NAME OF THE MEDICINE

Eptifibatide

Chemical structure:

Chemical Name:

cyclo(S-S)-mercaptopropionyl-L-homoarginylglycyl-L-aspartyl- L-tryptophyl-L-prolyl-L-cysteinamide

CAS Registry No. :

157630-07-4

DESCRIPTION

INTEGRILIN is a clear, colourless solution containing the acetate salt of the active ingredient, eptifibatide, a synthetic cyclic heptapeptide containing six amino acids, including one cysteine amide and one mercaptopropionyl (desamino cysteinyl) residue. It is formulated as a sterile solution for injection in two dosage administration forms, bolus injection and intravenous infusion. The bolus injection is a single dose 10 mL vial containing eptifibatide 20 mg (2 mg/mL) and the solution for intravenous infusion is a single dose 100 mL vial containing eptifibatide 75 mg (0.75 mg/mL). Each vial also contains citric acid monohydrate, sodium hydroxide and water for injections.

PHARMACOLOGY

Pharmacodynamic Properties

Eptifibatide belongs to the class of RGD (arginine-glycine-aspartate)-mimetics and binds to the platelet receptor glycoprotein (GP) IIb-IIIa of human platelets. It reversibly inhibits platelet aggregation by preventing the binding of fibrinogen, von Willebrand factor and other adhesive ligands to GP IIb-IIIa. When administered intravenously, eptifibatide inhibits ex vivo platelet aggregation in a dose- and concentration-dependent manner. Measurement of ADP-induced ex vivo platelet aggregation at physiologic calcium concentrations (D-phenylalanyl-L-propyl-L-arginine chloromethyl ketone [PPACK] anticoagulant) in patients presenting with unstable angina and non-Q-wave myocardial infarction showed a mean IC50 (50% inhibitory concentration) of 557 ng/mL and a mean IC80 (80% inhibitory concentration) of 1107 ng/mL). The effect of eptifibatide is observed immediately after administration of a 180 microgram/kg intravenous bolus. When followed by a 2.0 microgram/kg/min continuous infusion, this regimen produces a >80% inhibition of ex vivo platelet aggregation at physiologic calcium concentrations in more than 80% of patients. Platelet aggregation inhibition is reversible following cessation of the eptifibatide infusion (see Table 1).

Pharmacokinetic Properties

The pharmacokinetics of eptifibatide are linear and dose proportional for bolus doses ranging from 90 to 250 ug/kg and infusion rates from 0.5 to 3.0 ug/kg/min. In patients with coronary artery disease, the volume of distribution is estimated to be 185 to 260 mL/kg. During administration of the recommended treatment regimen, plasma concentrations of eptifibatide peak immediately after the 180 microgram/kg bolus and decline to a mean steady state level of 2.2 microgram/mL within 4-6 hours after commencement of the 2.0 microgram/kg/min infusion. The extent of eptifibatide binding to human plasma protein is about 25%. No major metabolites have been detected in human plasma, but deamination takes place in the urine. In patients with coronary artery disease, the mean clearance of eptifibatide is estimated to be 55 to 80 mL/kg/h and plasma elimination half life is approximately 2.5 hours. In healthy subjects, renal excretion accounted for approximately 50% of total body clearance. A modest increase in half-life and volume of distribution is seen with increased age, decreased weight (<74 kg) and/or decreased creatinine clearance (CrCl). The pharmacokinetics are unaffected by dose and gender. No dose adjustment of the bolus or infusion is required in the case of mild renal impairment (CrCl of >=50 mL/min using the Cockcroft-Gault equation *). Dose adjustment is recommended for cases of moderate to severe renal impairment (CrCl <50 mL/min using the Cockcroft-Gault equation *). In patients with moderate to severe renal insufficiency (CrCl <50 mL/min), the clearance of eptifibatide is reduced by approximately 50% and steady-state plasma levels are approximately doubled (see Clinical Trials, Precautions, Dosage and Administration).

Pre-clinical Data

In vitro

studies of the inhibition of ADP-induced platelet aggregation by INTEGRILIN showed marked species differences, with much higher concentrations of INTEGRILIN required for inhibition of platelet aggregation in rats and rabbits than in monkeys and humans.

Toxicology studies conducted with INTEGRILIN included single dose studies in the rat, rabbit and monkey, repeat-dose studies in the rat and monkey, reproduction studies in the rat and rabbit, and irritation, hypersensitivity and antigenicity studies. The preclinical acute and repeat dose toxicity studies have been conducted in only one animal species possessing a suitable GPIIb-IIIa receptor, namely the monkey. No unexpected toxic effects for an agent with this pharmacological profile were observed and findings were predictive of clinical experience, with bleeding and haemorrhages occurring in monkeys at high doses of INTEGRILIN. There were no effects in rats and rabbits. In the monkey, tissue and organ haemorrhages were seen at plasma eptifibatide concentrations approximating those attained in humans during therapy with the recommended dose. Preclinical studies of the concurrent use of eptifibatide with heparin and aspirin were not conducted.

Clinical Trials

INTEGRILIN has not been directly compared with abciximab or any other GPIIb-IIIa inhibitor in clinical trials.

Clinical Pharmacology Trials:

The pharmacodynamic and pharmacokinetic properties of eptifibatide were studied in subjects with various degrees of renal function1. The purpose of this study was to determine appropriate dose adjustment in patients with decreased renal function. Tolerability of eptifibatide when administered to patients with reduced renal function was also assessed. Subjects were divided into four groups according to renal function based on estimated CrCl using the Cockcroft-Gault equation (refer to Dosage and Administration). Subjects with differing renal function (normal [Group 1, CrCl >80 ml/min], mild renal impairment [Group 2, CrCl 51-80 mL/min], moderate renal impairment [Group 3, CrCl 30-50 mL/min], or severe renal impairment [Group 4, CrCl <30 mL/min]), received a 24-hour eptifibatide infusion of 2.0 ug/kg/min (Groups 1, 2, and 3) or 1.0 ug/kg/min (Group 4). A strong correlation was found between eptifibatide clearance and CrCl. In patients with moderate or severe renal impairment (CrCl <=50 mL/min), clearance rates and steady state concentrations of eptifibatide were approximately 50 % lower and almost 2-fold higher respectively, than in patients with normal renal function or mild renal impairment (CrCl >50 mL/min) (see Table 2). These findings support adjustment of the infusion dose of eptifibatide from 2.0 ug/kg/min to 1.0 ug/kg/min in patients with moderately or severely impaired renal function (see Dosage and Administration, Precautions, Pharmacokinetics).

Css = steady-state plasma eptifibatide concentration (calculated); Cmax = maximal plasma drug concentration; Cltotal

= total body clearance; Clrenal = renal eptifibatide clearance; AUC0-[?] = area under the plasma concentration-time curve from time 0 to infinity; T1/2 = terminal plasma half-life; Vl = apparent volume of distribution; Vss = apparent steady-state central volume of distribution.

+

Corrected for a 2.0 ug/kg/min infusion (actual values were 50 % of those reported in table)

++

Compartmental estimate

1 Gretler DD et al. Pharmacokinetic and pharmacodynamic properties of eptifibatide in subjects with normal or impaired renal function. Clinical Therapeutics 2004; 26:390-398.

PURSUIT Trial:

(UA/NQM)

Dose-ranging studies using clinical efficacy endpoints have not been conducted. The recommended dose of INTEGRILIN has been extrapolated from in vitro data and was shown to be effective in the PURSUIT trial. The pivotal clinical trial for unstable angina (UA)/non-Q-wave myocardial infarction (NQMI) was PURSUIT. This study was a 726-centre, 27-country, double-blind, randomised, placebo- controlled study in 10,948 patients presenting with UA or NQMI. Patients could be enrolled only if they had experienced cardiac ischaemia at rest (10 minutes) within the previous 24 hours and had:

• either ST-segment changes: ST depression > 0.5 mm of less than 30 minutes or persistent ST elevation > 0.5 mm not requiring re-perfusion therapy or thrombolytic agents, T-wave inversion (> 1 mm),

• or increased CK-MB (serum concentration of the myocardial band isoenzyme of creatine kinase).

Patients were randomised to either placebo, INTEGRILIN 180 ug/kg bolus followed by a 2 ug/kg/min infusion (180/2.0) or INTEGRILIN 180 ug/kg bolus followed by a 1.3 ug/kg/min infusion (180/1.3). The infusion was continued until hospital discharge, until the time of coronary artery bypass grafting (CABG) or for up to 72 hours, whichever occurred first. If percutaneous coronary intervention (PCI) was performed, the INTEGRILIN infusion was continued for 24 hours after the procedure, allowing for a duration of infusion up to 96 hours. The 180/1.3 arm was stopped after an interim analysis, as prespecified in the protocol, when the two active-treatment arms appeared to have a similar incidence of bleeding. This was a "real world" study; each patient was managed according to the usual standards of the investigational site, therefore, the frequencies of angiography, PCI and CABG differed widely from site to site and from country to country. INTEGRILIN was used in combination with standard medical therapies and/or percutaneous coronary intervention (PCI). Of the patients in PURSUIT, 13% were managed with PCI during INTEGRILIN infusion, of whom approximately 50% received intracoronary stents; 87% were managed medically (without PCI during infusion). The vast majority of patients received aspirin (75-325 mg once daily). Heparin was administered intravenously or subcutaneously at the physician's discretion, most commonly as an intravenous bolus of 5000 U followed by a continuous infusion of 1000 U/hour. A target aPTT of 50-70 seconds was recommended. A total of 1250 patients underwent PCI within 72 hours after randomisation, in which case they received intravenous heparin to maintain an activated clotting time (ACT) of 300-350 seconds. The primary endpoint of the study was the occurrence of death from any cause or new myocardial infarction (MI) (evaluated by a blinded Clinical Events Committee, CEC) within 30 days of randomisation. Compared to placebo, INTEGRILIN administered as 180/2.0 significantly reduced the incidence of endpoint events at 96 hours, 7 days and 30 days (Table 3). Although there was no CEC assessment of myocardial infarction after 30 days, analysis of the incidence of death/investigator-assessed myocardial infarction revealed a sustained reduction of clinical events at 6 months (see Table 4 and Figure 2). The difference in efficacy between INTEGRILIN and placebo was due primarily to differences in the rate of myocardial infarction, with a relatively small contribution from reduced mortality. Results by gender, age, weight and race are provided in Figure 1 below. Significant clinical benefit was not demonstrated in women, patients under the age of 50 and those weighing less than 74 kg.

Fig 1. Odds Ratios and 95% Confidence Intervals for Incidence of Death and CEC-Adjudicated Ml at 30 days by Gender, Age (y), Weight (kg) and Race: Eptifibatide vs Placebo (Treated as Randomised Data Set)

Compared to placebo, INTEGRILIN was associated with an excess of major bleeding episodes (10.8% vs 9.3%), minor bleeding episodes (13.1% vs 7.6%) and transfusions (12.8% vs 10.4%). CEC-assessed myocardial infarctions were identified by a computer program which flagged elevated CK test results as well as other variables (e.g., patient symptoms, ECG data). As a result, approximately half the myocardial infarctions in the endpoint "CEC-assessed MI" were not clinically evident.

Fig. 2. Kaplan-Meier Plot of Time to Death/MI After Enrolment as Assessed by the Investigators for 6 Months ("Treated as Randomised" Data Set).

ESPRIT Trial:

(PCI with stenting)

ESPRIT (Enhanced Suppression of the Platelet IIb/IIIa Receptor with INTEGRILIN Therapy) was a pivotal trial for nonurgent PCI with intracoronary stenting. This was a 92-centre, double-blind, randomised, placebo-controlled trial conducted in the United States and Canada in 2,064 patients scheduled to undergo non-urgent PCI with stent implantation in native coronary vessels. Patients were excluded from the trial if treatment had been planned with a GP IIb/IIIa inhibitor prior to the PCI. Other reasons for exclusion were: if the patient had a myocardial infarction within the previous 24 hours before randomisation, ongoing chest pain (or anginal equivalent) leading to urgent referral, PCI within the previous 90 days before randomisation or prior stent in the target lesion. All patients received routine standard of care. Patients were randomised to either placebo or INTEGRILIN, two bolus doses of 180 ug/kg and a continuous infusion until discharge from hospital or a maximum of 18-24 hours. The first bolus injection and the infusion were started simultaneously, immediately before the PCI procedure. The second bolus was administered 10 minutes after the first bolus. The rate of infusion was 2.0 ug/kg/min for patients with serum creatinine 175 umol/L or 1.0 ug/kg/min for serum creatinine 175 up to 350 umol/L. Additionally, for any patient considered to be at high risk of bleeding, the infusion rate was allowed to be decreased to 0.5 ug/kg/min; however the standard infusion dose was to have been continued for at least 12 hours. In addition, investigators had the option to discontinue study medication and start open-label eptifibatide in the event of procedural complications, such as abrupt closure, no reflow or coronary thrombosis (defined as acute antithrombotic rescue therapy). A kit was provided that contained blinded trial drug for bolus administration, enabling investigators to switch their patients to open-label eptifibatide without unblinding the initial treatment regimen. The vast majority of patients received concomitant aspirin (162 - 325 mg before the procedure and daily thereafter) and the majority received a loading dose of clopidogrel (or ticlopidine) before the PCI. All patients received clopidogrel 75 mg daily or ticlopidine 250 mg twice daily after stent implantation. The ESPRIT trial used a simplified regimen of heparin dosing during PCI as compared to the PURSUIT trial where urgent PCI was performed. For those patients not treated with heparin in the 6 hours before PCI, an initial bolus of 60 U/kg was recommended. The target ACT during the procedure was 200-300 seconds. A heparin infusion regimen after the PCI was discouraged and the early removal of the vascular access sheath (approximately 4 hours after PCI) was suggested. In patients requiring a heparin infusion after PCI however, heparin was administered at a rate of 10 U/kg/hour or 800 U/hour, whichever was less. An aPTT was obtained within 4 hours of starting the heparin infusion with an aPTT target of 50-70 seconds. The primary endpoint of the trial was death (D), MI, urgent target vessel revascularisation (UTVR) and acute antithrombotic rescue with GP IIb/IIIa inhibitor therapy (RT) within 48 hours of randomisation. An independent, blinded Clinical Events Committee was responsible for adjudicating suspected endpoint events, including MI, UTVR and acute antithrombotic rescue therapy. During this trial, MI was defined as an "enzymatic" or "adjudicated investigator" MI.

Enzymatic MI

was identified per the CK/CK-MB core laboratory criteria. Within 24 hours after the index PCI procedure, MI occurred if there was at least two CK-MB values >=3x the upper limit of normal. Myocardial infarction meeting this criterion were not adjudicated.

Adjudicated MI

is an investigator reported MI, confirmed as MI after adjudication by the CEC. The investigators were blinded to the results of the core CK-MB values.]

INTEGRILIN significantly reduced the incidence of the primary endpoint (Table 5). This benefit occurred early (within 12 hours) and was principally attributed to a reduction in MI. Secondary endpoints of the trial included D, MI, UTVR and RT at 30 days, and D and MI at 30 days (Table 5). The reduction in individual components, D, MI, UTVR, of the endpoints at 48 hours and 30 days is shown in Table 6. For the individual components, statistical significance between INTEGRILIN and placebo was reached for MI only.

An independent data safety monitoring committee (DSMC) for the ESPRIT Trial recommended that the trial be terminated prematurely because the data demonstrated overwhelming efficacy in the absence of a safety concern.

CONTRAINDICATIONS

INTEGRILIN must not be used to treat patients with: evidence of gastrointestinal bleeding, gross genitourinary bleeding or other active abnormal bleeding (except menstrual bleeding) within the previous 30 days of treatment; history of stroke within 30 days or any history of haemorrhagic stroke; known history of intracranial disease (neoplasm, arteriovenous malformation, aneurysm); major surgery or severe trauma within past 6 weeks; a history of bleeding diathesis; thrombocytopenia (<100 x 109/L); prothrombin time >1.2 times control or International Normalised Ratio (INR)>2.0; severe hypertension (systolic blood pressure >200 mm Hg or diastolic blood pressure >110 mm Hg on antihypertensive therapy); dependency on renal dialysis; clinically significant hepatic impairment; concomitant or planned administration of a thrombolytic agent; concomitant or planned administration of another parenteral GP IIb-IIIa inhibitor; hypersensitivity to the active substance or to any of the excipients.

PRECAUTIONS

Bleeding

INTEGRILIN is an antithrombotic agent that acts by inhibition of platelet aggregation; therefore the patient must be observed carefully for indications of bleeding during treatment (see Adverse Reactions). Women, the elderly and patients with low body weight appear to have an increased risk of bleeding. Monitor these patients closely with regard to bleeding. The risk of bleeding is most common at the arterial access site in patients undergoing percutaneous arterial procedures. All potential bleeding sites, e.g., catheter insertion sites; arterial, venous or needle puncture sites; cutdown sites; gastrointestinal, genitourinary and retroperitoneal sites, and central and peripheral nervous system should be observed carefully. If serious bleeding occurs that is not controllable with pressure, the INTEGRILIN infusion and any unfractionated heparin that is given concomitantly should be stopped immediately. During the marketing of INTEGRILIN, very rare cases of fatal bleeding have been reported. Arterial and venous punctures, intramuscular injections, and the use of urinary catheters, nasotracheal intubation, and nasogastric tubes should be minimised. When obtaining intravenous access, non-compressible sites (eg subclavian or jugular veins) should be avoided.

Arterial Procedures

During treatment with eptifibatide there is a significant increase in bleeding rates from arterial puncture sites. If an arterial procedure is required during INTEGRILIN therapy, take care to ensure that only the anterior wall of the femoral artery is punctured. If an arterial sheath is used, it should be removed only after coagulation has returned to normal (e.g., when activated partial thromboplastin time [aPTT] is less than 45 seconds). After removal of the sheath, careful haemostasis must be ensured under close observation for at least 4 hours.

Thrombocytopenia and Immunogenicity related to GP IIb/IIIa Inhibitors

INTEGRILIN inhibits platelet aggregation, but does not appear in general to affect the viability of platelets. The incidence of thrombocytopenia was low, and similar in patients treated with INTEGRILIN or placebo as reported in clinical trials, and in rarely reported post-marketing instances of immune-mediated thrombocytopenia. The presence of transferable factors in plasma which appear to bind to eptifibatide GP IIb/IIIa receptor implies that an immune- mediated thrombocytopenic response may be seen in GP IIb/IIIa ligand-mimetic agent nayive patients or in patients re-exposed to INTEGRILIN. The mechanism, whether immune- and/or non-immune-mediated, by which eptifibatide may induce thrombocytopenia is not fully understood. Since either repeat exposure with any GP IIb/IIIa ligand-mimetic agent (such as abciximab or eptifibatide) or first-time exposure to a GP IIb/IIIa inhibitor may be associated with immune -mediated thrombocytopenic responses, care should be exercised to observe for possible thrombocytopenia associated with-hypotension, and/or other signs of hypersensitivity. In the PURSUIT trial, similar proportions (4.9% each) of patients given INTEGRILIN or placebo developed a platelet count <100 109/L. However, INTEGRILIN was associated with a small excess of patients with a 50% decrease in platelet count from baseline (5.5% vs 5.1%), a minimum platelet count <50 109/L (0.6% vs 0.4%), and a minimum platelet count <20 109/L (0.2% vs 0.04%). In the ESPRIT trial, 0.7% of patients given INTEGRILIN and 0.4% of patients given placebo developed a platelet count <100 x 109/L and 0.5% of patients given INTEGRILIN and 0.2% of patients given placebo had 50% decrease in platelet count from baseline. If either a confirmed platelet count decrease to <100 x 109L or acute profound thrombocytopenia is observed, discontinuation of each treatment medication having known or suspected thrombocytopenic effects, including INTEGRILIN, heparin and clopidogrel, should be immediately considered. Initiate supportive measures including monitoring of serial platelet counts to guide management and determine etiology. If thrombocytopenia is not attributed to eptifibatide, it may be resumed upon normalization of platelet count.

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 readily reversible upon discontinuation of the infusion with bleeding times returning towards baseline in approximately 6 hours. When administered alone, INTEGRILIN has no measurable effect on prothrombin time (PT) or activated partial thromboplastin time aPTT.

Heparin and Aspirin Use

INTEGRILIN should be administered in conjunction with heparin and antiplatelet doses of aspirin (see Dosage and Administration, Use with Heparin and Aspirin) unless a contraindication to the use of these drugs is present.

Hepatic Impairment

Experience in patients with hepatic impairment is very limited. Administer with caution to patients with hepatic impairment in whom coagulation could be affected (see Contraindications, prothrombin time).

Renal Impairment

INTEGRILIN may be administered at the standard dose to patients with mild renal impairment (CrCl >=50 mL/min using the Cockcroft-Gault equation *). In patients with moderate to severe renal insufficiency (creatinine clearance <50 mL/min using the Cockcroft-Gault equation *), the clearance of eptifibatide is reduced by approximately 50% and steady-state plasma levels are approximately doubled. Patients with moderate to severe renal insufficiency who receive the usual infusion dose of 2.0 ug/kg/min have an increased risk of bleeding. Therefore, the infusion dose should be reduced to 1.0 ug/kg/min in such patients (see Dosage and Administration, Clinical Trials). There has been limited study of eptifibatide in patients with severe renal insufficiency (i.e. those with CrCl < 30 mL/min). There has been no clinical trial experience in patients dependant on dialysis. INTEGRILIN is contraindicated in who are dependent on renal dialysis.

Monitoring of Laboratory Values

The following laboratory tests are recommended before treatment with INTEGRILIN to identify pre-existing haemostatic abnormalities: PT and aPTT, serum creatinine, platelet count, haemoglobin and haematocrit levels. Thereafter, haemoglobin, haematocrit and platelet count are to be monitored within 6 hours after start of therapy and at least once daily thereafter while on therapy (or more often if there is evidence of a marked decrease). If the platelet count falls below 100,000/mm3, further platelet counts are required to rule out pseudothrombocytopenia. Discontinue unfractionated heparin. In patients undergoing PCI, the ACT must be measured. Patients must be monitored for bleeding and treated if necessary (see Overdosage).

Effects on Fertility

INTEGRILIN had no effect on the fertility of male and female rats at doses of 72 mg/kg/day IV.

Use in Pregnancy

(Category C)

No clinical studies with INTEGRILIN have been conducted in pregnant women. An increased incidence of fetal loss and prematurity may be associated with maternal haemorrhage. Reproductive studies in rats and rabbits gave no evidence of fertility, embryo-fetal, or peri- /postnatal toxicity with daily INTEGRILIN doses of up to 72mg/kg in rats and 36mg/kg in rabbits (providing plasma eptifibatide concentrations similar to those expected in humans in both species); however, tissue and organ haemorrhages were seen in monkeys at plasma eptifibatide concentrations approximating those attained in humans with the recommended dose. These haemorrhages occurred despite the absence of concurrent aspirin and heparin. Because animal reproduction studies are not always predictive of human response, INTEGRILIN should be used during pregnancy only if the benefit to the mother outweighs the potential risk to the fetus.

Use in Lactation

It is not known whether INTEGRILIN is excreted in human milk. Interruption of breast-feeding during the treatment period is recommended.

Paediatric Use

Safety and efficacy in children and adolescents 18 years of age has not been established. Therefore, use in patients younger than 18 years of age is not recommended.

Carcinogenicity and Mutagenicity

The carcinogenic potential of INTEGRILIN has not been evaluated in long-term studies. INTEGRILIN showed no evidence of genotoxicity in a series of assays for gene mutations and chromosomal damage.

Effects on Ability to Drive and Use Machines

INTEGRILIN is intended for use in hospitalised patients. There are no data in patients treated with INTEGRILIN outside the hospital setting.

Interactions with Other Medicines

No formal pharmacokinetic interaction studies have been conducted. However, in a population pharmacokinetic study there was no evidence of a pharmacokinetic interaction between INTEGRILIN and the following concomitant medications: amlodipine, atenolol, atropine, captopril, cefazolin, diazepam, digoxin, diltiazem, diphenhydramine, enalapril, fentanyl, frusemide, heparin, lignocaine, lisinopril, metoprolol, midazolam, morphine, nifedipine, nitrates and warfarin, suggesting a low potential for a pharmacokinetic drug interaction between INTEGRILIN and these commonly used agents in patients with cardiac conditions. Because INTEGRILIN inhibits platelet aggregation, it should be used cautiously with other medications that affect haemostasis, including ticlopidine, clopidogrel, thrombolytics, oral anticoagulants, dextran solutions (see Dosage and Administration), adenosine, low molecular weight heparins, sulfinpyrazone, prostacyclin, non-steroidal anti-inflammatory agents and dipyridamole. INTEGRILIN did not appear to increase the risk of major and minor bleeding associated with concomitant use of warfarin and dipyridamole. INTEGRILIN-treated patients who had a prothrombin time (PT) >14.5 seconds and received warfarin concomitantly did not appear to be at an increased risk of bleeding. There is very limited experience with INTEGRILIN and low molecular weight heparins. Thus coadministration of low molecular weight heparins with INTEGRILIN must be done with caution. INTEGRILIN should not be used in conjunction with thrombolytic agents due to a high risk of bleeding. When the 180/2.0 dose of INTEGRILIN was combined with streptokinase in a clinical trial, 15% of patients developed severe bleeding and 19% required transfusion (compared with no severe bleeding or transfusion in placebo-treated patients). Stop the INTEGRILIN infusion immediately if circumstances arise that necessitate thrombolytic therapy or if the patient must undergo an emergency CABG surgery or requires an intraortic balloon pump. In a trial in patients undergoing nonurgent PCI with stenting, 95% received clopidogrel concomitantly with aspirin before PCI and daily thereafter (see Clinical Trials). Bleeding events were more frequent in patients receiving concurrent heparin while undergoing PTCA, when ACT exceeded 350 seconds (See Dosage and Administration; Use with Heparin and Aspirin). INTEGRILIN is not compatible with frusemide in the same intravenous line. There are no data on the use of INTEGRILIN in combination with Dextran. In the absence of data, INTEGRILIN should not be mixed with drugs other than those tested and found to be compatible (See Instructions for Use, Handling and Disposal).

DOSAGE AND ADMINISTRATION

INTEGRILIN is for hospital use only, by specialist physicians experienced in the management of acute coronary syndromes or PCI. There has been limited study of eptifibatide in patients with severe renal insufficiency (i.e. those with CrCl < 30 mL/min). (See Clinical Trials.)

Adults (18 years of age) undergoing Percutaneous Coronary Intervention (PCI):

The recommended dosage of eptifibatide in patients with creatinine clearance >=50 mL/min (using the Cockcroft-Gault equation *) is an intravenous bolus of 180 ug/kg administered immediately prior to the procedure, followed by a second bolus of 180 ug/kg 10 minutes after the first bolus injection. Simultaneously with the first bolus, a continuous infusion should be started at a dose of 2.0 ug/kg/min. Continue the infusion until hospital discharge or up to a maximum of 18-24 hours post PCI. A minimum 12 hours of infusion is recommended.

Adults (18 years of age) undergoing PCI with Creatinine Clearance <50 mL/min:

The recommended dosage of eptifibatide in patients with an estimated creatinine clearance <50 mL/min (using the Cockcroft-Gault equation *) is an intravenous bolus of 180 ug/kg administered immediately prior to the procedure, followed by a second bolus of 180 ug/kg 10 minutes after the first bolus injection. Simultaneously with the first bolus dose, a continuous infusion should be started at a dose of 1.0 ug/kg/min. Continue the infusion until hospital discharge or up to a maximum of 18-24 hours post PCI. A minimum 12 hours of infusion is recommended.

Adults ( 18 years of age) presenting with UA/NQMI:

The recommended dosage of eptifibatide in patients with creatinine clearance >=50 mL/min (using the Cockcroft-Gault equation *) is an intravenous bolus of 180 ug/kg administered as soon as possible following diagnosis, followed by a continuous infusion of 2.0 ug/kg/min for up to 72 hours, until initiation of coronary artery bypass graft surgery or until discharge from the hospital (whichever occurs first). If PCI is performed during INTEGRILIN therapy for UA/NQMI, continue the infusion for 20-24 hours post- PCI for an overall maximum duration of therapy of 96 hours.

Adults ( 18 years of age) presenting with UA/NQMI with Creatinine Clearance

<50 mL/min:

The recommended dosage of eptifibatide in patients with UA/NQMI with an estimated creatinine clearance <50 mL/min (using the Cockcroft-Gault equation *) is an intravenous bolus of 180 ug/kg administered as soon as possible following diagnosis, immediately followed by a continuous infusion of 1.0 ug/kg/min for up to 72 hours, until initiation of coronary artery bypass graft (CABG) surgery or until discharge from the hospital (whichever occurs first). If PCI is performed during INTEGRILIN therapy for UA/NQMI, continue the infusion for 20-24 hours post-PCI for an overall maximum duration of therapy of 96 hours. *Use the Cockcroft-Gault equation with actual body weight to calculate the estimated creatinine clearance in mL/min: Males: (140 - age in years) x (actual body weight in kg) 72 x (serum creatinine in mg/dL) Females: (140 - age in years) x actual body weight in kg) x (0.85) 72 x (serum creatinine in mg/dL)

Emergency or Semi-elective Surgery

If the patient requires emergency or urgent cardiac surgery during the course of INTEGRILIN therapy, terminate the infusion immediately. If the patient requires semi-elective surgery, stop the INTEGRILIN infusion at an appropriate time to allow time for platelet function to return towards normal.

Use with Heparin and Aspirin

INTEGRILIN should be used in conjunction with heparin and antiplatelet doses of aspirin, unless a contraindication (such as a history of thrombocytopenia associated with the use of heparin) to the use of these drugs is present. UA/NQMI: For a patient who weighs 70 kg, it is recommended that a bolus dose of 5,000 units is given, followed by a constant intravenous infusion of 1,000 units/hour. If the patient weighs < 70 kg, a bolus dose of 60 units/kg is recommended, followed by an infusion of 12 units/kg/hour. The aPTT must be monitored in order to maintain a value between 50 and 70 seconds. Higher aPTT values may be associated with an increased risk of haemorrhage, but the risk has not been quantified.

If PCI is to be performed in the setting of UA/NQMI

, monitor the activated clotting time (ACT) to maintain a value between 300-350 seconds. Stop heparin administration if the ACT exceeds 300 seconds; do not administer until the ACT falls below 300 seconds.

Non-urgent PCI with intracoronary stenting

: For those patients not treated with heparin within 6 hours before intervention, an initial heparin bolus of 60 U/kg is recommended. The target ACT during the procedure is 200-300 seconds. Additional bolus of heparin may be administered during the PCI procedure to maintain the ACT within this range.

Instructions for Use, Handling and Disposal

INTEGRILIN solution for infusion must be used in conjunction with INTEGRILIN solution for injection. Before using, inspect the vial contents. Do not use if particulate matter or discoloration is present. Protection of INTEGRILIN solution from light is not necessary during administration. Physical and chemical compatibility testing indicate that INTEGRILIN may be administered through an intravenous line with atropine sulfate, dobutamine, heparin, lignocaine, meperidine, metoprolol, midazolam, morphine, glyceryl trinitrate, tissue plasminogen activator or verapamil. INTEGRILIN is compatible with 0.9 % sodium chloride solution for injection and with glucose 5 % in Normosol R, in the presence or absence of potassium chloride. In the absence of incompatibility studies, INTEGRILIN must not be mixed with other medicinal products except those mentioned above. As INTEGRILIN does not contain any antimicrobial agent, the product is for single use only and any unused residue should be discarded.

OVERDOSAGE

The experience in humans with overdosage of INTEGRILIN is extremely limited. 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. In the PURSUIT trial, there were 9 patients who received bolus and/or infusion doses more than double that specified in the protocol or who were identified by the investigator as having received an overdose. There was no excessive bleeding in any of these patients, except for one patient undergoing CABG surgery who was reported as having had a moderate bleed. Importantly, no patients experienced an intracranial bleed. Potentially, an overdose of INTEGRILIN 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. Thus, although INTEGRILIN can also be dialysed, the need for dialysis is unlikely. Contact the Poisons Information Centre (telephone 13 11 26) for advice regarding management of overdose.

PRESENTATION AND STORAGE CONDITIONS

INTEGRILIN is formulated as a sterile solution for intravenous (IV) injection in two dosage administration forms, bolus injection and intravenous infusion. The bolus injection is a single dose 10 mL glass vial containing eptifibatide 20 mg (2 mg/mL) closed with a butyl rubber stopper and sealed with a crimped aluminium seal. The solution for intravenous infusion is a single dose 100 mL glass vial containing eptifibatide 75 mg (0.75 mg/mL) closed with a butyl rubber stopper and sealed with a crimped aluminium seal. Packs contain one single vial. Store at 2oC to 8oC (Refrigerate. Do not freeze.) Protect from light until administration.

SHELF LIFE

3 years

NAME AND ADDRESS OF THE SPONSOR

Merck Sharp & Dohme (Australia) Pty Limited 54-68 Ferndell Street, South Granville, NSW 2142, Australia Merck Sharp & Dohme (New Zealand) Limited P O Box 99851 Newmarket Auckland 1149 New Zealand

POISON SCHEDULE OF THE MEDICINE

S4 Prescription only medicine

DATE OF APPROVAL

This Product Information was approved by the Therapeutic Goods Administration on 24 July 2007. Date of most recent amendment: 26 August, 2011 Copyright (c) 2007 Schering Corporation, a subsidiary of Merck & Co., Inc. All rights reserved. V5