Integrilin (Solution) Instructions for Use

Marketing Authorization Holder

GlaxoSmithKline Trading, JSC (Russia)

Manufactured By

Glaxo Operations UK Limited (United Kingdom)

ATC Code

B01AC16 (Eptifibatide)

Active Substance

Eptifibatide (Rec.INN registered by WHO)

Dosage Forms

	Integrilin	Solution for intravenous administration 0.75 mg/1 ml: bottle 100 ml 1 pc. in a set with a device for hanging the bottle.
		Solution for intravenous administration 2 mg/1 ml: bottle 10 ml 1 pc.

Dosage Form, Packaging, and Composition

Solution for intravenous administration transparent, colorless.

Excipients: citric acid monohydrate, sodium hydroxide, water for injections.

100 ml – glass bottles made of hydrolytic type 1 glass, sealed with a rubber stopper with an aluminum cap and a plastic cap (1) in a set with a polyethylene bottle hanging device – cardboard packs.

Solution for intravenous administration transparent, colorless.

Excipients: citric acid monohydrate, sodium hydroxide, water for injections.

10 ml – glass bottles made of hydrolytic type 1 glass, sealed with a rubber stopper with an aluminum cap and a plastic cap (1) – cardboard packs.

Clinical-Pharmacological Group

Antiplatelet agent

Pharmacotherapeutic Group

Antithrombotic agents; antiplatelet agents, other than heparin

Pharmacological Action

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

Eptifibatide causes dose- and concentration-dependent suppression of platelet aggregation, which has been demonstrated ex vivo using adenosine diphosphate (ADP) and other agonists that induce platelet aggregation. The effect of eptifibatide is observed immediately after IV bolus administration at a dose of 180 mcg/kg. A regimen with subsequent continuous IV infusion at a dose of 2 mcg/kg/min provides more than 80% inhibition of ADP-induced platelet aggregation ex vivo at physiological calcium concentrations in more than 80% of patients. Inhibition of platelet aggregation is reversible; 4 hours after discontinuation of a continuous infusion at a dose of 2 mcg/kg/min, platelet function recovers to more than 50% of baseline. In measurements of ADP-induced platelet aggregation ex vivo at physiological calcium concentrations (anticoagulant D-phenylalanyl-L-prolyl-L-arginine chloromethyl ketone (PPACK)) in patients with unstable angina and non-Q-wave myocardial infarction, concentration-dependent inhibition was revealed with an IC₅₀ (concentration inhibiting aggregation by 50%) of 557 ng/ml and an IC₈₀ (concentration inhibiting aggregation by 80%) of 1107 ng/ml. Bleeding time with Integrilin IV bolus and infusion reversibly increases up to 5 times, this indicator returns to baseline within 2-6 hours after stopping the infusion. When used as monotherapy, Eptifibatide does not have a significant effect on prothrombin time (PT) and activated partial thromboplastin time (aPTT).

Pharmacokinetics

The pharmacokinetics of eptifibatide are linear and dose-dependent with bolus administration from 90 to 250 mcg/kg and infusion at a rate from 0.5 to 3 mcg/kg/min. With drug infusion at a dose of 2.0 mcg/kg/min in patients with coronary artery disease, the mean steady-state plasma concentration (C_ss) of eptifibatide is established within 1.5-2.2 mcg/ml. This plasma concentration is achieved faster if the infusion is preceded by a bolus injection at a dose of 180 mcg/kg. The degree of binding of eptifibatide to human plasma proteins is about 25%. In the same patient population, the plasma T_1/2 is approximately 2.5 hours, plasma clearance is 55-80 ml/kg/h, V_d is 185-260 ml/kg. In healthy patients, the proportion of renal excretion of total clearance is about 50%; approximately 50% of the excreted amount is excreted unchanged.

A moderate increase in T_1/2 and V_d is observed in elderly patients, patients with low body weight (<74 kg) and/or reduced creatinine clearance. The dose and patient gender do not affect the pharmacokinetics of Integrilin. In mild renal impairment (CrCl≥50 ml/min according to the Cockcroft-Gault formula), dose adjustment for bolus or infusion administration is not required. In moderate renal impairment (CrCl≥30-<50 ml/min according to the Cockcroft-Gault formula), dose adjustment is recommended. In patients with moderate or severe renal impairment (CrCl<50 ml/min), a decrease in eptifibatide clearance of approximately 50% and an increase in plasma C_ss of approximately 2 times are observed (see sections “Special Instructions”, “Dosage Regimen”).

Indications

• Early prevention of myocardial infarction in patients with unstable angina or non-Q-wave myocardial infarction who experienced the 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).

The drug Integrilin is intended for use together with acetylsalicylic acid and unfractionated heparin.

ICD codes

Dosage Regimen

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

The solution for intravenous administration with a concentration of 0.75 mg/ml (for infusion) and the solution for intravenous administration with a concentration of 2 mg/ml (for bolus administration) should be used together according to the instructions.

Simultaneous use of the drug Integrilin and heparin is recommended, except in situations where the use of heparin is contraindicated, for example, in the case of a history of heparin-induced thrombocytopenia.

The drug Integrilin is also intended for simultaneous use with acetylsalicylic acid, since acetylsalicylic acid is a standard component of treatment for patients with acute coronary syndrome, except in cases where the use of acetylsalicylic acid is contraindicated.

Patients undergoing percutaneous coronary intervention (PCI)

The recommended dose of eptifibatide for adult patients with CrCl≥50 ml/min (according to the Cockcroft-Gault formula) is an IV bolus of 180 mcg/kg immediately before the start of the procedure, 10 minutes after the first bolus, another 180 mcg/kg is administered as a bolus. Simultaneously with the first bolus, a continuous infusion of the drug is started at a dose of 2.0 mcg/kg/min. The infusion is continued until the patient is discharged from the hospital or for 18-24 hours after PCI. The minimum recommended duration of infusion is 12 hours.

Patients with CrCl≥ 30-< 50 ml/min undergoing percutaneous coronary intervention (PCI)

The recommended dose of eptifibatide for adult patients with CrCl≥30-<50 ml/min (according to the Cockcroft-Gault formula) is an IV bolus of 180 mcg/kg immediately before the start of the procedure, 10 minutes after the first bolus, another 180 mcg/kg is administered as a bolus. Simultaneously with the first bolus, a continuous infusion of the drug is started at a dose of 1.0 mcg/kg/min. The infusion is continued until the patient is discharged from the hospital or for 18-24 hours after PCI. The minimum recommended duration of infusion is 12 hours.

Patients with acute coronary syndrome (patients with unstable angina or non-Q-wave myocardial infarction)

The recommended dose of eptifibatide for adult patients with CrCl≥50 ml/min (according to the Cockcroft-Gault formula) is an IV bolus of 180 mcg/kg as early as possible after diagnosis, then a continuous infusion is started at a dose of 2.0 mcg/kg/min, which is continued for up to 72 hours until the start of coronary artery bypass graft surgery or until discharge from the hospital, whichever occurs first.

If PTCA is performed during treatment, the infusion is continued for another 20-24 hours after PTCA, the maximum total duration of administration is 96 hours.

Patients with acute coronary syndrome (patients with unstable angina or non-Q-wave myocardial infarction) and CrCl≥ 30-< 50 ml/min

The recommended dose of eptifibatide for adult patients with CrCl≥30-<50 ml/min (according to the Cockcroft-Gault formula) is an IV bolus of 180 mcg/kg as early as possible after diagnosis, then a continuous infusion is immediately started at a dose of 1.0 mcg/kg/min, which is continued for up to 72 hours until the start of coronary artery bypass graft surgery or until discharge from the hospital, whichever occurs first.

If PTCA is performed during treatment, the infusion is continued for another 20-24 hours after PTCA, the maximum total duration of administration is 96 hours.

To calculate CrCl in ml/min, use the Cockcroft-Gault formula with the indicator of actual body weight

Men:(140 – age in years) × (actual body weight in kg)/72 × (serum creatinine in mg/dl)

Women (140 – age in years) × (actual body weight in kg) × (0.85)/72 × (serum creatinine in mg/dl)

For patients with body weight over 121 kg, no more than 22.6 mg of the drug should be administered as a bolus and no more than 15 mg/hour (with creatinine concentration below 2.0 mg/dl) or 7.5 mg/hour (with creatinine concentration from 2.0 to 4.0 mg/dl) as an infusion.

Emergency or planned surgical intervention

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

Patients requiring thrombolytic therapy (e.g., transmural myocardial infarction with a new pathological Q wave on ECG)

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

Instructions for administration of the drug Integrilin

1. Before administration, the solution should be checked for cloudiness or foreign particles or discoloration; the solution can only be administered in their absence. Protection of the solution from light during administration is not required.
2. The drug Integrilin can be administered in the same system with alteplase, atropine sulfate, dobutamine, heparin, lidocaine, pethidine, metoprolol, midazolam, morphine, nitroglycerin, verapamil.

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

1. The drug Integrilin can be administered in the same system with 0.9% sodium chloride solution or its mixture with 5% dextrose. When using any of these solvents, the solution for administration may also contain up to 60 mmol/l of potassium chloride. No incompatibility with the materials used for the manufacture of IV administration systems has been noted.

It is not recommended to mix the drug Integrilin with drugs for which compatibility has not been established.

1. For bolus administration, the drug Integrilin should be drawn into a syringe from a bottle containing 10 ml of the drug and administered IV as a bolus, over 1-2 minutes.
2. Immediately after bolus administration, IV drip infusion of the drug should be started. If a pump that allows regulation of the infusion rate is available, the drug Integrilin can be administered directly from a bottle containing 100 ml of the drug, without dilution. The system for administering the drug Integrilin from a bottle containing 100 ml of the drug must have an air vent; the needle for connecting the system to the bottle should be inserted strictly through the center of the bottle stopper.

The residue of the drug in the bottle is not suitable for further use and must be disposed of.

Adverse Reactions

Most adverse events when using the drug Integrilin are associated with the development of bleeding or the occurrence of disorders of the heart or cardiovascular system, which is often observed in this patient population.

Clinical data

The frequency of adverse events presented below was formed on the basis of two phase III clinical trials (PURSUIT and ESPRIT).

PURSUIT is a double-blind, randomized study of the efficacy and safety of the drug Integrilin compared with placebo for reducing mortality and the number of recurrent myocardial infarctions in patients with unstable angina or non-Q-wave myocardial infarction.

ESPRIT is a double-blind, multicenter, randomized, placebo-controlled, parallel-group study to evaluate 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 study were collected from hospital discharge until the 30-day visit. Bleeding events in the ESPRIT study were recorded for 48 hours, and events not related to bleeding were recorded for 30 days. The TIMI bleeding criteria (classification according to the Thrombolysis in Myocardial Infarction Study Group criteria) were used to classify the frequency of major and minor bleeding in the PURSUIT and ESPRIT studies. Data from the PURSUIT study were collected over 30 days, while data obtained in the ESPRIT study were limited to events that occurred within 48 hours or before discharge, whichever occurred first.

When used in 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 (coronary artery bypass grafting or when accessing the femoral artery) were most often accompanied by bleeding.

In the PURSUIT study, minor 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 in the absence of a visible source of bleeding. Minor bleeding was a very common complication of Integrilin use (> 1/10 or 13.1% with Integrilin use compared to 7.6% with placebo). Bleeding was more common in patients simultaneously receiving heparin during PCI when the activated clotting time (ACT) exceeded 350 s (see section “Special Instructions”, subsection “Use of heparin”).

In the PURSUIT study, major bleeding was defined as intracranial bleeding or a decrease in hemoglobin concentration of more than 5 g/dl. Major bleeding with Integrilin use in this study was observed very often (≥1/10 or 10.8% with Integrilin use compared to 9.3% with placebo), excluding the vast majority of patients who did not undergo coronary artery bypass grafting within 30 days of study entry, in whom this phenomenon was infrequent. In patients who underwent coronary artery bypass grafting, the frequency of bleeding with Integrilin use did not increase compared to patients receiving placebo. In the subgroup of patients who underwent PCI, extensive bleeding was observed frequently: in 9.7% of patients with Integrilin use compared to 4.6% in patients receiving placebo. The frequency of severe or life-threatening bleeding with Integrilin use was 1.9% compared to 1.1% with placebo. The need for hemotransfusions was moderately increased with Integrilin use (11.8% – Integrilin, 9.3% – placebo).

The adverse events presented below are listed according to the affected organs and organ systems and frequency of occurrence. The frequency of occurrence is defined as follows: very common (≥1/10), common (≥1/100 and < 1/10), uncommon (≥1/1,000 and < 1/100), rare (≥1/10,000 and < 1/1,000), very rare (< 1/10,000, including isolated cases). The absolute frequency of reports is indicated without taking into account the frequency with placebo use. If data on individual adverse events from two studies (PURSUIT and ESPRIT) are available, the highest indicated frequency was used to determine the frequency of adverse events.

It should be noted that a relationship with drug use has not been established for all adverse events.

The frequency of serious adverse events not related to bleeding (arterial hypotension, etc.) with Integrilin use does not differ from that with placebo use.

From the blood and lymphatic system: very common – bleeding (major and minor bleeding, included bleeding during coronary artery bypass grafting, femoral artery access, gastrointestinal bleeding, genitourinary bleeding, retroperitoneal bleeding, intracranial bleeding, hematemesis, hematuria, intraoral/oropharyngeal bleeding, bleeding that reduces hematocrit/hemoglobin, others); uncommon – thrombocytopenia.

Nervous system disorders: uncommon – cerebral ischemia.

Cardiac disorders: common – cardiac arrest, ventricular fibrillation, ventricular tachycardia, congestive heart failure, AV block, atrial fibrillation.

Vascular disorders: common – cardiogenic shock, arterial hypotension, phlebitis. Cardiac arrest, congestive heart failure, atrial fibrillation, arterial hypotension, and cardiogenic shock, which were frequently reported in the PURSUIT study, were events associated with the underlying disease.

Post-marketing surveillance data

Blood and lymphatic system disorders: very rare – fatal bleeding (primarily involving the CNS and peripheral nervous system – hemorrhagic stroke or intracranial bleeding); pulmonary hemorrhage, acute profound thrombocytopenia, hematoma.

Immune system disorders: very rare – anaphylactic reactions.

Skin and subcutaneous tissue disorders: very rare – rash, administration site reactions (e.g., urticaria).

Contraindications

• Hypersensitivity to the active substance or any of the excipients;
• Gastric or intestinal bleeding, major genital and urinary bleeding, or other significant pathological bleeding within the last 30 days;
• Acute cerebrovascular accident within the last 30 days or history of hemorrhagic stroke;
• History of intracranial disease (neoplasm, arteriovenous malformation, aneurysm);
• “major” surgical intervention or severe trauma within the last 6 weeks;
• History of hemorrhagic diathesis;
• Thrombocytopenia (<100,000 cells/mm³);
• Prothrombin time greater than 1.2 times control or INR≥2;
• Severe arterial hypertension (systolic BP above 200 mm Hg or diastolic BP above 110 mm Hg) despite antihypertensive therapy;
• Clinically significant hepatic impairment;
• Concurrent or planned use of another glycoprotein IIb/IIIa receptor inhibitor;
• Severe renal impairment (CrCl<30 ml/min);
• Need for hemodialysis.

With caution

Caution should be exercised when using Integrilin concomitantly with other drugs affecting hemostasis: thrombolytics, oral anticoagulants, dextran, adenosine, NSAIDs, including sulfinpyrazone, drugs containing prostacyclin; dipyridamole; ticlopidine and clopidogrel.

The risk of bleeding increases with the concomitant administration of Integrilin and streptokinase used for the treatment of acute myocardial infarction.

Concomitant use of Integrilin and heparin is recommended in all cases, in the absence of contraindications to heparin use, for example, a history of heparin-associated thrombocytopenia.

Due to the lack of clinical experience, Integrilin should be used with caution concomitantly with low molecular weight heparin.

Children under 18 years of age the safety and efficacy of Integrilin in patients under 18 years of age have not been established, therefore use in this category of patients is not recommended.

Use in Pregnancy and Lactation

Pregnancy

No clinical studies have been conducted on the use of Integrilin in pregnant women. However, reproductive toxicity studies were conducted in rats and rabbits using doses 8 and 4 times the human dose, respectively. These studies revealed no evidence of impaired fertility or harm to the fetus due to eptifibatide. Since animal studies are not always predictive of human response, Integrilin should be used during pregnancy only if clearly needed, when the potential benefit justifies the potential risk to the fetus.

Breastfeeding

Data on the passage of eptifibatide into breast milk are not available. Breastfeeding should be discontinued during Integrilin therapy.

Use in Hepatic Impairment

Experience with Integrilin in patients with hepatic impairment is very limited, therefore Integrilin should be administered with caution to such patients.

Use in Renal Impairment

Patients with renal impairment with unstable angina or non-Q-wave myocardial infarction, requiring and not requiring PCI, with mild renal impairment (CrCl ≥50 ml/min) Integrilin can be administered at standard doses. In patients with moderate renal impairment (CrCl ≥30 ml/min and <50 ml/min) the infusion dose of Integrilin should be 1 mcg/kg/min. Clinical data regarding the use of Integrilin in patients with severe renal impairment (CrCl < 30 ml/min) and patients on hemodialysis are insufficient to recommend its use in this category of patients.

Pediatric Use

The safety and efficacy of Integrilin in children under 18 years of age have not been established, therefore use in this category of patients is not recommended.

Special Precautions

Integrilin is intended for use only in a hospital setting.

Bleeding

Integrilin is an antithrombotic agent that inhibits platelet aggregation; therefore, all patients should be carefully examined for possible bleeding, especially women, elderly patients, and patients with low body weight, as they have the highest risk of bleeding (see section “Adverse Reactions”). If serious bleeding occurs that cannot be controlled by applying a pressure bandage, the infusion of Integrilin and any concomitant heparin should be discontinued immediately.

The risk of bleeding in patients undergoing PCI is greatest at the arterial access site. Potential bleeding sites, such as the catheter insertion site, arteriopuncture site, venipuncture or needle puncture site, venesection site, should be carefully monitored, and the possibility of gastrointestinal and genitourinary bleeding, retroperitoneal bleeding should be considered. Bleeding in the CNS and peripheral nervous system is also possible.

Femoral artery access site control

When using Integrilin, the risk of bleeding is greatest at the femoral artery catheter insertion site during PCI. Femoral artery puncture should be performed with caution, ensuring that only the anterior wall is punctured. The femoral artery introducer sheath can be removed after coagulation function returns to normal (activated clotting time – less than 180 seconds, usually 2-6 hours after heparin discontinuation). After sheath removal, hemostasis should be achieved followed by careful observation until hospital discharge.

Thrombocytopenia and immunogenicity associated with IIb/IIIa receptor inhibitor use

Integrilin inhibits platelet aggregation but does not affect platelet viability. The incidence of thrombocytopenia was low and similar to that in patients receiving placebo, as observed in clinical trials and in rare reports of immune thrombocytopenia during post-marketing surveillance. The presence of plasma transferable factors that can bind to eptifibatide and glycoprotein IIb/IIIa receptors means that an immune thrombocytopenic response may develop upon first exposure to glycoprotein IIb/IIIa receptor inhibitors or in patients re-exposed to Eptifibatide.

The mechanism (immune and/or non-immune) of eptifibatide’s effect on thrombocytopenia development is not fully understood. Since re-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 a thrombocytopenic immune-mediated response, caution should be exercised and possible cases of thrombocytopenia accompanied by arterial hypotension and/or other hypersensitivity symptoms should be monitored.

If a decrease in platelet count to < 100,000/mm³ or acute profound thrombocytopenia is confirmed, immediate discontinuation of any medications that may have thrombocytopenic effects, including eptifibatide, heparin, and clopidogrel, should be considered. Supportive therapy should be initiated, and platelet count monitoring should be performed to adjust treatment and determine the etiology. If thrombocytopenia is not related to eptifibatide use, its therapy can be resumed after platelet count normalization.

Increased bleeding time

Bleeding time increases up to 5 times with intravenous bolus and infusion administration of Integrilin. This increase is rapidly reversible after infusion cessation, with this parameter returning to baseline within 2-6 hours. When used as monotherapy, Integrilin does not significantly affect prothrombin time (PT) and aPTT.

Use of heparin

Concomitant use of Integrilin and heparin is recommended in all cases, in the absence of contraindications to heparin use, for example, a history of heparin-associated thrombocytopenia.

Patients with unstable angina or non-Q-wave myocardial infarction

For patients weighing 70 kg or more, the recommended bolus dose is 5000 IU, followed by a continuous infusion of 1000 IU/h. For patients weighing less than 70 kg, the bolus dose is 60 IU/kg, followed by an infusion of 12 IU/kg/h. aPTT should be monitored to maintain values in the range of 50-70 seconds.

Coronary angioplasty

During PCI, patients’ ACT (activated clotting time) should be monitored, and its values should be within 300-350 seconds. If blood ACT exceeds 300 seconds, heparin use should be discontinued and not resumed until the value decreases below 300 seconds.

Non-emergent PCI with intracoronary stenting

For patients who have not received heparin within 6 hours prior to the intervention, an initial heparin bolus of 60 IU/kg is recommended. The target ACT during the procedure is 200-300 seconds. During PCI, additional heparin boluses can be administered to maintain ACT within this range.

Patients with hepatic impairment

Experience with eptifibatide in patients with hepatic impairment is extremely limited (see section “Contraindications”). In hepatic impairment, the drug should be used with caution, as it may affect blood coagulation in such patients.

Patients with renal impairment

In mild renal impairment (CrCl≥50 ml/min by Cockcroft-Gault formula), Integrilin can be safely used at the standard dosage. In moderate or severe renal impairment (CrCl<50 ml/min by Cockcroft-Gault formula), the clearance of eptifibatide is reduced by approximately 50%, and steady-state plasma concentrations are increased approximately 2-fold. In patients with moderate or severe renal impairment receiving standard infusions at a dose of 2 mcg/kg/min, there is an increased risk of bleeding. Therefore, in such patients, the infusion dose should be reduced to 1 mcg/kg/min (see section "Dosage and Administration"). No clinical studies have been conducted in patients on dialysis.

Use in children

The safety and efficacy of Integrilin in children have not been established.

Laboratory parameter monitoring

Changes in laboratory parameters during Integrilin treatment are a consequence of its known pharmacological properties, e.g., inhibition of platelet aggregation. Thus, changes in laboratory parameters characterizing bleeding (e.g., bleeding time) are common and expected. No apparent differences were observed between Integrilin and placebo in such parameters as hemoglobin, hematocrit, platelet count, liver function tests (AST, ALT, ALP concentration, and bilirubin concentration) and renal function tests (serum creatinine concentration, blood urea nitrogen).

Effect on ability to drive and use machines

No studies on the effects of eptifibatide on the ability to drive or use machines have been performed. The pharmacological properties of eptifibatide suggest no negative impact on such activities. When assessing the ability to perform activities requiring quick decision-making, specific motor and cognitive skills, the patient’s general condition and the adverse event profile of eptifibatide should be taken into account.

Overdose

Information on Integrilin overdose in humans is very limited.

Symptoms no signs of serious adverse events associated with accidental administration of large bolus doses, rapid infusion administration, reported as overdose, or exceeding cumulative doses were observed. There were reports of 9 patients who, as part of the PURSUIT clinical trial, received a bolus dose and/or infusion dose more than twice the protocol-specified dose, or who were identified by the investigator as having received an overdose. No major bleeding was observed in any of these patients; one patient underwent coronary artery bypass graft surgery and had only moderate bleeding. No intracranial bleeding was observed in any patient.

In case of Integrilin overdose, the possibility of bleeding cannot be excluded.

Treatment due to the short half-life and rapid clearance, Integrilin activity can be rapidly reduced by discontinuing the infusion. Integrilin can also be removed by hemodialysis. In some cases, blood transfusion may be required to treat overdose.

Drug Interactions

Integrilin does not cause an increase in the risk of major and minor bleeding when used concomitantly with warfarin and dipyridamole. In patients with prothrombin time ≥ 14.5 seconds receiving Integrilin concomitantly with warfarin, no increased risk of bleeding was noted.

There are limited data on the use of Integrilin in patients receiving thrombolytic drugs. There are no confirmed data indicating that Integrilin increases the risks of major and minor bleeding associated with tissue plasminogen activator in patients undergoing PCI or in patients with acute myocardial infarction. However, in clinical trials, Integrilin increased the risk of bleeding when administered with streptokinase in patients with acute myocardial infarction. In a study of 181 patients with acute myocardial infarction, Integrilin (bolus dose up to 180 mcg/kg, followed by infusion up to 2 mcg/kg/min for up to 72 hours) was administered concomitantly with streptokinase (1.5 million IU over 60 minutes). At the maximum infusion rates (1.3 mcg/kg/min and 2 mcg/kg/min), Integrilin use was associated with an increased frequency of bleeding and transfusion requirements compared to streptokinase monotherapy.

In a clinical trial in patients with ST-segment elevation myocardial infarction, concomitant use of a combination of reduced doses of tenecteplase and Integrilin led to a significant increase in the risk of major and minor bleeding (compared to placebo and Integrilin use without tenecteplase).

Integrilin is incompatible with furosemide.

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

No specific studies on the pharmacokinetic interaction of Integrilin with other drugs have been conducted. However, clinical trials have not revealed any pharmacokinetic interaction between Integrilin and drugs commonly used in patients with cardiovascular diseases, such as amlodipine, atenolol, atropine, captopril, cefazolin, diazepam, digoxin, diltiazem, diphenhydramine, enalapril, fentanyl, furosemide, heparin, lidocaine, lisinopril, metoprolol, midazolam, morphine, nitrates, nifedipine, warfarin.

Storage Conditions

The drug should be stored in the original package protected from light at a temperature between 2°C (35.6°F) and 8°C (46.4°F). Keep out of reach of children.

Shelf Life

Shelf life – 3 years.

Dispensing Status

The drug is dispensed by prescription.

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.