Source: European Medicines Agency (EU) Revision Year: 2019 Publisher: GlaxoSmithKline (Ireland) Limited, 12 Riverwalk, Citywest Business Campus, Dublin 24, Ireland
INTEGRILIN must not be used to treat patients with:
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.
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.
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.
If either a confirmed platelet decrease to < 100,000/mm 3 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 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.
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.
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.
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.
There are no adequate data from the use of eptifibatide in pregnant women.
Animal studies are insufficient with respect to effects on pregnancy, embryonal/foetal development, parturition or postnatal development (see section 5.3). The potential risk for humans is unknown.
INTEGRILIN should not be used during pregnancy unless clearly necessary.
It is not known whether eptifibatide is excreted in human milk. Interruption of breast-feeding during the treatment period is recommended.
Not relevant, as INTEGRILIN is intended for use only in hospitalised patients.
The majority of adverse reactions experienced by patients treated with eptifibatide were generally related to bleeding or to cardiovascular events that occur frequently in this patient population.
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.
Note that causality has not been determined for all adverse reactions.
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.
Uncommon: Cerebral ischaemia.
Common: Cardiac arrest, ventricular fibrillation, ventricular tachycardia, congestive heart failure, atrioventricular block, atrial fibrillation.
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).
Very rare: Fatal bleeding (the majority involved central and peripheral nervous system disorders: cerebral or intracranial haemorrhages); pulmonary haemorrhage, acute profound thrombocytopenia, haematoma.
Very rare: Anaphylactic reactions.
Very rare: Rash, application site disorders such as urticaria.
Reporting suspected adverse reactions after authorisation of the medicinal product is important. 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.
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.
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