Integrilin

1 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX I 
 

SUMMARY OF PRODUCT CHARACTERISTICS 



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1. NAME OF THE MEDICINAL PRODUCT 
 
INTEGRILIN 0.75 mg/ml solution for infusion 
 
 
2. QUALITATIVE AND QUANTITATIVE COMPOSITION 
 
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. 
 
For the full list of excipients, see section 6.1. 
 
 
3. PHARMACEUTICAL FORM 
 
Solution for infusion. 
 
Clear, colourless solution.  
 
 
4. CLINICAL PARTICULARS 
 
4.1 Therapeutic indications 
 
INTEGRILIN is intended for use with acetylsalicylic acid and unfractionated heparin. 
 
INTEGRILIN is indicated for the prevention of early myocardial infarction in adults presenting 
with unstable angina or non-Q-wave myocardial infarction, with the last episode of chest pain 
occurring within 24 hours and with electrocardiogram (ECG) changes and/or elevated cardiac 
enzymes. 
 
Patients most likely to benefit from INTEGRILIN treatment are those at high risk of developing 
myocardial infarction within the first 3-4 days after onset of acute angina symptoms including for 
instance those that are likely to undergo an early PTCA (Percutaneous Transluminal Coronary 
Angioplasty) (see section 5.1).  
 
4.2 Posology and method of administration 
 
This product is for hospital use only. It should be administered by specialist physicians experienced 
in the management of acute coronary syndromes. 
 
INTEGRILIN solution for infusion must be used in conjunction with INTEGRILIN solution for 
injection.  
 
Concurrent administration of heparin is recommended unless this is contraindicated for reasons 
such 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 part 
of standard management of patients with acute coronary syndromes, unless its use is 
contraindicated. 
 
Posology 
 
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 
possible following diagnosis, followed by a continuous infusion of 2 microgram/kg/min for up to 



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72 hours, until initiation of coronary artery bypass graft (CABG) surgery, or until discharge from 
the hospital (whichever occurs first). If Percutaneous Coronary Intervention (PCI) is performed 
during eptifibatide therapy, continue the infusion for 20-24 hours post-PCI for an overall maximum 
duration of therapy of 96 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 
eptifibatide infusion at an appropriate time to allow time for platelet function to return towards 
normal. 
 
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 section 4.3, prothrombin time). It 
is contraindicated in patients with clinically significant hepatic impairment. 
 
Renal impairment 
In patients with moderate renal impairment (creatinine clearance ≥ 30 - < 50 ml/min), an intravenous 
bolus of 180 microgram/kg should be administered followed by a continuous infusion dose of 
1.0 microgram/kg/min for the duration of therapy. This recommendation is based on 
pharmacodynamic and pharmacokinetic data. The available clinical evidence cannot however confirm 
that this dose modification results in a preserved benefit (see section 5.1). Use in patients with more 
severe renal impairment is contraindicated (see section 4.3). 
 
Paediatric population 
It is not recommended for use in children and adolescents below 18 years of age, due to a lack of data 
on safety and efficacy. 
 
4.3 Contraindications 
 
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 abnormal 
 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 (< 100,000 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 
 



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4.4 Special warnings and precautions for use 
 
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 section 4.8). 
Women, the elderly, patients with low body weight or with moderate renal impairment (creatinine 
clearance > 30 - < 50 ml/min) may have an increased risk of bleeding. Monitor these patients closely 
with 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 a 
double bolus before the infusion (see section 5.1). 
 
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 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 with 
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 INTEGRILIN and low molecular weight heparins.  
 
There is limited therapeutic experience with INTEGRILIN in patients for whom thrombolytic therapy 
is generally indicated (e.g. acute transmural myocardial infarction with new pathological Q-waves or 
elevated ST-segments or left bundle branch block in the ECG). Consequently the use of INTEGRILIN 
is not recommended in these circumstances (see section 4.5). 
 
INTEGRILIN infusion should be stopped immediately if circumstances arise that necessitate 
thrombolytic therapy or if the patient must undergo an emergency CABG surgery or requires an 
intraortic balloon pump. 
 
If serious bleeding occurs that is not controllable with pressure, the INTEGRILIN infusion should be 
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 the 
femoral artery area, where the catheter sheath is introduced. Take care to ensure that only the anterior 
wall of the femoral artery is punctured. Arterial sheaths may be removed when coagulation has 
returned 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 haemostasis 
must 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. As 
demonstrated in clinical trials, the incidence of thrombocytopenia was low, and similar in patients 
treated with eptifibatide or placebo. Thrombocytopaenia, including acute profound 
thrombocytopaenia, 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 induce 
thrombocytopaenia is not fully understood. However, treatment with eptifibatide was associated with 
antibodies that recognise GPIIb/IIIa occupied by eptifibatide, suggesting an immune-mediated 



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mechanism. Thrombocytopaenia occurring after first exposure to a GPIIb/IIIa inhibitor may be 
explained 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-mediated 
thrombocytopenic responses, monitoring is required, i.e. platelet counts should be monitored prior to 
treatment, within 6 hours of administration, and at least once daily thereafter while on therapy and 
immediately at clinical signs of unexpected bleeding tendency. 
 
If either a confirmed platelet decrease to < 100,000/mm3 or acute profound thrombocytopaenia is 
observed, discontinuation of each treatment medication having known or suspected thrombocytopenic 
effects, including eptifibatide, heparin and clopidogrel, should be considered immediately. The 
decision 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/IIIa 
inhibitors, there are no data with the use of INTEGRILIN.  Therefore, it is not recommended to 
administer eptifibatide 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 of 
thrombocytopenia 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 is 
given, followed by a constant intravenous infusion of 1,000 units/hr. If the patient weighs < 70 kg, a 
bolus dose of 60 units/kg is recommended, followed by an infusion of 12 units/kg/hr. The activated 
partial thromboplastin time (aPTT) must be monitored in order to maintain a value between 50 and 
70 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) 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. 
 
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 be 
monitored 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 pseudothrombocytopenia. Discontinue 
unfractionated heparin. In patients undergoing PCI, measure the ACT also. 
 
4.5 Interaction with other medicinal products and other forms of interaction 
 
Warfarin 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.  
 
INTEGRILIN and thrombolytic agents 
Data are limited on the use of INTEGRILIN in patients receiving thrombolytic agents. There was no 
consistent evidence that eptifibatide increased the risk of major or minor bleeding associated with 
tissue plasminogen activator in either a PCI or an acute myocardial infarction study. Eptifibatide 
appeared to increase the risk of bleeding when administered with streptokinase in an acute myocardial 
infarction study. The combination of reduced dose tenecteplase and eptifibatide compared to placebo 



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and eptifibatide significantly increased the risk of both major and minor bleeding when administered 
concomitantly in an acute ST-elevation myocardial infarction study. 
 
In an acute myocardial infarction study involving 181 patients, eptifibatide (in regimens up to a bolus 
injection 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 highest 
infusion rates (1.3 microgram/kg/min and 2.0 microgram/kg/min) studied, eptifibatide was associated 
with an increased incidence of bleeding and transfusions compared to the incidence seen when 
streptokinase was given alone. 
 
4.6 Fertility, pregnancy and lactation  
 
Pregnancy 
 
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. 
 
Breast-feeding 
 
It is not known whether eptifibatide is excreted in human milk. Interruption of breast-feeding during 
the treatment period is recommended. 
 
4.7 Effects on ability to drive and use machines 
 
Not relevant, as INTEGRILIN is intended for use only in hospitalised patients.  
 
4.8 Undesirable effects 
 
The majority of adverse reactions experienced by patients treated with eptifibatide were generally 
related 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 III 
clinical studies (PURSUIT and ESPRIT). These trials are briefly described below. 
 
PURSUIT: This was a randomised, double-blind evaluation of the efficacy and safety of Integrilin 
versus placebo for reducing mortality and myocardial (re)infarction in patients with unstable angina or 
non-Q-wave myocardial infarction.  
 
ESPRIT: This was a double-blind, multicentre, randomised, parallel-group, placebo-controlled trial 
evaluating 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 day 
visit. In ESPRIT, bleeding events were reported at 48 hours, and non-bleeding events were reported at 
30 days. While Thrombolysis in Myocardial Infarction TIMI bleeding criteria were used to categorize 
the incidence of major and minor bleeding in both the PURSUIT and the ESPRIT trials, PURSUIT 
data was 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 body system and frequency. Frequencies are defined as very 
common (≥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 into 



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account 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/haematocrit decreased and other). 

Uncommon Thrombocytopenia. 
Nervous System disorders 
Uncommon Cerebral ischaemia. 
Cardiac Disorders 
Common Cardiac arrest, ventricular fibrillation, ventricular tachycardia, congestive heart 

failure, atrioventricular block, atrial fibrillation. 
Vascular Disorders 
Common Shock, hypotension, phlebitis. 

 
Cardiac arrest, congestive heart failure, atrial fibrillation, hypotension, and shock, which are 
commonly 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 classified 
by 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 complication 
encountered during eptifibatide therapy. The most common bleeding complications were associated 
with cardiac invasive procedures (coronary artery bypass grafting (CABG)-related or at femoral artery 
access site).  
 
Minor bleeding was defined in the PURSUIT trial as spontaneous gross haematuria, spontaneous 
haematemesis, observed blood loss with a haemoglobin decrease of more than 3 g/dl, or a 
haemoglobin decrease of more than 4 g/dl in the absence of an observed bleeding site. During 
treatment with Integrilin in this study, minor bleeding was a very common complication (>1/10, or 
13.1% for Integrilin versus 7.6% for placebo). Bleeding events were more frequent in patients 
receiving concurrent heparin while undergoing PCI, when ACT exceeded 350 seconds (see section 
4.4, heparin use). 
 
Major bleeding was defined in the PURSUIT trial as either an intracranial haemorrhage or a decrease 
in haemoglobin concentrations of more than 5 g/dl. Major bleeding was also very common and 
reported 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 within 
30 days of inclusion in the study. In patients undergoing CABG, the incidence of bleeding was not 
increased by Integrilin compared to the patients treated with placebo. In the subgroup of patients 
undergoing 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 of 
platelet aggregation. Thus, changes in laboratory parameters associated with bleeding (e.g. bleeding 
time) are common and expected. No apparent differences were observed between patients treated with 
eptifibatide or with placebo in values for liver function (SGOT/AST, SGPT/ALT, bilirubin, alkaline 
phosphatase) or renal function (serum creatinine, blood urea nitrogen). 
 
 
 



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Post-marketing experience 
 
Blood and lymphatic system disorders 
Very rare Fatal bleeding (the majority involved central and peripheral nervous system 

disorders: cerebral or intracranial haemorrhages); pulmonary haemorrhage, 
acute profound thrombocytopenia, haematoma. 

Immune system disorders 
Very rare Anaphylactic reactions. 
Skin and subcutaneous tissue disorders 
Very rare Rash, application site disorders such as urticaria. 

 
 
Reporting of suspected adverse reactions 
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It 
allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare 
professionals are asked to report any suspected adverse reactions via the national reporting system 
listed in Appendix V. 
 
4.9 Overdose  
 
The experience in humans with overdose of eptifibatide is extremely limited. There was no indication 
of severe adverse reactions 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 the recommended dose, or who were 
identified by the investigator as having received an overdose. There was no excessive bleeding in any 
of these patients, 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 rapid 
clearance, the activity of eptifibatide may be halted readily by discontinuing the infusion. Thus, 
although eptifibatide can be dialysed, the need for dialysis is unlikely.  
 
 
5. PHARMACOLOGICAL PROPERTIES 
 
5.1 Pharmacodynamic properties 
 
Pharmacotherapeutic group: Antithrombotic agent (platelet aggregation inhibitors excl. heparin), ATC 
code: B01AC16 
 
Mechanism of action 
 
Eptifibatide, a synthetic cyclic heptapeptide containing six amino acids, including one cysteine amide 
and one mercaptopropionyl (desamino cysteinyl) residue, is an inhibitor of platelet aggregation and 
belongs 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. 
 
Pharmacodynamic effects 
 
Eptifibatide inhibits platelet aggregation in a dose- and concentration-dependent manner as 
demonstrated by ex vivo platelet aggregation using adenosine diphosphate (ADP) and other agonists to 
induce platelet aggregation. 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 ADP-induced ex vivo platelet aggregation, at physiologic 
calcium concentrations, in more than 80 % of patients. 



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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 with 
unstable angina and Non Q-Wave Myocardial Infarction showed a concentration-dependent inhibition 
with an IC50 (50 % inhibitory concentration) of approximately 550 ng/ml and an IC80 (80 % inhibitory 
concentration) of approximately 1,100 ng/ml. 
 
There is limited data with regards to platelet inhibition in patients with renal impairment.  In patients 
with moderate renal impairment, (creatinine clearance 30 – 50mL/min) 100% inhibition was achieved 
at 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 in 
more than 80% of patients at 24 hours.  
 
Clinical efficacy and safety 
 
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-controlled 
study in 10,948 patients presenting with UA or NQMI. Patients could be enrolled only if they had 
experienced 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 ST 

elevation > 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 a 
2.0 microgram/kg/min infusion (180/2.0), or eptifibatide 180 microgram/kg bolus followed by a 
1.3 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 
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. 
 
Patients were managed according to the usual standards of the investigational site; frequencies of 
angiography, 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 whom 
approximately 50 % received intracoronary stents; 87 % were managed medically (without PCI during 
eptifibatide 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. 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 unfractionated 
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) within 30 days of randomisation. 
The component MI could be defined as asymptomatic with enzymatic elevation of CK-MB or new Q 
wave. 
 



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Compared to placebo, eptifibatide administered as 180/2.0 significantly reduced the incidence of the 
primary 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-Value 
 

 
30 days 

 
743/4,697 
(15.8 %) 

 
667/4,680 
(14.3 %) 

 
0.034a 

 
 
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 
during 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 developing 
myocardial infarction within the first 3-4 days after onset of acute angina.  
According to epidemiological findings, a higher incidence of cardiovascular events has been 
associated 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 syndromes 
was different from that of present times in terms of thienopyridine use and the routine use of 
intracoronary stents.  
 
ESPRIT trial 
ESPRIT (Enhanced Suppression of the Platelet IIb/IIIa Receptor with eptifibatide Therapy) was a 
double-blind, randomised, placebo-controlled trial (n= 2,064) for nonurgent PCI with intracoronary 
stenting.  
 
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 a 
maximum of 18-24 hours). 
 
The first bolus and the infusion were started simultaneously, immediately before the PCI procedure 
and were followed by a second bolus 10 minutes after the first. The rate of infusion was 
2.0 microgram/kg/min for patients with serum creatinine ≤ 175 micromols/l or 1.0 microgram/kg/min 
for 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 % received 
a thienopyridine, (clopidogrel in 95.4 % and ticlopidine in 2.7 %). On the day of PCI, prior to 
catheterization, 53.2 % received a thienopyridine (clopidogrel 52.7 %; ticlopidine 0.5 %) – mostly as a 



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loading 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 of 
60 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/IIIa 
inhibitor therapy (RT) within 48 hours of randomisation.  
 
MI was identified per the CK-MB core laboratory criteria. For this diagnosis, within 24 hours after the 
index 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 an 
investigator 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 % absolute reduction in the eptifibatide group (6.6 % events versus 10.5 %, p = 0.0015). Results 
on 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 the 
placebo 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 triple 
composite 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 early 
during 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 in 
bleeding time. This increase is readily reversible upon discontinuation of the infusion with bleeding 
times returning towards baseline in approximately 6 (2-8) hours. When administered alone, 
eptifibatide has no measurable effect on prothrombin time (PT) or activated partial thromboplastin 
time (aPTT).  
 



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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 of 
eptifibatide 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 drug 
for 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 
managed with an invasive strategy did not result in a statistically significant reduction in the 
composite primary endpoint of rate of death, MI, RI-UR, and TBO within 96 hours compared with a 
regimen of delayed provisional eptifibatide (9.3% in early eptifibatide patients vs. 10.0% in patients 
assigned 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 with 
early routine eptifibatide (7.4% vs. 5.0% in delayed provisional eptifibatide group; p <0.001). Similar 
differences were noted for TIMI major haemorrhage (118 [2.5%] in early routine use vs. 83 [1.8%] in 
delayed provisional use; p=0.016).  
 
No statistically significant benefit of early routine eptifibatide strategy was demonstrated in the 
subgroup 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 with 
moderate renal impairment is inconclusive. The primary endpoint event rate was 11.9 % in patients 
who received a reduced dose (1microgram/kg/min) vs 11.2% in patients who received the standard 
dose (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 patients 
who received 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 the standard dose (2microgram/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% 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. 
 
5.2 Pharmacokinetic properties  
 
The pharmacokinetics of eptifibatide are linear and dose proportional for bolus doses ranging from 
90 to 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 from 
1.5 to 2.2 microgram/ml in patients with coronary artery disease. These plasma concentrations are 
achieved rapidly when the infusion is preceded by a 180 microgram/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 volume of 
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 severe 
renal insufficiency (creatinine clearance < 50 ml/min), the clearance of eptifibatide is reduced by 
approximately 50% and steady-state plasma levels are approximately doubled.  
 
No formal pharmacokinetic interaction studies have been conducted. However, in a population 
pharmacokinetic study there was no evidence of a pharmacokinetic interaction between eptifibatide 
and the following concomitant medicinal products: amlodipine, atenolol, atropine, captopril, cefazolin, 



 13 

diazepam, digoxin, diltiazem, diphenhydramine, enalapril, fentanyl, furosemide, heparin, lidocaine, 
lisinopril, metoprolol, midazolam, morphine, nitrates, nifedipine, and warfarin. 
 
5.3 Preclinical safety data  
 
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 toxicity 
studies, and irritation, hypersensitivity and antigenicity studies. No unexpected toxic effects for an 
agent with this pharmacologic profile were observed and findings were predictive of clinical 
experience, with bleeding effects being the principal adverse event. No genotoxic effects were 
observed with eptifibatide. 
 
Teratology studies have been performed by continuous intravenous infusion of eptifibatide in pregnant 
rats at total daily doses of up to 72 mg/kg/day (about 4 times the recommended maximum daily human 
dose 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). These 
studies 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 in 
humans are not available. Consequently these studies are not suitable to evaluate the toxicity of 
eptifibatide on reproductive function (see section 4.6). 
 
The carcinogenic potential of eptifibatide has not been evaluated in long-term studies. 
 
 
6. PHARMACEUTICAL PARTICULARS 
 
6.1 List of excipients 
 
Citric acid monohydrate 
Sodium hydroxide 
Water for injections 
 
6.2 Incompatibilities  
 
INTEGRILIN is not compatible with furosemide. 
 
In the absence of compatibility studies, INTEGRILIN must not be mixed with other medicinal 
products except those mentioned in 6.6. 
 
6.3 Shelf life 
 
3 years 
 
6.4 Special precautions for storage  
 
Store in a refrigerator (2°C - 8°C).  
Store in the original package in order to protect from light. 
 
6.5 Nature and contents of container  
 
One 100 ml Type I glass vial, closed with a butyl rubber stopper and sealed with a crimped aluminium 
seal. 
 
6.6  Special precautions for disposal and other handling 
 
Physical and chemical compatibility testing indicate that INTEGRILIN may be administered through 
an intravenous line with atropine sulfate, dobutamine, heparin, lidocaine, meperidine, metoprolol, 



 14 

midazolam, morphine, nitroglycerin, tissue plasminogen activator, or verapamil. INTEGRILIN is 
compatible with 0.9 % sodium chloride solution for infusion and with dextrose 5 % in Normosol R 
with 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. 
 
 
7. MARKETING AUTHORISATION HOLDER 
 
GlaxoSmithKline (Ireland) Limited  
12 Riverwalk  
Citywest Business Campus 
Dublin 24 
Ireland 
 
 
8. MARKETING AUTHORISATION NUMBER 
 
EU/1/99/109/001 
 
 
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 
 
Date of first authorisation: 01.07.1999 
Date of latest renewal: 09.07.2009 
 
 

10. DATE OF REVISION OF THE TEXT 
 
 
Detailed information on this medicinal product is available on the website of the European Medicines 
Agency  http://www.ema.europa.eu 
 



 15 

1. NAME OF THE MEDICINAL PRODUCT 
 
INTEGRILIN 2 mg/ml solution for injection 
 
 
2. QUALITATIVE AND QUANTITATIVE COMPOSITION 
 
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. 
 
For the full list of excipients, see section 6.1. 
 
 
3. PHARMACEUTICAL FORM 
 
Solution for injection. 
 
Clear, colourless solution.  
 
 
4. CLINICAL PARTICULARS 
 
4.1 Therapeutic indications 
 
INTEGRILIN is intended for use with acetylsalicylic acid and unfractionated heparin. 
 
INTEGRILIN is indicated for the prevention of early myocardial infarction in adults presenting 
with unstable angina or non-Q-wave myocardial infarction, with the last episode of chest pain 
occurring within 24 hours and with electrocardiogram (ECG) changes and/or elevated cardiac 
enzymes. 
 
Patients most likely to benefit from INTEGRILIN treatment are those at high risk of developing 
myocardial infarction within the first 3-4 days after onset of acute angina symptoms including for 
instance those that are likely to undergo an early PTCA (Percutaneous Transluminal Coronary 
Angioplasty) (see section 5.1).  
 
4.2 Posology and method of administration 
 
This product is for hospital use only. It should be administered by specialist physicians experienced 
in the management of acute coronary syndromes. 
 
INTEGRILIN solution for injection must be used in conjunction with INTEGRILIN solution for 
infusion.  
 
Concurrent administration of heparin is recommended unless this is contraindicated for reasons 
such 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 part 
of standard management of patients with acute coronary syndromes, unless its use is 
contraindicated. 
 
Posology 
 
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 
possible following diagnosis, followed by a continuous infusion of 2 microgram/kg/min for up to 



 16 

72 hours, until initiation of coronary artery bypass graft (CABG) surgery, or until discharge from 
the hospital (whichever occurs first). If Percutaneous Coronary Intervention (PCI) is performed 
during eptifibatide therapy, continue the infusion for 20-24 hours post-PCI for an overall maximum 
duration of therapy of 96 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 
eptifibatide infusion at an appropriate time to allow time for platelet function to return towards 
normal. 
 
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 section 4.3, prothrombin time). It 
is contraindicated in patients with clinically significant hepatic impairment. 
 
Renal impairment 
In patients with moderate renal impairment (creatinine clearance ≥ 30 - < 50 ml/min), an intravenous 
bolus of 180 microgram/kg should be administered followed by a continuous infusion dose of 
1.0 microgram/kg/min for the duration of therapy. This recommendation is based on 
pharmacodynamic and pharmacokinetic data. The available clinical evidence cannot however confirm 
that this dose modification results in a preserved benefit (see section 5.1). Use in patients with more 
severe renal impairment is contraindicated (see section 4.3). 
 
Paediatric population 
It is not recommended for use in children and adolescents below 18 years of age, due to a lack of data 
on safety and efficacy. 
 
4.3 Contraindications 
 
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 abnormal 
 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 (< 100,000 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 
 
4.4 Special warnings and precautions for use 
 
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 section 4.8). 
Women, the elderly, patients with low body weight or with moderate renal impairment (creatinine 
clearance > 30 - < 50 ml/min) may have an increased risk of bleeding. Monitor these patients closely 
with regard to bleeding. 
 



 17 

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 a 
double bolus before the infusion (see section 5.1). 
 
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 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 with 
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 INTEGRILIN and low molecular weight heparins.  
 
There is limited therapeutic experience with INTEGRILIN in patients for whom thrombolytic therapy 
is generally indicated (e.g. acute transmural myocardial infarction with new pathological Q-waves or 
elevated ST-segments or left bundle branch block in the ECG). Consequently the use of INTEGRILIN 
is not recommended in these circumstances (see section 4.5). 
 
INTEGRILIN infusion should be stopped immediately if circumstances arise that necessitate 
thrombolytic therapy or if the patient must undergo an emergency CABG surgery or requires an 
intraortic balloon pump. 
 
If serious bleeding occurs that is not controllable with pressure, the INTEGRILIN infusion should be 
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 the 
femoral artery area, where the catheter sheath is introduced. Take care to ensure that only the anterior 
wall of the femoral artery is punctured. Arterial sheaths may be removed when coagulation has 
returned 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 haemostasis 
must 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. As 
demonstrated in clinical trials, the incidence of thrombocytopenia was low, and similar in patients 
treated with eptifibatide or placebo. Thrombocytopaenia, including acute profound 
thrombocytopaenia, 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 induce 
thrombocytopaenia is not fully understood. However, treatment with eptifibatide was associated with 
antibodies that recognise GPIIb/IIIa occupied by eptifibatide, suggesting an immune-mediated 
mechanism. Thrombocytopaenia occurring after first exposure to a GPIIb/IIIa inhibitor may be 
explained 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-mediated 
thrombocytopenic responses, monitoring is required, i.e. platelet counts should be monitored prior to 
treatment, within 6 hours of administration, and at least once daily thereafter while on therapy and 
immediately at clinical signs of unexpected bleeding tendency. 
 



 18 

 
If either a confirmed platelet decrease to < 100,000/mm3 or acute profound thrombocytopaenia is 
observed, discontinuation of each treatment medication having known or suspected thrombocytopenic 
effects, including eptifibatide, heparin and clopidogrel, should be considered immediately. The 
decision 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/IIIa 
inhibitors, there are no data with the use of INTEGRILIN.  Therefore, it is not recommended to 
administer eptifibatide 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 of 
thrombocytopenia 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 is 
given, followed by a constant intravenous infusion of 1,000 units/hr. If the patient weighs < 70 kg, a 
bolus dose of 60 units/kg is recommended, followed by an infusion of 12 units/kg/hr. The activated 
partial thromboplastin time (aPTT) must be monitored in order to maintain a value between 50 and 
70 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) 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. 
 
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 be 
monitored 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 pseudothrombocytopenia. Discontinue 
unfractionated heparin. In patients undergoing PCI, measure the ACT also. 
 
4.5 Interaction with other medicinal products and other forms of interaction 
 
Warfarin 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. 
 
INTEGRILIN and thrombolytic agents  
Data are limited on the use of INTEGRILIN in patients receiving thrombolytic agents. There was no 
consistent evidence that eptifibatide increased the risk of major or minor bleeding associated with 
tissue plasminogen activator in either a PCI or an acute myocardial infarction study. Eptifibatide 
appeared to increase the risk of bleeding when administered with streptokinase in an acute myocardial 
infarction study. The combination of reduced dose tenecteplase and eptifibatide compared to placebo 
and eptifibatide significantly increased the risk of both major and minor bleeding when administered 
concomitantly in an acute ST-elevation myocardial infarction study. 
 
In an acute myocardial infarction study involving 181 patients, eptifibatide (in regimens up to a bolus 
injection 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 highest 
infusion rates (1.3 microgram/kg/min and 2.0 microgram/kg/min) studied, eptifibatide was associated 
with an increased incidence of bleeding and transfusions compared to the incidence seen when 
streptokinase was given alone. 



 19 

 
4.6 Fertility, pregnancy and lactation  
 
Pregnancy 
 
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. 
 
Breast-feeding 
 
It is not known whether eptifibatide is excreted in human milk. Interruption of breast-feeding during 
the treatment period is recommended. 
 
4.7 Effects on ability to drive and use machines 
 
Not relevant, as INTEGRILIN is intended for use only in hospitalised patients.  
 
4.8 Undesirable effects 
 
The majority of adverse reactions experienced by patients treated with eptifibatide were generally 
related 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 III 
clinical studies (PURSUIT and ESPRIT). These trials are briefly described below. 
 
PURSUIT: This was a randomised, double-blind evaluation of the efficacy and safety of Integrilin 
versus placebo for reducing mortality and myocardial (re)infarction in patients with unstable angina or 
non-Q-wave myocardial infarction.  
 
ESPRIT: This was a double-blind, multicentre, randomised, parallel-group, placebo-controlled trial 
evaluating 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 day 
visit. In ESPRIT, bleeding events were reported at 48 hours, and non-bleeding events were reported at 
30 days. While Thrombolysis in Myocardial Infarction TIMI bleeding criteria were used to categorize 
the incidence of major and minor bleeding in both the PURSUIT and the ESPRIT trials, PURSUIT 
data was 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 body system and frequency. Frequencies are defined as very 
common (≥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 into 
account 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.  
 
 
 
 
 
 
 
 



 20 

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/haematocrit decreased and other). 

Uncommon Thrombocytopenia. 
Nervous System disorders 
Uncommon Cerebral ischaemia. 
Cardiac Disorders 
Common Cardiac arrest, ventricular fibrillation, ventricular tachycardia, congestive heart 

failure, atrioventricular block, atrial fibrillation. 
Vascular Disorders 
Common Shock, hypotension, phlebitis. 

 
Cardiac arrest, congestive heart failure, atrial fibrillation, hypotension, and shock, which are 
commonly 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 classified 
by 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 complication 
encountered during eptifibatide therapy. The most common bleeding complications were associated 
with cardiac invasive procedures (coronary artery bypass grafting (CABG)-related or at femoral artery 
access site).  
 
Minor bleeding was defined in the PURSUIT trial as spontaneous gross haematuria, spontaneous 
haematemesis, observed blood loss with a haemoglobin decrease of more than 3 g/dl, or a 
haemoglobin decrease of more than 4 g/dl in the absence of an observed bleeding site. During 
treatment with Integrilin in this study, minor bleeding was a very common complication (>1/10, or 
13.1% for Integrilin versus 7.6% for placebo). Bleeding events were more frequent in patients 
receiving concurrent heparin while undergoing PCI, when ACT exceeded 350 seconds (see section 
4.4, heparin use). 
 
Major bleeding was defined in the PURSUIT trial as either an intracranial haemorrhage or a decrease 
in haemoglobin concentrations of more than 5 g/dl. Major bleeding was also very common and 
reported 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 within 
30 days of inclusion in the study. In patients undergoing CABG, the incidence of bleeding was not 
increased by Integrilin compared to the patients treated with placebo. In the subgroup of patients 
undergoing 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 of 
platelet aggregation. Thus, changes in laboratory parameters associated with bleeding (e.g. bleeding 
time) are common and expected. No apparent differences were observed between patients treated with 
eptifibatide or with placebo in values for liver function (SGOT/AST, SGPT/ALT, bilirubin, alkaline 
phosphatase) or renal function (serum creatinine, blood urea nitrogen). 
 
 
 
 
 
 



 21 

Post-marketing experience 
 
Blood and lymphatic system disorders 
Very rare Fatal bleeding (the majority involved central and peripheral nervous system 

disorders: cerebral or intracranial haemorrhages); pulmonary haemorrhage, 
acute profound thrombocytopenia, haematoma. 

Immune system disorders 
Very rare Anaphylactic reactions. 
Skin and subcutaneous tissue disorders 
Very rare Rash, application site disorders such as urticaria. 

 
 
Reporting of suspected adverse reactions 
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It 
allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare 
professionals are asked to report any suspected adverse reactions via the national reporting system 
listed in Appendix V. 
 
4.9 Overdose  
 
The experience in humans with overdose of eptifibatide is extremely limited. There was no indication 
of severe adverse reactions 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 the recommended dose, or who were 
identified by the investigator as having received an overdose. There was no excessive bleeding in any 
of these patients, 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 rapid 
clearance, the activity of eptifibatide may be halted readily by discontinuing the infusion. Thus, 
although eptifibatide can be dialysed, the need for dialysis is unlikely.  
 
 
5. PHARMACOLOGICAL PROPERTIES 
 
5.1 Pharmacodynamic properties 
 
Pharmacotherapeutic group: Antithrombotic agent (platelet aggregation inhibitors excl. heparin), ATC 
code: B01AC16 
 
Mechanism of action 
 
Eptifibatide, a synthetic cyclic heptapeptide containing six amino acids, including one cysteine amide 
and one mercaptopropionyl (desamino cysteinyl) residue, is an inhibitor of platelet aggregation and 
belongs 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. 
 
Pharmacodynamic effects 
 
Eptifibatide inhibits platelet aggregation in a dose- and concentration-dependent manner as 
demonstrated by ex vivo platelet aggregation using adenosine diphosphate (ADP) and other agonists to 
induce platelet aggregation. 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 ADP-induced ex vivo platelet aggregation, at physiologic 
calcium concentrations, in more than 80 % of patients. 



 22 

 
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 with 
unstable angina and Non Q-Wave Myocardial Infarction showed a concentration-dependent inhibition 
with an IC50 (50 % inhibitory concentration) of approximately 550 ng/ml and an IC80 (80 % inhibitory 
concentration) of approximately 1,100 ng/ml. 
 
There is limited data with regards to platelet inhibition in patients with renal impairment.  In patients 
with moderate renal impairment, (creatinine clearance 30 – 50mL/min) 100% inhibition was achieved 
at 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 in 
more than 80% of patients at 24 hours.  
 
Clinical efficacy and safety 
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-controlled 
study in 10,948 patients presenting with UA or NQMI. Patients could be enrolled only if they had 
experienced 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 ST 

elevation > 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 a 
2.0 microgram/kg/min infusion (180/2.0), or eptifibatide 180 microgram/kg bolus followed by a 
1.3 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 
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. 
 
Patients were managed according to the usual standards of the investigational site; frequencies of 
angiography, 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 whom 
approximately 50 % received intracoronary stents; 87 % were managed medically (without PCI during 
eptifibatide 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. 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 unfractionated 
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) within 30 days of randomisation. 
The component MI could be defined as asymptomatic with enzymatic elevation of CK-MB or new Q 
wave. 
 



 23 

Compared to placebo, eptifibatide administered as 180/2.0 significantly reduced the incidence of the 
primary 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-Value 

 
 

30 days 
 

743/4,697 
(15.8 %) 

 
667/4,680 
(14.3 %) 

 
0.034a 

 
 
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 
during 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 developing 
myocardial infarction within the first 3-4 days after onset of acute angina.  
According to epidemiological findings, a higher incidence of cardiovascular events has been 
associated 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 syndromes 
was different from that of present times in terms of thienopyridine use and the routine use of 
intracoronary stents.  
 
ESPRIT trial 
ESPRIT (Enhanced Suppression of the Platelet IIb/IIIa Receptor with eptifibatide Therapy) was a 
double-blind, randomised, placebo-controlled trial (n= 2,064) for nonurgent PCI with intracoronary 
stenting.  
 
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 a 
maximum of 18-24 hours). 
 
The first bolus and the infusion were started simultaneously, immediately before the PCI procedure 
and were followed by a second bolus 10 minutes after the first. The rate of infusion was 
2.0 microgram/kg/min for patients with serum creatinine ≤ 175 micromols/l or 1.0 microgram/kg/min 
for 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 % received 
a thienopyridine, (clopidogrel in 95.4 % and ticlopidine in 2.7 %). On the day of PCI, prior to 
catheterization, 53.2 % received a thienopyridine (clopidogrel 52.7 %; ticlopidine 0.5 %) – mostly as a 
loading dose (300 mg or more). The placebo arm was comparable (aspirin 99.7 %, clopidogrel 95.9 %, 
ticlopidin 2.6 %).  



 24 

 
The ESPRIT trial used a simplified regimen of heparin during PCI that consisted of an initial bolus of 
60 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/IIIa 
inhibitor therapy (RT) within 48 hours of randomisation.  
 
MI was identified per the CK-MB core laboratory criteria. For this diagnosis, within 24 hours after the 
index 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 an 
investigator 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 % absolute reduction in the eptifibatide group (6.6 % events versus 10.5 %, p = 0.0015). Results 
on 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 the 
placebo 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 triple 
composite 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 early 
during 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 in 
bleeding time. This increase is readily reversible upon discontinuation of the infusion with bleeding 
times returning towards baseline in approximately 6 (2-8) hours. When administered alone, 
eptifibatide has 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 of 
eptifibatide 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 drug 
for 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 
managed with an invasive strategy did not result in a statistically significant reduction in the 
composite primary endpoint of rate of death, MI, RI-UR, and TBO within 96 hours compared with a 
regimen of delayed provisional eptifibatide (9.3% in early eptifibatide patients vs. 10.0% in patients 
assigned 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 with 
early routine eptifibatide (7.4% vs. 5.0% in delayed provisional eptifibatide group; p <0.001). Similar 
differences were noted for TIMI major haemorrhage (118 [2.5%] in early routine use vs. 83 [1.8%] in 
delayed provisional use; p=0.016).  
 
No statistically significant benefit of early routine eptifibatide strategy was demonstrated in the 
subgroup of patients who were managed medically or during the medical management periods prior to 
PCI or CABG. 
 



 25 

In a post hoc analysis of the EARLY ACS trial the risk benefit of dose reduction in patients with 
moderate renal impairment is inconclusive. The primary endpoint event rate was 11.9 % in patients 
who received a reduced dose (1microgram/kg/min) vs 11.2% in patients who received the standard 
dose (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 patients 
who received 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 the standard dose (2microgram/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% 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. 
 
5.2 Pharmacokinetic properties  
 
The pharmacokinetics of eptifibatide are linear and dose proportional for bolus doses ranging from 
90 to 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 from 
1.5 to 2.2 microgram/ml in patients with coronary artery disease. These plasma concentrations are 
achieved rapidly when the infusion is preceded by a 180 microgram/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 volume of 
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 severe 
renal insufficiency (creatinine clearance < 50 ml/min), the clearance of eptifibatide is reduced by 
approximately 50% and steady-state plasma levels are approximately doubled.  
 
No formal pharmacokinetic interaction studies have been conducted. However, in a population 
pharmacokinetic study there was no evidence of a pharmacokinetic interaction between eptifibatide 
and 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. 
 
5.3 Preclinical safety data  
 
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 toxicity 
studies, and irritation, hypersensitivity and antigenicity studies. No unexpected toxic effects for an 
agent with this pharmacologic profile were observed and findings were predictive of clinical 
experience, with bleeding effects being the principal adverse event. No genotoxic effects were 
observed with eptifibatide. 
 
Teratology studies have been performed by continuous intravenous infusion of eptifibatide in pregnant 
rats at total daily doses of up to 72 mg/kg/day (about 4 times the recommended maximum daily human 
dose 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). These 
studies 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 in 
humans are not available. Consequently these studies are not suitable to evaluate the toxicity of 
eptifibatide on reproductive function (see section 4.6). 
 
The carcinogenic potential of eptifibatide has not been evaluated in long-term studies. 
 
 
 
 



 26 

6. PHARMACEUTICAL PARTICULARS 
 
6.1 List of excipients 
 
Citric acid monohydrate 
Sodium hydroxide 
Water for injections 
 
6.2 Incompatibilities  
 
INTEGRILIN is not compatible with furosemide. 
 
In the absence of compatibility studies, INTEGRILIN must not be mixed with other medicinal 
products except those mentioned in 6.6. 
 
6.3 Shelf life 
 
3 years 
 
 
6.4 Special precautions for storage  
 
Store in a refrigerator (2°C - 8°C). Store in the original package in order to protect from light. 
 
6.5 Nature and contents of container  
 
One 10 ml Type I glass vial, closed with a butyl rubber stopper and sealed with a crimped aluminium 
seal. 
 
6.6  Special precautions for disposal and other handling 
 
Physical and chemical compatibility testing indicate that INTEGRILIN may be administered through 
an intravenous line with atropine sulfate, dobutamine, heparin, lidocaine, meperidine, metoprolol, 
midazolam, morphine, nitroglycerin, tissue plasminogen activator, or verapamil. INTEGRILIN is 
compatible with 0.9 % sodium chloride solution for injection and with dextrose 5 % in Normosol R 
with 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. 
 
 
7. MARKETING AUTHORISATION HOLDER 
 
GlaxoSmithKline (Ireland) Limited  
12 Riverwalk  
Citywest Business Campus 
Dublin 24 
Ireland 
 
 
8. MARKETING AUTHORISATION NUMBER 
 
EU/1/99/109/002 
 



 27 

 
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 
 
Date of first authorisation: 01.07.1999 
Date of latest renewal: 09.07.2009   
 
 
10. DATE OF REVISION OF THE TEXT 
 
Detailed information on this medicinal product is available on the website of the European Medicines 
Agency http://www.ema.europa.eu 

 



 28 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX II 
 
A. MANUFACTURER(S) RESPONSIBLE FOR BATCH 

RELEASE 
 
B. CONDITIONS OR RESTRICTIONS REGARDING 

SUPPLY AND USE 
 
C. OTHER CONDITIONS AND REQUIREMENTS OF THE 

MARKETING AUTHORISATION 
 
D. CONDITIONS OR RESTRICTIONS WITH REGARD TO 

THE SAFE AND EFFECTIVE USE OF THE 
MEDICINAL PRODUCT 

 



 29 

A. MANUFACTURER(S) RESPONSIBLE FOR BATCH RELEASE 
 
Name and address of the manufacturer responsible for batch release 
 
Glaxo Operations UK Ltd. 
(Trading as Glaxo Wellcome Operations) 
Harmire Road 
Barnard Castle 
Co. Durham 
DL12 8DT 
United Kingdom 
 
or 
 
GlaxoSmithKline Manufacturing S.P.A. 
Strada Provinciale Asolana No. 90 
San Polo di Torrile 43056 
Parma 
Italy 
 
The printed package leaflet of the medicinal product must state the name and address of the 
manufacturer responsible for the release of the concerned batch. 
 
 
B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE 
 
 
Medicinal product subject to restricted medical prescription (See Annex I: Summary of Product 
Characteristics, 4.2) 
 
C.  OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING 

AUTHORISATION 
 

• Periodic Safety Update Reports 
 
The requirements for submission of periodic safety update reports for this medicinal product are set 
out in the list of Union reference dates (EURD list) provided for under Article 107c(7) of Directive 
2001/83/EC and any subsequent published on the European medicines web-portal. 
 
 
D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND 

EFFECTIVE USE OF THE MEDICINAL PRODUCT 
 

• Risk Management Plan (RMP) 
 
The MAH shall perform the required pharmacovigilance activities and interventions detailed in the 
agreed RMP presented in Module 1.8.2 of the Marketing Authorisation and any agreed subsequent 
updates of the RMP. 
 
An updated RMP should be submitted: 

• At the request of the European Medicines Agency; 
• Whenever the risk management system is modified, especially as the result of new 

information being received that may lead to a significant change to the benefit/risk profile or 
as the result of an important (pharmacovigilance or risk minimisation) milestone being 
reached. 

 
 



 30 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX III 
 

LABELLING AND PACKAGE LEAFLET 
 



 31 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

A. LABELLING 



 32 

 
PARTICULARS TO APPEAR ON THE OUTER PACKAGING  
 
CARTON 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
INTEGRILIN 0.75 mg/ml solution for infusion 
eptifibatide 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each ml of solution for infusion contains 0.75 mg of eptifibatide. 
 
One 100 ml vial contains 75 mg of eptifibatide. 
 
 
3. LIST OF EXCIPIENTS 
 
Citric acid monohydrate, sodium hydroxide, water for injections. 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
Solution for infusion 
 
1 vial of 100 ml 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Intravenous use 
Read the package leaflet before use.  
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 
 
Keep out of the sight and reach of children. 
 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
Inspect the vial content. Do not use if particulate matter or discolouration is present. 
 
 
8. EXPIRY DATE 
 
EXP  
 



 33 

9. SPECIAL STORAGE CONDITIONS 
 
Store in a refrigerator.  
 
Store in the original package in order to protect from light. 
 
 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
Discard any unused material after opening. 
 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
GlaxoSmithKline (Ireland) Limited, 12 Riverwalk, Citywest Business Campus, Dublin 24, Ireland 
 
 
12. MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/99/109/001  
 
 
13. BATCH NUMBER 
 
Batch 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
Medicinal product subject to medical prescription. 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 

 
Justification for not including Braille accepted 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
 
 
18. UNIQUE IDENTIFIER – HUMAN READABLE DATA 
 
PC: 
SN: 
NN: 
 
 



 34 

 
MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS 
 
LABEL 
 
 
1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION 
 
INTEGRILIN 0.75 mg/ml solution for infusion 
eptifibatide 
 
Intravenous use  
 
2. METHOD OF ADMINISTRATION 
 
Read the package leaflet before use 
 
 
3. EXPIRY DATE 
 
EXP 
 
 
4. BATCH NUMBER 
 
Batch 
 
 
5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 
 
1 vial of 100 ml 
 



 35 

 
PARTICULARS TO APPEAR ON THE OUTER PACKAGING  
 
CARTON 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
INTEGRILIN 2 mg/ml solution for injection 
eptifibatide 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each ml of solution for injection contains 2 mg of eptifibatide. 
 
One 10 ml vial contains 20 mg of eptifibatide. 
 
 
3. LIST OF EXCIPIENTS 
 
Citric acid monohydrate, sodium hydroxide, water for injections. 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
Solution for injection 
 
1 vial of 10 ml 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Intravenous use 
 
Read the package leaflet before use.  
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 
 
Keep out of the sight and reach of children. 
 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
Inspect the vial content. Do not use if particulate matter or discolouration is present. 
 
 
8. EXPIRY DATE 
 
EXP  
 



 36 

9. SPECIAL STORAGE CONDITIONS 
 
Store in a refrigerator.  
 
Store in the original package in order to protect from light. 
 
 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
Discard any unused material after opening. 
 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
GlaxoSmithKline (Ireland) Limited, 12 Riverwalk, Citywest Business Campus, Dublin 24, Ireland 
 
 
12. MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/99/109/002  
 
 
13. BATCH NUMBER 
 
Batch 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
Medicinal product subject to medical prescription. 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 

 
 

Justification for not including Braille accepted 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
 
 
18. UNIQUE IDENTIFIER – HUMAN READABLE DATA 
 
PC: 
SN: 
NN: 
 
 



 37 

 
MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS 
 
LABEL 
 
 
1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION 
 
INTEGRILIN 2 mg/ml solution for injection 
eptifibatide 
 
Intravenous use  
 
2. METHOD OF ADMINISTRATION 
 
Read the package leaflet before use 
 
 
3. EXPIRY DATE 
 
EXP 
 
 
4. BATCH NUMBER 
 
Batch 
 
 
5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 
 
1 vial of 10 ml 
 



 38 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

B. PACKAGE LEAFLET 



 39 

 
Package leaflet: Information for the patient 

 
Integrilin 0.75 mg/ml solution for infusion 

eptifibatide 
 

Read all of this leaflet carefully before you start using this medicine because it contains 
important information for you. 
− Keep this leaflet. You may need to read it again. 
− If you have any further questions, ask your doctor or hospital pharmacist or nurse. 
− If you get any side effects talk to your doctor or hospital pharmacist or nurse. This includes any 

possible side effects not listed in this leaflet. See section 4. 
 
What is in this leaflet:  
1. What Integrilin is and what it is used for 
2. What you need to know before you are given Integrilin 
3. How to use Integrilin 
4. Possible side effects 
5. How to store Integrilin 
6. Contents of the pack and other information 
 
 
1. What Integrilin is and what it is used for 
 
Integrilin is an inhibitor of platelet aggregation. This means that it helps to prevent blood clots from 
forming.  
 
It is used in adults with manifestation of severe coronary insufficiency defined as spontaneous and recent 
chest pain with electrocardiographic abnormalities or biological changes. It is usually given with aspirin 
and unfractionated heparin. 
 
 
2. What you need to know before you are given Integrilin 
 
You must not be given Integrilin: 
− if you are allergic to eptifibatide or any of the other ingredients of this medicine (listed in section 

6). 
− if you have recently had bleeding from your stomach, intestines, bladder or other organs, for 

example if you have seen abnormal blood in your stool or urine (except from menstrual bleeding) 
in the past 30 days. 

− if you have had a stroke within the past 30 days or any haemorrhagic stroke (also, be sure your 
doctor knows if you ever had a stroke). 

− if you have had a brain tumour or a condition that affects the blood vessels around the brain. 
− if you had a major operation or severe injury during the past 6 weeks. 
− if you have or have had bleeding problems. 
− if you have or have had difficulty with your blood clotting or a low blood platelet count. 
− if you have or have had severe hypertension (high blood pressure). 
− if you have or have had severe kidney or liver problems. 
− if you have been treated with another medicineof the same type as Integrilin. 
 
Please tell your doctor if you have had any of these conditions. If you have any questions, ask your 
doctor or hospital pharmacist or nurse. 
 
Take special care with Integrilin: 
− Integrilin is recommended for use only in adult, hospitalised patients in coronary care units. 
− Integrilin is not intended for use in children or adolescents less than 18 years of age. 



 40 

− Before and during your treatment with Integrilin, samples of your blood will be tested as a safety 
measure to limit the possibility of unexpected bleeding. 

− During use of Integrilin, you will be checked carefully for any signs of unusual or unexpected 
bleeding. 
 

Other medicines and Integrilin 
To avoid the possibility of interactions with other medicines please tell your doctor or hospital 
pharmacist or nurse if you are taking or have recently taken or might take any other medicines, 
including medicines obtained without a prescription. Particularly: 
− blood thinners (oral anticoagulants) or 
− medicines that prevent blood clots, including warfarin, dipyridamole, ticlopidine, aspirin (except 

those that you may be given as part of Integrilin treatment).  
 
Pregnancy and breast-feeding 
Integrilin is not usually recommended for use during pregnancy. Tell your doctor if you are pregnant, 
think you might be pregnant or are planning to have a baby. Your doctor will weigh up the benefit to 
you against the risk to your baby of using Integrilin while you are pregnant. 
 
If you are breast-feeding a baby, breast-feeding should be interrupted during the treatment period. 
 
 
3. How to use Integrilin 
 
Integrilin is given into the vein by direct injection followed by an infusion (drip solution). The dose 
given is based on your weight. The recommended dose is 180 microgram/kg administered as a bolus 
(rapid intravenous injection), followed by an infusion (drip solution) of 2 microgram/kg/minute for up to 
72 hours. If you have kidney disease, the infusion dose may be reduced to 1 microgram/kg/minute. 
 
If percutaneous coronary intervention (PCI) is performed during Integrilin therapy, the intravenous 
solution may be continued for up to 96 hours. 
 
You must also be given doses of aspirin and heparin (if not contraindicated in your case). 
 
If you have any further questions on the use of this product, ask your doctor or hospital pharmacist or 
nurse. 
 
 
4.  Possible side effects 
 
Like all medicines, this medicine can cause side effects, although not everybody gets them.  
 
Very common side effects 
These may affect more than 1 in 10 people 
− minor or major bleeding, (for example, blood in urine, blood in stool, vomiting blood, or bleeding 

with surgical procedures). 
− anaemia (decreased number of red blood cells).  
 
Common side effects 
These may affect up to 1 in 10 people 
− inflammation of a vein. 
 
Uncommon side effects 
These may affect up to 1 in 100 people 
− reduction in the number of platelets (blood cells necessary for blood clotting). 
− reduced blood flow to the brain. 
 



 41 

Very rare side effects 
These may affect up to 1 in 10,000 people 
− serious bleeding (for example, bleeding inside the abdomen, inside the brain, and into the 

lungs). 
− fatal bleeding. 
− severe reduction in the number of platelets (blood cells necessary for blood clotting). 
− skin rash (such as hives). 
− sudden, severe allergic reaction. 
 
If you notice any signs of bleeding, notify your doctor or hospital pharmacist or nurse immediately. Very 
rarely, bleeding has become severe and even fatal. Safety measures to prevent this from happening 
include blood tests and careful checking by the healthcare professionals taking care of you.  
 
If you develop severe allergic reaction or hives, notify your doctor or hospital pharmacist or nurse 
immediately. 
 
Other events that may occur in patients, who require this type of treatment, include those that are 
related to the condition you are having treated, such as rapid or irregular heartbeat, low blood pressure, 
shock or cardiac arrest. 
 
 
Reporting of side effects 
If you get any side effects, talk to your doctor, hospital pharmacist or nurse. This includes any possible 
side effects not listed in this leaflet. You can also report side effects directly via the national reporting 
system listed in Appendix V. By reporting side effects you can help provide more information on the 
safety of this medicine. 
 
 
5. How to store Integrilin 
 
Keep this medicine out of the sight and reach of children  
 
Do not use this medicine after the expiry date (EXP) stated on the package and the vial. The expiry date 
refers to the last day of that month. 
 
Store in a refrigerator (2°C – 8°C). 
 
Keep the vial in the outer package in order to protect from light. However, protection of Integrilin solution 
from light is not necessary during administration. 
 
Before using, the vial contents should be inspected. 
Integrilin should not be used if it is noticed that particulate matter or discoloration is present.  
 
Any unused medicine after opening should be thrown away.   
 
Do not throw away any medicines via wastewater or household waste. Ask your hospital pharmacist how 
to throw away medicines you no longer use. 

 
 

6. Contents of the pack and other information 
 
What Integrilin contains 
− The active substance is eptifibatide. 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.  
− The other ingredients are citric acid monohydrate, sodium hydroxide and water for injections. 
 



 42 

What Integrilin looks like and contents of the pack 
Integrilin solution for infusion: 100 ml vial, pack of one vial.  
 
The clear, colourless solution is contained in a 100 ml glass vial, which is closed with a butyl rubber 
stopper and sealed with a crimped aluminium seal. 
 
Marketing Authorisation Holder and manufacturer 
 
Marketing Authorisation Holder: 
 
GlaxoSmithKline (Ireland) Limited, 12 Riverwalk, Citywest Business Campus, Dublin 24, Ireland 
 
Manufacturer: 
 
Glaxo Operations UK Ltd., (Trading as Glaxo Wellcome Operations), Harmire Road, Barnard Castle, 
Co. Durham, DL12 8DT, United Kingdom 
 
GlaxoSmithKline Manufacturing S.P.A., Strada Provinciale Asolana No. 90, San Polo di Torrile 
43056, Parma, Italy 
 
For any information about this medicine, please contact the local representative of the Marketing 
Authorisation Holder. 
 
België/Belgique/Belgien  
GlaxoSmithKline Pharmaceuticals s.a./n.v. 
Tél/Tel: + 32 (0)10 85 52 00 
 

Lietuva  
GlaxoSmithKline Lietuva UAB 
Tel: + 370 5 264 90 00 
info.lt@gsk.com 
 

България 
ГлаксоСмитКлайн ЕООД 
Тел. + 359 2 953 10 34 

Luxembourg/Luxemburg  
GlaxoSmithKline Pharmaceuticals s.a./n.v. 
Belgique/Belgien 
Tél/Tel: + 32 (0) 10 85 52 00 
 

Česká republika  
GlaxoSmithKline s.r.o. 
Tel: + 420 222 001 111 
cz.info@gsk.com 
 

Magyarország  
GlaxoSmithKline Kft. 
Tel.: + 36 1 225 5300 

Danmark  
GlaxoSmithKline Pharma A/S 
Tlf: + 45 36 35 91 00 
dk-info@gsk.com 
 

Malta 
GlaxoSmithKline (Malta) Limited 
Tel: + 356 21 238131 

Deutschland 
GlaxoSmithKline GmbH & Co. KG 
Tel.: + 49 (0)89 36044 8701 
produkt.info@gsk.com 
 

Nederland 
GlaxoSmithKline BV 
Tel: + 31 (0)30 6938100 
nlinfo@gsk.com 

Eesti 
GlaxoSmithKline Eesti OÜ 
Tel: + 372 6676 900 
estonia@gsk.com 
 

Norge 
GlaxoSmithKline AS 
Tlf: + 47 22 70 20 00 
 



 43 

Ελλάδα  
GlaxoSmithKline A.E.B.E. 
Τηλ: + 30 210 68 82 100 

Österreich  
GlaxoSmithKline Pharma GmbH 
Tel: + 43 (0)1 97075 0 
at.info@gsk.com 
 

España  
GlaxoSmithKline, S.A. 
Tel: + 34 902 202 700 
es-ci@gsk.com 
 

Polska  
GSK Services Sp. z o.o. 
Tel.: + 48 (0)22 576 9000 
 

France  
Laboratoire GlaxoSmithKline 
Tél.: + 33 (0)1 39 17 84 44 
diam@gsk.com 
 

Portugal  
GlaxoSmithKline – Produtos Farmacêuticos, Lda  
Tel: + 351 21 412 95 00 
FI.PT@gsk.com 
 

Hrvatska 
GlaxoSmithKline d.o.o. 
Tel: + 385 1 6051 999 
 

România 
GlaxoSmithKline (GSK) S.R.L.  
Tel: + 4021 3028 208 
 

Ireland  
GlaxoSmithKline (Ireland) Limited 
Tel: + 353 (0)1 4955000 
 

Slovenija  
GlaxoSmithKline d.o.o. 
Tel: + 386 (0)1 280 25 00 
 medical.x.si@gsk.com 
 

Ísland  
Vistor hf. 
Sími: + 354 535 7000 
 

Slovenská republika  
GlaxoSmithKline Slovakia s. r. o. 
Tel: + 421 (0)2 48 26 11 11 
recepcia.sk@gsk.com 
 

Italia  
GlaxoSmithKline S.p.A. 
Tel: + 39 (0)45 9218 111 
 

Suomi/Finland  
GlaxoSmithKline Oy 
Puh/Tel: + 358 (0)10 30 30 30 
Finland.tuoteinfo@gsk.com 
 

Κύπρος  
GlaxoSmithKline (Cyprus) Ltd 
Τηλ: + 357 22 39 70 00 
gskcyprus@gsk.com 
 

Sverige  
GlaxoSmithKline AB 
Tel: + 46 (0)8 638 93 00 
info.produkt@gsk.com 
 

Latvija  
GlaxoSmithKline Latvia SIA 
Tel: + 371 67312687 
lv-epasts@gsk.com 
 

United Kingdom  
GlaxoSmithKline UK Ltd 
Tel: + 44 (0)800 221441 
customercontactuk@gsk.com 

 
This leaflet was last revised in 
 
Other sources of information 
 
Detailed information on this medicine is available on the European Medicines Agency web site: 
http://www.ema.europa.eu 

 



 44 

Package leaflet: Information for the patient 
 

Integrilin 2 mg/ml solution for injection 
eptifibatide 

 
Read all of this leaflet carefully before you start using this medicine because it contains 
important information for you. 
 
− Keep this leaflet. You may need to read it again. 
− If you have any further questions, ask your doctor or hospital pharmacist or nurse. 
− If you get side effects talk to your doctor or hospital pharmacist or nurse. This includes any 

possible side effects not listed in this leaflet. See section 4. 
 
What is in this leaflet:  
1. What Integrilin is and what it is used for 
2. What you need to know before you are given Integrilin 
3. How to use Integrilin 
4. Possible side effects 
5. How to store Integrilin 
6. Contents of the pack and other information 
 
 
1. What Integrilin is and what it is used for 
 
Integrilin is an inhibitor of platelet aggregation. This means that it helps to prevent blood clots from 
forming. 
 
It is used in adults with manifestation of severe coronary insufficiency defined as spontaneous and recent 
chest pain with electrocardiographic abnormalities or biological changes. It is usually given with aspirin 
and unfractionated heparin. 
 
 
2. What you need to know before you are given Integrilin 
 
You must not be given Integrilin: 
− if you are allergic to eptifibatide or any of the other ingredients of this medicine (listed in section 

6). 
− if you have recently had bleeding from your stomach, intestines, bladder or other organs, for 

example if you have seen abnormal blood in your stool or urine (except from menstrual bleeding) 
in the past 30 days. 

− if you have had a stroke within the past 30 days or any haemorrhagic stroke (also, be sure your 
doctor knows if you ever had a stroke). 

− if you have had a brain tumour or a condition that affects the blood vessels around the brain. 
− if you had a major operation or severe injury during the past 6 weeks. 
− if you have or have had bleeding problems. 
− if you have or have had difficulty with your blood clotting or a low blood platelet count. 
− if you have or have had severe hypertension (high blood pressure). 
− if you have or have had severe kidney or liver problems. 
− if you have been treated with another medicine of the same type as Integrilin. 
 
Please tell your doctor if you have had any of these conditions. If you have any questions, ask your 
doctor or hospital pharmacist or nurse. 
 
Take special care with Integrilin: 
− Integrilin is recommended for use only in adult, hospitalised patients in coronary care units. 
− Integrilin is not intended for use in children or adolescents less than 18 years of age. 



 45 

− Before and during your treatment with Integrilin, samples of your blood will be tested as a safety 
measure to limit the possibility of unexpected bleeding. 

− During use of Integrilin, you will be checked carefully for any signs of unusual or unexpected 
bleeding. 
 

Other medicines and Integrilin 
To avoid the possibility of interactions with other medicines please tell your doctor or hospital 
pharmacist if you are taking or have recently taken or might take any other medicines, including 
medicines obtained without a prescription. Particularly: 
− blood thinners (oral anticoagulants) or 
− medicines that prevent blood clots, including warfarin, dipyridamole, ticlopidine, aspirin (except 

those that you may be given as part of Integrilin treatment).  
 
Pregnancy and breast-feeding 
Integrilin is not usually recommended for use during pregnancy. Tell your doctor if you are pregnant, 
think you might be pregnant or are planning to have a baby. Your doctor will weigh up the benefit to 
you against the risk to your baby of using Integrilin while you are pregnant. 
 
If you are breast-feeding a baby, breast-feeding should be interrupted during the treatment period. 
 
 
3. How to use Integrilin 
 
Integrilin is given into the vein by direct injection followed by an infusion (drip solution). The dose 
given is based on your weight. The recommended dose is 180 microgram/kg administered as a bolus 
(rapid intravenous injection), followed by an infusion (drip solution) of 2 microgram/kg/minute for up to 
72 hours. If you have kidney disease, the infusion dose may be reduced to 1 microgram/kg/minute. 
 
If percutaneous coronary intervention (PCI) is performed during Integrilin therapy, the intravenous 
solution may be continued for up to 96 hours. 
 
You must also be given doses of aspirin and heparin (if not contraindicated in your case). 
 
If you have any further questions on the use of this product, ask your doctor or hospital pharmacist or 
nurse. 
 
 
4.  Possible side effects 
 
Like all medicines, this medicine can cause side effects, although not everybody gets them.  
 
Very common side effects 
These may affect more than 1 in 10 people 
− minor or major bleeding, (for example, blood in urine, blood in stool, vomiting blood, or bleeding 

with surgical procedures). 
− anaemia (decreased number of red blood cells). 
 
Common side effects 
These may affect up to 1 in 10 people 
− inflammation of a vein. 
 
Uncommon side effects 
These may affect up to 1 in 100 people 
− reduction in the number of platelets (blood cells necessary for blood clotting). 
− reduced blood flow to the brain. 
 



 46 

Very rare side effects 
These may affect up to 1 in 10,000 people 
− serious bleeding (for example, bleeding inside the abdomen, inside the brain, and into the lungs) 
− fatal bleeding. 
− severe reduction in the number of platelets (blood cells necessary for blood clotting). 
− skin rash (such as hives). 
− sudden, severe allergic reaction. 
 
If you notice any signs of bleeding, notify your doctor or hospital pharmacist or nurse immediately. Very 
rarely, bleeding has become severe and even fatal. Safety measures to prevent this from happening 
include blood tests and careful checking by the healthcare professionals taking care of you.  
 
If you develop severe allergic reaction or hives, notify your doctor or hospital pharmacist or nurse 
immediately. 
 
Other events that may occur in patients, who require this type of treatment, include those that are 
related to the condition you are having treated, such as rapid or irregular heartbeat, low blood pressure, 
shock or cardiac arrest. 
 
 
Reporting of side effects 
If you get any side effects, talk to your doctor, hospital pharmacist or nurse. This includes any possible 
side effects not listed in this leaflet. You can also report side effects directly via the national reporting 
system listed in Appendix V. By reporting side effects you can help provide more information on the 
safety of this medicine. 
 
 
5. How to store Integrilin 
 
Keep this medicine out of the sight and reach of children  
 
Do not use this medicine after the expiry date (EXP) stated on the package and the vial. The expiry date 
refers to the last day of that month. 
 
Store in a refrigerator (2°C – 8°C). 
 
Keep the vial in the outer package in order to protect from light. However, protection of Integrilin solution 
from light is not necessary during administration. 
 
Before using, the vial contents should be inspected. 
 
Integrilin should not be used if it is noticed that particulate matter or discoloration is present.  
 
Any unused medicine after opening should be thrown away. 
 
Do not throw away any medicines via wastewater or household waste. Ask your hospital pharmacist how 
to throw away medicines you no longer use. 
 
 
6. Contents of the pack and other information 
 
What Integrilin contains 
− The active substance is eptifibatide. Each ml of solution for injection contains 2 mg of 

eptifibatide. One vial of 10 ml solution for injection contains 20 mg of eptifibatide. 
− The other ingredients are citric acid monohydrate, sodium hydroxide and water for injections. 
 



 47 

What Integrilin looks like and contents of the pack 
Integrilin solution for injection: 10 ml vial, pack of one vial. 
 
The clear, colourless solution is contained in a 10 ml glass vial, which is closed with a butyl rubber 
stopper and sealed with a crimped aluminium seal. 
Marketing Authorisation Holder and manufacturer 
 
Marketing Authorisation Holder: 
 
GlaxoSmithKline (Ireland) Limited, 12 Riverwalk, Citywest Business Campus, Dublin 24, Ireland 
 
Manufacturer: 
 
Glaxo Operations UK Ltd., (Trading as Glaxo Wellcome Operations), Harmire Road, Barnard Castle, 
Co. Durham, DL12 8DT, United Kingdom 
 
GlaxoSmithKline Manufacturing S.P.A., Strada Provinciale Asolana No. 90, San Polo di Torrile 
43056, Parma, Italy 
 
For any information about this medicine, please contact the local representative of the Marketing 
Authorisation Holder. 
 
België/Belgique/Belgien  
GlaxoSmithKline Pharmaceuticals s.a./n.v. 
Tél/Tel: + 32 (0) 10 85 52 00 
 

Lietuva  
GlaxoSmithKline Lietuva UAB 
Tel: + 370 5 264 90 00 
info.lt@gsk.com 
 

България 
ГлаксоСмитКлайн ЕООД 
Тел. + 359 2 953 10 34 

Luxembourg/Luxemburg  
GlaxoSmithKline Pharmaceuticals s.a./n.v. 
Belgique/Belgien 
Tél/Tel: + 32 (0) 10 85 52 00 
 

Česká republika  
GlaxoSmithKline s.r.o. 
Tel: + 420 222 001 111 
cz.info@gsk.com 
 

Magyarország  
GlaxoSmithKline Kft. 
Tel.: + 36 1 225 5300 

Danmark  
GlaxoSmithKline Pharma A/S 
Tlf: + 45 36 35 91 00 
dk-info@gsk.com 
 

Malta 
GlaxoSmithKline (Malta) Limited 
Tel: + 356 21 238131 

Deutschland 
GlaxoSmithKline GmbH & Co. KG 
Tel.: + 49 (0)89 36044 8701 
produkt.info@gsk.com 
 

Nederland 
GlaxoSmithKline BV 
Tel: + 31 (0)30 6938100 
nlinfo@gsk.com 

Eesti 
GlaxoSmithKline Eesti OÜ 
Tel: + 372 6676 900 
estonia@gsk.com 
 

Norge 
GlaxoSmithKline AS 
Tlf: + 47 22 70 20 00 
 

Ελλάδα  
GlaxoSmithKline A.E.B.E. 
Τηλ: + 30 210 68 82 100 
 

Österreich  
GlaxoSmithKline Pharma GmbH 
Tel: + 43 (0)1 97075 0 
at.info@gsk.com 
 



 48 

España  
GlaxoSmithKline, S.A. 
Tel: + 34 902 202 700 
es-ci@gsk.com 
 

Polska  
GSK Services Sp. z o.o. 
Tel.: + 48 (0)22 576 9000 

France  
Laboratoire GlaxoSmithKline 
Tél.: + 33 (0)1 39 17 84 44 
diam@gsk.com 
 

Portugal  
GlaxoSmithKline – Produtos Farmacêuticos, Lda  
Tel: + 351 21 412 95 00 
FI.PT@gsk.com 

Hrvatska 
GlaxoSmithKline d.o.o. 
Tel: + 385 1 6051 999 
 

România 
GlaxoSmithKline (GSK) S.R.L.  
Tel: + 4021 3028 208 
 

Ireland  
GlaxoSmithKline (Ireland) Limited 
Tel: + 353 (0)1 4955000 
 

Slovenija  
GlaxoSmithKline d.o.o. 
Tel: + 386 (0)1 280 25 00 
 medical.x.si@gsk.com 

Ísland  
Vistor hf. 
Sími: + 354 535 7000 
 

Slovenská republika  
GlaxoSmithKline Slovakia s. r. o. 
Tel: + 421 (0)2 48 26 11 11 
recepcia.sk@gsk.com 

Italia  
GlaxoSmithKline S.p.A. 
Tel: + 39 (0)45 9218 111 
 

Suomi/Finland  
GlaxoSmithKline Oy 
Puh/Tel: + 358 (0)10 30 30 30 
Finland.tuoteinfo@gsk.com 
 

Κύπρος  
GlaxoSmithKline (Cyprus) Ltd 
Τηλ: + 357 22 39 70 00 
gskcyprus@gsk.com 
 

Sverige  
GlaxoSmithKline AB 
Tel: + 46 (0)8 638 93 00 
info.produkt@gsk.com 
 

Latvija  
GlaxoSmithKline Latvia SIA 
Tel: + 371 67312687 
lv-epasts@gsk.com 
 

United Kingdom  
GlaxoSmithKline UK Ltd 
Tel: + 44 (0)800 221441 
customercontactuk@gsk.com 

 
This leaflet was last revised in 
 
Other sources of information 
 
Detailed information on this medicine is available on the European Medicines Agency web site: 
http://www.ema.europa.eu 
 


	SUMMARY OF PRODUCT CHARACTERISTICS
	A. MANUFACTURER(S) RESPONSIBLE FOR BATCH RELEASE
	B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE
	C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION
	D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT
	A. LABELLING
	B. PACKAGE LEAFLET