PRODUCT MONOGRAPH

INTEGRILIN (r) Injection (eptifibatide) Solution for Intravenous Injection Platelet Aggregation Inhibitor Date of Preparation: SCHERING CANADA INC. September 22, 2005 3535 Trans Canada Pointe-Claire, Quebec H9R 1B4 Control#: 101191

(r) Registered trademark of Millennium Pharmaceuticals, Inc. Lic. User Schering Canada Inc..

INTEGRILIN Injection (eptifibatide)

Solution for Intravenous Injection

Platelet Aggregation Inhibitor

ACTION AND CLINICAL PHARMACOLOGY

GENERAL: Eptifibatide reversibly inhibits platelet aggregation by preventing the binding of fibrinogen, von Willebrand factor and other adhesive ligands to glycoprotein IIb/IIIa (GP IIb/IIIa). When administered intravenously, eptifibatide inhibits ex vivo platelet aggregation in a dose- and concentration-dependent manner. Platelet aggregation inhibition is reversible following cessation of eptifibatide; this is thought to result from dissociation of eptifibatide from the platelet receptor. PHARMACODYNAMICS: Eptifibatide inhibits platelet aggregation induced by adenosine diphosphate (ADP) and other agonists in a dose- and concentration-dependent manner. The effect of eptifibatide is observed immediately after administration of a 180 :g/kg intravenous bolus. When followed by a 2.0 :g/kg/min continuous infusion, this regimen produces a >80% inhibition of 20 :M ADP-induced ex vivo platelet aggregation, (at physiologic calcium concentrations) in more than 80% of patients, after more than 8 hours of infusion. Platelet inhibition was reversed, with a >50% return of platelet function towards baseline 4 hours after discontinuation of an infusion of 2.0 :g/kg/min. The eptifibatide dosing regimen used in the ESPRIT study was similar to that used in the PURSUIT study (a 180 :g/kg bolus followed by a 2.0 :g/kg/min infusion), but added a second 180 :g/kg bolus ten minutes after the first bolus to avoid a transient decrease in platelet aggregation inhibition before reaching steady-state with the continuous 2.0 :g/kg/min infusion. This dosing regimen is recommended in order to maintain platelet aggregation inhibition above 80% in the early time points when percutaneous coronary intervention (PCI) is performed (see PHARMACOKINETICS). Administration of eptifibatide by intravenous bolus and infusion to healthy male subjects causes up to a 5-fold increase in bleeding time, which is reversible upon discontinuation of the infusion with bleeding times returning toward baseline within 4 to 6 hours. When administered alone, eptifibatide has no measurable effect on prothrombin time (PT) or activated partial thromboplastin time (aPTT) (see also PRECAUTIONS; DRUG INTERACTIONS). There were no important differences between age groups on the inhibition by eptifibatide of adenosine diphosphate-induced platelet aggregation. Differences among ethnic groups have not been assessed.

PHARMACOKINETICS:

The pharmacokinetics of eptifibatide are linear and dose- proportional for bolus doses ranging from 90 to 250 :g/kg and infusion rates from 0.5 to

3.0 :g/kg/min. The administration of a single bolus followed by an infusion produces an early peak level, followed by a small decline until steady state plasma concentrations are achieved (within 4-6 hours). In situations in which continuous inhibition is critical during the first 1-2 hours, e.g., when PCI is performed, this decline can be prevented by administering a second 180 :g/kg bolus ten minutes after the first. Plasma elimination half-life is approximately 2.5 hours. The extent of eptifibatide binding to human plasma protein is about 25%. In patients with unstable angina/non-ST-segment elevation myocardial infarction (UA/NSTEMI), plasma clearance is 55 mL/kg/h and the volume of distribution is approximately 185 mL/kg. In healthy subjects, renal clearance accounts for approximately 50% of total body clearance, with the majority of the drug excreted in the urine as eptifibatide, deamidated eptifibatide, and other more polar metabolites. No major metabolites have been detected in human plasma. Total drug clearance is decreased by approximately 50% and steady-state plasma eptifibatide concentrations are doubled in patients with an estimated creatinine clearance of <50 mL/min (using the Cockcroft-Gault equation) (see DOSAGE AND ADMINISTRATION for the Cockcroft-Gault equation). Clinical studies have included 2,418 patients with serum creatinine between 1.0 and 2.0 mg/dL (for the 180 :g/kg bolus followed by a 2.0 :g/kg/min infusion) and 7 patients with serum creatinine between 2.0 and 4.0 mg/dL (for the 135 :g/kg bolus and the 0.5 :g/kg/min infusion), without dose adjustment. An additional 8 patients with serum creatinine between 2.0 and 4.0 mg/dL were enrolled in the ESPRIT study and received an intravenous bolus of 180 :g/kg, immediately followed by a continuous infusion of 1.0 :g/kg/min and a second 180 :g/kg bolus administered ten minutes after the first.

Special Populations

: Patients in clinical studies were older than the subjects in clinical pharmacology studies, and they had lower total body clearance and higher eptifibatide plasma levels. However, clinical studies were conducted in patients with UA/NSTEMI ranging in age from 20 to 94 years, without dose adjustment for age. Limited data are available for patients over 75 years of age weighing less than 50 kg. Men and women showed no important differences in the pharmacokinetics of eptifibatide.

CONTRAINDICATIONS

Treatment with eptifibatide is contraindicated in patients with: A history of bleeding diathesis, or evidence of active abnormal bleeding within the previous 30 days. Severe hypertension (systolic blood pressure >200 mm Hg or diastolic blood pressure >110 mm Hg) not adequately controlled on antihypertensive therapy. Major surgery within the preceding 6 weeks. History of stroke within 30 days or any history of hemorrhagic stroke. Current or planned administration of another parenteral GP IIb/IIIa inhibitor. Dependency on renal dialysis. Known hypersensitivity to any component of the product. Clinically significant liver disease.

WARNINGS

BLEEDING: Bleeding is the most common complication encountered during INTEGRILIN (eptifibatide) therapy. Administration of INTEGRILIN is associated with an increase in major and minor bleeding, as classified by the Thrombolysis in Myocardial Infarction Study group (TIMI) criteria (see ADVERSE REACTIONS). Most major bleeding associated with INTEGRILIN has been at the arterial access site for cardiac catheterization or from the gastrointestinal or genitourinary tract. All potential bleeding sites (e.g., catheter insertion sites, arterial, venous or needle puncture sites; cutdown sites; gastrointestinal, genitourinary and retroperitoneal sites) should be observed carefully. In patients undergoing PCI, patients receiving INTEGRILIN experienced an increase in major bleeding compared to those receiving placebo without a significant increase in transfusion requirement. Special care should be employed to minimize the risk of bleeding among these patients (see PRECAUTIONS). IF BLEEDING CANNOT BE CONTROLLED WITH PRESSURE, INFUSION OF INTEGRILIN AND ANY CONCOMITANT HEPARIN SHOULD BE STOPPED IMMEDIATELY. Clinical data suggest that the risk of major and minor bleeding due to INTEGRILIN therapy may be increased in patients weighing less than 70 kg.

PLATELET COUNT <100,000/mm3:

Because it is an inhibitor of platelet aggregation, caution should be exercised when administering eptifibatide to patients with a platelet count

<100,000/mm3; there has been no clinical experience with eptifibatide initiated in patients with a platelet count <100,000/mm3.

PRECAUTIONS

BLEEDING:

Coronary artery bypass grafting (CABG)

: Treatment with INTEGRILIN (eptifibatide) is not associated with an increase in bleeding in association with CABG. INTEGRILIN infusion should be discontinued prior to undergoing CABG.

Percutaneous coronary intervention - Care of the femoral artery access site

: Treatment with INTEGRILIN is associated with an increase in major and minor bleeding particularly at the site of arterial access for femoral sheath placement. In patients undergoing PCI, INTEGRILIN infusion should be continued for up to 18-24 hours post-procedure or until hospital discharge, whichever comes first. Heparin use is discouraged after the PCI procedure. The femoral artery sheath may be removed during treatment with INTEGRILIN. It is recommended that heparin be discontinued 3-4 hours prior to sheath removal and a decline in aPTT to <45 seconds or activated clotting time (ACT) to <150 seconds be documented. Heparin and INTEGRILIN should be discontinued and sheath hemostasis should be achieved at least 2-4 hours before hospital discharge.

Maintaining Target aPTT and ACT

: The aPTT should be maintained between 50 and 70 seconds unless PCI is to be performed. For angioplasty done during the PURSUIT study, a target ACT of 300 to 350 seconds was stipulated. Patients receiving an INTEGRILIN 180 :g/kg bolus followed by a 2 :g/kg/min infusion experienced an increased incidence of bleeding relative to placebo, primarily at the femoral access site. The ESPRIT study stipulated a target ACT of 200 to 300 seconds during intracoronary stenting. Patients receiving an INTEGRILIN 180 :g/kg bolus followed by a 2 :g/kg/min infusion and a second 180 :g/kg bolus ten minutes after the first (mean ACT 284 seconds) experienced an increased incidence of bleeding relative to placebo (mean ACT 276 seconds), primarily at the femoral artery access site. At these lower ACTs, bleeding was less than previously reported with eptifibatide in the PURSUIT and IMPACT II studies. Moreover, there was little increase in transfusion requirements.

PRIDE was a randomized, placebo-controlled, multi-center trial conducted in 126 patients with coronary artery disease undergoing angioplasty, prior to the PURSUIT study. The pharmacodynamics of three dosing regimens of INTEGRILIN were assessed. All infusions were continued for 24 hours post-angioplasty. The incidence of bleeding events in patients receiving INTEGRILIN as a 180 :g/kg bolus and 2 :g/kg/min infusion and heparin targeted at an ACT of 200-250 was similar to that seen in patients receiving placebo and heparin targeted at an ACT of 300-350 seconds. The study was not powered to assess clinical efficacy. The aPTT or ACT should be checked prior to arterial sheath removal. The sheath should not be removed unless the aPTT is <45 seconds or the ACT is <150 seconds.

Table 1

displays the risk of major bleeding according to the maximum aPTT attained within 72 hours in the PURSUIT study.

Table 1

Major Bleeding by Maximal aPTT Within 72 Hours in the PURSUIT Study

Maximum aPTT (seconds)

Placebo

n (%)

Eptifibatide

180 :g/kg bolus,

2.0 :g/kg/min infusion

n (%)

< 50 44/721 (6.1%) 44/743 (5.9%)

50-70 (recommended) 92/908 (10.1%) 99/883 (11.2%)

>70 281/2,786 (10.1%) 345/2,811 (12.3%)

Care of puncture sites

: Arterial and venous punctures, intramuscular injections, and the use of urinary catheters, nasotracheal intubation, nasogastric tubes, and automatic blood pressure cuffs should be minimized. When obtaining intravenous access, non-compressible sites (e.g., subclavian or jugular veins) should be avoided. Document and monitor vascular puncture sites. Consider using saline or heparin locks for blood drawing. Remove dressings gently.

Laboratory Monitoring

: Before infusion of INTEGRILIN, the following tests should be conducted: platelet count, hematocrit or hemoglobin, serum creatinine and PT/aPTT. In patients undergoing PCI, the ACT should also be measured in patients who have already received heparin. During and following INTEGRILIN treatment, platelet counts and extent of heparin anticoagulation, as assessed by ACT, should be monitored closely. Platelet counts should be monitored 2 to 4 hours following administration of the INTEGRILIN bolus, and at 24 hours post-infusion termination or prior to patient discharge, whichever occurs first.

Thrombocytopenia: If a patient experiences a platelet decrease (<100,000/mm3), additional platelet counts should be determined (see ADVERSE REACTIONS, Tables 9, 10 and 11). If thrombocytopenia is confirmed, INTEGRILIN and heparin should be discontinued immediately and the condition appropriately monitored and treated. From post market experience, acute thrombocytopenia has been reported. Upon discontinuation of Integrilin, acute thrombocytopenia has been reported to be reversible. The rapid reversibility of the pharmacologic action is due to the short plasma half-life of INTEGRILIN (approximately 2.5 hours) and the rapid disassociation of INTEGRILIN from the platelet receptor GP IIb/IIIa.

Prolongation of bleeding time

: Administration of INTEGRILIN by intravenous bolus and infusion causes up to a 5-fold increase in bleeding time. This increase is reversible upon discontinuation of the infusion with bleeding times returning towards baseline within 4 to 6 hours. When administered alone, INTEGRILIN has no measurable effect on prothrombin time (PT) or activated partial thromboplastin time (aPTT).

RENAL IMPAIRMENT:

ADMINISTRATION DOSAGE AND

Renal and non-renal clearance of eptifibatide account for approximately 50% each. Total drug clearance is decreased by approximately 50% and steady-state plasma eptifibatide concentrations are doubled in patients with an estimated creatinine clearance of <50 mL/min (using Cockcroft-Gault equation) (see

for the Cockcroft-Gault equation).

Therefore, the infusion dose should be reduced to 1.0 :g/kg/min in such patients or, if an estimated creatinine clearance is not available, in patients with a serum creatinine >2.0 mg/dL. No clinical data are available for patients dependent on renal dialysis. In vitro studies have indicated that eptifibatide may be cleared from plasma by dialysis.

PREGNANCY:

Reproduction and teratology studies have been performed by continuous intravenous infusion of eptifibatide in pregnant rats at total daily doses of up to 72 mg/kg/day (24 times the recommended maximum daily human dose of 3 mg/kg/day) and pregnant rabbits at total daily doses of up to 36 mg/kg/day (12 times the recommended maximum daily human dose). These studies revealed no evidence of impaired fertility or harm to the fetus due to eptifibatide. Eptifibatide has been shown to cross the placenta in pregnant rats. There are, however, no adequate and well-controlled studies in pregnant women with eptifibatide. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.

NURSING MOTHERS:

It is not known whether eptifibatide is excreted in human milk. Therefore, nursing should be discontinued during the period of drug administration.

PEDIATRIC USE:

Safety and effectiveness of eptifibatide in children have not been established.

USE IN ELDERLY: Table 2

Table 3

and

show bleeding events and transfusions for patients

$65 years old and $75 years old, respectively, in the PURSUIT study. The incidence of bleeding complications was higher in the elderly in both placebo and eptifibatide groups, and the incremental risk of eptifibatide-associated bleeding was greater in older patients. No dose adjustment was made in the elderly population, but patients over 75 years of age had to weigh at least 50 kg to be enrolled in the PURSUIT study; no such limitation was stipulated in the ESPRIT study (see ADVERSE REACTIONS).

Table 2

Bleeding Events and Transfusions Within 30 Days of Randomization for Patients $65 Years Old PURSUIT Study

a: For major and minor bleeding, patients are counted only once according to the most severe classification.

b: Includes transfusions of any type: whole blood, packed red blood cells, fresh frozen plasma, cryoprecipitate, platelets, and autotransfusion during the initial hospitalization.

c: Incidence in patients with sufficient clinical information to determine bleeding status.

Table 3

Bleeding Events and Transfusions Within 30 Days of Randomization for Patients $75 Years Old PURSUIT Study

a: For major and minor bleeding, patients are counted only once according to the most severe classification.

b: Includes transfusions of any type: whole blood, packed red blood cells, fresh frozen plasma, cryoprecipitate, platelets, and autotransfusion during the initial hospitalization.

c: Incidence in patients with sufficient clinical information to determine bleeding status.

DRUG INTERACTIONS: INTEGRILIN has been studied concomitantly with heparin and ASA (see CLINICAL TRIALS). The use of INTEGRILIN, in combination with heparin and ASA, has been associated with an increase in bleeding compared to heparin and ASA alone. Because eptifibatide inhibits platelet aggregation, caution should be employed when it is used with other medications that affect hemostasis, including thrombolytics, oral anticoagulants, non-steroidal anti-inflammatory drugs, dipyridamole, ticlopidine and clopidogrel. To avoid potentially additive pharmacological effects, concomitant treatment with other inhibitors of platelet receptor GP IIb/IIIa should be avoided. In the ESPRIT study, clopidogrel or, in a few cases, ticlopidine were used routinely starting the day of intracoronary stenting. Bleeding events were more frequent in patients receiving concurrent heparin while undergoing PCI when ACT exceeded 350 seconds (see PRECAUTIONS).

Thrombolytics

: Limited data are available on the use of INTEGRILIN with thrombolytic agents. In a 180 patient study with the accelerated alteplase regimen, the coadministration of INTEGRILIN up to 180 :g/kg and 0.75 :g/kg/min did not increase the incidence of major bleeding or transfusions compared to patients receiving alteplase alone. In another 181 patient study with streptokinase (1.5 million units over 60 minutes), the coadministration of increasing INTEGRILIN doses was well tolerated up to an infusion rate of 1.3 and 2.0

:g/kg/min, where there was an increased incidence of bleeding and transfusions. Based on the limited data on the use of INTEGRILIN in patients receiving thrombolytic agents, the bleeding risk due to combination with thrombolytic therapy cannot be estimated. Therefore, the concomitant treatment with thrombolytic agents should be used judiciously after the risk and benefit are carefully assessed for individual patients by the physician. Lastly, experience in 40 patients who received a combination of full dose INTEGRILIN (180 :g/kg and 2.0 :g/kg/min) and full dose thrombolytic therapy revealed a 25% incidence of major bleeding events.

Pharmacokinetic and Pharmacodynamic Interaction with Enoxaparin

: The use of enoxaparin dosed as a 1.0 mg/kg subcutaneous injection every 12 hours in place of unfractionated heparin did not alter the pharmacokinetics of eptifibatide or the level of platelet aggregation inhibition.

SYMPTOMS AND TREATMENT OF OVERDOSAGE

Potentially, an overdose of INTEGRILIN (eptifibatide) could result in bleeding. Because of its short half-life and rapid clearance, the activity of INTEGRILIN may be halted readily by discontinuing the infusion. INTEGRILIN can also be dialyzed. In certain cases, treatment of overdose may require transfusion. There was no indication of severe adverse events associated with administration of accidental large bolus doses, rapid infusion reported as overdose, or large cumulative doses. There has been only limited experience with overdosage of eptifibatide. There were 9 patients in the PURSUIT study, 8 patients in the IMPACT II study and no patient in the ESPRIT study who received bolus doses and/or infusion doses more than double those called for in the protocols. In the PURSUIT study, there was no excessive bleeding in any of these patients, although one patient undergoing CABG was reported as having had a moderate bleed. None of these patients experienced an intracranial bleed or other major bleeding.

DOSAGE AND ADMINISTRATION

Unstable angina/non-ST-segment elevation myocardial infarction

The recommended adult dosage of INTEGRILIN (eptifibatide) in patients with UA/NSTEMI is an intravenous bolus of 180 :g/kg (as soon as possible following diagnosis), followed immediately by a continuous infusion of 2.0 :g/kg/min until hospital discharge or initiation of CABG surgery, up to 72 hours. If a patient undergoes PCI, INTEGRILIN infusion should be continued until hospital discharge or for up to 18-24 hours after the procedure, whichever comes first, allowing for 96 hours of therapy. Patients weighing more than 121 kg should receive a maximum bolus of 22.6 mg (11.3 mL of the 2 mg/mL injection) followed by a maximum infusion rate of 15 mg (20 mL of the 0.75 mg/mL injection) per hour. The recommended adult dosage of eptifibatide in patients with an estimated creatinine clearance (using the Cockcroft-Gault equation) of <50 mL/min or, if creatinine clearance is not available a serum creatinine >2.0 mg/dL, is an intravenous bolus of 180 :g/kg as soon as possible following diagnosis, immediately followed by a continuous infusion of 1.0 :g/kg/min (see DOSAGE AND ADMINISTRATION for the Cockcroft-Gault equation). Patients weighing more than 121 kg should receive a maximum bolus of 22.6 mg (11.3 mL of the 2 mg/mL injection) followed by a maximum infusion rate of 7.5 mg (10 mL of the 0.75 mg/mL injection) per hour.

Percutaneous coronary intervention

The recommended adult dosage of INTEGRILIN is an intravenous bolus of 180 :g/kg administered immediately before the initiation of PCI followed by a continuous infusion of 2.0 :g/kg/min and a second 180 :g/kg bolus 10 minutes after the first bolus. Infusion should be continued until hospital discharge or for up to 18-24 hours, whichever comes first. A minimum of 12 hours of infusion is recommended. Patients weighing more than121 kg should receive a maximum of 22.6 mg (11.3 mL of the 2 mg/mL injection) per bolus followed by a maximum infusion rate of 15 mg (20 mL of the 0.75 mg/mL injection) per hour. The recommended adult dose of eptifibatide in patients with an estimated creatinine clearance (using the Cockcroft-Gault equation) of <50 mL/min or, if creatinine clearance is not available a serum creatinine >2.0 mg/dL, is an intravenous bolus of 180 :g/kg administered immediately before the initiation of the procedure, immediately followed by a continuous infusion of 1.0 :g/kg/min and a second 180 :g/kg bolus administered 10 minutes after the first (see DOSAGE AND ADMINISTRATION for the Cockcroft-Gault equation). Patients weighing more than 121 kg should receive a maximum bolus of 22.6 mg (11.3 mL of the 2 mg/mL injection) followed by a maximum infusion rate of 7.5 mg (10 mL of the 0.75 mg/mL injection) per hour. In patients who undergo coronary artery bypass graft surgery, eptifibatide infusion should be discontinued prior to surgery. Using the Cockcroft-Gault equation, creatinine clearance is calculated as: Males: (140 - age) x (body weight in kg) 72 x (serum creatinine) Females: (140 - age) x (body weight in kg) x (0.85) 72 x (serum creatinine)

HEPARIN AND ASA DOSING RECOMMENDATIONS:

In the PURSUIT, IMPACT II and

ESPRIT trials, most patients received concomitant ASA and heparin (see CLINICAL TRIALS).

Unstable angina/non-ST-segment elevation myocardial infarction

ASA

: 160 - 325 mg, given orally, initially and daily thereafter.

Heparin

: Target aPTT 50 - 70 seconds during medical management

• if weight $70 kg, 5,000 U bolus followed by infusion of 1,000 U/h.

• if weight <70 kg, 60 U/kg bolus followed by infusion of 12 U/kg/h.

Target ACT 200 - 300 seconds during PCI If heparin is initiated prior to PCI, additional boluses during PCI to maintain an ACT target of 200 - 300 seconds. Heparin infusion after the PCI is discouraged.

Percutaneous coronary intervention

ASA

: 160 - 325 mg po 1 - 24 hours prior to PCI and daily thereafter.

Heparin

: Target ACT 200 - 300 seconds

• 60 U/kg bolus initially in patients not treated with heparin within 6 hours prior to PCI.

• Additional boluses during PCI to maintain ACT within target.

• Heparin infusion after the PCI is strongly discouraged.

Patients requiring thrombolytic therapy should have eptifibatide infusions stopped (see PRECAUTIONS; THROMBOLYTICS).

Instructions for Administration

1. Like other parenteral drug products, INTEGRILIN (eptifibatide) solutions should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

2. INTEGRILIN may be administered in the same intravenous line as alteplase, atropine, dobutamine, heparin, lidocaine, meperidine, metoprolol, midazolam, morphine, nitroglycerin, or verapamil. INTEGRILIN should not be administered through the same intravenous line as furosemide.

3. INTEGRILIN may be administered in the same IV line with 0.9% NaCl or 0.9% NaCl/5% dextrose. With either vehicle, the infusion may also contain up to 60 mEq/L of potassium chloride. No incompatibilities have been observed with intravenous administration sets. No compatibility studies have been performed with PVC bags.

4. The bolus dose(s) of INTEGRILIN should be withdrawn from the 10-mL vial into a syringe. The bolus dose(s) should be administered by IV push.

5. Immediately following the bolus dose administration, a continuous infusion of INTEGRILIN should be initiated. When using an intravenous infusion pump, INTEGRILIN should be administered undiluted directly from the 100- mL vial. The 100-mL vial should be spiked with a vented infusion set. Care should be taken to center the spike within the circle on the stopper top.

INTEGRILIN is to be administered by volume according to patient weight. Patients should receive INTEGRILIN according to the following table:

PHARMACEUTICAL INFORMATION

DRUG SUBSTANCE:

Eptifibatide is a cyclic heptapeptide containing six amino acids and one mercaptopropionyl (des-aminocystinyl) residue. It is produced by solution-phase peptide synthesis, and is purified by preparative reverse-phase high pressure liquid chromatography and lyophilized.

Proper Name

: Eptifibatide

Chemical Name: N6 -(aminoiminomethyl)-N2 -(3-mercapto-1-oxopropyl-L- lysylglycyl-L-"-aspartyl-L-tryptophyl-L-prolyl-L-cysteinamide, cyclic(1-6)-disulfide.

Structural Formula: Molecular Formula: C35H49N11O9S2 Molecular Weight: 832

Description

: Eptifibatide is a white non-crystalline solid that is soluble in polar

and aqueous solvents and is insoluble in non-polar solvents.

pH

: Between 5.0 and 5.5 with citrate buffer

Melting point

: Since eptifibatide is an amorphous powder, it does not have a

true melting point.

COMPOSITION:

INTEGRILIN is a clear, colorless, sterile, non-pyrogenic solution for intravenous (IV) use. Each 10-mL vial contains 2 mg/mL of eptifibatide in a 25 mM citric acid

buffer, pH 5.0 to 5.5 and each 100-mL vial contains 0.75 mg/mL of eptifibatide in a 25 mM citric acid buffer, pH 5.0 to 5.5. Inactive ingredients: citric acid monohydrate, sodium hydroxide (used for adjusting pH), and water for injection.

COMPATIBILITY:

INTEGRILIN may be administered in the same IV line with the following IV solutions: 0.9% NaCl, 0.9% NaCl and 5% dextrose and with IV solutions containing up to 60 mEq potassium chloride per liter. No incompatibilities have been observed with intravenous administration sets. No compatibility studies have been performed with PVC bags. Physical and chemical compatibility testing indicate that INTEGRILIN may be administered through an intravenous line with alteplase, atropine, dobutamine, heparin, lidocaine, meperidine, metoprolol, midazolam, morphine, nitroglycerin, or verapamil.

INTEGRILIN should not be administered through an intravenous line with furosemide. STABILITY AND STORAGE RECOMMENDATIONS: Vials should be stored refrigerated at 2-8degC. Vials may be transferred to controlled room temperature storage (25degC with excursions permitted between 15-30oC) protected from light, for a period not to exceed 2 months. Upon transfer, vials must be marked with a "DISCARD BY" date (2 months from the transfer date), which may not exceed the labeled expiration date.

AVAILABILITY OF DOSAGE FORMS

INTEGRILIN (eptifibatide) Injection is supplied as a sterile solution: 10-mL vial containing 20 mg of eptifibatide (2.0 mg/mL) 100-mL vial containing 75 mg of eptifibatide (0.75 mg/mL) Vials are for single use.

PHARMACOLOGY

ANIMAL PHARMACOLOGY

The antithrombotic efficacy of INTEGRILIN (eptifibatide) Injection was evaluated in a well- defined canine model of coronary artery thrombosis known as the Folts Model. Eptifibatide was found to inhibit in vitro canine platelet aggregation with an IC50 of 1.9 :M. Eptifibatide, at doses of 1, 2, or 4 :g/kg/min, inhibited the cyclic flow reductions (and thus thrombus formation) within 20 minutes of starting the infusion. In another canine study, eptifibatide inhibited ex vivo platelet aggregation at doses of 2- 10 :g/kg/min and increased bleeding at doses of 5-10 :g/kg/min. Eptifibatide accelerated the rate of rt-PA-induced thrombolysis and reduced reocclusion. The hematological effects of a continuous infusion of eptifibatide at 3.5, 5 and 10 :g/kg/min were determined in the baboon. After approximately 25 min, the infusion of eptifibatide caused a dose-dependent inhibition of platelet aggregation with complete inhibition being achieved at infusion rates greater or equal to 5 :g/kg/min. In addition, eptifibatide at a continuous dose of 5 :g/kg/min and 10 :g/kg/min caused a dose-dependent prolongation of bleeding time. In a second baboon study, eptifibatide alone increased bleeding time from 4.4 min to 7.3, 11.7, and >30 min at 0, 5, 10, and 20 :g/kg/min, respectively. Heparin alone and ASA alone did not affect bleeding time. The combination of eptifibatide (5 :g/kg/min) with ASA and heparin produced a prolongation of bleeding time to 21.7 and 26.9 min, respectively. PHARMACOKINETICS: In rats, plasma concentrations of 14C-eptifibatide-derived radioactivity declined rapidly with a terminal phase half-life (t1/2) of about 5 hours following a single 2 mg/kg IV dose of the radiolabeled drug. Unchanged eptifibatide declined with an apparent t1/2 of about 8 min. Following single 2 and 20 mg/kg IV doses, the plasma concentrations of eptifibatide were dose-proportional and the t1/2 (11 to 12 min) was dose- independent, indicating linear kinetics within the 2 to 20 mg/kg dose range. In Cynomolgus monkeys, plasma concentrations of 14C-eptifibatide-derived radioactivity declined with a t1/2 of about 12 hours following a single 2 mg/kg IV dose of 14C-eptifibatide. Unchanged eptifibatide, which accounted for approximately 93% of total plasma 14C at 5 min post-dose, was eliminated rapidly with a t1/2 of 17 min. At 2 hours post-dose, approximately 2% of plasma 14C was due to unchanged drug. Excretion of 14C-eptifibatide-derived radioactivity was rapid in both rats and monkeys, and occurred primarily in the urine. In rats, approximately 14% of the radioactive dose was estimated to undergo enterohepatic circulation before being eliminated. Approximately 11 to 12% of the 14C-eptifibatide dose was eliminated as 14CO , and this appeared to be independent of the position of the 14C label in the molecule. However, the loss of 14C seemed to occur primarily from the portion of the 14C-eptifibatide dose undergoing enterohepatic circulation. Approximately 71% of the 14C dose was recovered in urine and feces of Cynomolgus monkeys, suggesting that in this species, as in rats, a significant amount of the dose administered may have been eliminated as 14CO . Following 3-day continuous IV infusion of eptifibatide in rats and Cynomolgus monkeys at the doses (1.44 to 72 mg/kg/day for rats and 1.44 to 18 mg/kg/day for monkeys) used in the 28-day continuous IV infusion toxicology studies, steady-state plasma concentrations were reached by 0.5 hour in rats and 8 hours in monkeys, and were dose-related. At termination of the IV infusion, the plasma drug concentrations declined rapidly with an apparent half-life of about 0.5 hour in rats and 1.2 to 1.5 hour in monkeys. Eptifibatide was found to bind poorly to plasma proteins of rats (11 to 13%), rabbits (13 to 15%), Cynomolgus monkeys (17 to 19%). In all species, the binding was independent of concentration within the concentration range of 0.05 to 15 :g/mL. In male rats, 14C-eptifibatide-derived radioactivity distributed rapidly into tissues, with the highest concentrations generally observed at the first evaluated time points (0.1 and 0.25 h) following IV administration. At 0.1 hour, the highest concentrations occurred in the urinary bladder and kidneys, and at the 0.25 hour, the highest concentrations occurred in the kidneys, content of small intestine, urinary bladder and liver. The radioactivity declined rapidly from all tissues. Whole-body autoradiography (WBA) confirmed the distribution pattern of 14C observed by quantitative tissue dissection. In 19-day pregnant female rats, the distribution of 14C following IV administration of 14C-eptifibatide was generally similar to that described for male rats. Maximum concentrations of 14C occurred at 0.1 hour post-dose in most maternal tissues. 14C-eptifibatide penetrated the placental barrier slowly. The maximum concentrations of 14C in fetal tissues (0.2 :g eq/g) were very low relative to the maximum concentrations observed in maternal tissues (14-24 :g eq/g).

C-eptifibatide was extensively metabolized to deamidated eptifibatide and to several polar metabolites by both rats and monkeys. The drug-derived radioactivity excreted into the bile by rats, and identified as deamidated eptifibatide, was reabsorbed from the intestinal tract and further metabolized to more polar metabolites. The plasma and urine metabolite profiles in rats and monkeys indicate that the metabolic disposition of eptifibatide is similar for the two species.

CLINICAL TRIALS

INTEGRILIN (eptifibatide) was evaluated in three placebo-controlled, randomized studies, one (PURSUIT) in patients with acute coronary syndrome (UA or NSTEMI) and two (IMPACT II and ESPRIT) in patients about to undergo PCI. Patients underwent primarily balloon angioplasty in IMPACT II and intracoronary stent placement, with or without angioplasty, in ESPRIT.

Unstable Angina/Non-ST-segment Elevation Myocardial Infarction

PURSUIT was a double-blind, randomized, placebo-controlled clinical study in 10,948 patients presenting with UA/NSTEMI, enrolled at 726 investigational centers in 27 countries. The single region with the largest contribution to enrolment was North America (United States and Canada, n=4,358). Patients were enrolled only if they had experienced cardiac ischemia at rest ($10 minutes) within the previous 24 hours and had either ST- segment changes (elevations between 0.6 mm and 1 mm or depression >0.5 mm), T-wave inversion (>1 mm), or increased CK-MB. Patients were randomized to either placebo or eptifibatide 180 :g/kg bolus followed by a :g/kg/min continuous infusion, or eptifibatide 180 :g/kg bolus followed by a 1.3 :g/kg/min continuous infusion. The infusion was continued for 72 hours, until hospital discharge, or until initiation of coronary artery bypass graft (CABG), whichever occurred first. If coronary angioplasty was performed, the eptifibatide infusion was continued for 24 hours after the procedure, allowing for a duration of infusion up to 96 hours. As prescribed by the protocol, the lower infusion-rate arm was discontinued after the first interim analysis when the two active-treatment arms showed similar safety profiles (incidence of bleeding). Patients' age ranged between 20 and 94 (mean 63) years, and 65% were male. The patients were 89% Caucasian, 5% Black, 5% Hispanic, and 1% others. Forty percent of patients were enrolled in North America, 39% in Western Europe, 16% in Eastern Europe, and 4% in Latin America. PURSUIT was a "real world" study with each patient managed according to the usual standards of the investigational site. Therefore, frequencies of angiography, frequencies/timing of coronary angioplasty and CABG, use of concomitant medication (heparin and ASA) differed widely among countries and sites. In the study, 13% of patients were managed with coronary angioplasty during drug infusion and 87% were managed medically (no coronary angioplasty during infusion). The North American population represents the single, most homogenous subgroup in terms of medical management. In this population, 24% were managed with coronary angioplasty and 76% were managed medically. The majority of patients received ASA (75-325 mg once daily). Heparin was administered intravenously or subcutaneously, at the physician's discretion, usually as an intravenous bolus of 5,000 U followed by a continuous infusion of 1,000 U/h. For patients weighing less than 70 kg, the recommended heparin bolus dose was 60 U/kg followed by a continuous infusion of 12 U/kg/h. A target aPTT of 50-70 seconds was recommended. A total of 1,250 patients underwent coronary angioplasty within 72 hours after randomization, in which case they received intravenous heparin to maintain an activated clotting time (ACT) of between 300-350 seconds. The primary endpoint of the study was the occurrence of death from any cause or non-fatal myocardial infarction (MI) (evaluated by a blinded Clinical Events Committee) within 30 days of randomization. A secondary endpoint of the study was the occurrence of death from any cause or new myocardial infarction (as reported by the investigators) within 6 months of randomization. Eptifibatide administered as a 180 :g/kg bolus followed by a 2.0 :g/kg/min infusion significantly (p=0.042) reduced the incidence of death or myocardial infarction at 30 days compared to placebo (Table 13). The reduction in the incidence of death and myocardial infarction in patients receiving eptifibatide was evident early (at 72 hours; 7.6% and 5.9% for placebo and eptifibatide, respectively) during treatment and this reduction was maintained through six months (Figure 1).

Table 13

From Pearson's chi-square test of differences between placebo and eptifibatide

Compared to placebo, treatment with eptifibatide reduced the incidence of the combined endpoint, as well as its components, death and myocardial infarction. As shown in the Kaplan-Meier curve in Figure 1, investigators reported a reduction in death or MI from 13.6% with placebo to 12.1% with eptifibatide (p=0.021 log rank) within 6 months of randomization.

Figure 1:

Kaplan-Meier Curve for Time to Death or Myocardial Infarction within 6 Months of Randomization

The analysis of the PURSUIT results revealed a complex interaction between treatment and region. Figure 2 shows the odds ratio for death or nonfatal MI in various subgroups and as defined by geographic region. The results were also very heterogeneous among various geographic regions, with the greatest benefit observed in North American patients (see Factors Affecting the Outcomes in the North American Patient Population).

Figure 2:

Odds Ratios for Death or Nonfatal Myocardial Infarction at 30 Days in Selected Subgroups of Patients. The horizontal lines indicate 95% confidence intervals. MI denotes myocardial infarction, and CABG coronary- artery bypass graft surgery.

Table 14

summarizes the incidence of the primary endpoint in the worldwide and North American study population in patients who did and did not undergo coronary angioplasty within 72 hours of randomization.

Table 14

Endpoint at 30 Days for Patients With and Without Coronary Angioplasty in the First 72 Hours After Randomization PURSUIT Study

p-value <0.05 versus placebo

The incidence of death or myocardial infarction was lower in the patients treated with eptifibatide compared to placebo, regardless of whether they were managed medically or underwent coronary angioplasty. In North America, patients treated with eptifibatide and managed medically showed a statistically significant reduction in the incidence of death or MI at 30 days. Worldwide, the degree of benefit in patients managed medically was less than that seen in North America. In addition, among those patients who underwent coronary angioplasty within the first 72 hours after randomization, a reduction in the incidence of myocardial infarction was seen prior to the procedure in the patients receiving eptifibatide in the worldwide population (5.5% for placebo versus 1.8% for eptifibatide) and the North American sub-population (4.5% for placebo versus 1.7% for eptifibatide). Treatment with eptifibatide reduced clinical events in patients undergoing coronary angioplasty during drug administration and in those receiving medical management alone. Table 15 shows the incidence of death or MI within 72 hours of randomization.

Table 15

All of the effect of eptifibatide was established within 72 hours (during the period of drug infusion). Moreover, for patients undergoing early coronary angioplasty, a reduction in events was evident prior to the procedure. The benefit in coronary angioplasty patients was derived primarily from North American patients as 75% of the procedures were performed in North America.

Factors Affecting Outcomes in the North American Patient Population

: There are a number of differences between North American patients and those from the rest of the world that may potentially affect the response to treatment. The major differences arise from different medical practices during the course of the trial, as well as from different entry characteristics.

Differences that reflect practice patterns (such as early catheterization, early coronary angioplasty, and concomitant heparin/aspirin use) and those that reflect a different health status at baseline interact in a very complex manner to produce different patient prognoses.

Table 16

summarizes those variables that may reflect important differences in practice patterns or patient populations. In brief, the North American patients had a higher incidence of concomitant anti-thrombotic therapy (both heparin and ASA), more prior and concomitant cardiovascular (diagnostic and surgical) procedures, greater history of cardiovascular disease, less severe symptoms of cardiovascular disease at presentation, lower blood pressure on admission, and weighed more.

Table 16

Variables in Practice Patterns and Patient Populations (North America vs. Outside North America) PURSUIT Study

Percutaneous Coronary Intervention

IMPACT II (INTEGRILIN to Minimize Platelet Aggregation and Prevent Coronary Thrombosis) IMPACT II, the first large study conducted with eptifibatide, was a multi-center, double-blind, randomized, placebo-controlled study conducted in the United States in 4,010 patients undergoing coronary angioplasty. Major exclusion criteria included a history of bleeding diathesis, major surgery within 6 weeks of treatment, gastrointestinal bleeding within 30 days, any stroke or structural CNS abnormality, uncontrolled hypertension, PT >1.2 times control, hematocrit <30%, platelet count <100,000/mm3, and pregnancy. Patient age ranged from 24 to 89 (mean 60) years, and 75% were male. The patients were 92% Caucasian, 5% Black, and 3% Hispanic. Forty-one percent of the patients underwent coronary angioplasty for ongoing acute coronary syndrome. Patients were randomly assigned to one of three treatment regimens, each incorporating a bolus dose initiated immediately prior to coronary angioplasty followed by a continuous infusion lasting 20-24 hours: 1) 135 :g/kg bolus followed by a continuous infusion of 0.5 :g/kg/min of eptifibatide (135/0.5); 2) 135 :g/kg bolus followed by a continuous infusion of 0.75 :g/kg/min of eptifibatide (135/0.75); or 3) a matching placebo bolus followed by a matching placebo continuous infusion. Each patient received aspirin and an intravenous heparin bolus of 100 U/kg, with additional bolus infusions of up to 2,000 additional units of heparin every 15 minutes to maintain an ACT of 300-350 seconds. The primary endpoint was the composite of death, MI, or urgent revascularization, analyzed at 30 days after randomization in all patients who received at least one dose of study drug. As shown in Table 17, each eptifibatide regimen reduced the rate of death, MI, or urgent intervention, although at 30 days, this finding was statistically significant only in the lower-dose eptifibatide group. As in the PURSUIT study, the effects of eptifibatide were seen early and persisted throughout the 30-day period.

Table 17

Clinical Events in the IMPACT II Study

* Kaplan-Meier estimate of event rate

ESPRIT (Enhanced Suppression of the Platelet IIb/IIIa Receptor with INTEGRILIN Therapy)

INTEGRILIN was evaluated in ESPRIT (Enhanced Suppression of the Platelet IIb/IIIa Receptor with INTEGRILIN Therapy), a multi-center, double-blind, randomized, placebo- controlled study conducted in the United States and Canada that enrolled 2,064 patients undergoing elective or urgent intracoronary stenting. Exclusion criteria included MI within the previous 24 hours, ongoing chest pain, administration of any oral anti-platelet or oral anticoagulant other than aspirin within 30 days of intracoronary stenting (although loading doses of thienopyridine on the day of intracoronary stenting were encouraged), planned intracoronary stenting of a saphenous vein graft or subsequent "staged" intracoronary stenting, prior stent placement in the target lesion, intracoronary stenting within the previous

90 days, a history of bleeding diathesis, major surgery within 6 weeks of treatment, gastrointestinal bleeding within 30 days, any stroke or structural CNS abnormality, uncontrolled hypertension, PT >1.2 times control, hematocrit <30%, platelet count <100,000/mm3, and pregnancy. Patient age ranged from 24 to 93 (mean 62) years and 73% of patients were male. The study enrolled 90% Caucasian, 5% African American, 2% Hispanic and 1% Asian patients. Patients were randomized either to placebo or eptifibatide administered as an intravenous bolus of 180 :g/kg followed immediately by a continuous infusion of 2.0 :g/kg/min, and a second bolus of 180 :g/kg administered 10 minutes later. Eptifibatide infusion was continued for up to 18-24 hours after intracoronary stenting or until hospital discharge, whichever came first. Each patient received at least one dose of aspirin (162-325 mg) and 60 U/kg of heparin as a bolus (not to exceed 6,000 units) if not already receiving a heparin infusion. Additional boluses of heparin (10-40 U/kg) could be administered in order to reach a target ACT between 200 and 300 seconds. Based upon this study design, ESPRIT was intended to evaluate the incremental benefits and risks of adding GP IIb/IIIa inhibitor therapy to currently employed management strategies at the time of intracoronary stenting, which include deployment of single or multiple stents of varying lengths and sizes in difficult-to-treat coronary vessels, almost universal use of thienopyridine therapy (primarily front-loaded clopidogrel) on the day of the procedure, and administration of low-dose heparin (i.e., ACT of 200-300 seconds) at time of intracoronary stenting. The primary endpoint of the ESPRIT study was the composite of death, myocardial infarction, urgent target vessel revascularization and "bail-out" to open label eptifibatide due to a thrombotic complication of intracoronary stenting (thrombotic "bail-out") (e.g., visible thrombus, "no reflow", or abrupt closure) at 48 hours. Myocardial infarction, urgent target vessel revascularization and thrombotic "bail-out" were evaluated by a blinded Clinical Events Committee. As shown in Table 18, the incidence of each of the primary endpoint and selected secondary endpoints was significantly reduced in patients who received eptifibatide. A treatment benefit in patients who received eptifibatide was seen by 48 hours and at the end of the 30-day observation period.

Table 18

The need for thrombotic "bail-out" was significantly reduced with eptifibatide at 48 hours (2.1% for placebo, 1.0% for eptifibatide; p=0.029). Consistent with previous studies of GP IIb/IIIa inhibitors, most of the benefit achieved acutely with eptifibatide was in the reduction of MI. Eptifibatide reduced the occurrence of MI at 48 hours from 9.0% for placebo to 5.4% (p=0.0015) and maintained that effect with significance at 30 days. In the ESPRIT study, diabetics did not have more major or minor bleeding, tranfusion requirement or access site complications. The efficacy of eptifibatide was similar in diabetic and non-diabetic patients. Although ESPRIT was not initially designed to study clinical outcomes for more than 30 days, the protocol was amended at the end of the original study to follow-up consenting patients (n = 2064) for a period of 1 year. This long-term observation revealed a sustained reduction in the composite endpoint of death or MI at 6 months from 11.5% in the placebo group to 7.4% in the INTEGRILIN treated group (odds ratio 0.631 [95% CI 0.473, 0.841], p = 0.0015) and at 1 year from 12.4% in the placebo group to 8.0% in the INTEGRILIN treated group (odds ratio 0.630 [95% CI 0.478, 0.832], p = 0.001). A reduction in the composite endpoint of death, MI or target vessel revascularization was also maintained at 6 months from 18.5% in the placebo group to 14.3% in the INTEGRILIN treated group (odds ratio 0.744 [95% CI 0.599, 0.924], p = 0.0072) and at 1 year from 22.1% in the placebo group to 17.5% in the INTEGRILIN treated group (odds ratio 0.762 [95% CI 0.626, 0.929], p = 0.0068). At 1 year, a consistent treatment effect was seen between patients with and without diabetes. The rate of death or myocardial infarction was 7.8% and 13.4% in the INTEGRILIN and placebo groups respectively (n=466).

TOXICOLOGY

ACUTE TOXICITY:

The safety evaluation studies conducted with eptifibatide do not indicate any evidence of unexpected significant toxic effects. Single dose toxicity studies were conducted in rats, rabbits and monkeys; doses up to 500 :g/kg/minute administered by continuous intravenous infusion for 90 minutes did not cause mortality and were well- tolerated by all species.

In rabbits, a dose-dependent decrease in platelet counts of the 50 and 500 :g/kg/minute (for 90 minutes)-dosed females was attributed to administration of eptifibatide. Findings in the monkeys were limited to petechial hemorrhages in the femoral and/or abdominal regions, which lasted for one to three days.

LONG-TERM TOXICITY:

Repeated dose studies were conducted in rats and monkeys by continuous intravenous infusion for 14 days and 28 days. The 28-day studies were followed by 14-day recovery periods. There were no findings in rats from either study attributable to the administration of eptifibatide. The no-effect level in rats was greater than 72.0 mg/kg/day (24 times the maximum recommended daily human dose of 3 mg/kg/day).

In monkeys, administration of up to 7.2 mg/kg/day of eptifibatide for 28 days by continuous intravenous infusion did not produce any sign of toxicity. One 18 mg/kg/day-dosed monkey had evidence of hemorrhage in the skeletal muscles, which may have contributed to the decreased blood cell count, hemoglobin, hematocrit, mean cell volume and mean cell hemoglobin and the increased reticulocyte count. The effects observed in the monkeys are the expected pharmacologic responses to high doses of eptifibatide. The no-toxic effect level in the 14-day monkey study was 7.2 mg/kg/day (2.4 times the maximum recommended daily human dose). The hemorrhages observed in one 7.2 mg/kg/dosed monkey were considered to be equivocal. Three out of five monkeys administered 72.0 mg/kg/day died or were sacrificed during the study due to contusions, excessive bleeding and/or petechial hemorrhages, which resulted in anemia. Total protein albumin and globulin values were reduced in all 72.0 mg/kg dosed monkeys. At necropsy, focal hemorrhages in various organs were observed. Long-term studies in animals have not been performed to determine the carcinogenic potential of eptifibatide. No carcinogenicity studies were conducted because clinical use of eptifibatide is limited to short-term intravenous dosing.

MUTAGENICITY:

The mutagenic potential of eptifibatide was tested in four assays. Eptifibatide was not genotoxic in the Ames assay at doses up to 667 :g/mL, in the mouse lymphoma cell forward mutation assay at doses up to 1,000 :g/mL, in the human lymphocyte chromosome aberrations test or in the mouse micronucleus test.

REPRODUCTION AND FERTILITY:

In a fertility study in rats, dosing with eptifibatide had no effect on the course of pregnancy. No evidence of fertility or parental toxicity nor effects upon parental reproductive performance were observed at daily doses up to 72.0 mg/kg (24 times the maximum recommended daily human dose).

TERATOLOGY:

Embryo-fetal toxicity studies in rats and rabbits showed that treatment with eptifibatide had no effect on the course of pregnancy, or embryo or fetal viability. There was no toxicologically significant maternal toxicity, embryo lethality, fetotoxicity or teratogenicity at daily doses of eptifibatide up to 72.0 mg/kg in rats or up to 36.0 mg/kg in rabbits (24 and 12 times the maximum recommended daily human dose, respectively). In a peri- and postnatal study in rats, there was no evidence of maternal toxicity at daily doses up to

72.0 mg/kg of eptifibatide. Post-weaning, physical, reflex, behavioral and reproductive development of the rats showed no eptifibatide-related effects.

LOCAL TOLERANCE:

The potential intravenous irritation of eptifibatide was studied in rabbits; no difference in the degree of erythema between eptifibatide and the vehicle-treated ears was observed at 24 or 72 hours, after a single 15-minute infusion of 10 :g/kg/min.

OTHER STUDIES:

Studies in mice and guinea pigs demonstrated that eptifibatide does not induce delayed-type hypersensitivity in mice and is not antigenic in guinea pigs.

Two in vitro studies demonstrated that eptifibatide did not produce hemolysis or plasma protein flocculation. A 14-day toxicity study of degraded eptifibatide in monkeys did not produce any signs of toxicity at daily doses up to 7.2 mg/kg. These results were similar to those of the previous 14- and 28-day toxicity studies conducted in monkeys.

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