Integrilin, 2 mg/ml, 10 ml

Pharmacotherapeutic group: Antiplatelet agent

ATC code: B01AC16

Pharmacological properties

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 glycoprotein IIb/IIIa receptors of platelets.

Eptifibatide causes dose- and concentration-dependent suppression of platelet aggregation, which has been demonstrated ex vivo using adenosine diphosphate (ADP) and other platelet aggregation-inducing agonists. The action of eptifibatide is seen immediately after intravenous bolus administration at a dose of 180 μg/kg. Regimen followed by continuous intravenous infusion at a dose of 2.0 mcg/kg/min provides more than 80% inhibition of platelet aggregation ex vivo, induced by ADP, at physiological concentrations of calcium, in more than 80% of patients.

The inhibition of platelet aggregation is reversible; 4 h after cessation of continuous infusion at a dose of 2.0 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 O-phenylalanyl-b-prolyl-barginine chloromethyl ketone (PPASK)) in patients with unstable angina and myocardial infarction without Q-wave were found to be concentration-dependent inhibition with IC50 (concentration, 50% aggregation inhibitory concentration of 557 ng/mL and IC80 (80% aggregation inhibitory concentration) of 1107 ng/mL. Bleeding time when using Integrilin intravenously as a bolus and infusion is reversibly increased up to 5 times, this figure returns to the initial level within 2-6 hours after stopping the infusion. When used as monotherapy, eptifibatide has no significant effect on prothrombin time (PT) and activated partial thromboplastin time (APT).

Indications

• Early prevention of myocardial infarction in patients with unstable angina or myocardial infarction without Q-wave, who noted last painful attack within 24 hours, with ECG changes and/or increased activity of cardiospecific enzymes;
• prevention of sudden vessel closure and associated acute ischemic complications during percutaneous transluminal coronary angioplasty (PTCA).Integrilin is intended for use with acetylsalicylic acid and unfractionated heparin.
  

Active ingredient

Eptifibatid

Composition

Active ingredient:

eptifibatide – 2.0 mg;

Excipients:

citric acid monohydrate – 5.25 mg,

sodium hydroxide (to pH 5.25) – 1.7-220 mg,

water d/i – to 1 ml.

How to take, the dosage

Integrilin is intended for use in adults aged 18 years and older.

Intravenous solution with a concentration of 0.75 mg/ml (for infusion) and intravenous solution with a concentration of 2 mg/ml (for bolus injection) should be used together as directed.

The simultaneous use of Intergyline and heparin is recommended except in situations where heparin is contraindicated, such as a history of heparin-associated thrombocytopenia.

The drug Integrilin is also intended for concomitant use with acetylsalicylic acid, since acetylsalicylic acid is a standard component of treatment of patients with acute coronary syndrome, unless the use of acetylsalicylic acid is contraindicated.

Patients undergoing percutaneous coronary intervention (PCI)

The recommended dose of eptifibatide for adult patients with CK>50 ml/min (using the Cockcroft-Gault formula) Intravenous 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.

At the same time as the first bolus, a continuous infusion of the drug at a dose of 2.0 mcg/kg/min is started. 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 creatinine clearance >30-<50 ml/min who are undergoing percutaneous coronary intervention (PCI)

The recommended dose of eptifibatide for adult patients with a CK of >30-<50 ml/min (using the Cockcroft-Gault formula) Intravenously bolus at a dose of 180 mcg/kg just before manipulation, administered another 180 mcg/kg as a bolus 10 min after the first bolus.

At the same time as the first bolus, a continuous infusion of the drug at a dose of 1.0 mcg/kg/min is started. 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 CKG >50 ml/min (according to the Cockroft-Gault formula) Intravenously bolus at a dose of 180 mcg/kg as early as possible after diagnosis, then begin continuous infusion at a dose of 2.0 mcg/kg/min, which continues until 72 h before aortocoronary bypass surgery or hospital discharge, whichever occurs first.

If CTCA is performed during treatment, the infusion continues for an additional 20-24 h after CTCA, with a maximum total duration of administration of 96 h.

Patients with acute coronary syndrome (patients with unstable angina or myocardial infarction without Q-wave) and creatinine clearance >30-< 50 mL/min

The recommended dose of eptifibatide for adult patients with CK >30-< 50 mL/min (using the Cockcroft-Gault formula): Intravenously bolus at a dose of 180 mcg/kg as soon as possible after diagnosis, followed immediately by continuous infusion at a dose of 1.0 mcg/kg/min, which continues until 72 h before aortocoronary bypass surgery or hospital discharge, whichever occurs first.

If CTCA is performed during treatment, the infusion continues for an additional 20-24 h after CTCA, with a maximum total duration of administration of 96 h.

To calculate creatinine clearance in mL/min, the Cockcroft-Gault formula with a measure of actual body weight is used:

Men:

(140 – age in years) * (actual body weight in kg)

__________________________________________________

72 x (serum creatinine in mg/dL)

Women:

(140 – age in years) * (actual body weight in kg) * (0.85)

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72 x (serum creatinine in mg/dL)

Patients with a body weight greater than 121 kg are administered no more than 22.6 mg of the drug as a bolus and no more than 15 mg/hour (for creatinine concentrations below 2.0 mg/dL) or 7.5 mg/hour (for creatinine concentrations 2.0 to 4.0 mg/dL) as an infusion.

Emergency or “elective” surgery

If a patient requires emergency or urgent cardiac surgery during therapy with Integrilin, the infusion should be stopped immediately. If the patient needs a “planned” intervention, the infusion should be stopped to allow time for platelet function to return to normal.

Patients who require thrombolytic therapy (e.g., transmural myocardial infarction with a new abnormal Q wave on the ECG)

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

Integrilin Instructions for Administration

1. The solution should be checked for turbidity or foreign particles or discoloration before administration; the solution should only be injected if this is not present. The solution does not need to be protected from light during administration.
2. The drug Integrilin can be administered in the same system as alteplase, atropine sulfate, dobutamine, heparin, lidocaine, pethidine, metoprolol, midazolam, morphine, nitroglycerin, verapamil.

The drug Integrilin should not be administered in the same system as furosemide.

1. The drug Integrilin can be administered in one system with 0,9% sodium chloride solution or its mixture with 5% dextrose. When either of these solvents is used, the solution for administration may also contain up to 60 mmol/L potassium chloride. Incompatibilities with materials used for manufacturing systems for intravenous administration have not been observed. It is not recommended to mix Integrilin with drugs with which compatibility has not been established.
2. For bolus administration of Integrilin, it is necessary to draw a syringe from the bottle with 10 ml of the drug and push intravenously for 1-2 min.
3. After bolus administration, intravenous drop infusion of the drug should be started. If there is a pump allowing controlling the infusion rate, Integrilin can be administered directly from the bottle containing 100 ml of the drug without dilution. The system for administering Integrilin from a bottle containing 100 ml of the drug must have an air vent; the needle for connection of the system to the bottle must be inserted strictly through the center of the vial plug.
   

Interaction

Integrilin does not increase the risk of major and minor bleeding when used concomitantly with warfarin and dipyridamole. In patients with prothrombin time >14.5 s who received Integrilin concomitantly with warfarin, there was no increase in the risk of bleeding.

There are limited data on the use of Integrilin in patients treated with thrombolytics. There is no unequivocal evidence that Integrilin increases the risks of major and minor bleeding associated with tissue plasminogen activator both in patients undergoing CTCA and in patients with acute myocardial infarction. However, in clinical trials, Integrilin increased bleeding risks when administered with streptokinase in patients with acute myocardial infarction. In a study in 181 patients with acute myocardial infarction, Integrilin (bolus injection dose up to 180 mcg/kg, subsequent infusion up to 2 mcg/kg/min up to 72 h) was administered simultaneously with streptokinase (1.5 million units over 60 min). For maximum infusion rates (1.3 µg/kg/min and 2.0 µg/kg/min), use of Integrilin was associated with increased bleeding rates and transfusion requirements compared with streptokinase monotherapy.

In a clinical trial in patients with acute ST-segment elevation myocardial infarction, the combined use of reduced-dose tenectaplase and Integrilin resulted in a significant increase in the risk of massive and minor bleeding (compared to placebo and Integrilin without tenectaplase). Integrilin 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 special studies on pharmacokinetic interactions of Integrilin with other drugs. However, no pharmacokinetic interaction between the drug Integrilin and such frequently used drugs in patients with cardiovascular diseases was found during clinical studies, such as amlodipine, atenolol, atropine, captopril, cephazolin, diazepam, digoxin, diltiazem, diphenhydramine, enalapril, fentanyl, furosemide, heparin, lidocaine, lisinopril, metoprolol, midazolam, morphine, nitrates, nifedipine, warfarin.

Special Instructions

Integrilin is intended for hospital use only.

Bleeding

The drug Integrilin is an antithrombotic agent that inhibits platelet aggregation; therefore during treatment with Integrilin all patients should be carefully examined for possible bleeding, especially women, elderly patients and patients with low body weight as having the highest risk of bleeding (see section “Side effects”). If severe bleeding occurs that cannot be stopped by application of 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 the site of catheter insertion, the site of arteriopuncture, venipuncture or needle puncture, the site of venesection, and the possibility of gastrointestinal and genitourinary tract bleeding and retroperitoneal bleeding should be carefully monitored. Bleeding in the central and peripheral nervous system is also possible.

Control of femoral artery access

When using Integrilin, 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 introducer can be removed after the coagulation function has returned to normal: an activated clotting time of less than 180 s (usually 2-6 hours after heparin withdrawal). After removal of the intromedullary artery hemostasis should be performed, followed by close monitoring until discharge from the hospital.

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

The drug Integrilin inhibits platelet aggregation but does not affect platelet viability. The incidence of thrombocytopenia was low and similar to that of patients receiving placebo, which was 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 when first administered with glycoprotein IIb/IIIa receptor inhibitors or in patients receiving eptifibatide repeatedly.

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 (abciximab or eptifibatide, etc.) or primary exposure to glycoprotein IIb/IIIa receptor inhibitors may be accompanied by an immune-mediated thrombocytopenic response, care should be taken to monitor possible cases of 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 the use of eptifibatide, therapy with it may be resumed after platelet count normalization.

Bleeding time increase

The bleeding time when using Integrilin intravenously as a bolus and infusion is increased up to 5 times. This increase is rapidly reversible after stopping the infusion, this figure returns to baseline within 2-6 hours. When used as monotherapy, Integrilin has no significant effect on prothrombin time (PT) and activated partial thromboplastin time (APT).

The use of heparin

The combined use of Integrilin and heparin is recommended in all cases, if there are no contraindications to the use of heparin, such as a history of heparin-associated thrombocytopenia.

Patients with unstable angina or myocardial infarction without a 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, followed by 12 units/kg/h infusion. The AFV should be monitored to maintain values in the range of 50-70 s.

Coronary angioplasty

In patients undergoing CTCA, ABC (activated clotting time) should be monitored; its values should be in the range of 300-350 s. If the activated clotting time exceeds 300 s, heparin administration should be stopped and not resumed until the value is lower than 300 s.

Non-emergency CTCA with intracoronary stenting

For patients who have not had heparin for 6 h before the intervention, an initial bolus injection of heparin at a dose of 60 U/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 in this range.

Patients with hepatic impairment

Eptifibatide has very limited experience in patients with hepatic impairment (see section “Contraindications”), The drug should be used with caution in hepatic impairment because it may affect blood clotting in these patients.

Patients with renal failure

In mild renal failure (CK>50 ml/min by Cockroft-Gault formula), Integrilin can be safely used in standard dosage. In moderate to severe renal failure (CQ<50 ml/min by the Cockroft-Gault formula), the clearance of eptifibatide is reduced by approximately 50% and equilibrium plasma concentrations are approximately doubled. Patients with moderate to severe renal impairment who are given conventional infusions at a dose of 2 µg/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 section “Dosage and administration”). No clinical studies with the participation of patients on dialysis have been conducted.

The use in children

The safety and efficacy of the drug

Integrilin in children has not been established.

Laboratory monitoring

Changes in laboratory values during treatment with Integrilin are a consequence of the known pharmacological properties of the drug, such as inhibition of platelet aggregation. Thus, changes in laboratory parameters characterizing bleeding (e.g. bleeding time) are observed frequently and are expected. When using Integrilin and placebo, no obvious differences were observed in parameters such as hemoglobin, hematocrit, platelet count, liver function parameters (aspartate aminotransferase, alanine aminotransferase, bilirubin, alkaline phosphatase concentration) and renal function (serum creatinine, blood urea nitrogen concentration).

Impact on the ability to drive and operate vehicles

There have been no studies on the effect of eptifibatide on the ability to drive or operate machinery. The pharmacological properties of eptifibatide indicate the absence of any adverse effect on this type of activity. When evaluating the ability to perform activities requiring rapid decision-making, special motor and cognitive skills, the patient’s general condition and the adverse event profile of eptifibatide should be considered.

Synopsis

Transparent, colorless solution

Contraindications

• Hypersensitivity to the active ingredient or any other drug component;
• Gastric or intestinal bleeding, severe genital or urological bleeding or other significant pathological bleeding (except menstrual bleeding) within the last 30 days;
• acute cerebral haemorrhage within the past 30 days or a history of haemorrhagic stroke;
• “major” surgical intervention within the last 6 weeks;
• haemorrhagic diathesis in the history;
• thrombocytopenia (<100,000 cells/mm3);
• prothrombin time greater than 1.2 of control or international normalized ratio (MHO) >2.0;
• Developed arterial hypertension (systolic BP above 200 mmHg Systolic BP greater than 200 mmHg or diastolic BP greater than 110 mmHg.) against a background of antihypertensive therapy;
• clinically significant hepatic insufficiency;
• concurrent or planned use of another glycoprotein IIb / IIIa receptor inhibitor;
• severe renal insufficiency (creatinine clearance < 30 ml/min);
• need for hemodialysis.

Cautions

Cautions should be taken when using Integrilin concomitantly with other drugs that affect the hemostatic system: thrombolytics, oral anticoagulants, dextran solutions, adenosine, nonsteroidal anti-inflammatory drugs including sulfinpyrazone, drugs containing prostacyclin, dipyridamole, ticlopidine and clopidogrel.

The risk of bleeding increases with concomitant administration of Integrilin and streptokinase used to treat acute myocardial infarction.

The co-administration of Integrilin and heparin is recommended in all cases in the absence of contraindications to the use of heparin, such as a history of heparin-associated thrombocytopenia.

In the absence of clinical experience, caution should be exercised when using Integrilin concomitantly with low molecular weight heparin.

In children under 18 years of age

The safety and effectiveness of the drug Integrilin in patients under 18 years of age has not been established; therefore it is not recommended for this category of patients.

Side effects

The majority of adverse events with Integrilin are associated with bleeding or cardiac or cardiovascular events, which are frequently seen 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-a double-blind, randomized trial of the efficacy and safety of Integrilin versus placebo to reduce mortality and recurrent myocardial infarction in patients with unstable angina or myocardial infarction without a Q-wave.

The ESPRIT-double-blind, multicenter, randomized, placebo-controlled, parallel-group study of the safety and efficacy of eptifibatide in patients scheduled for non-emergency percutaneous coronary intervention (PCI) with intracoronary stenting.

Data on adverse events, including bleeding, in the PURSUIT trial were obtained from the time of hospital discharge to the 30-day visit. Bleeding events in the ESPRIT study were recorded within 48 hours, 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 hemoglobin concentration of more than 3 g/dL or a decrease in hemoglobin concentration of more than 4 g/dL with no apparent source of bleeding. Mild bleeding was a very common complication of Integrilin (>1/10, or 13.1% with Integrilin compared to 7.6% with placebo). Bleeding has been observed more frequently in patients receiving heparin concomitantly during PCI when the activated clotting time (ABC) exceeded 350 s (see section “Special Precautions”, subsection “Heparin Use”).

In the PURSUIT study, massive bleeding was defined as intracranial bleeding or a decrease in hemoglobin concentration of more than 5 g/dL. Massive bleeding with Integrilin was very common in this study (>1/10 or 10.8% with Integrilin versus 9.3% with placebo), excluding the vast majority of patients who did not undergo coronary artery bypass surgery within 30 days of study in whom it was infrequent. In patients undergoing coronary artery bypass grafting, the incidence of bleeding with Integrilin did not increase compared to patients receiving placebo. In the subgroup of patients undergoing PCI, major bleeding occurred frequently: 9.7% of patients with Integrilin compared to 4.6% of patients receiving placebo.

The incidence of major or life-threatening bleeding with Integrilin was 1.9% compared to 1.1% with placebo. There was a moderate increase in the need for blood transfusions when using Integrilin (11.8% Integrilin, 9.3% placebo).

The undesired phenomena presented below are listed according to organ and organ system involvement and frequency of occurrence. The frequency of occurrence is defined as follows: very frequently (>1/10), frequently (>1/100 and < 1/10), infrequently (>1/1000 and < 1/100), rarely (>1/10000 and < 1/1000), very rarely (< 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 (arterial hypotension, etc.) when using Integrilin does not differ from that when using placebo.

Disorders of the blood and lymphatic system

Very often: 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/hemoglobin and others).

Infrequent: thrombocytopenia.

Nervous system disorders

Infrequent: cerebral ischemia.

Cardiac disorders

Often: cardiac arrest, ventricular fibrillation, ventricular tachycardia, congestive heart failure, atrioventricular block, atrial fibrillation.

Vascular disorders

Often: 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 phenomena related to the underlying disease.

Post-registration observational data

Blood and lymphatic disorders

Very rare: Fatal bleeding (mainly 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: rash, adverse events at the injection site (e.g., urticaria).

Overdose

Information about overdose with Integrilin in humans is very limited. There were no indications of serious adverse events associated with accidental high-dose bolus administration, rapid infusion, which was reported as overdose, or excessive cumulative doses. Nine patients were reported in the PURSUIT clinical trial who received a bolus dose and/or infusion dose that was more than twice the protocol’s indicated dose or who were identified by the investigator as having received an overdose. No patients experienced massive bleeding; one patient underwent aortocoronary bypass surgery and experienced only moderate bleeding. Intracranial bleeding was not observed in any patient.

In an overdose of Integrilin, the possibility of bleeding cannot be excluded. Due to the short half-life and fast clearance, the activity of Integrilin can be quickly reduced by stopping the infusion. Integrilin may also be excreted by hemodialysis. In some cases, a blood transfusion may be needed to treat an overdose.

Pregnancy use

Pregnancy

There have been no clinical studies on the use of Integrilin in pregnant women. 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. Because animal studies are not considered sufficient to predict possible reactions in humans, Integrilin should be used during pregnancy only when the benefit to the mother exceeds the potential risk to the fetus.

Breastfeeding

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