Description
Pharmacological action
Pharmacotherapeutic group: antiplatelet agent.
ATX code: B01AC16.
Pharmacological action
Pharmacodynamics
Eptifibatide is a synthetic cyclic heptapeptide containing 6 amino acid residues, including one cysteinamide and one mercaptopropionyl residue – desaminocysteinyl. Eptifibatide is an inhibitor of platelet aggregation and belongs to the class of arginine-glycine-aspartate mimetics. Eptifibatide reversibly inhibits platelet aggregation, preventing the binding of fibrinogen, von Willebrand factor and other adhesive ligands to platelet glycoprotein IIb / IIIa receptors.
Eptifibatide induces dose-dependent and concentration-dependent inhibition of platelet aggregation, which has been demonstrated ex vivo using adenosine diphosphate (ADP) and other platelet aggregation inducing agonists. The action of eptifibatide is observed immediately after intravenous bolus administration at a dose of 180 mcg / kg. A regimen followed by continuous intravenous infusion at a dose of 2.0 Ñg / kg / min provides more than 80% inhibition of platelet aggregation ex vivo induced by ADP at physiological calcium concentrations, in more than 80% of patients. Inhibition of platelet aggregation is reversible 4 hours after the cessation of continuous infusion at a dose of 2 Ñg / kg / min, platelet function is restored to its original level by more than 50%. When measuring ADP-induced platelet aggregation ex vivo at physiological calcium concentrations (anticoagulant D-phenylalanyl-L-prolyl-L-arginine chloromethylketone (PPAC)) in patients with unstable angina and myocardial infarction without Q wave, concentration-dependent inhibition with IC50 (concentration inhibiting aggregation by 50%) of 557 ng / ml and IC80 (concentration inhibiting aggregation of 80%) of 1107 ng / ml. The bleeding time when using the drug Koromaks intravenously in the form of a bolus and infusion reversibly increases up to 5 times, this indicator returns to its original level within 2-6 hours after the end of the infusion. When used as monotherapy, eptifibatide has no significant effect on prothrombin time (PV) and activated partial thromboplastin time (APTT).
Pharmacokinetics
The pharmacokinetics of eptifibatide are linear and dose-dependent in bolus administration over a dose range of 90 to 250 mcg / kg and infusion at a rate of 0.5-3 mcg / kg / min. When infusion at a dose of 2.0 Ñg / kg / min in patients with coronary heart disease, the average equilibrium plasma concentration of eptifibatide is set in the range of 1.5-2.2 Ñg / ml. This plasma concentration is reached faster if the infusion is preceded by a bolus administration of 180 Ñg / kg.
The degree of binding of eptifibatide to human plasma proteins is about 25%.
In the same patient population, the plasma half-life is approximately 2.5 hours, plasma clearance is 55-80 ml / kg / h, and the distribution volume is approximately 185-260 ml / kg. In healthy patients, the proportion of renal excretion of the total clearance is about 50%, approximately 50% of the excreted amount of the substance is excreted in unchanged form.
A moderate increase in elimination half-life and distribution volume is observed in older patients, patients with reduced body weight (<74 kg) and / or decreased creatinine clearance (CC). The dose and gender of the patient do not affect the pharmacokinetics of the drug Koromaks. In renal failure of mild severity (CC ² °Ò 50 ml / min according to the Cockroft-Gault formula), dose adjustment for bolus or infusion administration is not required. In renal failure of moderate severity (KK 30 - <50 ml / min according to the Cockcroft-Gault formula), dose adjustment is recommended. In patients with moderate or severe renal insufficiency (CC <50 ml / min), a decrease in the clearance of eptifibatide by approximately 50% and an increase in equilibrium plasma concentrations by approximately two times are observed (see sections Special instructions, Dosage and administration). Contraindications Hypersensitivity to eptifibatide or any other component of the preparation, gastric or intestinal bleeding, severe genital (except menstrual bleeding) and urological bleeding or other severe pathological bleeding during the last 30 days acute cerebral hemorrhage during the last 30 days or hemorrhagic stroke in the history of intracranial diseases (neoplasia, arteriovenous malformation, aneurysm) “b lshoe “surgery or severe trauma in prothrombin time (PT) During the last 6 weeks hemorrhagic diathesis in history thrombocytopenia (<100,000 cells / mm ) of more than 1, 2 from PV control plasma or international normalized ratio (INR)> 2.0
severe arterial hypertension (systolic blood pressure above 200 mmHg or diastolic blood pressure above 110 mmHg) with anti-hypertensive therapy
clinically significant liver failure
severe renal failure (creatinine clearance <30 ml / min) or the need for hemodialysis simultaneous or planned use of another inhibitor of platelet IIb / IIIa glycoprotein receptors for parenteral administration of Det cue age of 18 years (experience of missing). Caution Caution should be exercised while the use of eptifibatide with other drugs that affect the hemostatic system: thrombolytics, oral anticoagulants, dextran solutions, adenosine, non-steroidal anti-inflammatory drugs, including sulfinpyrazone, drugs containing prostacyclin, dipyridamole, ticlopidine and clopidogrel. The risk of bleeding while using the drug eptifibatide and streptokinase used to treat acute myocardial infarction increases. The combined use of the drug eptifibatide and heparin is recommended in all cases, in the absence of contraindications to the use of heparin, for example, a history of thrombocytopenia associated with heparin. Due to the lack of clinical experience, it is necessary to use the drug eptifibatide simultaneously with low molecular weight heparin with caution. Use during pregnancy and lactation Clinical studies on the use of eptifibatide in pregnant women have not been conducted. However, studies on the effect on reproductive function were carried out in rats and rabbits using doses correspondingly 8 and 4 times higher than the dose intended for humans. In these studies, there were no signs 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 be used during pregnancy only in cases where the benefit to the mother outweighs the potential risk to the fetus. There is no data on the penetration of eptifibatide into breast milk. It is recommended to stop breastfeeding with the use of eptifibatide. Special instructions Eptifibatide is intended for use only in a hospital setting. Bleeding eptifibatide is an antithrombotic, inhibiting platelet aggregation, therefore, during the treatment with Eptifibatide, all patients should be carefully examined to identify possible bleeding, especially women, elderly patients, as well as patients with low body weight, as having the greatest risk of bleeding (see section ² ÑSide effects ² Ñ). 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 PTCA is greatest at the site of arterial access. It is necessary to carefully monitor the places of possible bleeding, for example, the place of insertion of the catheter, the place of arterial puncture, venipuncture or needle puncture, the place of venesection, it should be borne in mind the possibility of bleeding from the gastrointestinal tract and genitourinary tract, retroperitoneal bleeding. Bleeding in the central and peripheral nervous system is also possible. Control of access to the femoral artery When using Eptifibatide, the risk of bleeding is greatest at the site of insertion of the catheter into the femoral artery during PTCA. Care should be taken to ensure that only the anterior wall of the femoral artery is punctured. The introducer sheath from the femoral artery can be removed after restoration of coagulation function to normal: the activated blood coagulation time is less than 180 s (usually 2-6 hours after discontinuation of heparin). After removal of the introducer sheath, hemostasis should be performed, followed by careful monitoring until discharge from the hospital. Thrombocytopenia and immunogenesis, associated with the use of inhibitors of IIb / IIIa receptors Eptifibatide inhibits platelet aggregation, but does not affect their viability. The incidence of thrombocytopenia was low and similar to that in patients receiving placebo, which was observed both during clinical trials and in rare reports of cases of the development of immune thrombocytopenia during post-registration observations. The presence of transmissible factors in the plasma that can bind to the eptifibatide and glycoprotein IIb / IIIa receptors means that an immune thrombocytopenic response may develop with the first use of glycoprotein IIb / IIIa receptor inhibitors or in patients re-receiving eptifibatide. The mechanism (immune and / or non-immune) of the effect of eptifibatide on the development of thrombocytopenia is not fully understood. Due to the fact that repeated exposure to any inhibitor of glycoprotein IIb / IIIa receptors (abciximab or eptifibatide, etc.) or the primary effect of inhibitors of glycoprotein IIb / IIIa receptors may be accompanied by a thrombocytopenic immune-mediated response, caution should be exercised and control for possible cases accompanied by arterial hypotension and / or other symptoms of hypersensitivity. When confirming a decrease in platelet count to <100000 / mm or acute acute thrombocytopenia should immediately consider discontinuing treatment with any medication that may have a thrombocytopenic effect, including eptifibatide, heparin and clopidogrel. You need to start maintenance therapy, and also monitor platelet counts to correct treatment and establish etiology. If thrombocytopenia is not associated with the use of eptifibatide, he can resume therapy after normalizing the platelet count. Increased bleeding time The bleeding time when using Eptifibatide intravenously in the form of a bolus and infusion is increased up to 5 times. This increase is quickly reversible after the termination of the infusion, this indicator returns to the initial level within 2-6 hours. When used as a monotherapy, Eptifibatide does not significantly affect prothrombin time (PV) and activated partial thromboplastin time (APTT). The use of heparin The combined use of eptifibatide and heparin is recommended in all cases, in the absence of contraindications for the use of heparin, for example, a history of thrombocytopenia associated with heparin. Patients with unstable angina or myocardial infarction without Q wave For patients weighing 70 kg or more, the recommended bolus dose is 5000 units, followed by a continuous infusion of 1000 units / hour. For patients weighing less than 70 kg, the bolus dose is 60 units / kg, followed by infusion 12 units / kg / h. APTT should be monitored to maintain values ² ¹ ² ¹in the range of 50-70 s. Coronary angioplasty When performing PTCA in patients, it is necessary to control ABC (activated coagulation time), its values ² ¹ ² ¹should be within 300-350 s. If the value of the activated blood coagulation time exceeds 300 s, the use of heparin should be stopped and not renewed until the value decreases to less than 300 s. Non-emergency PTCA with intracoronary stenting For patients who have not been injected with heparin for 6 hours before surgery, an initial bolus of 60 units / kg is recommended. The target ABC during the procedure is 200-300 s. During the PTCA procedure, heparin can be additionally bolus administered to maintain ABC in this range. Patients with hepatic insufficiency Experience with the use of eptifibatide in patients with hepatic insufficiency is extremely limited (see section “Contraindications”). In case of liver failure, the drug should be used with caution, since in such patients the drug may affect blood coagulation. Patients with renal failure For renal failure of mild severity (CC ² °Ò 50 ml / min according to the Cockcroft-Gault formula) Eptifibatide can be safely used in a standard dosage. In moderate or severe renal failure (CC <50 ml / min according to the Cockcroft-Gault formula), the clearance of eptifibatide is reduced by approximately 50%, and the equilibrium plasma concentrations are approximately doubled. Patients with moderate or severe renal insufficiency who undergo routine infusions at a dose of 2 Ñg / kg / min are at increased risk of bleeding. Therefore, in such patients, the dose during the infusion should be reduced to 1 Ñg / kg / min (see section "Dosage and administration"). Clinical studies involving dialysis patients have not been conducted. Children under the age of 18 The safety and effectiveness of the use of eptifibatide in patients under the age of 18 has not been established, and therefore, use in this category of patients is not recommended. Monitoring of laboratory parameters Changes in laboratory parameters during treatment with eptifibatide are a consequence of the known pharmacological properties of the drug, for example, inhibition of platelet aggregation. Thus, changes in laboratory parameters characterizing bleeding (for example, bleeding time) are often observed and are expected. When using Eptifibatide and when using placebo, there were no obvious differences in such indicators as hemoglobin, hematocrit, platelet count, liver function indicators (concentration of aspartate aminotransferase, alanine aminotransferase, bilirubin, alkaline phosphatase) and kidney function (concentration of serum creatinine, blood urea nitrogen). Effect on the ability to drive vehicles, mechanisms Eptifibatid is intended for use in a hospital. There is no data on the use of eptifibatide in outpatients. Composition of In 1 ml of an intravenous solution contains: Active ingredient: eptifibatide – 0.75 mg or 2.0 mg Excipients: citric acid monohydrate – 5.25 mg, sodium hydroxide – up to pH 5.25 ( from 1.7 to 220 mg), water for injection – qs to 1.0 ml. Side effects Most adverse events associated with the use of eptifibatide 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 evidence The frequency of adverse events presented below was based on two phase III clinical trials (PURSUIT and ESPRIT). PURSUIT – a double-blind, randomized study of the efficacy and safety of Eptifibatide versus placebo to reduce mortality and the number of cases of recurrent myocardial infarction in patients with unstable angina or Q-wave myocardial infarction. ESPRIT – double-blind, multicenter, randomized, placebo study in parallel groups on the safety and efficacy of eptifibatide in patients with planned non-emergency transdermal cortex -stationary intervention (PCI) with intracoronary stenting. Data on adverse events, including bleeding, in the PURSUIT study was obtained from the time of discharge from the hospital until the visit on day 30. Bleeding events in the ESPRIT study were recorded for 48 hours, and non-bleeding events were recorded for 30 days. The TIMI bleeding criteria (classification according to the criteria of the Group for the Study of Thrombolysis in Myocardial Infarction) was used to classify the frequency of massive and light bleeding in the PURSUIT and ESPRIT studies. PURSUIT study data were collected over 30 days, while data from the ESPRIT study were limited to events that occurred within 48 hours or before discharge, whichever happened first. When used in recommended therapeutic doses, used in the PURSUIT study (involving about 11,000 patients), bleeding was the most common complication of eptifibatide therapy. Invasive procedures on the heart (coronary artery bypass grafting or access to the femoral artery) were most often accompanied by bleeding. In the PURSUIT study, light bleeding was defined as spontaneous macrohematuria, spontaneous hemathemesis, 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. Light bleeding was a very frequent complication of the use of eptifibatide (> 1/10, or 13.1% when using eptifibatide compared to 7.6% when using placebo). Bleeding was more common in patients concurrently receiving heparin during PCI. when the activated blood coagulation time (ABC) exceeded 350 s (see Special Instructions, subsection Use of heparin),
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 Eptifibatide was very common in this study (> 1/10 or 10.8% with Eptifibatide compared with 9.3% with placebo), excluding the vast majority of patients who did not have coronary artery bypass grafting for 30 days after inclusion in the study, in which this phenomenon was observed infrequently. In patients who underwent coronary artery bypass grafting, the bleeding rate with Eptifibatide did not increase compared with patients who received placebo. In the subgroup of patients who underwent PCI. extensive bleeding was observed frequently: in 9.7% of patients using Eptifibatide compared with 4.6% in patients receiving placebo.
The incidence of severe or life-threatening bleeding with eptifibatide was 1.9% compared with 1.1% with placebo. With the use of Eptifibatide, the need for blood transfusions was moderately increased (11.8% – Eptifibatide, 9.3% – placebo).
The adverse events listed below are listed according to organ and organ damage and frequency of occurrence. The frequency of occurrence is determined as follows: very often (? 1/10), often (? 1/100 and <1/10), infrequently (? 1/1000 and <1/100), rarely (? 1/10000 and <1 / 1000), very rarely (? 1/10000, including isolated cases). The absolute frequency of messages without taking into account the frequency when using a placebo is indicated. When data were available on individual adverse events from two studies (PURSUIT and ESPRIT), the highest indicated frequency was used to determine the frequency of adverse events. It should be noted that the connection with the use of the drug was not established for all adverse events. The frequency of serious adverse events not associated with bleeding (arterial hypotension, etc.) when using Eptifibatide does not differ from that when using placebo. Violations of the blood and lymphatic system Very often: bleeding (massive and light bleeding, including bleeding with coronary artery bypass grafting and access through the femoral artery, gastrointestinal bleeding, urogenital bleeding, retroperitoneal and intracranial hemorrhages, hemathemesis, hematuria, intraoral / oropharyngeal bleeding. bleeding that reduces hematocrit / hemoglobin and others). Infrequently: thrombocytopenia. Disorders of the nervous system Infrequently: cerebral ischemia. Heart disorders Often: cardiac arrest, ventricular fibrillation, ventricular tachycardia, congestive heart failure, atrioventricular block, atrial fibrillation. Vascular disorders Often: cardiogenic shock, arterial hypotension, phlebitis. Cardiac arrest, congestive heart failure, atrial fibrillation, arterial hypotension and cardiogenic shock, which were often reported in the PURSUIT study, were phenomena associated with the underlying disease. Post-registration observation data Blood and lymphatic disorders Very rare: fatal bleeding (mainly affecting the central and peripheral nervous system: hemorrhagic stroke or intracranial hemorrhage) pulmonary hemorrhage, acute deep thrombocytopenia, hematoma. Immune system disorders Very rare: anaphylactic reactions. Disorders of the skin and subcutaneous tissue Very rare: skin rash, adverse effects at the injection site (eg, urticaria). Drug Interactions Eptifibatide does not increase the risk of major and minor bleeding while using warfarin and dipyridamole. In patients having a prothrombin time of 14.5 seconds, receiving eptifibatide simultaneously with warfarin, there was no increased risk of bleeding. There is limited evidence for the use of eptifibatide in patients receiving thrombolytic drugs. There is no confirmed evidence that eptifibatide increases the risk of major and minor bleeding associated with tissue plasminogen activator in patients undergoing PTCA and in patients with acute myocardial infarction. However, in clinical studies, eptifibatide increased the risk of bleeding when given with streptokinase in patients with acute myocardial infarction. In a study of 181 patients with acute myocardial infarction, eptifibatide (bolus injection dose reached 180 mcg / kg, subsequent infusion – up to 2 mcg / kg / min for up to 72 hours) was administered simultaneously with streptokinase (1.5 million units for more than 60 minutes). At the maximum infusion rate (1.3 μg / kg / min and 2.0 μg / kg / min), the use of eptifibatide was associated with an increase in the frequency of bleeding cases and the need for transfusions compared with streptokinase monotherapy. In a clinical study in patients with acute myocardial infarction with ST-segment elevation, the combined use of a combination of reduced doses of tenecteplase and eptifibatide led to a significant increase in the risk of massive and light bleeding (compared with placebo and the use of eptifibatide without tenectoplase). Eptifibatide is not compatible with furosemide. In clinical trials, 95% of patients who underwent non-emergency PCI with intracoronary stenting were prescribed clopidogrel simultaneously with acetylsalicylic acid before or within 48 hours after PCI and daily after PCI. Special studies to study the pharmacokinetic interaction of eptifibatide with other drugs have not been conducted. During clinical trials, there was no pharmacokinetic interaction between eptifibatide and drugs commonly used in patients with cardiovascular diseases such as: amlodipine, atenolol, atropine, captopril, cefazolin, diazepam, digoxin, diltiazem, diphenhydramine, fentylidryl, enemlapri, enemlapri heparin, lidocaine, lisinopril, metoprolol, midazolam, morphine, nitrates, nifedipine, warfarin. Overdose of Information on overdose of eptifibatide is very limited. There is no evidence of serious adverse reactions associated with accidental overdose during jet or drip administration, or when the cumulative dose is exceeded. In a PURSUIT clinical trial, 9 patients were reported who received a bolus and / or infusion dose that was more than 2 times the recommended dose. Moreover, none of the patients had uncontrollable bleeding, one of the patients underwent coronary artery bypass grafting, and only moderate bleeding was observed in any patient, no intracranial bleeding was observed. Potentially an overdose of eptifibatide can cause bleeding. Due to the short half-life and high clearance, the effect of the drug can be quickly stopped by stopping the introduction. Storage conditions At a temperature of 2 to 8 ° C. Do not freeze. Keep out of the reach of children. Expiration 3 years. Deystvuyuschee substances ptyfybatyd
