Coromax 0.75 mg/ml 100 ml

Pharmacotherapeutic group: anti-aggregant.

ATC code: B01AC16.

Pharmacodynamics

Eptifibatide is a synthetic cyclic heptapeptide containing 6 amino acid residues, including one cysteinamide and one mercaptopropionyl residue – desaminocysteinyl. Eptifibatide is a platelet aggregation inhibitor and belongs to the class of arginine-glycine-aspartate mimetics. Eptifibatide reversibly inhibits platelet aggregation by preventing binding of fibrinogen, Willebrand factor and other adhesive ligands to the glycoprotein IIb/IIIa receptors of platelets.

Eptifibatide causes dose- and concentration-dependent suppression of platelet aggregation, which has been demonstrated ex vivo with ADP and other platelet aggregation-inducing agonists. The action of eptifibatide is seen immediately after an intravenous bolus injection at a dose of 180 μg/kg. A regimen followed by continuous IV infusion at a dose of 2 µg/kg/min provides more than 80% inhibition of ADP-induced platelet aggregation ex vivo, at physiological calcium concentrations, in more than 80% of patients. The inhibition of platelet aggregation is reversible; 4 h after cessation of continuous infusion at a dose of 2 μg/kg/min, platelet function is more than 50% restored to baseline. Measurements of ADP-induced platelet aggregation ex vivo at physiological calcium concentrations (anticoagulant D-phenylalanyl-L-prolyl-L-arginine chloromethyl ketone) in patients with unstable angina and myocardial infarction without Q-wave were found to have concentration-dependent inhibition with IC50 (concentration, inhibiting aggregation by 50%) of 557 ng/mL and IC80 (concentration inhibiting aggregation by 80%) of 1107 ng/mL. Bleeding time is reversibly increased up to 5 times when Coromax is administered by bolus and infusion, and it returns to baseline within 2-6 h after stopping the infusion. When used as monotherapy, eptifibatide has no significant effect on PV and AHR.

Pharmacokinetics

The pharmacokinetics of eptifibatide are linear and dose-dependent with bolus administration in the dose range of 90 to 250 µg/kg and infusion at a rate of 0.5-3 µg/kg/min. When infused at a dose of 2 µg/kg/min in patients with CHD, the average plasma Css of eptifibatide is set at 1.5-2.2 µg/mL. This plasma concentration is achieved more rapidly if the infusion is preceded by a bolus infusion at a dose of 180 µg/kg.

The degree of binding of eptifibatide to human plasma proteins is about 25%.

In the same patient population, the T1/2 from plasma is approximately 2.5 h, plasma clearance is 55-80 ml/kg/h, Vd is approximately 185-260 ml/kg. In healthy patients the proportion of renal excretion from total clearance is about 50%; approximately 50% of the substance is excreted unchanged.

Moderate increase in T1/2 and Vd is observed in elderly patients, patients with low body weight (< 74 kg) and/or low Cl creatinine. The dose and sex of the patient do not affect the pharmacokinetics of Coromax. In mild renal failure (creatinine Cl ≥50 ml/min by Cockcroft-Gault formula) no dose adjustment is required by bolus or infusion. In moderate renal failure (creatinine Cl ≥30 – < 50 ml/min by the Cockcroft-Gault formula) a dose adjustment is recommended. In patients with renal insufficiency of moderate or severe degree (creatinine Cl < 50 ml/min) a decrease of eptifibatide clearance by approximately 50% and increase of Css in plasma by approximately 2 times is observed (see “Special notes”, “Dosage and administration”).

Indications

Eptifibatide is indicated for use with acetylsalicylic acid and unfractionated heparin.

Active ingredient

Composition

How to take, the dosage

IV.

Eptifibatide is indicated for use in adults 18 years of age and older.

The 0.75 mg/ml IV solution (for infusion) and the 2 mg/ml IV solution (for bolus injection) should be used together as directed.

The concomitant use of eptifibatide and heparin is recommended except in situations where heparin is contraindicated, including a history of heparin-related thrombocytopenia. Eptifibatide is also intended for concomitant use with acetylsalicylic acid, since acetylsalicylic acid is a standard component of treatment of patients with acute coronary syndrome, except in cases when the use of acetylsalicylic acid is contraindicated.

Patients undergoing percutaneous coronary intervention (PCI)

The recommended dose of eptifibatide for adult patients with creatinine Cl ≥50 ml/min (using the Cockcroft-Gault formula) IV bolus at a dose of 180 mcg/kg just before manipulation, administer another 180 mcg/kg as a bolus 10 min after the first bolus. Simultaneously with the first bolus, a continuous infusion of the drug is started at a dose of 2 µg/kg/min. The infusion continues until the patient is discharged from the hospital or for 18-24 h after PCI. The minimum recommended duration of infusion is 12 hours.

The recommended dose of eptifibatide for adult patients with creatinine Cl ≥30 – < 50 ml/min (according to the Cockcroft-Gault formula): by IV bolus at a dose of 180 µg/kg immediately before the manipulation, 10 min after the first bolus another 180 µg/kg as a bolus. Simultaneously with the first bolus, a continuous infusion of the drug is started at a dose of 1 µg/kg/min. The infusion continues until the patient is discharged from the hospital or for 18-24 h after PCI. The minimum recommended duration of infusion is 12 hours.

Patients with acute coronary syndrome (patients with unstable angina pectoris or myocardial infarction without Q wave)

The recommended dose of eptifibatide for adult patients with creatinine Cl ≥50 ml/min (according to the Cockcroft-Gault formula) IV bolus at a dose of 180 mcg/kg as early as possible after diagnosis, then begin continuous infusion at a dose of 2 mcg/kg/min, which continues until 72 h before aortocoronary bypass surgery or discharge from the hospital, whichever occurs first. If ChTCA is performed during treatment, the infusion is continued for an additional 20-24 h after ChTCA, with a maximum total duration of administration of 96 h.

The recommended dose of eptifibatide for adult patients with creatinine Cl ≥30 is < 50 ml/min (using the Cockcroft-Gault formula): IV bolus at a dose of 180 mcg/kg as soon as possible after diagnosis, followed immediately by continuous infusion at a dose of 1 mcg/kg/min, which continues until 72 h before aortocoronary bypass surgery or discharge from the hospital, whichever occurs first. If ChTCA is performed during treatment, the infusion is continued for an additional 20-24 h after ChTCA, with a maximum total duration of administration of 96 h.

The Cockcroft-Gault formula with a measure of actual body weight is used to calculate Cl creatinine in ml/min.

Women: Cl creatinine (ml/min) = 0.85 × the value calculated using the formula for men.

Patients with a body weight greater than 121 kg are given no more than 22.6 mg of the drug as a bolus and no more than 15 mg/h (for creatinine concentrations below 2 mg/dL) or 7.5 mg/h (for creatinine concentrations between 2 and 4 mg/dL) as an infusion.

Ergent or planned surgical intervention

If a patient requires emergency or urgent cardiac surgery during therapy with eptifibatide, the infusion should be stopped immediately. If the patient requires elective surgery, the infusion should be stopped to allow time for platelet function to return to normal.

Patients who require thrombolytic therapy (including transmural myocardial infarction with a new abnormal Q wave on the ECG)

There is no experience with this group of patients, use of the drug is not recommended.

Interaction

Eptifibatide does not cause an increased risk of major and minor bleeding when used concomitantly with warfarin and dipyridamole. In patients with a PV value of 14.5 s receiving eptifibatide concomitantly with warfarin, no increased risk of bleeding has been observed.

There are limited data on the use of eptifibatide in patients receiving thrombolytics. There are no confirmed data indicating that eptifibatide increases the risks of major and minor bleeding associated with tissue plasminogen activator in both patients undergoing CTCA and patients with acute myocardial infarction. However, in clinical trials, eptifibatide increased bleeding risks when administered with streptokinase in patients with acute myocardial infarction. In a study in 181 patients with acute myocardial infarction, eptifibatide (bolus injection dose up to 180 mcg/kg, subsequent infusion up to 2 mcg/kg/min up to 72 h) was administered concurrently with streptokinase (1.5 million units over 60 min). For maximum infusion rates (1.3 µg/kg/min and 2 µg/kg/min), use of eptifibatide was associated with an increased incidence of bleeding and increased need for transfusions compared with streptokinase monotherapy.

In a clinical trial in patients with acute ST-segment elevation myocardial infarction, the combined use of reduced-dose tenecteplase and eptifibatide resulted in a significant increased risk of massive and minor bleeding (compared with placebo and use of eptifibatide without tenecteplase).

Eptifibatide is not compatible with furosemide.

In clinical trials, 95% of patients who underwent non-emergency PCI with intracoronary stenting were prescribed clopidogrel concomitantly with acetylsalicylic acid before or within 48 hours after PCI and daily after PCI.

There have been no specific studies of eptifibatide with other drugs. In clinical studies, no FKV has been identified between eptifibatide and drugs frequently used in patients with cardiovascular disease, such as amlodipine, atenolol atropine, captopril, cephazoline, diazepam, digoxin, diltiazem, diphenhydramine, enalapril, fentanyl, furosemide, heparin, lidocaine, lisinopril, metoprolol, midazolam, morphine, nitrates, nifedipine, warfarin.

Special Instructions

Eptifibatide is intended for inpatient use only.

Bleeding

Eptifibatide is an antithrombotic agent that inhibits platelet aggregation; therefore, during treatment with eptifibatide all patients should be carefully evaluated for possible bleeding, especially women, elderly patients, and patients with low body weight as having the highest risk of bleeding (see “Side effects. “Side effects). If serious bleeding occurs that cannot be stopped by applying a pressure dressing, the infusion of the drug and any concomitant heparin should be stopped immediately.

The risk of bleeding in patients undergoing CTCA is greatest at the arterial access site. The sites of possible bleeding, such as catheter insertion, arteriopuncture, venipuncture or needle puncture, and venesection, must be carefully monitored; the possibility of GI tract and urogenital bleeding and retroperitoneal bleeding must be kept in mind. Bleeding in the central and peripheral nervous system is also possible.

Control of femoral artery access

When using eptifibatide, the risk of bleeding is greatest at the site of catheter insertion into the femoral artery during CTCA. Care should be taken to ensure that only the anterior wall of the femoral artery is punctured. The femoral artery intraductor can be removed after the coagulation function has been restored to normal: ABC less than 180 s (usually 2-6 h after heparin withdrawal). After removal of the intraductor hemostasis should be performed, followed by close follow-up until discharge from the hospital.

Thrombocytopenia and immunogenicity associated with the use of IIb/IIIa receptor inhibitors

Eptifibatide inhibits platelet aggregation but does not affect platelet viability. The incidence of thrombocytopenia was low and similar to that of patients receiving placebo, as observed both in clinical trials and in rare reports of immune thrombocytopenia in post-registration observations. The presence in plasma of transposable factors that can bind to eptifibatide and glycoprotein IIb/IIIa receptors means that an immune thrombocytopenic response may develop in first-time therapy with glycoprotein IIb/IIIa receptor inhibitors or in patients re-treated with eptifibatide.

The mechanism (immune and/or nonimmune) of the effect of eptifibatide on the development of thrombocytopenia is not fully understood. Because repeated exposure to any glycoprotein IIb/IIIa receptor inhibitor (including abciximab or eptifibatide) or primary exposure to glycoprotein IIb/IIIa receptor inhibitors may be accompanied by an immune-mediated thrombocytopenic response, care should be taken to monitor for possible thrombocytopenia accompanied by arterial hypotension and/or other hypersensitivity symptoms.

If a decrease in platelet count to < 100000/mm3 or acute deep thrombocytopenia is confirmed, discontinuation of treatment with any medications that may have thrombocytopenic effects, including eptifibatide, heparin and clopidogrel, should be considered immediately. Maintenance therapy should be initiated, and platelet counts should be monitored to adjust treatment and establish etiology. If thrombocytopenia is not associated with eptifibatide use, therapy with it may be resumed after platelet count normalization.

Bleeding time increase

Bleeding time increases up to 5 times when using eptifibatide by bolus and infusion. This increase is rapidly reversible after stopping the infusion; this rate returns to baseline within 2-6 hours. When used as monotherapy, eptifibatide has no significant effect on PV and AHR.

The use of heparin

The combined use of eptifibatide and heparin is recommended in all cases, if there are no contraindications to the use of heparin, including thrombocytopenia associated with heparin administration in the history.

Patients with unstable angina pectoris or myocardial infarction without Q-wave. For patients with a body weight of 70 kg or more, the recommended bolus dose is 5000 IU, followed by a continuous infusion of 1000 IU/h. For patients with body weight less than 70 kg, the bolus dose is 60 units/kg, subsequent infusion 12 units/kg/h. The AFV should be monitored to maintain values in the range of 50-70 s.

Coronary angioplasty. In patients undergoing PCI, ABT should be monitored; its values should be in the range of 300-350 s. If the ABC value exceeds 300 s, heparin use should be discontinued and not resumed until the value is lower than 300 s.

Non-emergency PCI with intracoronary stenting. For patients who did not receive heparin for 6 h before the intervention, an initial bolus injection of heparin at a dose of 60 units/kg is recommended. The target ABC during the procedure is 200-300 s. An additional bolus of heparin can be administered during the CTCA procedure to maintain the ABC rate in this range.

Patients with hepatic impairment

Eptifibatide has very limited experience in patients with hepatic impairment (see “Contraindications”). In patients with hepatic insufficiency, the drug should be used with caution because in such patients the drug may affect blood clotting.

Patients with renal failure

In mild renal failure (creatinine Cl ≥50 ml/min by the Cockroft-Gault formula), eptifibatide can be safely used in standard dosage. In moderate to severe renal failure (creatinine Cl < 50 ml/min by the Cockcroft-Gault formula), the clearance of eptifibatide is reduced by approximately 50% and plasma Css are increased approximately twofold. Patients with moderate to severe renal impairment who are given conventional infusions at a dose of 2 mcg/kg/min are at increased risk of bleeding. Therefore, in such patients the dose during infusion should be reduced to 1 µg/kg/min (see “Dosage and administration”). No clinical studies with the participation of patients on dialysis have been conducted.

Children under 18 years of age

The safety and effectiveness of eptifibatide in patients under 18 years of age has not been established; therefore, use in this patient population is not recommended.

Laboratory Monitoring

Laboratory changes during treatment with eptifibatide are a consequence of the known pharmacological properties of the drug, including platelet aggregation inhibition. Thus, changes in laboratory parameters characterizing bleeding (including bleeding time) are observed frequently and are expected. When using eptifibatide and when using placebo, no obvious differences were observed in such parameters as Hb, hematocrit, platelet count, liver function parameters (concentration of AST, ALT, bilirubin, ALP) and kidney (concentration of serum creatinine, blood urea nitrogen).

Impact on the ability to drive vehicles, mechanisms. Eptifibatide is intended for use in a hospital setting. There are no data on the use of eptifibatide in outpatients.

Contraindications

Side effects

The majority of adverse events with eptifibatide are associated with bleeding or cardiac or cardiac events, which are common in this patient population.

The clinical data

The frequency of adverse events presented below was generated from two phase III clinical trials (PURSUIT and ESPRIT).

PURSUIT is a double-blind, randomized trial of the efficacy and safety of eptifibatide versus placebo to reduce mortality and recurrent myocardial infarction in patients with unstable angina or myocardial infarction without a Q-wave.

The ESPRIT is a double-blind, multicenter, randomized, parallel-group, placebo-controlled trial investigating the safety and efficacy of eptifibatide in patients scheduled for non-emergency PCI with intracoronary stenting.

The data on adverse events, including bleeding, in the PURSUIT study were obtained from the time of hospital discharge until the visit on day 30. Bleeding events in the ESPRIT study were recorded within 48 h, and non-bleeding events were recorded within 30 days. TIMI (Thrombolysis in Myocardial Infarction Study Group) bleeding criteria were used to classify the incidence of major and minor bleeding in the PURSUIT and ESPRIT studies. Data from the PURSUIT study were collected over 30 days, whereas data from the ESPRIT study were limited to events that occurred within 48 h or before discharge, whichever occurred first.

When used at the recommended therapeutic doses used in the PURSUIT study (involving about 11,000 patients), bleeding was the most common complication of eptifibatide therapy. Invasive cardiac procedures (aortocoronary bypass or femoral artery access) were the most common with bleeding.

In the PURSUIT study, mild bleeding was defined as spontaneous macrohematuria, spontaneous hematemesis, bleeding with a decrease in Hb concentration ≥3 g/dL or a decrease in Hb concentration ≥4 g/dL with no apparent source of bleeding. Mild bleeding was a very frequent complication of eptifibatide use (>1/10 or 13.1% with eptifibatide versus 7.6% with placebo). Bleeding occurred more frequently in patients receiving heparin concomitantly during PCI when the activated clotting time (ABC) exceeded 350 s (see “Special Precautions,” Heparin Use).

In the PURSUIT study, massive bleeding was defined as intracranial bleeding or a decrease in Hb concentration ≥5 g/dL. Massive bleeding with eptifibatide in this study was very common (>1/10 or 10.8% with eptifibatide versus 9.3% with placebo), excluding the vast majority of patients who did not undergo aortocoronary bypass within 30 days of study inclusion, in whom this phenomenon was infrequent. The incidence of bleeding did not increase in patients undergoing aortocoronary bypass surgery when using eptifibatide compared to patients receiving placebo. In the subgroup of patients undergoing PCI, major bleeding occurred frequently: in 9.7% of patients with eptifibatide compared with 4.6% in patients receiving placebo.

The incidence of severe or life-threatening bleeding with eptifibatide was 1.9% compared to 1.1% with placebo. The need for hemotransfusions was moderately increased with eptifibatide (11.8% for eptifibatide, 9.3% for placebo).

The undesirable events presented below are listed according to organ and organ system involvement and frequency of occurrence. The frequency of occurrence is defined as follows: very common (≥1/10); common (≥1/100 and < 1/10); infrequent (≥1/1000 and < 1/100); rare (≥1/10000 and < 1/1000); very rare (≥1/10000, including individual cases). The absolute frequency of reports is given without taking into account the frequency when using placebo. When data on individual adverse events from two studies (PURSUIT and ESPRIT) were available, the highest reported frequency was used to determine the frequency of adverse events.

It should be noted that not all adverse events were associated with the use of the drug.

The incidence of serious adverse events unrelated to bleeding (including arterial hypotension) with eptifibatide does not differ from that with placebo.

Blood and lymphatic system disorders: Very common – bleeding (massive and mild bleeding, including bleeding during aortocoronary bypass and femoral artery access, gastrointestinal bleeding, urogenital bleeding, retroperitoneal and intracranial bleeding, hematemesis, hematuria, intraoral/ oropharyngeal bleeding, bleeding that reduces hematocrit/Hb); infrequent – thrombocytopenia.

Nervous system disorders: infrequent cerebral ischemia.

Cardiac disorders: often – cardiac arrest, ventricular fibrillation, ventricular tachycardia, congestive heart failure, AV-blockade, atrial fibrillation.

Vascular disorders: frequently – cardiogenic shock, arterial hypotension, phlebitis.

The cardiac arrest, congestive heart failure, atrial fibrillation, arterial hypotension, and cardiogenic shock that were frequently reported in the PURSUIT study were events related to the underlying disease.

Post-registration observational data

Blood and lymphatic system disorders: very rare – fatal bleeding (mostly affecting the central and peripheral nervous system: hemorrhagic stroke or intracranial bleeding), pulmonary bleeding, acute deep thrombocytopenia, hematoma.

Immune system disorders: very rare – anaphylactic reactions.

Skin and subcutaneous tissue disorders: very rare – skin rash, adverse events at the injection site (including urticaria).

Overdose

Information on overdose of eptifibatide is very limited. There are no reports of serious adverse reactions associated with accidental overdose by jet or drip infusion, or when the cumulative dose is exceeded.

The PURSUIT clinical trial reported 9 patients who received a bolus and/or infusion dose greater than twice the recommended dose. However, none of the patients had unstopped bleeding; one patient underwent coronary artery bypass surgery and had only moderate bleeding; no patient had intracranial bleeding.

Potentially, an overdose of eptifibatide can cause bleeding.

Treatment: Because of the short T1/2 and high clearance, the effects of the drug can be quickly stopped by stopping the administration.

Pregnancy use

Clinical studies on the use of eptifibatide in pregnant women have not been conducted. However, fertility studies have been conducted in rats and rabbits using doses 8 and 4 times the human dose, respectively. In these studies, there was no evidence of impaired fertility or adverse effects on the fetus associated with the use of eptifibatide.

Since animal studies are not considered sufficient to predict possible reactions in humans, eptifibatide should only be used during pregnancy when the benefit to the mother outweighs the potential risk to the fetus.

There are no data on penetration of eptifibatide into breast milk. It is recommended to stop breastfeeding when using eptifibatide.