ReoPro

Description for ReoPro

Abciximab, ReoPro®, is the Fab fragment of the chimeric human-murine monoclonal antibody 7E3. Abciximab binds to the glycoprotein (GP) IIb/IIIa receptor of human platelets and inhibits platelet aggregation. Abciximab also binds to the vitronectin (α_vβ₃) receptor found on platelets and vessel wall endothelial and smooth muscle cells.

The chimeric 7E3 antibody is produced by continuous perfusion in mammalian cell culture. The 47,615 dalton Fab fragment is purified from cell culture supernatant by a series of steps involving specific viral inactivation and removal procedures, digestion with papain and column chromatography.

ReoPro® is a clear, colorless, sterile, non-pyrogenic solution for intravenous (IV) use. Each single use vial contains 2 mg/mL of Abciximab in a buffered solution (pH 7.2) of 0.01 M sodium phosphate, 0.15 M sodium chloride and 0.001% polysorbate 80 in Water for Injection. No preservatives are added.

Uses for ReoPro

ReoPro^® (abciximab) is indicated as an adjunct to percutaneous coronary intervention for the prevention of cardiac ischemic complications:

• in patients undergoing percutaneous coronary intervention.
• in patients with unstable angina not responding to conventional medical therapy when percutaneous coronary intervention is planned within 24 hours.

ReoPro^® use in patients not undergoing percutaneous coronary intervention has not been studied.

ReoPro^® is intended for use with acetylsalicylic acid and heparin and has been studied only in that setting.

Geriatrics (> 65 Years Of Age)

See WARNINGS AND PRECAUTIONS, Special Populations, Geriatrics

Pediatrics (< 18 Years Of Age)

See WARNINGS AND PRECAUTIONS, Special Populations, Pediatrics

Dosage for ReoPro

Dosing Considerations

• The safety and efficacy of ReoPro^® (abciximab) have only been investigated with concomitant administration of heparin and acetylsalicylic acid.
• Acetylsalicylic acid should be administered orally at a daily dose of 300 to 325 mg.
• For heparin anticoagulation guidelines see WARNINGS AND PRECAUTIONS, Bleeding Precautions, Heparin.
• In patients with failed PTCAs, the continuous infusion of ReoPro^® should be stopped because there is no evidence for ReoPro^® efficacy in that setting.
• In the event of serious bleeding that cannot be controlled by compression, ReoPro^® and heparin should be discontinued immediately (see WARNINGS AND PRECAUTIONS, Restoration of Platelet Function).

Recommended Dose And Dosage Adjustment

Adults

The recommended dose of ReoPro^® is a 0.25 mg/kg intravenous bolus followed by a 0.125 μg/kg/min (to a maximum of 10 μg/min) continuous intravenous infusion.

For the stabilization of unstable angina patients, the bolus dose followed by the infusion should be started up to 24 hours prior to the possible intervention.

For the prevention of ischemic cardiac complications in patients undergoing PCI, and who are not currently receiving a ReoPro^® infusion, the bolus should be administered 10-60 minutes prior to the intervention, followed by the infusion for twelve (12) hours.

Administration

1. Parenteral drug products should be inspected visually for particulate matter prior to administration. Preparations of ReoPro^® containing visibly opaque particles should NOT be used.
2. Hypersensitivity reactions should be anticipated whenever protein solutions such as ReoPro^® are administered. Epinephrine, dopamine, theophylline, antihistamines and corticosteroids should be available for immediate use. If symptoms of an allergic reaction or anaphylaxis appear, the infusion should be stopped and appropriate treatment given.
3. As with all parenteral drug products, aseptic procedures should be used during the administration of ReoPro^®.
4. Withdraw the necessary amount of ReoPro^® for bolus injection into a syringe. Filter the bolus injection using a sterile, non-pyrogenic, low protein-binding 0.2 or 0.22 μm filter.
5. Withdraw the necessary amount of ReoPro^® for the continuous infusion into a syringe. Inject into an appropriate container of sterile 0.9% saline or 5% dextrose and infuse at the calculated rate via a continuous infusion pump. The continuous infusion should be filtered either upon admixture using a sterile, non-pyrogenic, low protein-binding 0.2 or 0.22 μm syringe filter or upon administration using an in-line, sterile, non-pyrogenic, low protein-binding 0.2 or 0.22 μm filter.
6. Discard the unused portion at the end of the infusion.
7. Although incompatibilities have not been observed with intravenous infusion fluids or commonly used cardiovascular drugs, it is recommended that ReoPro^® be administered in a separate intravenous line whenever possible and not mixed with other medications.
8. No incompatibilities have been observed with glass bottles or polyvinyl chloride bags and administration sets.

HOW SUPPLIED

Dosage Forms, Composition And Packaging

ReoPro^® (abciximab) is available in solution for intravenous injection and supplied in a 5 mL (10 mg) vial in packages of single vials. The vial stopper is free of natural rubber latex.

Each mL contains 2 mg of abciximab in a buffered solution (pH 7.2) of 0.01 M sodium phosphate, 0.15 M sodium chloride and 0.001% polysorbate 80. No preservatives are added.

Storage And Stability

Vials should be stored at 2 to 8°C (36 to 46°F). Do not freeze. Do not shake. Do not use beyond the expiration date. Discard any unused portion left in the vial.

Drug Substance

Proper name: abciximab (ReoPro^®)

Chemical name: abciximab

Molecular mass: 47,615 daltons

Physicochemical properties: ReoPro^® is a clear, colourless, sterile, non-pyrogenic solution for intravenous (IV) use.

Product Characteristics

ReoPro^® (abciximab) is a chimeric Fab fragment that binds to platelet glycoprotein IIb/IIIa. Abciximab is generated by papain cleavage of the intact chimeric monoclonal antibody 7E3 comprising antigen-binding variable regions of murine monoclonal antibody 7E3 and constant regions of human IgG_1κ.

REFERENCES

10. Coller BS, Folts JD, Scudder LE, Smith SR. Antithrombotic effect of a monoclonal antibody to the platelet glycoprotein IIb/IIIa receptor in an experimental animal model. Blood 1986;68:783-786.

11. Coller BS, Folts JD, Smith SR, Scudder LE, Jordan R. Abolition of in vivo platelet thrombus formation in primates with monoclonal antibodies to the platelet GPIIb/IIIa receptor. Circ 1989;80:1766-1773.

12. Sherman CT, Litvock F, Grundfest W, Lee M, Hickey A, Chaux A, Kass R, Blanche C, Matloff J, Morgenstern L, Ganz W, Swan HJC, Forrester J. Coronary angioscopy in patients with unstable angina pectoris. N Eng J Med 1986;315:913-919.

Prepared by Janssen Inc. Toronto, Ontario M3C 1L9. Revised: June 2019

Side Effects for ReoPro

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 WARNINGS AND PRECAUTIONS, 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 (%)

	EPIC:
	Placebo (n=696)	ReoPro® (Bolus+Infusion) (n=708)
Majora	23 (3.3)	75 (10.6)
Minor	64 (9.2)	119 (16.8)
Requiring Transfusionb	14 (2.0)	55 (7.8)
	CAPTURE:
	Placebo (n=635)	ReoPro® (n=630)
Majora	12 (1.9)	24 (3.8)
Minor	13 (2.0)	30 (4.8)
Requiring Transfusionb	9 (1.4)	15 (2.4)
	EPILOG:
	Placebo + Std-dose Heparin (n=939)	ReoPro® + Std-dose Heparin (n=918)	ReoPro® + Lowdose Heparin (n=935)
Majora	10 (1.1)	17 (1.9)	10 (1.1)
Minor	32 (3.4)	70 (7.6)	37 (4.0)
Requiring Transfusionb	10 (1.1)	7 (0.8)	6 (0.6)
aPatients who had bleeding in more than one classification are counted only once according to the most severe classification. Patients with multiple bleeding events of the same classification are also counted once within that classification. bPacked red blood cells or whole blood

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. (see WARNINGS AND PRECAUTIONS, Restoration of Platelet Function).

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 (see WARNINGS AND PRECAUTIONS, Pulmonary Hemorrhage).

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^® (see WARNINGS AND PRECAUTIONS, Re-administration) 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. See also WARNINGS AND PRECAUTIONS, Hypersensitivity Reactions.

In a study of readministration of ReoPro^® to patients (See PRECAUTIONS: Readministration) 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 (see WARNINGS AND PRECAUTIONS, 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

	ReoPro® Bolus + Infusion n= 3111 (%)	Placebo n= 2226 (%)
Cardiac disorders
Bradycardia	4.5%	3.5%
Gastrointestinal disorders
Nausea	13.6%	11.5%
Vomiting	7.3%	6.8%
General disorders and administration site conditions
Chest pain	11.4%	9.3%
Puncture site pain	3.6%	2.6%
Abdominal pain	3.1%	2.2%
Musculoskeletal and connective tissue disorders
Back pain	17.6%	13.7%
Nervous system disorders
Headache	6.4%	5.5%
Vascular disorders
Hypotension	14.4%	10.3%
Peripheral edema	1.6%	1.1%

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^® (see WARNINGS AND PRECAUTIONS, Bleeding Events).

Drug Interactions for ReoPro

Formal drug interaction studies with ReoPro^® have not been conducted. ReoPro^® has been administered to patients with ischemic heart disease treated concomitantly with a broad range of medications used in the treatment of angina, myocardial infarction and hypertension. These medications have included heparin, warfarin, beta-adrenergic receptor blockers, calcium channel antagonists, angiotensin converting enzyme inhibitors, intravenous and oral nitrates, and acetylsalicylic acid. Heparin, other anticoagulants, thrombolytics, and antiplatelet agents are associated with an increase in bleeding. Because ReoPro^® inhibits platelet aggregation, caution should be employed when used with other drugs affecting hemostasis.

Patients with HACA titers may have allergic or hypersensitivity reactions when treated with other diagnostic or therapeutic monoclonal antibodies.

Because of concern about observed synergistic effects on bleeding, ReoPro^® therapy should be used judiciously in patients who have received systemic thrombolytic therapy. The GUSTO V trial randomized patients with acute myocardial infarction to treatment with combined ReoPro^® and half-dose Reteplase, or full-dose Reteplase alone (7). In this trial, the incidence of moderate or severe nonintracranial bleeding was increased in those patients receiving ReoPro^® and halfdose Reteplase versus those receiving Reteplase alone (4.6% versus 2.3%, respectively). This increase was more pronounced in patients above age 75. Also noted in this age group, but not in other age groups, was a trend towards increased incidence of intracranial hemorrhage in those patients receiving ReoPro^® and half-dose Reteplase versus those receiving Reteplase alone.

If urgent intervention is required for refractory symptoms, it is recommended that PTCA using ReoPro^® be attempted first to salvage the situation. Should PTCA and any other appropriate procedures fail, and should the angiographic appearance suggest that the etiology is due to thrombosis, consideration may be given to the administration of adjunctive thrombolytic therapy via the intracoronary route. Prior to surgical interventions, the bleeding time should be determined by the Ivy method and should be 12 minutes or less (see WARNINGS AND PRECAUTIONS, Restoration of Platelet Function).

REFERENCES

7. Data on file.

Warnings for ReoPro

Included as part of the "PRECAUTIONS" Section

Precautions for ReoPro

General

Requirement For Specialist Facilities

ReoPro^® (abciximab) should only be administered in conjunction with extensive specialist medical and nursing care. In addition, there must be availability of laboratory tests of hematology function and facilities for administration of blood products.

Carcinogenesis And Mutagenesis

In vitro and in vivo mutagenicity studies have not demonstrated any mutagenic effect. Long-term studies in animals have not been performed to evaluate carcinogenic potential. See Toxicology section.

Hematologic

Use of Thrombolytics, Anticoagulants and Other Antiplatelet Agents

Because ReoPro^® inhibits platelet aggregation, caution should be employed when used with other drugs affecting hemostasis such as heparin, oral anticoagulants such as warfarin, nonsteroidal anti-inflammatory drugs, thrombolytics, and antiplatelet agents other than acetylsalicylic acid, such as dipyridamole, ticlopidine or low molecular weight dextrans.

ReoPro^® has the potential to increase the risk of bleeding, particularly in the presence of excessive anticoagulation, e.g., from heparin or thrombolytics. Cases of fatal bleeding have been reported (See ADVERSE REACTIONS, Bleeding).

The risks of major bleeds due to ReoPro^® therapy is increased in patients receiving thrombolytics and should be weighed against the anticipated benefits .

Should serious bleeding occur that is not controllable with pressure, the infusion of ReoPro^® and any concomitant heparin should be stopped.

Bleeding Precautions

Results of the EPILOG clinical trial show that bleeding can be reduced to the level of placebo by the use of low-dose, weight-adjusted heparin regimens, early sheath removal, careful patient and access site management and weight-adjustment of the ReoPro^® infusion dose.

Before infusion of ReoPro^®, platelet count, prothrombin time, activated clotting time (ACT) and activated partial thromboplastin time (APTT) should be measured to identify pre-existing hemostatic abnormalities.

Low-Dose, Weight-Adjusted Heparin

1. Percutaneous Coronary Intervention (PCI)

Heparin Bolus Pre-PTCA

If a patient's ACT is less than 200 seconds prior to the start of the PTCA procedure, an initial bolus of heparin should be given upon gaining arterial access according to the following algorithm:

    ACT <150 seconds: administer 70 U/kg
    ACT 150-199 seconds: administer 50 U/kg

The initial heparin bolus dose should not exceed 7,000 U.

ACT should be checked a minimum of 2 minutes after the heparin bolus. If the ACT is < 200 seconds, additional heparin boluses of 20 U/kg may be administered. Should the ACT remain < 200 seconds, additional 20 U/kg boluses are to be given until an ACT ≥ 200 seconds is achieved.

Should a situation arise where higher doses of heparin are considered clinically necessary in spite of the possibility of a greater bleeding risk, it is recommended that heparin be carefully titrated using weight-adjusted boluses and that the target ACT not exceed 300 seconds.

Heparin Bolus during PTCA

During the PTCA procedure, ACT should be checked every 30 minutes. If ACT is < 200 seconds, additional heparin boluses of 20 U/kg may be administered. Should the ACT remain < 200 seconds, additional 20 U/kg boluses may be given until an ACT ≥ 200 seconds is achieved.

ACT should be checked prior to and a minimum of 2 minutes after each heparin bolus.

Heparin Infusion after PTCA

Discontinuation of heparin immediately following completion of the procedure, with removal of the arterial sheath within 6 hours, is strongly recommended. In individual patients, if prolonged heparin therapy after PTCA or later sheath removal is used, then an initial infusion rate of 7 U/kg/hr is recommended (see Bleeding Precautions: Femoral Artery Sheath Removal). In all circumstances, heparin should be discontinued at least 2 hours prior to arterial sheath removal.

2. Stabilization of unstable Angina

Anticoagulation should be initiated with heparin to a target APTT of 60-85 seconds. The heparin infusion should be maintained during the ReoPro^® infusion. Following angioplasty, heparin management is outlined above under 1. Percutaneous Coronary Intervention.

Femoral Artery Access Site

ReoPro^® is associated with an increase in bleeding rate particularly at the site of arterial access for femoral artery sheath placement. The following are specific recommendations for access site care:

Femoral artery Sheath Insertion

• When appropriate, place only an arterial sheath for vascular access (avoid venous sheath placement)
• Puncture only the anterior wall of the artery or vein when establishing vascular access
• The use of a through and through technique to identify the vascular structure is strongly discouraged

While Femoral Artery Sheath Is In Place

• Check sheath insertion site and distal pulses of affected leg(s) every 15 minutes for 1 hour, then hourly for 6 hours
• Maintain complete bed rest with head of bed ≤ 30°
• Maintain affected leg(s) straight via sheet tuck method or soft restraint
• Medicate for back/groin pain as necessary
• Educate patient on post-PTCA care via verbal instructions

Femoral Artery Sheath Removal

• Heparin should be discontinued at least 2 hours prior to arterial sheath removal
• Check APTT or ACT prior to arterial sheath removal: do not remove sheath unless APTT ≤ 50 seconds or ACT ≤ 175 seconds
• Apply pressure to access site for at least 30 min following sheath removal, using either manual compression or a mechanical device
• Apply pressure dressing after hemostasis has been achieved

After Femoral Artery Sheath Removal

• Check groin for bleeding/hematoma and distal pulses every 15 minutes for the first hour or until stable, then hourly
• Continue complete bed rest with head of bed ≤ 30° and affected leg(s) straight for 6-8 hours following femoral artery sheath removal, 6-8 hours following discontinuation of ReoPro^® or 4 hours following discontinuation of heparin, whichever is later
• Remove pressure dressing prior to ambulation
• Continue to medicate for discomfort

Management of Femoral Access Site Bleeding/Hematoma Formation

In the event of groin bleeding with or without hematoma formation, the following procedures are recommended:

• Lower head of bed to 0°
• Apply manual pressure/compression device until hemostasis has been achieved
• Any hematoma should be measured and monitored for enlargement
• Change pressure dressing as needed
• If heparin is being given, obtain APTT and adjust heparin as needed
• Maintain intravenous access if sheath has been removed

If groin bleed continues or the hematoma expands during ReoPro^® infusion despite the above measures, the ReoPro^® infusion should be immediately discontinued and the arterial sheath removed according to the guidelines listed above. After sheath removal intravenous access should be maintained until bleeding is controlled.

Potential Bleeding Sites

Careful attention should be paid to all potential bleeding sites, including arterial and venous puncture sites, catheter insertion sites, cutdown sites, and needle puncture sites.

Retroperitoneal Bleeding

ReoPro^® is associated with an increased risk of retroperitoneal bleeding in association with femoral vascular puncture. The use of venous sheaths should be minimized and only the anterior wall of the artery or vein should be punctured when establishing vascular access.

Pulmonary (Mostly Alveolar) Hemorrhage

ReoPro^® has rarely been associated with pulmonary (mostly alveolar) hemorrhage (6). This can present with any or all of the following in close association with ReoPro^® administration: hypoxemia, alveolar infiltrates on chest x-ray, hemoptysis, or an unexplained drop in hemoglobin. If confirmed, ReoPro^® and all anticoagulant and other antiplatelet drugs should immediately be discontinued.

GI Bleeding Prophylaxis

In order to prevent spontaneous GI bleeding it is recommended that patients are pretreated with H₂-histamine receptor antagonists or liquid antacids. Antiemetics should be given as needed to prevent vomiting.

General Nursing Care

Unnecessary arterial and venous punctures, intramuscular injections, routine use of urinary catheters, nasotracheal intubation, nasogastric tubes and automatic blood pressure cuffs should be avoided. When obtaining intravenous access, non-compressible sites (e.g., subclavian or jugular veins) should be avoided. Saline or heparin locks should be considered for blood drawing. Vascular puncture sites should be documented and monitored. Gentle care should be provided when removing dressings.

Patient Monitoring

Before administration of ReoPro^®, platelet count, ACT, prothrombin time (PT) and APTT should be measured to identify pre-existing coagulation abnormalities. Hemoglobin and hematocrit measurements should be obtained prior to the ReoPro^® administration, at 12 hours following the ReoPro^® bolus injection, and again at 24 hours following the bolus injection. Twelve lead electrocardiograms (ECG) should be obtained prior to the bolus injection of ReoPro^®, and repeated once the patient has returned to the hospital ward from the catheterization laboratory, and at 24 hours after the bolus injection of ReoPro^®. Vital signs (including blood pressure and pulse) should be obtained hourly for the first 4 hours following the ReoPro^® bolus injection, and then at 6, 12, 18 and 24 hours following the ReoPro^® bolus injection.

Thrombocytopenia

To reduce the possibility of thrombocytopenia, platelet counts should be monitored prior to treatment, 2 to 4 hours following the bolus dose of ReoPro^®, at 24 hours, and periodically for 2 weeks. If a patient experiences an acute platelet decrease, (e.g., a platelet decrease to less than 100,000 cells/μL and a decrease of at least 25% from pretreatment value), additional platelet counts should be determined. These platelet counts should be drawn in three separate tubes containing ethylenediaminetetraacetic acid (EDTA), citrate and heparin, respectively, to exclude pseudothrombocytopenia due to in vitro anticoagulant interaction. If true thrombocytopenia is verified, ReoPro^® should be immediately discontinued and the condition appropriately monitored and treated. A daily platelet count should be obtained until it returns to normal. If a patient's platelet count drops to 60,000 cells/μL, heparin and acetylsalicylic acid should be discontinued. If a patient's platelet count drops below 50,000 cells/μL, platelets should be transfused.

In a registry study of ReoPro^® re-administration, a history of thrombocytopenia associated with prior use of ReoPro^® was predictive of an increased risk of recurrent thrombocytopenia. Readministration within 30 days was associated with an increased incidence and severity of thrombocytopenia, as was a positive human anti-chimeric antibody (HACA) test at baseline, compared to the rates seen in studies with first administration.

Restoration of Platelet Function

Transfusion of donor platelets has been shown to restore platelet function following ReoPro^® administration in animal studies and transfusions of fresh random donor platelets have been given empirically to restore platelet function in humans. In the event of serious uncontrolled bleeding or the need for surgery, a bleeding time should be determined. If the bleeding time is greater than 12 minutes, 10 units of platelets may be given. ReoPro^® may be displaced from endogenous platelet receptors and subsequently bind to platelets which have been transfused. Nevertheless, a single transfusion may be sufficient to reduce receptor blockade to 60% to 70% at which level platelet function is restored. Repeat platelet transfusions may be required to maintain the bleeding time at or below 12 minutes.

Immune

Re-administration

Administration of ReoPro^® may result in human anti-chimeric antibody (HACA) formation (see ADVERSE REACTIONS) that could potentially cause allergic or hypersensitivity reactions (including anaphylaxis), thrombocytopenia or diminished benefit upon re-administration of ReoPro^®. Re-administration of ReoPro^® to 29 patients known to be HACA-negative has not led to any change in ReoPro^® pharmacokinetics or to any reduction in antiplatelet potency.

Re-administration of ReoPro^® to patients undergoing PCI was assessed in a registry that included 1342 treatments in 1286 patients. Most patients were receiving their second ReoPro^® exposure; 15% were receiving the third or subsequent exposure. The overall rate of HACA positivity prior to the re-administration was 6% and increased to 27% post-re-administration. There were no reports of serious allergic reactions or anaphylaxis. Thrombocytopenia was observed at higher rates in the re-administration study than in the phase 3 studies of first-time administration (see WARNINGS AND PRECAUTIONS, Thrombocytopenia and ADVERSE REACTIONS: Thrombocytopenia), suggesting that re-administration may be associated with an increased incidence and severity of thrombocytopenia.

Hypersensitivity Reactions

Anaphylactic reactions have occurred very rarely in patients treated with ReoPro^®. Epinephrine, antihistamines and corticosteroids should be available for immediate use, in addition to equipment for resuscitation, in the event of a hypersensitivity reaction. Immediately, upon occurrence of anaphylaxis, administration of ReoPro^® should be stopped and appropriate resuscitative measures should be initiated.

Respiratory

Pulmonary hemorrhage associated with ReoPro^® use, although a very rare occurrence, can be a serious life-threatening complication that can be misdiagnosed and result in the patient not receiving timely treatment. Respiratory symptoms should be monitored closely for early detection of serious pulmonary hemorrhage in patients receiving ReoPro^®.

Special Populations

Pregnant Women

Animal reproduction studies have not been conducted with ReoPro^® and the effects on fertility in male or female animals are unknown. It is also not known whether ReoPro^® can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. ReoPro^® should be given to a pregnant woman only if clearly needed.

Nursing Women

It is not known if this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when ReoPro^® is administered to a nursing woman.

Pediatrics (< 18 Years Of Age)

Safety and effectiveness of ReoPro^® in children below the age of 18 have not been established.

Geriatrics (> 65 Years Of Age)

There is insufficient clinical experience to determine whether patients aged 75 years old or greater respond differently to ReoPro^® than younger patients.

REFERENCES

6. Kalra S, Bell MR, Rihal CS. Alveolar Hemorrhage as a Complication of Treatment with Abciximab. Chest 2001;120:126-131.

Overdose Information for ReoPro

There has been no experience of overdosage in human clinical trials.

Contraindications for ReoPro

Because Abciximab may increase the risk of bleeding, Abciximab is contraindicated in the following clinical situations:

• Active internal bleeding
• Recent (within six weeks) gastrointestinal (GI) or genitourinary (GU) bleeding of clinical significance.
• History of cerebrovascular accident (CVA) within two years, or CVA with a significant residual neurological deficit
• Bleeding diathesis
• Administration of oral anticoagulants within seven days unless prothrombin time is ≤ 1.2 times control
• Thrombocytopenia ( < 100,000 cells/μL)
• Recent (within six weeks) major surgery or trauma
• Intracranial neoplasm, arteriovenous malformation, or aneurysm
• Severe uncontrolled hypertension
• Presumed or documented history of vasculitis
• Use of intravenous dextran before PCI, or intent to use it during an intervention

Abciximab is also contraindicated in patients with known hypersensitivity to any component of this product or to murine proteins.

Clinical Pharmacology for ReoPro

Mechanism Of Action

ReoPro^® (abciximab) is the Fab fragment of the chimeric monoclonal antibody 7E3. It selectively binds to the glycoprotein IIb/IIIa (GPIIb/IIIa) receptor located on the surface of human platelets. ReoPro^® inhibits platelet aggregation by preventing the binding of fibrinogen, von Willebrand factor and other adhesive molecules to GPIIb/IIIa receptor sites on activated platelets. ReoPro^® also binds with similar affinity to the vitronectin (α_νβ₃) receptor found on platelets and vessel wall endothelial and smooth muscle cells. The vitronectin receptor mediates pro-coagulant properties of platelets and proliferative properties of vascular endothelial cells and smooth muscle cells.

Pharmacodynamics

Intravenous administration in humans of single bolus doses of ReoPro^® from 0.15 mg/kg to 0.30 mg/kg resulted in a dose-dependent blockade of platelet GPIIb/IIIa receptors and produced dosedependent inhibition of platelet function as measured by ex vivo platelet aggregation in response to ADP or by prolongation of bleeding time. At the two highest doses (0.25 and 0.30 mg/kg) at 2 hours post injection, over 80% of the GPIIb/IIIa receptors were blocked and platelet aggregation in response to 20 μM ADP was almost abolished. The median bleeding time increased to over 30 minutes at both doses compared with a baseline value of approximately 5 minutes.

Intravenous administration in humans of a single bolus dose of 0.25 mg/kg followed by a continuous infusion of 10 μg/min for periods of 12 to 96 hours produced sustained high-grade platelet inhibition (ex vivo platelet aggregation in response to 5 or 20 μM ADP less than 20% of baseline and bleeding time greater than 30 minutes) for the duration of the infusion in most patients. Equivalent results were obtained when a weight adjusted infusion dose (0.125 μg/kg/min to a maximum of 10 μg/min) was used in patients up to 80 kg. Results in patients who received the 0.25 mg/kg bolus followed by a 5 μg/min infusion for 24 hours showed a similar initial inhibition of platelet aggregation, but the response was not maintained throughout the infusion period. Following cessation of the infusion, platelet function typically returned to baseline values over a period of 24 to 48 hours.

Pharmacokinetics

Following intravenous administration of ReoPro^®, free plasma concentrations decreased very rapidly with an initial half-life of several minutes and a second phase half-life of about 30 minutes. This disappearance from the plasma is probably related to rapid binding to the platelet GPIIb/IIIa receptors (approximately 80,000 to 100,000 GPIIb/IIIa receptors on the surface of each platelet).

After a single bolus injection of ReoPro^®, the inhibitory effects on platelet function, as measured by inhibition of platelet aggregation, were evident within 10 minutes. The antibody remains in the circulation for 15 days or more in a platelet-bound state. Its disappearance follows a monoexponential time course.

Intravenous administration of a 0.25 mg/kg bolus dose of ReoPro^® followed by continuous infusion of 5 or 10 μg/min for periods of 12 to 96 hours produced relatively constant total plasma concentrations from the first time point measured (usually 2 hours) for all infusion rates and durations. However, although the total plasma concentrations resulting from the 5 μg/min infusion were only slightly lower than those from the 10 μg/min infusion, the 5 μg/min infusion was ineffective in inhibiting platelet function over the whole infusion period. At the termination of the infusion period, plasma concentrations fell rapidly for approximately 6 hours, then declined at a much slower rate.

Clinical Studies

Study Demographics And Trial Design

Table 3: Summary of patient demographics for clinical trials in specific indication

Study #	Trial design	Dosage, route of administration and duration	Study subjects (n=number)	Mean age (Range)	Gender (% Female)
EPIC Trial	Multicenter, doubleblind, placebocontrolled	ReoPro® bolus (0.25 mg/kg)/ ReoPro® infusion (10 μg/min) for 12 hours
		Bolus + Infusion	708
		Bolus	695	60.0±10.6 (26, 83)	27.9%
		Placebo	696
EPILOG Trial	Randomized, doubleblind, multicenter, placebo-controlled	ReoPro® bolus (0.25 mg/kg)/ ReoPro® infusion (0.125 μg/kg/min – maximum 10 μg/min) for 12 hours + heparin
		ReoPro® + Low-Dose Heparin	935
		ReoPro® + Standard Dose Heparin	918	59.7±11.0 (29, 89)	27.9%
		Placebo + Standard Dose Heparin	939

The EPIC Trial

The Evaluation of c7E3 to Prevent Ischemic Complications (EPIC) trial was a multicenter, double-blind, placebo-controlled trial of ReoPro^® (abciximab) in patients undergoing percutaneous transluminal coronary angioplasty or atherectomy (PTCA) (1-3). In the EPIC trial, 2099 patients between 26 and 83 years of age who were at high risk for abrupt closure of the treated coronary vessel were randomly allocated to one of three treatments: 1) a ReoPro^® bolus (0.25 mg/kg) followed by a ReoPro^® infusion (10 μg/min) for twelve hours (bolus plus infusion group); 2) a ReoPro^® bolus (0.25 mg/kg) followed by a placebo infusion (bolus group), or; 3) a placebo bolus followed by a placebo infusion (placebo group). Patients at high risk during or following PTCA were defined as those with unstable angina or a non-Q-wave myocardial infarction (n=489), those with an acute Q-wave myocardial infarction within twelve hours of symptom onset (n=66), and those who were at high risk because of coronary morphology and/or clinical characteristics (n=1544). Treatment with study agent in each of the three arms was initiated 10-60 minutes before the onset of PTCA. All patients initially received an intravenous heparin bolus (10,000 to 12,000 units) and boluses of up to 3,000 units thereafter to a maximum of 20,000 units during PTCA. Heparin infusion was continued for twelve hours to maintain a therapeutic elevation of activated partial thromboplastin time (APTT, 1.5-2.5 times normal). Unless contraindicated, acetylsalicylic acid (325 mg) was administered orally two hours prior to the planned procedure and then once daily.

The EPILOG Trial

A second trial (Evaluation of PTCA to Improve Long-term Outcome by c7E3 GPIIb/IIIa Receptor Blockade or EPILOG), also a randomized, double-blind, multicenter, placebocontrolled trial, evaluated ReoPro^® in a broad population of PTCA patients (but excluding patients myocardial infarction and unstable angina meeting the EPIC high risk criteria) (4). EPILOG tested the hypothesis that use of a low-dose, weight-adjusted heparin regimen, early sheath removal, better access site management and weight-adjustment of the ReoPro^® infusion dose could significantly lower the bleeding rate yet maintain the efficacy seen in the EPIC trial. EPILOG was a three treatment-arm trial of ReoPro^® plus standard dose, weight-adjusted heparin¹, ReoPro^® plus low dose, weight-adjusted heparin² and placebo plus standard dose, weight-adjusted heparin. The ReoPro^® dose regimen was the same as that used in the EPIC trial, except that the continuous infusion dose was weight adjusted in patients up to 80 kg³. Improved patient and access site management as well as a strong recommendation for early sheath removal were also incorporated into the trial. The 30-day Kaplan-Meier primary endpoint events for each treatment group by intention-to-treat analysis of all 2792 randomized patients are shown in Table 5. The EPILOG trial also achieved the objective of lowering the bleeding rate: in the ReoPro^® treatment arms major bleeding was reduced to the level of placebo (see ADVERSE REACTIONS: Bleeding).

¹ Bolus administration of 100 U/kg weight-adjusted heparin to achieve an activated clotting time (ACT) of ≥ 300 seconds (maximum initial bolus 10,000 units).

² Bolus administration of 70 U/kg weight-adjusted heparin to achieve an activated clotting time (ACT) of 200 seconds (maximum initial bolus 7,000 units).

³ Bolus administration of 0.25 mg/kg ReoPro^® 10 to 60 minutes before PTCA immediately followed by a 0.125 μg/kg/min infusion (maximum 10 μg/min) for 12 hours.

Study Results

The EPIC Trial

The primary endpoint was the occurrence of any of the following events within 30 days of PTCA: death, myocardial infarction (MI), or the need for urgent intervention for recurrent ischemia (i.e. urgent PTCA, urgent coronary artery bypass graft (CABG) surgery, a coronary stent, or an intra-aortic balloon pump). The 30-day (Kaplan-Meier) primary endpoint events for each treatment group by intention-to-treat analysis of all randomized patients are shown in Table 4. The 4.5% lower incidence of the primary endpoint in the bolus plus infusion treatment group, compared with the placebo group, was statistically significant, whereas the 1.3% lower incidence in the bolus treatment group was not. A lower incidence of the primary endpoint was observed in the bolus plus infusion treatment arm for all three high-risk subgroups: patients with unstable angina, patients presenting within twelve hours of the onset of symptoms of an acute myocardial infarction, and patients with other high-risk clinical and/or morphologic characteristics. The treatment effect was largest in the first two subgroups and smallest in the third subgroup.

Table 4: Primary Endpoint Events at 30-Days -EPIC Trial

	Placebo (n=696)	Bolus (n=695)	Infusion (n=708)
Event	Number of Patients (%)
Primary Endpointa	89 (12.8)	79 (11.5)	59 (8.3)
p-value vs. placebo		0.428
Components of Primary Endpointb
Death	12 (1.7)	9 (1.3)	12 (1.7)
Acute myocardial infarctions in surviving patients	55 (7.9)	40 (5.8)	31 (4.4)
Urgent interventions in surviving patients without an acute myocardial infarction	22 (3.2)	30 (4.4)	16 (2.2)
a Patients who experienced more than one event in the first 30 days are counted only once. b Patients are counted only once under the most serious component (death > acute MI > urgent intervention).

The primary endpoint events in the bolus plus infusion treatment group were reduced mostly in the first 48 hours and this benefit was sustained through blinded evaluations at 30 days (1), 6 months (2) and 3 years (3). At the 6 months follow-up visit this event rate remained lower in the bolus plus infusion arm (12.3%) than in the placebo arm (17.6%) (p=0.006 vs. placebo). At 3 years the absolute reduction in events was maintained with an event rate of 19.6% in the bolus plus infusion arm and 24.4% in the placebo arm (p=0.027).

The EPILOG Trial

The 30-day Kaplan-Meier primary endpoint events for each treatment group by intention-to-treat analysis of all 2792 randomized patients are shown in Table 5. The EPILOG trial also achieved the objective of lowering the bleeding rate: in the ReoPro^® treatment arms major bleeding was reduced to the level of placebo (see ADVERSE REACTIONS, Bleeding).

Table 5: Primary Endpoint Events at 30 Days -EPILOG Trial

	Placebo + Standard Dose	ReoPro® + Standard Dose	ReoPro® + Low Dose
	Heparin (n=939)	Heparin (n=918)	Heparin (n=935)
Event	Number of Patients (%)
Death or MIa	85 (9.1)	38 (4.2)	35 (3.8)
p-value vs. Placebo		<0.0001	<0.0001
Death, MI or urgent interventiona	109 (11.7)	49 (5.4)	48 (5.2)
p-value vs. Placebo		<0.0001	<0.0001
Endpoint componentsb
Death	7 (0.8)	4 (0.4)	3 (0.3)
MI in surviving patients	78 (8.4)	34 (3.7)	32 (3.4)
Urgent intervention in surviving patients without acute MI	24 (2.6)	11 (1.2)	13 (1.4)
a Patients who experienced more than 1 event in the first 30 days are counted only once. b Patients are counted only once under the most serious component (death > acute MI > urgent intervention)

As seen in the EPIC trial, the endpoint events in the ReoPro^® treatment groups were reduced mostly in the first 48 hours and this benefit was sustained through blinded evaluations at 30 days and 6 months. At the 6 month follow-up visit the event rate for death, MI or urgent intervention remained lower in the combined ReoPro^® treatment arms (8.3% and 8.4%, respectively, for the standard- and low-dose heparin arms) than in the placebo arm (14.7%) (p<0.001 for both treatment arms vs. placebo).

The proportionate reductions in the composite endpoints death and MI, and death, MI and urgent intervention, were similar in high and low risk patients, although overall event rates were higher in high risk patients. The proportionate reductions in endpoints were also similar irrespective of the type of coronary intervention used (balloon angioplasty, atherectomy or stent placement).

Mortality was uncommon in both the EPIC and EPILOG trials. Similar mortality rates were observed in all arms in the EPIC trial; mortality rates were lower in the ReoPro^® treatment arms than the placebo treatment arm in the EPILOG trial. In both trials the rate of acute myocardial infarctions was significantly lower in the groups treated with ReoPro^®. While most myocardial infarctions in both studies were non-Q-wave infarctions, patients in the ReoPro^® treated groups experienced a lower incidence of both Q-wave and non-Q-wave infarctions. Urgent intervention rates were also lower in the groups treated with ReoPro^®, mostly because of lower rates of emergency PTCA and, to a lesser extent, emergency CABG surgery.

Unstable Angina

Study demographics and trial design

Table 6: Summary of patient demographics for clinical trials in specific indication

Study #	Trial design	Dosage, route of administration and duration	Study subjects (n=number)	Mean age (Range)	Gender (% Female)
CAPTURE Trial	Randomized, doubleblind, multicenter, placebo-controlled	ReoPro® bolus (0.25 mg/kg)/ ReoPro® infusion (10 μg/min)
		ReoPro®	630	60.8 ± 10.0	27.3%
		Placebo	635	(32, 80)

The CAPTURE Trial

The CAPTURE (Chimeric Anti-Platelet Therapy in Unstable angina Refractory to standard medical therapy) trial was a randomized, double-blind, multicenter, placebo-controlled trial designed to determine if potent antiplatelet therapy would reduce ischemic complications and stabilize unstable angina patients not responding to conventional therapy who were candidates for percutaneous coronary intervention (5). In contrast to the EPIC and EPILOG trials, the CAPTURE trial involved the administration, in addition to conventional therapy, of placebo or ReoPro^® starting up to 24 hours prior to PTCA and continuing until 1 hour after completion of PTCA. The ReoPro^® dose was a 0.25 mg/kg bolus followed by a continuous infusion at a rate of 10 μg/min. The CAPTURE trial did incorporate weight adjustment of the standard heparin dose, but did not investigate the effect of a lower heparin dose, and arterial sheaths were left in place for approximately 40 hours.

Study Results

The CAPTURE Trial

The 30-day Kaplan-Meier primary endpoint events for each treatment group by intention-to-treat analysis of all 1265 randomized patients are shown in Table 7.

Table 7: Primary Outcome Events at 30 Days -CAPTURE Trial

	Placebo (n=635)	ReoPro® (n=630)
Event	Number of Patients (%)
Death, MI or urgent interventiona	101 (15.9%)	71 (11.3%)
p-value vs. placebo		(p=0.012)
Endpoint componentsb
Death	8 (1.3%)	6 (1.0%)
MI in surviving patients	49 (7.7%)	24 (3.8%)
Urgent intervention in surviving patients without acute MI	44 (6.9%)	41 (6.6%)
a Patients who experienced more than one event in the first 30 days are counted only once. b Patients are counted only once under the most serious component (death>acute MI>urgent intervention).

Figure 1 shows the Kaplan-Meier event rate curves for myocardial infarction for the periods from randomization to angioplasty and from angioplasty through 24 hours post angioplasty. A reduction in myocardial infarction is apparent both pre-and post-angioplasty. The 30-day results are consistent with the EPIC and EPILOG trials, with the greatest effects on the myocardial infarction and urgent revascularization components of the composite endpoint.

Figure 1. Kaplan-Meier event rates for myocardial infarction before and after PTCA.

Detailed Pharmacology

In Vitro Studies

c7E3 Fab has been studied extensively with regard to both antigen binding and functional ability to inhibit platelet aggregation. Using platelets from humans, cynomolgus monkey, and baboons, the chimeric 7E3 Fab fragment displayed a dose-dependent inhibition of platelet aggregation. Similar binding characteristics were observed to affinity-isolated human GPIIb/IIIa receptors.

Animal Studies

To determine whether the ability of 7E3 to inhibit platelet aggregation correlates with therapeutic potential in the treatment of vascular disease, 7E3 has been investigated in several animal models of vaso-occlusive disease. Dogs, monkeys, and baboons were employed in these studies because 7E3 cross-reacts with the GPIIb/IIIa receptor on canine and nonhuman primate platelets. Because the m7E3 F(ab')₂ and Fab fragments and the c7E3 Fab fragment are functionally equivalent with respect to platelet GPIIb/IIIa binding and inhibition of platelet aggregation, preclinical efficacy studies with any of these test materials provide valid data for determining potential clinical utility associated with 7E3 inhibition of platelet aggregation.

Establishment of In Vivo Dose-Response

A dose-response study in dogs established that doses of 0.81 mg/kg of m7E3 F(ab')₂ blocked 85% of GPIIb/IIIa receptors and almost completely abolished platelet aggregation in response to ADP 30 minutes after infusion (8). Both the inhibition of platelet aggregation and the number of blocked GPIIb/IIIa sites progressively decreased over the next days. No obvious ill effects were detected; there was no spontaneous bleeding and no evidence of coagulopathy.

In Vivo Equivalence of 7E3 Fab and F(ab')₂

A direct comparison of the in vivo activity of 7E3 Fab and m7E3 F(ab')₂ was performed in cynomolgus monkeys (9). Both fragments of m7E3 were found to inhibit ADP-induced platelet aggregation to a similar degree. Blockade of platelet GPIIb/IIIa receptors was also comparable in the two groups. To explore the comparative immunogenicity of the Fab and the F(ab')₂ fragments of m7E3, animals were administered several follow-up injections of antibody. The results of this comparative study established that while the in vivo antiplatelet activities of m7E3 Fab and m7E3 F(ab')₂ were comparable, Fab fragment exhibited decreased immunogenicity (9).

Prevention of Thrombosis at Sites of Vessel Wall Injury

The m7E3 F(ab')₂ fragment was tested in vivo models of platelet thrombus formation in stenosed coronary arteries in dogs and carotid arteries of monkeys developed by Folts (10, 11). This model was specifically designed to simulate the situation in partially stenosed vessels with underlying atherosclerotic lesions when patients suffer acute intermittent ischemia from injured (ruptured or fissured) atherosclerotic plaques, as in unstable angina and post-PTCA abrupt closure (cardiac circulation) or transient ischemic attacks (cerebral circulation) (12). An intravenous dose (0.8 mg/kg) of m7E3 F(ab')₂ , which completely inhibits ex vivo platelet aggregation, not only abolished thrombotic cycles, but also protected against their return by a variety of provocations. On occasion, a dose as low as 0.1 mg/kg, which produced only 41% platelet inhibition, could also abolish thrombus formation. More recent work in monkeys has demonstrated that both m7E3 Fab and c7E3 Fab are as effective as the m7E3 F(ab')₂ fragment in abolishing in vivo thrombus formation in the Folts mode (13).

Direct Current Internal Injury Model of Thrombosis

Mickelson et al. (14) confirmed that 7E3 F(ab')₂ prevents coronary artery thrombosis in an experimental dog model of vascular wall injury. In this model dose intimal injury is induced at the site of stenosis by delivery of anodal direct current which results in spontaneous oscillations in coronary blood flow preceding a final complete thrombotic occlusion. Compared to controls, a dose of 0.8 mg/kg F(ab')₂ : 1) prevented thrombotic left circumflex coronary artery occlusion, 2) inhibited platelet aggregation, 3) minimized platelet deposition on injured vascular endothelium and in established thrombi, and 4) stabilized left circumflex coronary artery blood flow for 5 hours after injury.

The 7E3 antibody has also been investigated in a model of acute thrombosis following injury induced by coronary angioplasty in dogs (15). This investigation established an effective model of acute occlusion that was dependent on platelet deposition following balloon-induced deep arterial injury. Treatment with m7E3F(ab')₂ prior to angioplasty prevented the formation of either occlusive or non-occlusive thrombi in 8 dogs. Acetylsalicylic acid, in contrast, was only partially effective.

Coronary Angioplasty Model

Studies by Bates et al. (15) examined whether m7E3 F(ab')₂ could prevent acute thrombosis following coronary angioplasty in a canine model. Coronary angioplasty was performed in the left anterior descending coronary artery of dogs pretreated with a bolus injection of either 0.8 mg/kg of 7E3 F(ab')₂ , 325 mg acetylsalicylic acid or saline control. This study demonstrated that m7E3 F(ab')₂ was superior to acetylsalicylic acid in inhibiting platelet aggregation, thrombosis and acute closure.

Enhancement of Thrombolytic Efficacy

Several studies have examined the combination of 7E3 with thrombolytic agents in promoting thrombolysis using different models of arterial thrombosis in dogs and primates. All have reported that the addition of 7E3 to a standard thrombolytic regiment enhances thrombolysis and prevents reocclusion.

Instilled Coronary Model

To test the role of 7E3 in enhancing the action of recombinant tissuetype plasminogen activator (rt-PA), Yasuda et al. (16) used a localized coronary thrombosis model in open chest dogs. A performed thrombus was placed at a site of intimal damage, immediately proximal to a constricted segment of the left anterior descending coronary artery in heparinized animals. Intravenous infusion of rt-PA at a rate of 15 μg/kg/minute (two-chain rt- PA) or 30 μg/kg/minute (single chain rt-PA) alone for 30-60 minutes failed to prevent reocclusion despite heparin anticoagulation. Intravenous injection of 0.8 mg/kg of m7E3 F(ab')₂ in addition to rt-PA prevented reocclusion during a 2-hour observation period. The antibody abolished ADP-induced platelet aggregation and prolonged bleeding time.

In another study, Gold et al. (17), using the canine model described above, administered intravenous bolus doses of rt-PA alone and in combination with m7E3 F(ab')₂ to determine whether thrombolysis could be accelerated in addition to preventing reocclusion. In this model, reocclusion occurred in animals treated with 450 μg/kg rt-PA alone. In contrast, accelerated thrombolysis without reocclusion was observed when bolus injections of 0.8 mg/kg m7E3 F(ab')₂ alone, without rt-PA.

Ziskind et al. demonstrated similar benefit of adding m7E3 F(ab')₂ to the combined thrombolytic regimen of rt-PA and single-chain urokinase-type plasminogen activator (scu-PA) in the same dog coronary thrombosis model (18). Although various dosage combinations of rt-PA and scu- PA produced synergistic effects in achieving thrombolysis, all animals experienced reocclusion. Reocclusion was abolished by combining a single pretreatment dose of 0.6 mg/kg m7E3 F(ab')₂.

Everted Coronary Artery Model

The ability of m7E3 F(ab')₂ to enhance rt-PA thrombolysis was also examined in a dog model of platelet-rich coronary artery thrombus using eversion of a circumflex coronary artery segment (19). In this model of highly resistant coronary thrombolysis, in which no animals treated with rt-PA alone had enduring successful thrombolysis, m7E3 F(ab')₂ was able to facilitate and maintain reperfusion with reduced doses of rt-PA. Again, occasional animals achieved sustained reperfusion with infusion of m7E3 F(ab')₂ alone, without rt-PA.

Direct Current Intimal Injury Model

The efficacy of m7E3 F(ab')₂ as an adjunct to thrombolytic therapy was demonstrated by Fitzgerald et al. (20) using an electrical current intimal injury model of coronary thrombosis in dogs. Coadministrations of several adjunctive antiplatelet regimens with 10 μg/kg/minute rt-PA were compared. Compared to prostacyclin (PGl2), acetylsalicylic acid, or thromboxane, At (TXA2) at doses sufficient to inhibit platelet aggregation, only m7E3 F(ab')₂ achieved accelerated thrombolysis without reocclusion, using reduced thrombolytic doses.

Instilled Femoral Artery Thrombus Model in Baboons

Chimeric 7E3 Fab was investigated in a baboon model of thrombin-induced thrombus formation (21) similar to the dog model developed by Gold et al. (22). An occlusive thrombus was instilled in the femoral artery after which intravenous bolus doses of rt-PA were administered to heparinized animals in combination with either c7E3 Fab or acetylsalicylic acid. Administration of c7E3 Fab in combination with rt-PA produced a more rapid and more stable reperfusion of the baboon femoral artery with a lower total dose of rt-PA in comparison to acetylsalicylic acid administered in combination with rt-PA.

Animal Toxicology

Acute Intravenous Studies

Single Dose Studies

Sprague-Dawley rats were injected with saline or 26.4 mg/kg c7E3 Fab. No mortality or drug related signs of toxicity were observed. Necropsy revealed no gross pathological changes.

Single intravenous dose studies in cynomolgus monkeys revealed that c7E3 Fab was well tolerated at doses up to 8 μg/kg. Transient gingival bleeding, epistaxis and bruising were observed post-dosing.

Multiple-Day Intravenous Studies

One-month Rat: rats were given c7E3 Fab once daily at 0, 0.5, 5.0, or 10.0 mg/kg/day for 30 days. No deaths or signs of toxicity considered to be c7E3 Fab-related were observed during the study.

Two-day Monkey: c7E3 Fab was given to cynomolgus monkeys as a 0.3 mg/kg bolus followed immediately by a 0.45 μg/kg/minute infusion. No signs of toxicity considered to be c7E3 Fabrelated were observed.

Four-day Monkey: c7E3 Fab as a 0.6 μg/kg bolus injection immediately followed by a 0.8 μg/kg/minute I.V. infusion over 96 hours was well tolerated in rhesus monkeys.

Two-week Monkey: Cynomolgus monkeys given c7E3 Fab once daily intravenously for fourteen days at doses up to 1 μg/kg/day tolerated the drug well for the first week of treatment. On days 11 through 13, significant signs of toxicity in all treatment groups became severe and frequent, especially in the high-dose animals. Due to the deteriorating condition and adverse hematological findings for some of the monkeys, treatment was discontinued. As expected following repeat bolus intravenous doses of a foreign protein, a monkey anti-chimeric antibody response was detected in the serum of animals in all c7E3 Fab treatment groups, which induced thrombocytopenia and consequent hemorrhaging and anemia during the second week of treatment. Following a 2-week recovery period, evidence of reversibility of effects was observed.

Interaction With Other Drugs

Concomitant administration of c7E3 Fab (0.3 μg/kg bolus dose followed by 0.45 or 0.5 μg/kg/min infusion for 48 hours) with heparin (100 U/kg bolus doses followed by 50 U/kg/hr infusion for 48 hours), rt-PA (1.25 mg/kg dose of Activase^® over 3 hours or Streptokinase at 30,000 U/kg over 1 hour) and acetylsalicylic acid (25 mg/day oral dose) was well tolerated in rhesus monkeys.

In Vitro Human Tissue Cross-Reactivity Studies

Immunohistochemical studies demonstrated that Murine 7E3 Fab and c7E3 Fab reacted with platelets from blood smears and megakaryocyte in the bone marrow at 3 different antibody dilutions. No cross-reactivity was observed with any other tissues or organs.
In Vitro and In Vivo Mutagenicity Studies

The mutagenic potential of c7E3 Fab was evaluated in three separate assays. c7E3 Fab did not exhibit mutagenic activity in the in vitro mammalian forward gene mutation assay (Chinese hamster ovary cells/hypoxanthine-guanine phosphoribosyl transferase; CHO/HPRT), in vitro chromosomal aberration analysis (CHO cells), or in vivo mouse micronucleus test.

REFERENCES

1. EPIC Investigators. Use of a monoclonal antibody directed against the platelet glycoprotein IIb/IIIa receptor in high-risk coronary angioplasty. N Eng J Med 1994; 300:956-961.

2. Topol EJ, Califf RM, Weisman HF, et al: Randomised trial of coronary intervention with antibody against platelet IIb/IIIa integrin for reduction of clinical restenosis: results at six months. Lancet 1994:343:881-886.

3. Topol EJ, Ferguson JJ, Weisman HF, et al. for the EPIC Investigators. Long term protection from myocardial ischemic events in a randomized trial of brief integrin blockade with percutaneous coronary intervention. JAMA 1997;278:479-484.

4. EPILOG Investigators. Platelet glycoprotein IIb/IIIa receptor blockade and low dose heparin during percutaneous coronary revascularization. N Eng J Med. 1997;336:1689- 1696.

5. CAPTURE Investigators. Randomized placebo-controlled trial of abciximab before, during and after coronary intervention in refractory unstable angina: the CAPTURE study. Lancet 1997;349:1429-1435.

8. Coller BS, Scudder LE. Inhibition of dog platelet function by in vivo infusion of F(ab’)₂ fragments of a monoclonal antibody. Blood 1985;66:1456-1459.

9. Jordan RE, Wagner CL, McAleer MF, Spitz MS, Mattis JA. Evaluation of the potency and immunogenicity of 7E3 F(ab’)₂ and Fab fragments in monkeys. Circ (Suppl III) 1990;82:661.

12. Sherman CT, Litvock F, Grundfest W, Lee M, Hickey A, Chaux A, Kass R, Blanche C, Matloff J, Morgenstern L, Ganz W, Swan HJC, Forrester J. Coronary angioscopy in patients with unstable angina pectoris. N Eng J Med 1986;315:913-919.

13. Folts Jd, University of Wisconsin, Madison, WI. Personal Communication.

14. Mickelson JK, Simpson PJ, Lucchesi BR. Antiplatelet monoclonal F(ab’)₂ antibody directed against the platelet GPIIb/IIIa receptor complex prevents coronary artery thrombosis in the canine heart. J Mol Cell Cardiol 1989;21:393-405.

15. Bates ER, McGillem MJ, Mickelson JK, Pitt B, Mancini GBJ. A monoclonal antibody against the platelet glycoprotein IIb/IIIa receptor complex prevents platelet aggregation and thrombosis in a canine model of coronary angioplasty. Circ 1991;84:2463-2469.

16. Yasuda T, Gold HK, Fallon JT, Leinbach RC, Guerrero JL, Scudder LE, Kanke M, Shealy D, Ross MJ, Collen D, Coller BS. Monoclonal antibody against the platelet glycoprotein (GP) IIb/IIIa receptor prevents coronary artery reocclusion after reperfusion with recombinant tissue-type plasminogen activator in dogs. J Clin Invest 1988;81:1284- 1291.

17. Gold HK, Coller BS, Yasuda T, Saito T, Fallon JT, Guerrero JL, Leinbach RC, Ziskind AA, Collen D. Rapid and sustained coronary artery recanalization with combined bolus injection of recombinant tissue-type plasminogen activator and monoclonal antiplatelet GPIIb/IIIa antibody in a canine preparation. Circ 1988;77:670-677.

18. Ziskind AA, Gold HK, Yasuda T, Kanke M, Guerrero JL, Fallon JT, Saito T, Collen D. Synergistic combinations of recombinant human tissue-type plasminogen activator and human single-chain urokinase-type plasminogen activator. Circ 1989;79:393-399.

19. Yasuda T, Gold HK, Leinbach RC, Saito T, Guerrero JL, Jang I-K, Holt R, Fallong JT, Collen D. Lysis of plasminogen activator-resistant platelet-rich coronary artery thrombus with combined bolus injection of recombinant tissue-type plasminogen activator and antiplatelet GPIIb/IIIa antibody. J Am Coll Card 1990;16:1728-1735.

20. Fitzgerald DJ, Wright F, Fitzgerald GA. Increased thromboxane biosynthesis during coronary thrombolysis. Circ Res 1989;65:83-94.

21. Kohmura C, Gold HK, Yasuda T, Holt R, Nedelman MA, Guerrero JL, Weisman HF, Collen D. A chimeric murine/human antibody Fab fragment directed against the platelet GPIIb/IIIa receptor enhances and sustains arterial thrombolysis with recombinant tissuetype plasminogen activator in baboons. Artherio Thromb 1993;13:1837-1842.

22. Gold HK, Gimple LW, Yasuda T, Leinbach RC, Werner W, Jordan R, Berger H, Collen D, Coller B. Pharmacodynamic study of F(ab’)₂ fragments of murine monoclonal antibody 7E3 directed against human platelet glycoprotein IIb/IIIa in patients with unstable angina pectoris. J Clin Invest 1990;86:651-659.

Overdose Information for ReoPro

There has been no experience of overdosage with ReoPro^® (abciximab) in human clinical trials. However, refer to Reversal of Antiplatelet Effects in the WARNINGS AND PRECAUTIONS section.

For management of a suspected drug overdose, contact your regional Poison Control Centre.

Contraindications for ReoPro

• ReoPro^® (abciximab) should not be administered to patients with known sensitivity to ReoPro^®, to murine monoclonal antibodies, or to any component of the product. For a complete listing, see the Dosage Forms, Composition And Packaging section of the product monograph.
• ReoPro^® is contraindicated in the following clinical situations: active internal bleeding; recent (within six weeks) gastrointestinal or genitourinary bleeding of clinical significance; history of cerebrovascular accident (CVA) within two years or a CVA with a significant residual neurological deficit; recent (within six weeks) major surgery or trauma; intracranial neoplasm, arteriovenous malformation or aneurysm; known bleeding diathesis or severe uncontrolled hypertension; pre-existing thrombocytopenia; vasculitis; use of intravenous dextran before percutaneous transluminal coronary angioplasty or atherectomy (PTCA), or intent to use it during PTCA; administration of oral anticoagulants within seven days unless prothrombin time is ≤ 1.2 times control.