REOPRO SIDE EFFECTS

SIDE EFFECTS

Adverse Drug Reaction Overview

Bleeding

Bleeding was classified as major or minor by the criteria of the Thrombolysis in Myocardial Infarction (TIMI) study group. Major bleeding events were defined as either an intracranial hemorrhage or decrease in hemoglobin greater than 5 g/dL. Minor bleeding events included spontaneous gross hematuria or hematemesis or observed blood loss with a hemoglobin decreasing more than 3 g/dL or with a decrease in hemoglobin of at least 4 g/dL with no observed blood loss.

In the EPIC trial, in which a non-weight-adjusted, standard heparin dose regimen was used, the most common complication during ReoPro^® (abciximab) therapy was bleeding during the first 36 hours. The incidences of major bleeding, minor bleeding and transfusion of blood products were approximately doubled. Approximately 70% of ReoPro^®-treated patients with major bleeding had bleeding at the arterial access site in the groin. ReoPro^®-treated patients also had a higher incidence of major bleeding events from gastrointestinal, genitourinary, retroperitoneal, and other sites.

In a subsequent clinical trial, EPILOG, using the heparin and ReoPro^® dosing, sheath removal and arterial access site guidelines described under, the incidence of major bleeding in patients treated with ReoPro^® and low-dose, weight-adjusted heparin (1.8%) was not significantly different from patients receiving placebo (3.1%) and there was no significant increase in the incidence of intracranial hemorrhage. The reduction in bleeding observed in the EPILOG trial was achieved without loss of efficacy.

The rates of major bleeding, minor bleeding and bleeding events requiring transfusions in the EPIC, CAPTURE and EPILOG trials are shown in Table 1.

Table 1: Non-CABG Bleeding in the EPIC, EPILOG and CAPTURE Trials Number of Patients with Bleeds (%)

Although data are limited, ReoPro^® treatment was not associated with excess major bleeding in patients who underwent CABG surgery. Some patients with prolonged bleeding times received platelet transfusions to correct the bleeding time prior to surgery.

The total incidence of intracranial hemorrhage and non-hemorrhagic stroke across all three trials was similar, 7/2225 (0.31%) for placebo patients and 10/3112 (0.32%) for ReoPro^®-treated patients. The incidence of intracranial hemorrhage was 0.13% in placebo patients and 0.19% in ReoPro^® patients.

Pulmonary hemorrhage with fatal outcome following administration of ReoPro^® has been reported. In many cases, patients received at least two co-suspect or concomitant medications such as heparin or aspirin. Although the outcomes of most cases were not provided, approximately 2/3 had fatal outcomes. Based on exposure data, the reporting rate for pulmonary hemorrhage is less than 1 case report per 10,000 patients.

Thrombocytopenia

In the clinical trials, patients treated with ReoPro^® were more likely than patients treated with placebo to experience decreases in platelet counts. The overall rates of thrombocytopenia (platelet counts < 100,000 cells/μL) in the EPIC, EPILOG and CAPTURE trials were 0.5% for placebo-treated patients and 2.9% for patients receiving ReoPro^® bolus plus infusion. The incidence of thrombocytopenia was lowest in the EPILOG trial (placebo: 1.5%; ReoPro^® and standard-dose, weight-adjusted heparin: 2.6%; ReoPro^® and low-dose, weight-adjusted heparin: 2.5%). The lowest rates of platelet transfusions in ReoPro^®-treated patients were also observed in the EPILOG trial, (placebo: 1.1%; ReoPro^® and standard-dose, weight-adjusted heparin: 1.6%; ReoPro^® and low-dose, weight-adjusted heparin: 0.9%).

In a readministration registry study of patients receiving a second or subsequent exposure to ReoPro^® the incidence of any degree of thrombocytopenia was 5%, with an incidence of profound thrombocytopenia of 2% (<20,000 cell/μL). Factors associated with an increased risk of thrombocytopenia were a history of thrombocytopenia on previous ReoPro^® exposure, readministration within 30 days, and a positive HACA assay prior to the readministration.

Among 14 patients who had thrombocytopenia associated with a prior exposure to ReoPro^®, 7 (50%) had recurrent thrombocytopenia. In 130 patients with a readministration interval of 30 days or less, 25 (19%) developed thrombocytopenia. Severe thrombocytopenia occurred in 19 of these patients. Among the 71 patients who had a positive HACA assay at baseline, 11 (15%) developed thrombocytopenia, 7 of which were severe.

Human Antichimeric Antibody (HACA)

Human antichimeric antibody (HACA) may appear in response to the administration of ReoPro^®. In the EPIC, EPILOG, and CAPTURE trials, positive responses occurred in approximately 5.8% of the ReoPro^®-treated patients. There was no excess of hypersensitivity or allergic reactions related to ReoPro^® treatment compared with placebo treatment..

In a study of readministration of ReoPro^® to patients the overall rate of HACA positivity prior to the readministration was 6% and increased postreadministration to 27%. Among the 36 subjects receiving a fourth or greater ReoPro^® exposure, HACA positive assays were observed post-readministration in 16 subjects (44%). There were no reports of serious allergic reactions or anaphylaxis. HACA positive status was associated with an increased risk of thrombocytopenia.

The data reflect the percentage of patients whose test results were considered positive for antibodies to ReoPro^® using an ELISA assay, and are highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody positivity in an assay may be influenced by several factors including sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to ReoPro^® with the incidence of antibodies to other products may be misleading.

Clinical Trial Adverse Drug Reactions

Because clinical trials are conducted under very specific conditions the adverse reaction rates observed in the clinical trials may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug. Adverse drug reaction information from clinical trials is useful for identifying drug-related adverse events and for approximating rates.

Table 2 below shows adverse drug reactions other than bleeding, intracranial hemorrhage and thrombocytopenia from the combined EPIC, EPILOG and CAPTURE trials which occurred in ≥1% of patients in either the ReoPro^® or placebo treatment arms.

Table 2: Adverse Drug Reactions Among Treated Patients in the EPIC, EPILOG and CAPTURE Trials

Less Common Clinical Trial Adverse Drug Reactions (<1%)

General disorders and administration site conditions: Injection site reaction

Immune system disorders: Allergic reactions

Post-Market Adverse Drug Reactions

Cases of anaphylaxis, sometimes fatal, have been very rarely observed and reported following marketing of ReoPro^®. Gastrointestinal hemorrhage has also been very rarely reported following marketing of ReoPro^®. Cases of fatal bleeding have been rarely reported following marketing of ReoPro^®.