti-D IGIV) licensed on March 24, 1995
• Licensed as WinRho currently marketed as
• WinRho SDF
• Licensed for
• ? suppression of Rh isoimmunization
• ? treatment of immune thrombocytopenic
  purpura
• (ITP) in Rho(D)-positive,
  non-splenectomized
• ? children with acute ITP
• ? children and adults with chronic ITP
• ? children and adults with ITP secondary to
  HIV infection

3

• Product Description
• As listed in professional package insert, anti-D
  IGIV contains known red blood cell (RBC)
  antibodies
• ? high-titered anti-D
• low-titered anti-A, anti-B, anti-C, and anti-E
• As reported in literature in 2000, anti-D IGIV
  may also contain other low-titered RBC antibodies
  (e.g., anti-Duffya anti-Fya, anti-Kidda
  anti-Jka)

4

• Presumed Mechanism of Action in ITP
• Extravascular hemolysis of anti-D-sensitized RBCs
  by
• splenic macrophages, which results in
• ? decreased splenic destruction of platelets
• ? increased platelet count
• Expected adverse events, consistent with
• extravascular hemolysis mechanism of action,
  may include
• ? decreased hemoglobin concentration
• ? positive direct and indirect antiglobulin
  tests

5

• Postmarketing Surveillance
• Routine postmarketing surveillance has detected 2
• serious, unexpected anti-D IGIV adverse
  events since
• licensure
• ? serious (as defined by FDA) includes
  life-threatening,
• medical intervention, among other
  criteria
• ? unexpected (as defined by FDA) not listed
  in
• professional package insert
• Both adverse events involve administration of
  anti-D IGIV
• for treatment of ITP
• ? acute hemoglobinemia and/or hemoglobinuria
• ? disseminated intravascular coagulation
  (DIC)

6

• Hemoglobinemia and/or Hemoglobinuria
• Clinical trials of anti-D IGIV for ITP identified
  2 cases of acute-onset hemoglobinuria consistent
  with intravascular hemolysis
• Between licensure and present, cases suggestive
  of acute hemoglobinemia and/or hemoglobinuria
  (acute hemolysis) submitted to FDAs adverse
  event reporting system, MedWatch
• (continued)

7

• Hemoglobinemia and/or Hemoglobinuria
• Cases of acute hemolysis received by FDA through
  April
• 1999 included 15 patients, 11 of whom had
  complications
• 7 developed sufficient anemia to prompt orders
  for packed RBC transfusions only 6 transfused
• 8 had onset or worsening of renal insufficiency
• 2 underwent dialysis
• 1 died from pulmonary edema and respiratory
  distress secondary to exacerbated anemia
• 6 had 2-3 of these complications
• (continued)

8

• Hemoglobinemia and/or Hemoglobinuria
• Review of those 15 cases suggested that acute
  hemolysis
• Seemed inconsistent with extravascular hemolysis
• mechanism of action in ITP patients
• Seemed consistent with intravascular hemolysis of
  
• acute hemolytic transfusion reactions
• Remains unexplained in terms of immune-mediated
  or
• other mechanisms of hemolysis
• (continued)

9

• Hemoglobinemia and/or Hemoglobinuria
• Risk communication efforts undertaken
• Cases reported in Blood on April 15, 2000, with
• suggestion that patients be monitored for
• ? acute hemolysis, clinically compromising
  anemia,
• and renal insufficiency
• ? other potential complications of
  hemoglobinemia,
• notably DIC
• Revisions to professional package insert
• distributed by manufacturer with Dear
  Healthcare
• Professional letter
• (continued)

10

• Disseminated Intravascular Coagulation
• Clinical trials of anti-D IGIV for ITP identified
  no reports of DIC (or any complications)
  associated with 2 cases of acute-onset
  hemoglobinuria consistent with intravascular
  hemolysis
• Between licensure and present, cases of DIC
  associated with acute hemolysis submitted to
  MedWatch
• (continued)

11

• Disseminated Intravascular Coagulation
• Cases of DIC received by FDA between May 1999 and
  
• November 2004 included 6 patients
• 5 died, with DIC or acute hemolysis assessed as
  having caused or contributed to each death
• 4 had onset or worsening of renal insufficiency
  2 underwent dialysis
• 4 developed sufficient anemia to prompt packed
  RBC transfusions
• 5 had 2-4 of these complications
• (continued)

12

• Disseminated Intravascular Coagulation
• Review of those 6 cases suggested that
• DIC seemed consistent with recognized, potential
• complication of acute hemolysis
• ? Previous uneventful anti-D IGIV administration
  does not preclude acute hemolysis upon subsequent
  anti-D IGIV administration
• (continued)

13

• Disseminated Intravascular Coagulation
• Risk communication efforts undertaken or in
  progress
• Cases published online in Blood on May 5, 2005,
• with suggestion that patients experiencing
  acute
• hemolysis be monitored for DIC
• Appropriate revisions to professional package
  insert
• under consideration
• print version scheduled to be published on
  September 1, 2005

14

• Adverse Event Reporting
• Physicians, other health care professionals, and
• patients encouraged to submit serious adverse
  event
• reports for anti-D IGIV or any FDA-approved
  product
• ? to FDA
• ? by Internet at 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 manufacturers or distributors contact
  information generally available in professional
  package inserts or on web sites