EPTIFIBATIDE ACCORD 0.75mg / ml infusion solution medication leaflet

Eptifibatide Accord 0.75 mg/ml solution for infusion

Each ml of solution for infusion contains 0.75 mg of eptifibatide.

One vial of 100 ml of solution for infusion contains 75 mg of eptifibatide.

Each vial contains 172 mg (7.5 mmol) sodium.

For the full list of excipients, see section 6.1.

Solution for infusion.

Clear, colourless solution.

Eptifibatide Accord is intended for use with acetylsalicylic acid and unfractionated heparin.

Eptifibatide Accord 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 pain occurringwithin 24 hours and with electrocardiogram (ECG) changes and/or elevated cardiac enzymes.

Patients most likely to benefit from Eptifibatide Accord 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 experienced inthe management of acute coronary syndromes.

Eptifibatide Accord solution for infusion must be used in conjunction with Eptifibatide Accordsolution for injection.

Concurrent administration of heparin is recommended unless this is contraindicated for reasons such asa history of thrombocytopenia associated with use of heparin (see ‘Heparin administration’, section 4.4).

Eptifibatide Accord is also intended for concurrent use with acetylsalicylic acid, as it is part of standardmanagement of patients with acute coronary syndromes, unless its use is contraindicated.

Adults ( 18 years of age) presenting with unstable angina (UA) or non-Q-wave myocardial infarction(NQMI)

The recommended dosage is an intravenous bolus of 180 microgram/kg administered as soon as possiblefollowing diagnosis, followed by a continuous infusion of 2 microgram/kg/min for up to 72 hours, untilinitiation of coronary artery bypass graft (CABG) surgery, or until discharge from the hospital(whichever occurs first). If Percutaneous Coronary Intervention (PCI) is performed during eptifibatidetherapy, continue the infusion for 20-24 hours post-PCI for an overall maximum duration of therapy of96 hours.

Emergency or semi-elective surgery

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

Experience in patients with hepatic impairment is very limited. Administer with caution to patients withhepatic impairment in whom coagulation could be affected (see section pct. 4.3, prothrombin time). It iscontraindicated 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 on pharmacodynamicand pharmacokinetic data. The available clinical evidence cannot however confirm that this dosemodification results in a preserved benefit (see section 5.1). Use in patients with more severe renalimpairment is contraindicated (see section 4.3).

The safety and efficacy of eptifibatide in children aged below 18 years have not been established, dueto lack of available data.

For instructions on dilution of the medicinal product before administration, see section 6.6.

Eptifibatide Accord 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.

Eptifibatide Accord 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 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 ofeptifibatide (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 a doublebolus 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 needle puncturesites; cutdown sites; gastrointestinal and genitourinary tracts) must be observed carefully. Otherpotential bleeding sites such as central and peripheral nervous system and retroperitoneal sites, must becarefully considered too.

Because Eptifibatide Accord inhibits platelet aggregation, caution must be employed when it is usedwith other 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 eptifibatide and low molecular weight heparins.

There is limited therapeutic experience with eptifibatide in patients for whom thrombolytic therapy isgenerally 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 Eptifibatide

Accord is not recommended in these circumstances (see section 4.5).

Eptifibatide Accord 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 Eptifibatide Accord infusion shouldbe stopped 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 has returnedto normal (e.g. when activated clotting time (ACT) is less than 180 seconds (usually 2-6 hours afterdiscontinuation of heparin). After removal of the introducer sheath, careful haemostasis must be ensuredunder close observation.

Thrombocytopenia and Immunogencity related to GP IIb/IIIa inhibitors

Eptifibatide Accord inhibits platelet aggregation, but does not appear to affect the viability of platelets.

As demonstrated in clinical trials, the incidence of thrombocytopenia was low, and similar in patientstreated with eptifibatide or placebo. Thrombocytopenia, including acute profound thrombocytopenia,has been observed with eptifibatide administration post-marketing (see section 4.8)

The mechanism, whether immune- and/or non-immune-mediated, by which eptifibatide may inducethrombocytopenia is not fully understood. However, treatment with eptifibatide was associated withantibodies that recognise GPIIb/IIIa occupied by eptifibatide, suggesting an immune-mediatedmechanism. Thrombocytopenia occurring after first exposure to a GPIIb/IIIa inhibitor may be explainedby 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 thrombocytopenia isobserved, discontinuation of each treatment medication having known or suspected thrombocytopeniceffects, including eptifibatide, heparin and clopidogrel, should be considered immediately. The decisionto use platelet transfusions should be based upon clinical judgment on an individual basis.

In patients with previous immune-mediated thrombocytopenia from other parenteral GP IIb/IIIainhibitors, there are no data with the use of eptifibatide. Therefore, it is not recommended to administereptifibatide in patients who have previously experienced immune mediated thrombocytopenia 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 and 70seconds, 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 Eptifibatide Accord, the following laboratory tests are recommended to identifypreexisting haemostatic abnormalities: prothrombin time (PT) and aPTT, serum creatinine, plateletcount, 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 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 pseudo thrombocytopenia. Discontinue unfractionatedheparin. In patients undergoing PCI, measure the ACT also.

This medicinal product contains 172 mg sodium per vial, equivalent to 8.6% of the WHO recommendedmaximum daily intake of 2 g sodium for an adult.

Warfarin and dipyridamole

Eptifibatide did not appear to increase the risk of major and minor bleeding associated with concomitantuse of warfarin and dipyridamole. Eptifibatide -treated patients who had a prothrombin time (PT) > 14.5seconds and received warfarin concomitantly did not appear to be at an increased risk of bleeding.

Eptifibatide and thrombolytic agents

Data are limited on the use of eptifibatide in patients receiving thrombolytic agents. There was noconsistent evidence that eptifibatide increased the risk of major or minor bleeding associated with tissueplasminogen activator in either a PCI or an acute myocardial infarction study. Eptifibatide appeared toincrease the risk of bleeding when administered with streptokinase in an acute myocardial infarctionstudy. The combination of reduced dose tenecteplase and eptifibatide compared to placebo andeptifibatide 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.

Eptifibatide Accord should not be used during pregnancy unless clearly necessary.

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

No human data on the effect of drug substance eptifibatide on fertility are available.

Not relevant, as Eptifibatide Accord 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 randomized, double-blind evaluation of the efficacy and safety of eptifibatideversus 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, randomized, parallel-group, placebo-controlled trialevaluating the safety and efficacy of eptifibatide therapy in patients scheduled to undergo non-emergentpercutaneous 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, PURSUIT datawas collected within 30 days while ESPRIT data was limited to events within 48 hours or discharge,whichever came first.

The undesirable effects are listed by system organ class 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< 1/1000); very rare (< 1/10,000); not known (cannot be estimated from available data). These areabsolute reporting frequencies without taking into account placebo rates. For a particular adversereaction, if data was available from both PURSUIT and ESPRIT, then the highest reported incidencewas 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 a haemoglobindecrease of more than 4 g/dl in the absence of an observed bleeding site. During treatment witheptifibatide in this study, minor bleeding was a very common complication (> 1/10, or 13.1 % foreptifibatide versus 7.6 % for placebo). Bleeding events were more frequent in patients receivingconcurrent heparin while undergoing PCI, when ACT exceeded 350 seconds (see section 4.4, heparinuse).

Major bleeding was defined in the PURSUIT trial as either an intracranial haemorrhage or a decrease inhaemoglobin concentrations of more than 5 g/dl. Major bleeding was also very common and reportedmore frequently with eptifibatide than with placebo in the PURSUIT study (> 1/10 or 10.8 % versus9.3 %), but it was infrequent in the vast majority of patients who did not undergo CABG within 30 daysof inclusion in the study. In patients undergoing CABG, the incidence of bleeding was not increased byeptifibatide compared to the patients treated with placebo. In the subgroup of patients undergoing PCI,major bleeding was observed commonly, in 9.7 % of eptifibatide -treated patients vs. 4.6 % of placebo-treated patients.

The incidence of severe or life threatening bleeding events with eptifibatide was 1.9 % compared to1.1 % with placebo. The need for blood transfusions was increased modestly by eptifibatide 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 nervoussystem disorders: cerebral or intracranial haemorrhages); pulmonaryhaemorrhage, 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. It allowscontinued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals areasked to report any suspected adverse reactions via the national reporting system listed 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, rapid infusionreported as overdose or large cumulative doses. In the PURSUIT trial, there were 9 patients whoreceived bolus and/or infusion doses more than double the recommended dose, or who were identifiedby the investigator as having received an overdose. There was no excessive bleeding in any of thesepatients, although one patient undergoing CABG surgery was reported as having had a moderate 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, althougheptifibatide 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(Dphenylalanyl-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 - 50 ml/min) 100 % inhibition was achievedat 24 hours following administration of 2 microgram/kg/min. In patients with severe renal impairment(creatinine clearance < 30 ml/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-waveinversion (> 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 eptifibatide infusionwas 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 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. Ofthe 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’s discretion,most commonly as an intravenous bolus of 5,000 U followed by a continuous infusion of 1,000 U/h. Atarget aPTT of 50-70 seconds was recommended. A total of 1,250 patients underwent PCI within 72hours after randomisation, in which case they received intravenous unfractionated heparin to maintainan 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 early duringtreatment (within the first 72-96 hours) and this reduction was maintained through 6 months, withoutany 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 (2bolus doses of 180 microgram/kg and a continuous infusion until discharge from hospital or a maximumof 18-24 hours).

The first bolus and the infusion were started simultaneously, immediately before the PCI procedure andwere followed by a second bolus 10 minutes after the first. The rate of infusion was 2.0microgram/kg/min for patients with serum creatinine ≤ 175 micromols/l or 1.0 microgram/kg/min forserum 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 vessel revascularisation(UTVR) and thrombolytic bail-out (TBO) at 48 hours] showed a 37 % relative and 3.9 % absolutereduction in the eptifibatide group (6.6 % events versus 10.5 %, p= 0.0015). Results on the primaryendpoint were mainly attributed to the reduction of enzymatic MI occurrence, identified as theoccurrence of early elevation of cardiac enzymes after PCI (80 out of 92 MIs in the placebo group vs.

47 out of 56 MIs in the eptifibatide group). The clinical relevance of such enzymatic MIs is stillcontroversial.

Similar results were also obtained for the 2 secondary endpoints assessed at 30 days: a triple compositeof 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 early duringtreatment. 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, eptifibatidehas no measurable effect on prothrombin time (PT) or activated partial thromboplastin time (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 were managedwith an invasive strategy did not result in a statistically significant reduction in the composite primaryendpoint of rate of death, MI, RI-UR, and TBO within 96 hours compared with a regimen of delayedprovisional eptifibatide (9.3 % in early eptifibatide patients vs. 10.0 % in patients assigned to delayedprovisional eptifibatide; odds ratio=0.920; 95 % CI=0.802-1.055; p=0.234). GUSTO severe/lifethreatening bleeding was uncommon and comparable in both treatment groups (0.8 %). GUSTOmoderate or severe/life threatening bleeding occurred significantly more often with early routineeptifibatide (7.4 % vs. 5.0 % in delayed provisional eptifibatide group; p <0.001). Similar differenceswere noted for TIMI major haemorrhage (118 [2.5 %] in early routine use vs. 83 [1.8 %] in delayedprovisional 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 patients whoreceived a reduced dose (1microgram/kg/min) vs 11.2 % in patients who received the standard dose(2 microgram/kg/min) when eptifibatide was administered in the early routine fashion (p=0.81). Withdelayed provisional eptifibatide administration, the event rates were 10 % vs 11.5 % in patients whoreceived reduced dose and standard dose respectively (p=0.61). TIMI major bleeding occurred in 2.7 %of patients who received a reduced dose (1microgram/kg/min) vs 4.2 % of patients who received thestandard dose (2 microgram/kg/min) when eptifibatide was administered in the early routine fashion(p=0.36). With delayed provisional eptifibatide administration, the TIMI major events were 1.4 % vs2.0 % in patients who received reduced dose and standard dose respectively (p=0.54).There were nonotable differences observed with GUSTO severe bleeding rates.

The pharmacokinetics of eptifibatide are linear and dose proportional for bolus doses ranging from 90to 250 microgram/kg and infusion rates from 0.5 to 3.0 microgram/kg/min.

For a 2.0 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 an 180microgram/kg bolus.

The extent of eptifibatide binding to human plasma protein is about 25 %. In the same population,plasma elimination half-life is approximately 2.5 hours, plasma clearance 55 to 80 ml/kg/hr and volumeof distribution 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 eptifibatide andthe 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, rabbitand monkey, reproduction studies in the rat and rabbit, in vitro and in vivo genetic toxicity studies, andirritation, hypersensitivity and antigenicity studies. No unexpected toxic effects for an agent with thispharmacologic profile were observed and findings were predictive of clinical experience, with bleedingeffects being the principal adverse event. No genotoxic effects were observed 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

Eptifibatide Accord is not compatible with furosemide.

In the absence of compatibility studies, Eptifibatide Accord 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 100 ml Type I glass vial, closed with a butyl rubber stopper and sealed with a flip-off aluminiumseal.

Physical and chemical compatibility testing indicate that Eptifibatide Accord may be administeredthrough an intravenous line with atropine sulfate, dobutamine, heparin, lidocaine, meperidine,metoprolol, midazolam, morphine, nitroglycerin, tissue plasminogen activator, or verapamil.

Eptifibatide Accord is chemically and physically compatible with 0.9 % sodium chloride solution forinfusion and with dextrose 5 % in Normosol R with or without potassium chloride up to 92 hours whenstored at 20-25°C. Please refer to the Normosol R Summary of Product Characteristics for details on itscomposition.

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

Protection of Eptifibatide Accord solution from light is not necessary during administration.

Discard any unused medicinal product after opening.

Any unused medicinal product or waste material should be disposed of in accordance with localrequirements.

Accord Healthcare S.L.U.

World Trade Center, Moll de Barcelona, s/n,

Edifici Est 6ª planta,08039 Barcelona,

Spain

EU/1/15/1065/001

Date of first authorisation: 11th January 2016

Date of latest renewal: 30 September 2020

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

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