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EPTIFIBATIDE 0.75 MG/ML SOLUTION FOR INFUSION

Active substance(s): EPTIFIBATIDE

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Package leaflet: Information for the user
Eptifibatide 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, pharmacist or nurse.

If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side
effects not listed in this leaflet. See section 4.
What is in this leaflet
1.
2.
3.
4.
5.
6.
1.

What Eptifibatide Infusion is and what it is used for
What you need to know before you are given Eptifibatide Infusion
How to use Eptifibatide Infusion
Possible side effects
How to store Eptifibatide Infusion
Contents of the pack and other information
What Eptifibatide Infusion is and what it is used for

The name of your medicine is ‘Eptifibatide 0.75 mg/ml, Solution for Infusion’ but in the rest of the leaflet
it will be called ‘Eptifibatide Infusion’.
Eptifibatide Infusion contains the active ingredient eptifibatide. It is an inhibitor of platelet aggregation.
This means that it helps to prevent blood clots from forming.
Eptifibatide Infusion 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 acetylsalicylic acid and unfractionated heparin.

2.

What you need to know before you are given Eptifibatide Infusion

You must not be given Eptifibatide Infusion:

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 bleeding in the brain (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 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 medicinal product of the same type as Eptifibatide

Please tell your doctor if you have had any of these conditions. If you have any questions, ask your doctor
or pharmacist.
Warnings and precautions

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

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

Eptifibatide Infusion is recommended for use only in adult, hospitalized patients in coronary care
units.
Children and adolescents

Eptifibatide Infusion is not intended for use in children or adolescents less than 18 years of age.
Other medicines and Eptifibatide Infusion
Tell your doctor or pharmacist if you are taking/using, have recently taken/used or might take/use any
other medicines.
In particular, tell your doctor of pharmacist if you are taking/using any of the following medicines:
- Blood thinners (oral anticoagulants such as warfarin or acenocoumarol) or
- Medicines that prevent blood clots, including low molecular weight heparin, dipyridamole,
ticlopidine, acetylsalicylic acid (except those that you may be given as part of Eptifibatide
treatment), thrombolytics, oral anticoagulants, dextran solutions, adenosine, sulfinpyrazone,
prostacyclin, non-steroidal anti-inflammatory agents.
Pregnancy and breast-feeding
If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask your
doctor or pharmacist for advice before using this medicine.
Eptifibatide Infusion is not usually recommended for use during pregnancy. Your doctor will weigh up
the benefit to you against the risk to your baby of using eptifibatide while you are pregnant.
If you are breast-feeding a baby, breast-feeding should be interrupted during the treatment period.
Eptifibatide Infusion contains sodium
This medicinal product contains 1.6 mg sodium per ml. To be taken into consideration by patients on a
controlled sodium diet.
3. How to use Eptifibatide Infusion
Eptifibatide 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 Eptifibatide therapy, the intravenous
solution may be continued for up to 96 hours.
You must also be given doses of acetylsalicylic acid and heparin (if not contraindicated in your case).

If you have any further questions on the use of this medicine, ask your doctor or pharmacist.
4. Possible side effects
Like all medicines, this medicine can cause side effects, although not everybody gets them.
If you notice any signs of bleeding, notify your doctor 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 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.
Very common side effects
(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
(may affect up to 1in 10people)

Inflammation of a vein

Low blood pressure

Shock or cardiac arrest

Heart rate and rhythm disorders (rapid or slow or irregular heartbeat)
Uncommon side effects
(may affect up to1 in 100 people)

Reduction in the number of platelets (blood cells necessary for blood clotting)

Reduced blood flow to the brain
Very rare side effects
(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: skin rash including red itchy skin, swelling of the hands, feet,
ankles, face, lips, mouth or throat (which may cause difficulty in swallowing or breathing) and you
may feel you are going to faint (it may be fatal).
Reporting of side effects
If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side effects
not listed in this leaflet.
You can also report side effects directly via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard.
By reporting side effects you can help provide more information on the safety of this medicine.

5. How to store Eptifibatide Infusion
Keep this medicine out of the sight and reach of children.
Single use only.
Once opened, use immediately. Any unused material after opening should be discarded.
Do not use this medicine after the expiry date which is stated on the carton and the vial after EXP. The
expiry date refers to the last day of that month.
After Dilution:
Chemical and physical in-use stability has been demonstrated for 24 hours at 25°C and 2-8°C.
From a microbiological point of view, unless the method of dilution precludes the risk of microbial
contamination, the product should be used immediately. If not used immediately, in-use storage times and
conditions prior to use are responsibility of the user.
Store in a refrigerator (2°C – 8°C). Store in the original package in order to protect from light. However,
protection of Eptifibatide from light is not necessary during administration.
Do not use this medicine if you notice that the visual appearance has changed.
Eptifibatide infusion should not be used if it is noticed that particulate matter or discoloration is present.
Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to throw
away medicines you no longer use. These measures will help protect the environment.
6. Contents of the pack and other information
What Eptifibatide Infusion 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 (for pH-adjustment), water for
injections.

What Eptifibatide Infusion looks like and contents of the pack
Eptifibatide infusion is a clear, colourless solution. It comes in a 100 ml Type I, clear glass, flint moulded
vial plugged with 20 mm grey bromobutyl omniflex plus coated rubber stopper closure and sealed with a
20 mm pink flip-off aluminium seal.
Pack size:
100 ml vial, pack of one vial
Marketing Authorization Holder
Mylan
Potters Bar, Hertfordshire, EN6 1TL, United Kingdom
Manufacturer
Agila Specialties Polska Sp.z.o.o.
10, Daniszewska Str

03-230 Warsaw
Poland
The leaflet was last revised in 09/2014.
---------------------------------------------------------------------------------------------------------------------------The following information is intended for healthcare professionals only:
The complete SmPC (as TIL) of Eptifibatide 0.75 mg/ml solution for injection is provided as a separate
document, with the objective to provide healthcare professionals with other additional scientific and
practical information about the administration and use of this medicinal product. Please refer to the TIL

The following information is intended for healthcare professionals only.
TECHNICAL LEAFLET
Eptifibatide 0.75 mg/ml solution for infusion
1.

NAME OF THE MEDICINAL PRODUCT

Eptifibatide 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.

Excipient with known effect:
Each ml contains 1.6 mg sodium.
For the full list of excipients, see section 6.1.
3.

PHARMACEUTICAL FORM

Solution for infusion.
Clear colourless solution
pH: Between 5.0 and 5.5
4.

CLINICAL PARTICULARS

4.1

Therapeutic indications

Eptifibatide is intended for use with acetylsalicylic acid and unfractionated heparin.
Eptifibatide 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 eptifibatide 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.
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 2.0 microgram/kg/min for up to 72 hours, until
initiation of coronary artery bypass graft (CABG) surgery, or until discharge from the hospital (whichever
occurs first). If 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
The safety and efficacy of eptifibatide in children and adolescents below 18 years of age has not been
established. No data are available.
Method of administration
Eptifibatide solution for infusion must be used in conjunction with Eptifibatide solution for injection.
Concurrent administration of unfractionated 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). Eptifibatide 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
4.3

Contraindications

Eptifibatide 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 hemorrhagic 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
Eptifibatide is an antithrombotic agent that acts by inhibition of platelet aggregation; therefore the patients
must be observed carefully for indications of bleeding during treatment (see section 4.8). Women, the
elderly, patient 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
eptifibatide (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 eptifibatide 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 antiinflammatory agents, or dypyridamole (see section 4.5).
There is no experience with eptifibatide and low molecular weight heparins.
There is limited therapeutic experience with eptifibatide in patients for whom thrombolytic therapy 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 eptifibatide is not
recommended in these circumstances (see section 4.5).
Eptifibatide 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 eptifibatide 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

Eptifibatide 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 thrombocytopenia, has been
observed with eptifibatide administration post-marketing (see section 4.8).
The mechanism, whether immune- and/or non-immune-mediated, by which eptifibatide may 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.
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 eptifibatide. 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 eptifibatide, 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.

This medicinal product contains 1.6 mg sodium per ml. To be taken into consideration by
patients on a controlled sodium diet.
4.5

Interaction with other medicinal products and other forms of interaction

Warfarin and dipyridamole
Eptifibatide did not appear to increase the risk of major and minor bleeding associated with concomitant
use of warfarin and dipyridamole. Eptifibatide-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.
Eptifibatide and thrombolytic agents
Data are limited on the use of eptifibatide 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.
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.
Eptifibatide should not be used during pregnancy unless clearly necessary.
Breastfeeding
It is unknown whether eptifibatide is excreted in human milk. Interruption of breast-feeding during the
treatment period is recommended.

Fertility
There is no data available regarding the effect of eptifibatide on fertility.
4.7

Effects on ability to drive and use machines

Not relevant, as eptifibatide is intended for use only in hospitalized patients.
4.8

Undesirable effects

The majority of undesirable effects 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 randomized, double-blind evaluation of the efficacy and safety of eptifibatide
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, randomized, 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 ESPIRIT, 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 below:
Very common (≥1/10)
Common (≥1/100 to < 1/10)
Uncommon (≥1/1,000 to < 1/100)
Rare (≥1/10,000 to < 1/1000)
Very rare (<1/10,000)
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.
Note that causality has not been determined for all adverse reactions.
Blood and lymphatic system disorders:
Very Common
Bleeding (major and minor bleeding including femoral artery
access,
CABGrelated,
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 epfitibatide 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 3g/dl, or a haemoglobin
decrease of more than 4g/dl in the absence of an observed bleeding site. During treatment with
eptifibatide in this study, minor bleeding was a very common complication (>1/10, or 13.1% for
eptifibatide 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 eptifibatide 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
eptifibatide compared to the patients treated with placebo. In the subgroup of patients undergoing PCI,
major bleeding was observed commonly, in 9.7 % of eptifibatide treated patients vs. 4.6 % of placebotreated patients.
The incidence of severe or life threatening bleeding events with eptifibatide was 1.9% compared to 1.1%
with placebo. The need for blood transfusions was increased modestly by eptifibatide treatment (11.8%
versus 9.3% for placebo).
Changes during eptifibatide treatment result from its known pharmacological action, i.e., inhibition 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).
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 Yellow Card Scheme at:
www.mhra.gov.uk/yellowcard.
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 excluding 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.
Platelet inhibition was readily reversed, with a return of platelet function towards baseline (> 50 %
platelet aggregation) 4 hours after stopping a continuous infusion of 2.0 microgram/kg/min.
Measurements of ADP-induced ex vivo platelet aggregation at physiologic calcium concentrations (Dphenylalanyl-L-prolyl-L-arginine chloromethyl ketone anticoagulant) in patients presenting 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.
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 doubleblind, 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 acetylsalicylic acid (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 (acetylsalicylic acid 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).
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

Absorption
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.

Distribution
The extent of eptifibatide binding to human plasma protein is about 25 %.
Biotransformation
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.
Elimination
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 impairment (creatinine clearance < 50 ml/min), the clearance of eptifibatide is reduced by
approximately 50% and steady-state plasma levels are approximately doubled.
Interactions
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.
6.

PHARMACEUTICAL PARTICULARS

6.1

List of excipients

Citric acid monohydrate
Sodium hydroxide (for pH-adjustment)
Water for injections
6.2

Incompatibilities

Eptifibatide is not compatible with furosemide.

In the absence of compatibility studies, Eptifibatide must not be mixed with other medicinal products
except those mentioned in section 6.6.
6.3

Shelf life

Unopened vial: 18 months
After Dilution:
Chemical and physical in-use stability has been demonstrated for 24 hours at 25°C and 2-8°C.
From a microbiological point of view, unless the method of dilution precludes the risk of microbial
contamination, the product should be used immediately. If not used immediately, in-use storage times
and conditions prior to use are responsibility of the user.

Once opened: use immediately
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. However, protection of eptifibatide solution
from light is not necessary during administration.
For storage conditions of the diluted medicinal product see section 6.3.
6.5

Nature and contents of container

Type I, clear glass, 100ml flint moulded vial plugged with 20 mm grey bromobutyl omniflex plus coated
rubber stopper closure and sealed with a 20 mm pink flip-off aluminium seal.
Packs containing 1 vial.
6.6

Special precautions for disposal and other handling

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

Single use only.
Physiological compatibility studies were performed at a concentration of 0.2 mg/mL for 96 hours
at 2°C-8°C & 25°C.
Before use, inspect the vial contents. Do not use if particulate matter or discoloration is present.
Protection of eptifibatide solution from light is not necessary during administration.
Any unused medicinal product or waste material should be disposed of in accordance with local
requirements.
7.

MARKETING AUTHORISATION HOLDER

Generics [UK] Limited t/a Mylan
Station Close
Potters Bar
Hertfordshire
EN6 1TL
United Kingdom
8.

MARKETING AUTHORISATION NUMBER

PL 04569/1550
9.

DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

To be completed nationally.
10. DATE OF REVISION OF THE TEXT
09/2014

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Source: Medicines and Healthcare Products Regulatory Agency

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