Eptifibatide

Chemical formula: C₃₅H₄₉N₁₁O₉S₂  Molecular mass: 831.316 g/mol 

Interactions

Eptifibatide interacts in the following cases:

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.

Moderate renal impairment (creatinine clearance ≥30 - <50 ml/min)

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.

Heparin

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.

Streptokinase

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.

High risk of bleeding

Eptifibatide 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, 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 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.

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 anti- inflammatory agents, or dypyridamole.

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.

Eptifibatide 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 eptifibatide infusion should be stopped immediately and any unfractionated heparin that is given concomitantly.

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. The potential risk for humans is unknown. Eptifibatide should not be used during pregnancy unless clearly necessary.

Nursing mothers

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

Effects on ability to drive and use machines

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

Adverse reactions


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 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, 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.

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 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.

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 placebo-treated 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.

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