INTEGRILIN 2mg / ml injectible solution medication leaflet

INTEGRILIN 2 mg/ml solution for injection

Each ml of solution for injection contains 2 mg of eptifibatide.

One vial of 10 ml of solution for injection contains 20 mg of eptifibatide.

Contains 13.8 mg of sodium per 10 ml vial

For the full list of excipients, see section 6.1.

Solution for injection.

Clear, colourless solution.

INTEGRILIN is intended for use with acetylsalicylic acid and unfractionated heparin.

INTEGRILIN is indicated for the prevention of early myocardial infarction in adults presentingwith unstable angina or non-Q-wave myocardial infarction, with the last episode of chest painoccurring within 24 hours and with electrocardiogram (ECG) changes and/or elevated cardiacenzymes.

Patients most likely to benefit from INTEGRILIN treatment are those at high risk of developingmyocardial infarction within the first 3-4 days after onset of acute angina symptoms including forinstance those that are likely to undergo an early PTCA (Percutaneous Transluminal Coronary

Angioplasty) (see section 5.1).

This product is for hospital use only. It should be administered by specialist physicians experiencedin the management of acute coronary syndromes.

INTEGRILIN solution for injection must be used in conjunction with INTEGRILIN solution forinfusion.

Concurrent administration of heparin is recommended unless this is contraindicated for reasonssuch as a history of thrombocytopenia associated with use of heparin (see ‘Heparin administration’,section 4.4). INTEGRILIN is also intended for concurrent use with acetylsalicylic acid, as it is partof standard management of patients with acute coronary syndromes, unless its use iscontraindicated.

Adults (≥ 18 years of age) presenting with unstable angina (UA) or non-Q-wave myocardialinfarction (NQMI)

The recommended dosage is an intravenous bolus of 180 microgram/kg administered as soon aspossible following diagnosis, followed by a continuous infusion of 2 microgram/kg/min for up to72 hours, until initiation of coronary artery bypass graft (CABG) surgery, or until discharge fromthe hospital (whichever occurs first). If Percutaneous Coronary Intervention (PCI) is performedduring eptifibatide therapy, continue the infusion for 20-24 hours post-PCI for an overall maximumduration of therapy of 96 hours.

Emergency or semi-elective surgery

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

Experience in patients with hepatic impairment is very limited. Administer with caution to patientswith hepatic impairment in whom coagulation could be affected (see section pct. 4.3, prothrombin time). Itis contraindicated in patients with clinically significant hepatic impairment.

In patients with moderate renal impairment (creatinine clearance ≥ 30 - < 50 ml/min), an intravenousbolus of 180 microgram/kg should be administered followed by a continuous infusion dose of1.0 microgram/kg/min for the duration of therapy. This recommendation is based onpharmacodynamic and pharmacokinetic data. The available clinical evidence cannot however confirmthat this dose modification results in a preserved benefit (see section 5.1). Use in patients with moresevere renal impairment is contraindicated (see section 4.3).

It is not recommended for use in children and adolescents below 18 years of age, due to a lack of dataon safety and efficacy.

INTEGRILIN must not be used to treat patients with:− hypersensitivity to the active substance or to any of the excipients listed in section 6.1− evidence of gastrointestinal bleeding, gross genitourinary bleeding or other active abnormalbleeding 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 (< 100,000 cells/mm3)− prothrombin time > 1.2 times control, or International Normalized Ratio (INR) ≥ 2.0− severe hypertension (systolic blood pressure > 200 mm Hg or diastolic blood pressure> 110 mm Hg on antihypertensive therapy)− severe renal impairment (creatinine clearance < 30 ml/min) or dependency on renal dialysis− clinically significant hepatic impairment− concomitant or planned administration of another parenteral glycoprotein (GP) IIb/IIIa inhibitor

INTEGRILIN is an antithrombotic agent that acts by inhibition of platelet aggregation; therefore thepatient must be observed carefully for indications of bleeding during treatment (see section 4.8).

Women, the elderly, patients with low body weight or with moderate renal impairment (creatinineclearance > 30 - < 50 ml/min) may have an increased risk of bleeding. Monitor these patients closelywith regard to bleeding.

An increased risk of bleeding may also be observed in patients who receive early administration of

INTEGRILIN (e.g. upon diagnosis) compared to receiving it immediately prior to PCI, as seen in the

Early ACS trial. Unlike the approved posology in the EU, all patients in this trial were administered adouble bolus before the infusion (see section 5.1).

Bleeding is most common at the arterial access site in patients undergoing percutaneous arterialprocedures. All potential bleeding sites, (e.g., catheter insertion sites; arterial, venous, or needlepuncture sites; cutdown sites; gastrointestinal and genitourinary tracts) must be observed carefully.

Other potential bleeding sites such as central and peripheral nervous system and retroperitoneal sites,must be carefully considered too.

Because INTEGRILIN inhibits platelet aggregation, caution must be employed when it is used withother medicinal products that affect haemostasis, including ticlopidine, clopidogrel, thrombolytics,oral anticoagulants, dextran solutions, adenosine, sulfinpyrazone, prostacyclin, non-steroidal anti-inflammatory agents, or dypyridamole (see section 4.5).

There is no experience with INTEGRILIN and low molecular weight heparins.

There is limited therapeutic experience with INTEGRILIN in patients for whom thrombolytic therapyis generally indicated (e.g. acute transmural myocardial infarction with new pathological Q-waves orelevated ST-segments or left bundle branch block in the ECG). Consequently the use of INTEGRILINis not recommended in these circumstances (see section 4.5).

INTEGRILIN infusion should be stopped immediately if circumstances arise that necessitatethrombolytic therapy or if the patient must undergo an emergency CABG surgery or requires anintraortic balloon pump.

If serious bleeding occurs that is not controllable with pressure, the INTEGRILIN infusion should bestopped immediately and any unfractionated heparin that is given concomitantly.

Arterial procedures

During treatment with eptifibatide there is a significant increase in bleeding rates, especially in thefemoral artery area, where the catheter sheath is introduced. Take care to ensure that only the anteriorwall of the femoral artery is punctured. Arterial sheaths may be removed when coagulation hasreturned to normal (e.g. when activated clotting time (ACT) is less than 180 seconds (usually 2-6 hours after discontinuation of heparin). After removal of the introducer sheath, careful haemostasismust be ensured under close observation.

Thrombocytopenia and Immunogencity related to GP IIb/IIIa inhibitors

INTEGRILIN inhibits platelet aggregation, but does not appear to affect the viability of platelets. Asdemonstrated in clinical trials, the incidence of thrombocytopenia was low, and similar in patientstreated with eptifibatide or placebo. Thrombocytopaenia, including acute profoundthrombocytopaenia, has been observed with eptifibatide administration post-marketing (see section4.8).

The mechanism, whether immune- and/or non-immune-mediated, by which eptifibatide may inducethrombocytopaenia is not fully understood. However, treatment with eptifibatide was associated withantibodies that recognise GPIIb/IIIa occupied by eptifibatide, suggesting an immune-mediatedmechanism. Thrombocytopaenia occurring after first exposure to a GPIIb/IIIa inhibitor may beexplained by the fact that antibodies are naturally present in some normal individuals.

Since either repeat exposure with any GP IIb/IIIa ligand-mimetic agent (like abciximab or eptifibatide)or first-time exposure to a GP IIb/IIIa inhibitor may be associated with immune-mediatedthrombocytopenic responses, monitoring is required, i.e. platelet counts should be monitored prior totreatment, within 6 hours of administration, and at least once daily thereafter while on therapy andimmediately at clinical signs of unexpected bleeding tendency.

If either a confirmed platelet decrease to < 100,000/mm3 or acute profound thrombocytopaenia isobserved, discontinuation of each treatment medication having known or suspected thrombocytopeniceffects, including eptifibatide, heparin and clopidogrel, should be considered immediately. Thedecision to use platelet transfusions should be based upon clinical judgment on an individual basis.

In patients with previous immune-mediated thrombocytopaenia from other parenteral GP IIb/IIIainhibitors, there are no data with the use of INTEGRILIN. Therefore, it is not recommended toadminister eptifibatide in patients who have previously experienced immune mediatedthrombocytopenia with GP IIb/IIIa inhibitors, including eptifibatide.

Heparin administration

Heparin administration is recommended unless a contraindication (such as a history ofthrombocytopenia associated with use of heparin) is present.

UA/NQMI: For a patient who weighs ≥ 70 kg, it is recommended that a bolus dose of 5,000 units isgiven, followed by a constant intravenous infusion of 1,000 units/hr. If the patient weighs < 70 kg, abolus dose of 60 units/kg is recommended, followed by an infusion of 12 units/kg/hr. The activatedpartial thromboplastin time (aPTT) must be monitored in order to maintain a value between 50 and70 seconds, above 70 seconds there may be an increased risk of bleeding.

If PCI is to be performed in the setting of UA/NQMI, monitor the activated clotting time (ACT) tomaintain a value between 300-350 seconds. Stop heparin administration if the ACT exceeds300 seconds; do not administer until the ACT falls below 300 seconds.

Monitoring of laboratory values

Before infusion of INTEGRILIN, the following laboratory tests are recommended to identify pre-existing haemostatic abnormalities: prothrombin time (PT) and aPTT, serum creatinine, platelet count,haemoglobin and haematocrit levels. Haemoglobin, haematocrit, and platelet count are to bemonitored as well within 6 hours after start of therapy and at least once daily thereafter while ontherapy (or more often if there is evidence of a marked decrease). If the platelet count falls below100,000/mm3, further platelet counts are required to rule out pseudothrombocytopenia. Discontinueunfractionated heparin. In patients undergoing PCI, measure the ACT also.

This medicinal product contains 13.8 mg sodium per 10 ml vial, equivalent to 0.69% of the WHOrecommended maximum daily intake of 2 g sodium for an adult.

Warfarin and dipyridamole

INTEGRILIN did not appear to increase the risk of major and minor bleeding associated withconcomitant use of warfarin and dipyridamole. INTEGRILIN-treated patients who had a prothrombintime (PT) > 14.5 seconds and received warfarin concomitantly did not appear to be at an increased riskof bleeding.

INTEGRILIN and thrombolytic agents

Data are limited on the use of INTEGRILIN in patients receiving thrombolytic agents. There was noconsistent evidence that eptifibatide increased the risk of major or minor bleeding associated withtissue plasminogen activator in either a PCI or an acute myocardial infarction study. Eptifibatideappeared to increase the risk of bleeding when administered with streptokinase in an acute myocardialinfarction study. The combination of reduced dose tenecteplase and eptifibatide compared to placeboand eptifibatide significantly increased the risk of both major and minor bleeding when administeredconcomitantly in an acute ST-elevation myocardial infarction study.

In an acute myocardial infarction study involving 181 patients, eptifibatide (in regimens up to a bolusinjection of 180 microgram/kg, followed by an infusion up to 2 microgram/kg/min for up to 72 hours)was administered concomitantly with streptokinase (1.5 million units over 60 minutes). At the highestinfusion rates (1.3 microgram/kg/min and 2.0 microgram/kg/min) studied, eptifibatide was associatedwith an increased incidence of bleeding and transfusions compared to the incidence seen whenstreptokinase was given alone.

There are no adequate data from the use of eptifibatide in pregnant women.

Animal studies are insufficient with respect to effects on pregnancy, embryonal/foetal development,parturition or postnatal development (see section 5.3). The potential risk for humans is unknown.

INTEGRILIN should not be used during pregnancy unless clearly necessary.

It is not known whether eptifibatide is excreted in human milk. Interruption of breast-feeding duringthe treatment period is recommended.

Not relevant, as INTEGRILIN is intended for use only in hospitalised patients.

The majority of adverse reactions experienced by patients treated with eptifibatide were generallyrelated to bleeding or to cardiovascular events that occur frequently in this patient population.

Clinical Trials

The data sources used to determine adverse reaction frequency descriptors included two phase IIIclinical studies (PURSUIT and ESPRIT). These trials are briefly described below.

PURSUIT: This was a randomised, double-blind evaluation of the efficacy and safety of Integrilinversus placebo for reducing mortality and myocardial (re)infarction in patients with unstable angina ornon-Q-wave myocardial infarction.

ESPRIT: This was a double-blind, multicentre, randomised, parallel-group, placebo-controlled trialevaluating the safety and efficacy of eptifibatide therapy in patients scheduled to undergo non-emergent percutaneous coronary intervention (PCI) with stent implantation.

In PURSUIT, bleeding and non-bleeding events were collected from hospital discharge to the 30 dayvisit. In ESPRIT, bleeding events were reported at 48 hours, and non-bleeding events were reported at30 days. While Thrombolysis in Myocardial Infarction TIMI bleeding criteria were used to categorizethe incidence of major and minor bleeding in both the PURSUIT and the ESPRIT trials, PURSUITdata was collected within 30 days while ESPRIT data was limited to events within 48 hours ordischarge, whichever came first.

The undesirable effects are listed by body system and frequency. Frequencies are defined as verycommon (≥1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1,000 to < 1/100); rare (≥ 1/10,000 to< 1/1,000); very rare (< 1/10,000). These are absolute reporting frequencies without taking intoaccount placebo rates. For a particular adverse reaction, if data was available from both PURSUIT and

ESPRIT, then the highest reported incidence was used to assign adverse reaction frequency.

Note that causality has not been determined for all adverse reactions.

Blood and Lymphatic System Disorder

Very common Bleeding (major and minor bleeding including femoral artery access, CABG-related, gastrointestinal, genitourinary, retroperitoneal, intracranial,haematemesis, haematuria, oral/oropharyngeal, haemoglobin/haematocritdecreased and other).

Uncommon Thrombocytopenia.

Nervous System disorders

Uncommon Cerebral ischaemia.

Cardiac Disorders

Common Cardiac arrest, ventricular fibrillation, ventricular tachycardia, congestive heartfailure, atrioventricular block, atrial fibrillation.

Vascular Disorders

Common Shock, hypotension, phlebitis.

Cardiac arrest, congestive heart failure, atrial fibrillation, hypotension, and shock, which arecommonly reported events from the PURSUIT trial, were events related to the underlying disease.

Administration of eptifibatide is associated with an increase in major and minor bleeding as classifiedby the criteria of the TIMI study group. At the recommended therapeutic dose, as administered in the

PURSUIT trial involving nearly 11,000 patients, bleeding was the most common complicationencountered during eptifibatide therapy. The most common bleeding complications were associatedwith cardiac invasive procedures (coronary artery bypass grafting (CABG)-related or at femoral arteryaccess site).

Minor bleeding was defined in the PURSUIT trial as spontaneous gross haematuria, spontaneoushaematemesis, observed blood loss with a haemoglobin decrease of more than 3 g/dl, or ahaemoglobin decrease of more than 4 g/dl in the absence of an observed bleeding site. Duringtreatment with Integrilin in this study, minor bleeding was a very common complication (>1/10, or13.1% for Integrilin versus 7.6% for placebo). Bleeding events were more frequent in patientsreceiving concurrent heparin while undergoing PCI, when ACT exceeded 350 seconds (see section4.4, heparin use).

Major bleeding was defined in the PURSUIT trial as either an intracranial haemorrhage or a decreasein haemoglobin concentrations of more than 5 g/dl. Major bleeding was also very common andreported more frequently with Integrilin than with placebo in the PURSUIT study (>1/10 or 10.8%versus 9.3%), but it was infrequent in the vast majority of patients who did not undergo CABG within30 days of inclusion in the study. In patients undergoing CABG, the incidence of bleeding was notincreased by Integrilin compared to the patients treated with placebo. In the subgroup of patientsundergoing PCI, major bleeding was observed commonly, in 9.7 % of Integrilin-treated patients vs.4.6 % of placebo-treated patients.

The incidence of severe or life threatening bleeding events with Integrilin was 1.9% compared to 1.1%with placebo. The need for blood transfusions was increased modestly by Integrilin treatment (11.8%versus 9.3% for placebo).

Changes during eptifibatide treatment result from its known pharmacological action, i.e., inhibition ofplatelet aggregation. Thus, changes in laboratory parameters associated with bleeding (e.g. bleedingtime) are common and expected. No apparent differences were observed between patients treated witheptifibatide or with placebo in values for liver function (SGOT/AST, SGPT/ALT, bilirubin, alkalinephosphatase) or renal function (serum creatinine, blood urea nitrogen).

Very rare Fatal bleeding (the majority involved central and peripheral nervous systemdisorders: cerebral or intracranial haemorrhages); pulmonary haemorrhage,acute profound thrombocytopenia, haematoma.

Very rare Anaphylactic reactions.

Very rare Rash, application site disorders such as urticaria.

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

The experience in humans with overdose of eptifibatide is extremely limited. There was no indicationof severe adverse reactions associated with administration of accidental large bolus doses, rapidinfusion reported as overdose or large cumulative doses. In the PURSUIT trial, there were 9 patientswho received bolus and/or infusion doses more than double the recommended dose, or who wereidentified by the investigator as having received an overdose. There was no excessive bleeding in anyof these patients, although one patient undergoing CABG surgery was reported as having had amoderate bleed. Specifically, no patients experienced an intracranial bleed.

Potentially, an overdose of eptifibatide could result in bleeding. Because of its short half-life and rapidclearance, the activity of eptifibatide may be halted readily by discontinuing the infusion. Thus,although eptifibatide can be dialysed, the need for dialysis is unlikely.

Pharmacotherapeutic group: Antithrombotic agent (platelet aggregation inhibitors excl. heparin), ATCcode: B01AC16

Eptifibatide, a synthetic cyclic heptapeptide containing six amino acids, including one cysteine amideand one mercaptopropionyl (desamino cysteinyl) residue, is an inhibitor of platelet aggregation andbelongs to the class of RGD (arginine-glycine-aspartate)-mimetics.

Eptifibatide reversibly inhibits platelet aggregation by preventing the binding of fibrinogen, von

Willebrand factor and other adhesive ligands to the glycoprotein (GP)IIb/IIIa receptors.

Eptifibatide inhibits platelet aggregation in a dose- and concentration-dependent manner asdemonstrated by ex vivo platelet aggregation using adenosine diphosphate (ADP) and other agonists toinduce platelet aggregation. The effect of eptifibatide is observed immediately after administration of a180 microgram/kg intravenous bolus. When followed by a 2.0 microgram/kg/min continuous infusion,this regimen produces a > 80 % inhibition of ADP-induced ex vivo platelet aggregation, at physiologiccalcium concentrations, in more than 80 % of patients.

Platelet inhibition was readily reversed, with a return of platelet function towards baseline (> 50 %platelet aggregation) 4 hours after stopping a continuous infusion of 2.0 microgram/kg/min.

Measurements of ADP-induced ex vivo platelet aggregation at physiologic calcium concentrations (D-phenylalanyl-L-prolyl-L-arginine chloromethyl ketone anticoagulant) in patients presenting withunstable angina and Non Q-Wave Myocardial Infarction showed a concentration-dependent inhibitionwith an IC50 (50 % inhibitory concentration) of approximately 550 ng/ml and an IC80 (80 % inhibitoryconcentration) of approximately 1,100 ng/ml.

There is limited data with regards to platelet inhibition in patients with renal impairment. In patientswith moderate renal impairment, (creatinine clearance 30 - 50mL/min) 100% inhibition was achievedat 24 hours following administration of 2 microgram/kg/min. In patients with severe renal impairment(creatinine clearance <30mL/min) administered 1microgram/kg/min , 80% inhibition was achieved inmore than 80% of patients at 24 hours.

PURSUIT trial

The pivotal clinical trial for Unstable Angina (UA)/Non-Q Wave Myocardial Infarction (NQMI) was

PURSUIT. This study was a 726-center, 27-country, double-blind, randomised, placebo-controlledstudy in 10,948 patients presenting with UA or NQMI. Patients could be enrolled only if they hadexperienced cardiac ischemia 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 STelevation > 0.5 mm not requiring reperfusion therapy or thrombolytic agents, T-wave inversion(> 1 mm),

* or increased CK-MB.

Patients were randomised to either placebo, eptifibatide 180 microgram/kg bolus followed by a2.0 microgram/kg/min infusion (180/2.0), or eptifibatide 180 microgram/kg bolus followed by a1.3 microgram/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 PCI was performed, the eptifibatideinfusion was continued for 24 hours after the procedure, allowing for a duration of infusion up to96 hours.

The 180/1.3 arm was stopped after an interim analysis, as prespecified in the protocol, when the twoactive-treatment arms appeared to have a similar incidence of bleeding.

Patients were managed according to the usual standards of the investigational site; frequencies ofangiography, PCI and CABG therefore differed widely from site to site and from country to country.

Of the patients in PURSUIT, 13 % were managed with PCI during eptifibatide infusion, of whomapproximately 50 % received intracoronary stents; 87 % were managed medically (without PCI duringeptifibatide infusion).

The vast majority of patients received acetylsalicylic acid (75-325 mg once daily).

Unfractionated heparin was administered intravenously or subcutaneously at the physician’sdiscretion, most commonly as an intravenous bolus of 5,000 U followed by a continuous infusion of1,000 U/h. A target aPTT of 50-70 seconds was recommended. A total of 1,250 patients underwent

PCI within 72 hours after randomisation, in which case they received intravenous unfractionatedheparin 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 myocardialinfarction (MI) (evaluated by a blinded Clinical Events Committee) within 30 days of randomisation.

The component MI could be defined as asymptomatic with enzymatic elevation of CK-MB or new Qwave.

Compared to placebo, eptifibatide administered as 180/2.0 significantly reduced the incidence of theprimary endpoint events (table 1): this represents around 15 events avoided for 1,000 patients treated:

Table 1

Incidence of Death/CEC-Assessed MI («Treated as Randomised»

Population)

Time Placebo Eptifibatide p-Value30 days 743/4,697 667/4,680 0.034a(15.8 %) (14.3 %)a: Pearson’s chi-square test of difference between placebo and eptifibatide.

Results on the primary endpoint were principally attributed to the occurrence of myocardial infarction.

The reduction in the incidence of endpoint events in patients receiving eptifibatide appeared earlyduring treatment (within the first 72-96 hours) and this reduction was maintained through 6 months,without any significant effect on mortality.

Patients most likely to benefit from eptifibatide treatment are those at high risk of developingmyocardial infarction within the first 3-4 days after onset of acute angina.

According to epidemiological findings, a higher incidence of cardiovascular events has beenassociated with certain indicators, for instance:− age− elevated heart rate or blood pressure− persistent or recurrent ischemic cardiac pain− marked ECG changes (in particular ST-segment abnormalities)− raised cardiac enzymes or markers (e.g. CK-MB, troponins) and− heart failure

PURSUIT was conducted at a time when the standard of care of managing acute coronary syndromeswas different from that of present times in terms of thienopyridine use and the routine use ofintracoronary stents.

ESPRIT trial

ESPRIT (Enhanced Suppression of the Platelet IIb/IIIa Receptor with eptifibatide Therapy) was adouble-blind, randomised, placebo-controlled trial (n= 2,064) for nonurgent PCI with intracoronarystenting.

All patients received routine standard of care and were randomised to either placebo or eptifibatide(2 bolus doses of 180 microgram/kg and a continuous infusion until discharge from hospital or amaximum of 18-24 hours).

The first bolus and the infusion were started simultaneously, immediately before the PCI procedureand were followed by a second bolus 10 minutes after the first. The rate of infusion was2.0 microgram/kg/min for patients with serum creatinine ≤ 175 micromols/l or 1.0 microgram/kg/minfor serum creatinine > 175 up to 350 micromols/l.

In the eptifibatide arm of the trial, virtually all patients received aspirin (99.7 %), and 98.1 % receiveda thienopyridine, (clopidogrel in 95.4 % and ticlopidine in 2.7 %). On the day of PCI, prior tocatheterization, 53.2 % received a thienopyridine (clopidogrel 52.7 %; ticlopidine 0.5 %) - mostly as aloading dose (300 mg or more). The placebo arm was comparable (aspirin 99.7 %, clopidogrel 95.9 %,ticlopidin 2.6 %).

The ESPRIT trial used a simplified regimen of heparin during PCI that consisted of an initial bolus of60 units/kg, with a target ACT of 200 - 300 seconds. The primary endpoint of the trial was death (D),

MI, urgent target vessel revascularisation (UTVR), and acute antithrombotic rescue with GP IIb/IIIainhibitor therapy (RT) within 48 hours of randomisation.

MI was identified per the CK-MB core laboratory criteria. For this diagnosis, within 24 hours after theindex PCI procedure, there had to be at least two CK-MB values ≥ 3 x the upper limit of normal; thus,validation by the CEC was not required. MI could also be reported following CEC adjudication of aninvestigator report.

The primary endpoint analysis [quadruple composite of death, MI, urgent target vesselrevascularisation (UTVR) and thrombolytic bail-out (TBO) at 48 hours] showed a 37 % relative and3.9 % absolute reduction in the eptifibatide group (6.6 % events versus 10.5 %, p = 0.0015). Resultson the primary endpoint were mainly attributed to the reduction of enzymatic MI occurrence,identified as the occurrence of early elevation of cardiac enzymes after PCI (80 out of 92 MIs in theplacebo group vs. 47 out of 56 MIs in the eptifibatide group). The clinical relevance of such enzymatic

MIs is still controversial.

Similar results were also obtained for the 2 secondary endpoints assessed at 30 days: a triplecomposite of death, MI and UTVR, and the more robust combination of death and MI.

The reduction in the incidence of endpoint events in patients receiving eptifibatide appeared earlyduring treatment. There was no increased benefit thereafter, up to 1 year.

Prolongation of bleeding time

Administration of eptifibatide by intravenous bolus and infusion causes up to a 5-fold increase inbleeding time. This increase is readily reversible upon discontinuation of the infusion with bleedingtimes returning towards baseline in approximately 6 (2-8) hours. When administered alone,eptifibatide has no measurable effect on prothrombin time (PT) or activated partial thromboplastintime (aPTT).

EARLY-ACS trial

EARLY ACS (Early Glycoprotein IIb/IIIa Inhibition in Non-ST-segment Elevation Acute Coronary

Syndrome) was a study of early routine eptifibatide versus placebo (with delayed provisional use ofeptifibatide in the catheterization laboratory) used in combination with antithrombotic therapies (ASA,

UFH, bivalirudin, fondaparinux or low molecular weight heparin), in subjects with high-risk NSTE

ACS. Patients were to undergo an invasive strategy for further management after receiving study drugfor 12 to 96 hours. Patients could be medically managed, proceed to coronary artery bypass graft(CABG), or undergo percutaneous coronary intervention (PCI). Unlike the approved posology in the

EU, the study used a double bolus of study drug (separated by 10 minutes) before the infusion.

Early routine eptifibatide in this high-risk NSTE-ACS optimally-treated population who weremanaged with an invasive strategy did not result in a statistically significant reduction in thecomposite primary endpoint of rate of death, MI, RI-UR, and TBO within 96 hours compared with aregimen of delayed provisional eptifibatide (9.3% in early eptifibatide patients vs. 10.0% in patientsassigned to delayed provisional eptifibatide; odds ratio=0.920; 95% CI=0.802-1.055; p=0.234).

GUSTO severe/life threatening bleeding was uncommon and comparable in both treatment groups(0.8%). GUSTO moderate or severe/life threatening bleeding occurred significantly more often withearly routine eptifibatide (7.4% vs. 5.0% in delayed provisional eptifibatide group; p <0.001). Similardifferences were noted for TIMI major haemorrhage (118 [2.5%] in early routine use vs. 83 [1.8%] indelayed provisional use; p=0.016).

No statistically significant benefit of early routine eptifibatide strategy was demonstrated in thesubgroup of patients who were managed medically or during the medical management periods prior to

PCI or CABG.

In a post hoc analysis of the EARLY ACS trial the risk benefit of dose reduction in patients withmoderate renal impairment is inconclusive. The primary endpoint event rate was 11.9 % in patientswho received a reduced dose (1microgram/kg/min) vs 11.2% in patients who received the standarddose (2microgram/kg/min) when eptifibatide was administered in the early routine fashion (p=0.81).

With delayed provisional eptifibatide administration, the event rates were 10% vs 11.5% in patientswho received reduced dose and standard dose respectively (p=0.61). TIMI major bleeding occurred in2.7 % of patients who received a reduced dose (1microgram/kg/min) vs 4.2% of patients whoreceived the standard dose (2microgram/kg/min) when eptifibatide was administered in the earlyroutine fashion (p=0.36). With delayed provisional eptifibatide administration, the TIMI major eventswere 1.4% vs 2.0% in patients who received reduced dose and standard dose respectively (p=0.54).

There were no notable differences observed with GUSTO severe bleeding rates.

The pharmacokinetics of eptifibatide are linear and dose proportional for bolus doses ranging from90 to 250 microgram/kg and infusion rates from 0.5 to 3.0 microgram/kg/min. For a2.0 microgram/kg/min infusion, mean steady-state plasma eptifibatide concentrations range from1.5 to 2.2 microgram/ml in patients with coronary artery disease. These plasma concentrations areachieved rapidly when the infusion is preceded by a 180 microgram/kg bolus. The extent ofeptifibatide binding to human plasma protein is about 25 %. In the same population, plasmaelimination half-life is approximately 2.5 hours, plasma clearance 55 to 80 ml/kg/hr and volume ofdistribution of approximately 185 to 260 ml/kg.

In healthy subjects, renal excretion accounted for approximately 50 % of total body clearance;approximately 50 % of the amount cleared is excreted unchanged. In patients with moderate to severerenal insufficiency (creatinine clearance < 50 ml/min), the clearance of eptifibatide is reduced byapproximately 50% and steady-state plasma levels are approximately doubled.

No formal pharmacokinetic interaction studies have been conducted. However, in a populationpharmacokinetic study there was no evidence of a pharmacokinetic interaction between eptifibatideand the following concomitant medicinal products: amlodipine, atenolol, atropine, captopril, cefazolin,diazepam, digoxin, diltiazem, diphenhydramine, enalapril, fentanyl, furosemide, heparin, lidocaine,lisinopril, metoprolol, midazolam, morphine, nitrates, nifedipine, and warfarin.

Toxicology studies conducted with eptifibatide include single and repeated dose studies in the rat,rabbit and monkey, reproduction studies in the rat and rabbit, in vitro and in vivo genetic toxicitystudies, and irritation, hypersensitivity and antigenicity studies. No unexpected toxic effects for anagent with this pharmacologic profile were observed and findings were predictive of clinicalexperience, with bleeding effects being the principal adverse event. No genotoxic effects wereobserved with eptifibatide.

Teratology studies have been performed by continuous intravenous infusion of eptifibatide in pregnantrats at total daily doses of up to 72 mg/kg/day (about 4 times the recommended maximum daily humandose on a body surface area basis) and in pregnant rabbits at total daily doses of up to 36 mg/kg/day(about 4 times the recommended maximum daily human dose on a body surface area basis). Thesestudies revealed no evidence of impaired fertility or harm to the foetus due to eptifibatide.

Reproduction studies in animal species where eptifibatide shows a similar pharmacologic activity as inhumans are not available. Consequently these studies are not suitable to evaluate the toxicity ofeptifibatide on reproductive function (see section 4.6).

The carcinogenic potential of eptifibatide has not been evaluated in long-term studies.

Citric acid monohydrate

Sodium hydroxide

Water for injections

INTEGRILIN is not compatible with furosemide.

In the absence of compatibility studies, INTEGRILIN must not be mixed with other medicinalproducts except those mentioned in 6.6.

3 years

Store in a refrigerator (2°C - 8°C). Store in the original package in order to protect from light.

One 10 ml Type I glass vial, closed with a butyl rubber stopper and sealed with a crimped aluminiumseal.

Physical and chemical compatibility testing indicate that INTEGRILIN may be administered throughan intravenous line with atropine sulfate, dobutamine, heparin, lidocaine, meperidine, metoprolol,midazolam, morphine, nitroglycerin, tissue plasminogen activator, or verapamil. INTEGRILIN iscompatible with 0.9 % sodium chloride solution for injection and with dextrose 5 % in Normosol Rwith or without potassium chloride. Please refer to the Normosol R Summary of Product

Characteristics for details on its composition.

Before using, inspect the vial contents. Do not use if particulate matter or discolouration is present.

Protection of INTEGRILIN solution from light is not necessary during administration.

Discard any unused medicinal product after opening.

GlaxoSmithKline (Ireland) Limited12 Riverwalk

Citywest Business Campus

Dublin 24

Ireland

EU/1/99/109/002

Date of first authorisation: 01.07.1999

Date of latest renewal: 09.07.2009

Detailed information on this medicinal product is available on the website of the European Medicines

Agency http://www.ema.europa.eu