Ann Gaines, PhD, MT(ASCP) Division of Epidemiology Office of Biostatistics and Epidemiology

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 * manufactured by Cangene Corporation, Winnipeg, Manitoba, Canada

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 FDA’s 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