GP IIb/IIIa inhibitors (antiplatelet agents).

Eptifibatide

INTEGRILIN solution for infusion contains 0.75 mg/ml of eptifibatide. INTEGRILIN solution for injection contains 2 mg/ml of eptifibatide.

Solution for infusion and solution for injection Clear, colourless solution

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

INTEGRILIN is indicated for the prevention of early myocardial infarction in patients presenting with unstable angina or non-Q-wave myocardial infarction with the last episode of chest pain occurring within 24 hours and with 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)

This product is for hospital use only, 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.

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

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.

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. Experience in patients with more severe renal impairment is limited.

Paediatric use

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.

Not recommended.

INTEGRILIN must not be used to treat patients with:

− hypersensitivity to the active substance or to any of the excipients

− 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

− thrombocytopaenia ( < 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 GP IIb/IIIa inhibitor

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. Women, the elderly and patients with low body weight may have an increased risk of bleeding. Monitor these patients closely with regard to bleeding.

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.

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.

Stop the INTEGRILIN infusion 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, immediately stop the INTEGRILIN infusion 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.

Thrombocytopaenia

INTEGRILIN inhibits platelet aggregation, but does not appear to affect the viability of platelets. As demonstrated in clinical trials, the incidence of thrombocytopaenia was low, and similar in patients treated with eptifibatide or placebo. Thrombocytopaenia, including acute profound thrombocytopaenia, has been observed with eptifibatide administration (see section 4.8). 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 the patient experiences a confirmed platelet decrease to < 100,000/mm³, discontinue INTEGRILIN and unfractionated heparin and monitor and treat the patient appropriately. The decision to use platelet transfusions should be based upon clinical judgment on an individual basis. In patients with previous thrombocytopaenia from other parenteral GP IIb/IIIa inhibitors, there are no data with the use of INTEGRILIN, and thus these patients require close monitoring as noted above.

Heparin administration

Heparin administration is recommended unless a contraindication (such as a history of thrombocytopaenia 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 before treatment 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 pseudothrombocytopaenia. Discontinue unfractionated heparin. In patients undergoing PCI, measure the ACT also.

Patients must be monitored for bleeding and treated if necessary.

Immunogenicity

Immunogenic response or antibodies against eptifibatide have been observed in isolated cases in naïve patients or in rare cases of patients re-exposed to eptifibatide. Only limited experience exists for readministration of INTEGRILIN. If treatment with INTEGRILIN is repeated, no diminished therapeutic response is expected.

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; however, eptifibatide appeared to increase the risk of bleeding when administered with streptokinase in an acute 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.

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.

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. Administration of eptifibatide is associated with an increase in major and minor bleeding, as classified by the criteria of the Thrombolysis in Myocardial Infarction (TIMI) study group.

Bleeding

Minor bleeding was a very common ( > 1/10) complication of eptifibatide administration (13.1 % eptifibatide vs 7.6 % placebo). Minor bleeding was defined as spontaneous gross haematuria, spontaneous haematemesis, observed blood loss with a haemoglobin decrease of more than 3 g/dl, or more than 4 g/dl in the absence of an observed bleeding site. Bleeding events were more frequent in patients receiving concurrent heparin while undergoing PCI, when ACT exceeded 350 seconds.

Major bleeding was also very common ( > 1/10) and reported more frequently in patients treated with eptifibatide than with placebo, i.e., 10.8 % vs 9.3 %, respectively. Major bleeding was defined as either an intracranial haemorrhage or a decrease in haemoglobin concentrations of more than 5 g/dl (see table 1).

The incidence of severe or life-threatening bleeding events with eptifibatide was common ( > 1/100, < 1/10); 1.9 % vs 1.1 % with placebo. Eptifibatide treatment increased the need for blood transfusions modestly (11.8 % vs 9.3 %, placebo).

In the subgroup of patients undergoing PCI, major bleeding was observed commonly, in 9.7 % of eptifibatide-treated patients vs 4.6 % of placebo-treated patients.

Other undesirable effects

Overall, in the same trial, serious non-bleeding adverse events were reported at a similar rate in patients treated with eptifibatide and those treated with placebo.

Commonly ( > 1/100, < 1/10) reported events (occurring in 2 % across all groups) in PURSUIT were events related to the underlying disease, such as atrial fibrillation, hypotension, congestive heart failure, cardiac arrest and shock.

Adverse events reported within 30 days of initiation of eptifibatide treatment in PURSUIT are reported in Table 1 below. Patients with unstable angina/non-Q wave myocardial infarction (NQMI) [PURSUIT trial] received an IV bolus of 180 microgram/kg followed by continuous infusion of 2.0 microgram/kg/min for up to 72 hours (96 hours if PCI performed).

Within each frequency grouping in the tables below, undesirable effects are presented in decreasing order of seriousness.

*Causality has not been determined for all adverse events.

Table 2 (below) depicts the incidence of bleeding by TIMI criteria and by invasive cardiac procedures in the PURSUIT trial.

The most common bleeding complications were associated with cardiac invasive procedures (CABG-related or at femoral artery access site). Major bleeding was infrequent in the PURSUIT trial in the large majority of patients who did not undergo CABG within 30 days of enrollment.

Adverse events reported in the ESPRIT trial are listed in Table 3.

*Causality has not been determined for all adverse events. Bleeding events were reported at 48 hours and non bleeding events are reported at 30 days.

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 thrombocytopaenia, haematoma, anaemia.

Immune system disorders

Very rare: anaphylactic reactions.

Skin and subcutaneous tissue disorders

Very rare: rash, application site disorders such as urticaria.

Laboratory values

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).

GlaxoSmithKline UK

(POM)