INTEGRILIN

Active material: Eptifiʙatid
When ATH: B01AC16
CCF: Antiplatelet
ICD-10 codes (testimony): I20.0, I21, I74, I82
When CSF: 01.12.11.06.01
Manufacturer: GlaxoSmithKline Trading Company (Russia)

PHARMACEUTICAL FORM, COMPOSITION AND PACKAGING

The solution for the on / in the clear, colorless.

Excipients: citric acid monohydrate, Sodium hydroxide (to pH 5.25), water d / and.

10 ml – glass bottles (1) – packs cardboard.

The solution for the on / in the clear, colorless.

Excipients: citric acid monohydrate, Sodium hydroxide (to pH 5.25), water d / and.

100 ml – glass bottles (1) – packs cardboard.

Pharmacological action

antiplatelet agent, platelet aggregation inhibitor. Blocker glycoprotein IIb / IIIa platelet receptors. It is a synthetic cyclic heptapeptide, comprising 6 amino acids, and the remainder merkaptopropionilovy – dezaminocisteinil. It is an inhibitor of platelet aggregation, belonging to the class of arginine-glycine-aspartate-mimetics. Inhibits platelet aggregation, preventing the binding of fibrinogen, von Willebrand factor and other adhesive ligands to the glycoprotein IIb / IIIa platelet receptors.

The on / in the introduction eptifibatide causes inhibition of platelet aggregation ex vivo using adenosine diphosphate and other agonists, inducing platelet aggregation, the extent of which depends on the dose and drug concentration. eptifibatide effect is observed immediately after the on / in the introduction of a bolus dose 180 mg / kg. The on / in infusion at a dose of 2 ug / kg / min such mode provides more than 80% inhibition of platelet aggregation ex vivo, at physiological calcium concentrations, in more than 80% patients.

Inhibition of platelet aggregation is reversible; through 4 hours after cessation of infusion platelet function recovers more than 50% compared with baseline.

Eptifibatide has no appreciable effect on prothrombin time and activated partial thromboplastin time (APTT).

The greatest effect of the Integrilina expected in patients with a high risk of heart attack within the first miokarada 3-4 days after an attack of angina pectoris, including cases of percutaneous transluminal coronary angioplasty (PTCA).

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

Pharmacokinetics

Pharmacokinetics эptifibatida imeet lineynыy and dozozavisimыy character in struynom vvedenii in doze of 90 to 250 mg / kg and the infusion at a rate of 0.5 to 3 ug / kg / min.

Absorption and distribution

When drug infusion at a dose of 2 ug / kg / min eptifibatide mean concentration in the plasma is established within 1.5-2.2 .mu.g / ml in patients with coronary artery disease, then slightly lowered and reaches equilibrium values ​​for 4-6 no. C_max plasma is faster, if the infusion is preceded by a bolus dose of 180 mg / kg.

Degree of eptifibatide binding to human plasma proteins is approximately 25%. V_d – 185-260 ml / kg.

Metabolism and excretion

T_1/2 eptifibatide from plasma is approximately 2.5 no, clearance – 55-58 ml / kg / h. In healthy people, the proportion of renal clearance of total clearance is about 50%. Most of eptifibatide is excreted in the urine unchanged and as metabolites. In human plasma major metabolites are not found.

Testimony

- early prevention of myocardial infarction in patients with unstable angina or myocardial infarction without tooth Q, marks the latest bout of pain for 24 no, with ECG changes and / or increased activity of cardiac enzymes;

- prevention of the sudden closure of the vessel and its associated acute ischemic complications of percutaneous transluminal coronary angioplasty (PTCA).

Dosage regimen

Integrilin as a solution for injection should be used for schemes described below.

Adult patients (aged 18 and older) from unstable angina or myocardial infarction without zubza Q immediately after establishing the diagnosis preparation is administered in / bolus dose 180 mg / kg, then begin a continuous infusion at a rate 2 ug / kg / min (when serum creatinine concentration less 2 mg / dL) or 1 ug / kg / min (when serum creatinine concentration 2-4 mg / dL), which continued until 72 no, prior to coronary artery bypass surgery or before discharge into zavismosti of, whichever occurs first. If the patient starts to carry out PTCA, Integrilina the infusion continued for 20-24 hours after intervention (the maximum total duration of administration – 96 no). Patients with body weight more 121 kg, Integrilin administered as a bolus at a dose of not more than 22.6 mg, as an infusion – no more 15 mg / h (serum creatinine less 2 mg / dL) or 7.5 mg / h (sыvorotochnыy creatinine 2-4 mg / dL).

At conducting PTCA immediately prior to manipulation introducing drug / bolus at a dose of 180 mg / kg, then begin a continuous drip at a rate of the drug 2 ug / kg / min (serum creatinine less 2 mg / dL) or 1 ug / kg / min (sыvorotochnыy creatinine 2-4 mg / dL). Through 10 minutes after the first bolus is administered more 180 ug / kg bolus. The infusion was continued for 18-24 hours or until hospital discharge of the patient, if it occurs earlier. The minimum duration of administration – 12 no. Patients with body weight more 121 kg no more 22.6 Integrilina mg administered as a bolus and not more 15 mg / h (serum creatinine less 2 mg / dL) or 7.5 mg / h (sыvorotochnыy creatinine 2-4 mg / dL) – as an infusion.

Integrilina dose can be determined depending on the weight of the table body of the patient:

Patients with impaired renal function from unstable angina or myocardial infarction without zubza Q, requiring and not requiring PTCA, from mild renal impairment (KK ≥50 mL / min) Integrilin may be administered in standard doses. In patients with moderate kidney dysfunction (KK ≥30 mL / min and <50 ml / min) Integrilina dose infusion should be 1 ug / kg / min. Clinical data on the use of at Integrilina patients with severely impaired renal function (CC < 30 ml / min) and patients, hemodialysis, enough to apply the recommendations of the drug in these patients.

Doses of aspirin and heparin while the use of Integrilinom

At Acute Coronary Syndrome acetylsalicylic acid administered in an initial dose inside 160-325 mg, then daily in the same dose.

Heparin APTT to maintain within 50-70 s administered bolus, followed by infusion at the following doses:

If this is carried PTCA, bolus heparin is further added to maintain an activated clotting time (ABC) within 200-300 sec. After completion of PTCA heparin infusion is not recommended.

At conducting PTCA acetylsalicylic acid is administered orally at a dose 160-325 mg for 1-24 hours before PTCA and further continuously on a daily basis. Heparin was administered at the beginning as a bolus dose 60 U / kg, if the patient did not receive heparin during 6 hours before PTCA. To maintain within the FAA 200-300 sec additionally administered heparin in a bolus. After PTCA closure heparin infusion is not recommended.

Terms Integrilina injection solutions

Before administration Integrilina solution should be checked for turbidity or foreign particles; solution can be administered only in their absence. During the introduction of the solution protection from light is required.

Integrilin may be administered in a single system with alteplase, atropynom, dobutaminom, geparinom, lidokainom, meperidine, metoprolol, midazolamom, morphine, nitrogliцerinom, verapamil.

Integrilin should not be administered in a single system with furosemide.

Integrilin may be administered in a single system with 0.9% sodium chloride solution or a mixture with 5% dekstrozoy. When using any of these solvent-solution for administration may also contain up to 60 mmol / l potassium chloride. Incompatibility with materials, used for the manufacture of systems for on / in the, not mentioned.

For bolus Integrilina solution must dial into the syringe from the vial volume 10 ml and put in / jet during 1-2 m.

Immediately after the bolus injection should be started / drip infusion of the drug. In the presence of the pump, Allows you to adjust the infusion rate, formulation may be administered directly from the vial volume 100 ml, undiluted. The system for administration of vial Integrilina 100 ml should be air bleed; needle to connect the system to the vial should be administered strictly through the center of the vial stopper.

The residue of the drug in the vial is not subject to further use and must be poured.

Side effect

Most adverse reactions when used Integrilina associated with the development of bleeding, cardiovascular disorders.

Bleeding. When applying Integrilina small bleeding occur very often (>1/10) (13.1% – Integrilin, 7.6% – placebo). Small bleeding manifested spontaneous severe hematuria, spontaneous hematemesis, blood loss with a hemoglobin decrease of more than 3 g / dl or more than 4 g / dl in case of, when bleeding localization has not been determined. Bleeding episodes were more frequent in patients, receiving concurrent heparin during PTCA, while the activated clotting time exceeded 350 sec. Massive bleeding were also observed very often (>1/10), at the same time more often in the group Integrilina, than placebo (10.8% and 9.3%, respectively). Massive bleeding manifested intracranial hemorrhages, decrease in hemoglobin concentration of more than 5 g / dl. Cases of severe or life-threatening bleeding in the application often observed Integrilina (>1/100, <1/10) (1.9% – Integrilin, 1.1% – placebo). Integrilin slightly increases the need for blood transfusion (11.8 – Integrilin, 9.3% – placebo). In the subgroup of patients, undergoing PTCA, major bleeding occurred more frequently: in 9.7% and when applying Integrilina 4.6% placebo.

Thrombocytopenia. The ESPRIT study the incidence of thrombocytopenia (platelet count less 100 000/mm³ or reduce their number by 50% or more from baseline) made 1.2% against 0.6% placebo. In other studies, the frequency of thrombocytopenia was at the level of the placebo.

Other adverse effects. The frequency of serious adverse events, not associated with bleeding (hypotension), when applying Integrilina not differ from that with placebo. Often (>1/100, <1/10, We observed in ≥2% in all groups) there is a reaction, related to the underlying disease, such as atrial fibrillation, gipotenziya, congestive heart failure, cardiac arrest, shock, ventricular tachycardia / fibrillation.

According to, derived from post-marketing spontaneous reports, The following adverse reactions have been observed.

On the part of the coagulation system: rarely – fatal bleeding (mainly cerebral and intracranial bleeding), pneumorrhagia, Acute severe thrombocytopenia, hematoma, anemia.

On the part of the immune system: rarely – anaphylactic reactions.

Skin and subcutaneous fat: rarely – rash, injection site reactions, such as urticaria.

Changes in laboratory parameters It is a consequence of the known pharmacological properties Integrilina, eg, inhibition of platelet aggregation. Thus, changes in laboratory parameters, characterizing bleeding (eg, bleeding time), They occur frequently and are expected. There were no differences in rates, characterize the function of the liver (ACT, GOLD, bilirubin, Alkaline phosphatase) and kidney function (the concentration of plasma creatinine, residual urea nitrogen) when applying Integrilina and with placebo.

Contraindications

- Stomach or intestinal bleeding, severe genital and urological bleeding or other abnormal bleeding expressed in the last 30 days;

- acute ischemic stroke within the last 30 days or hemorrhagic stroke in history;

- intracranial disease (neoplaziâ, arteriovenous malformation, aneurysm);

- major surgery or severe trauma within past 6 weeks;

- hemorrhagic diathesis in history;

- Thrombocytopenia (<100 000/mm³);

- prothrombin time more 1.2 by controlling or MHO≥2;

- severe hypertension (systolic blood pressure higher 200 mm Hg. Article. or diastolic HELL above 110 mm Hg. Art.) antihypertensive therapy;

- Severe renal insufficiency (CC <30 ml / min) or the need for dialysis;

- clinically significant hepatic impairment;

- simultaneous or application of another scheduled inhibitor IIb / IIIa platelet receptors for parenteral administration;

- Hypersensitivity to any component of the drug.

Observe caution while applying Integrilina with other drugs, affecting hemostasis (thrombolytics, oral anticoagulants, dekstranom, adenozinom, NSAIDs / including sulfinpirazon /; preparations, containing prostacyclin; dipiridamol; ticlopidine and clopidogrel).

The risk of bleeding when combined appointment Integrilina and streptokinase, used for the treatment of acute myocardial infarction, increases.

The use of heparin is recommended in all cases, in the absence of contraindications to its use, eg, thrombocytopenia, associated with heparin reception history.

Integrilina not recommended to use simultaneously with the low molecular weight heparin in the absence of clinical experience.

Previous applications Integrilina in patients with impaired liver function is very limited, in connection with Integrilin than such patients should be administered with caution.

In patients with moderate renal impairment (CC ≥ 30 ml / min < 50 ml / min) Integrilina clearance is reduced by about 50%, and its plasma concentrations are doubled, respectively,. Insufficient data to recommend the use of Integrilina in patients with severely impaired renal function (CC < 30 ml / min) and patients, hemodialysis.

Safety and effectiveness of Integrilina in children under the age of 18 s is not installed, therefore the use in these patients is not recommended.

Pregnancy and lactation

There is no adequate data on the use Integrilina in pregnant women.

Animal studies are not considered sufficient to judge the impact of a pregnancy Integrilina, embryonic development, birth or postnatal development. The potential risk for humans has not been studied. Integrilin should not be used during pregnancy, except in cases of emergency.

Information about, whether Integrilin passes into breast milk, no. It is recommended to stop breast-feeding when used Integrilina.

Cautions

Integrilin is intended for use only in a hospital.

Integrilin is an antithrombotic agent, overwhelming platelet aggregation; Therefore, all patients should be evaluated for possible bleeding, especially women, Elderly patients, as well as patients with low body weight.

The risk of bleeding is greatest at the site of arterial access in patients, undergoing PTCA. It is necessary to carefully monitor the possible bleeding places (incl. catheter site). It should be borne in mind the possibility of bleeding from the gastrointestinal tract and urinary tract, and retroperitoneal bleeding.

If during treatment Integrilinom situation arises, requiring thrombolytic therapy or of urgent coronary artery bypass grafting or intraaortic balloon counterpulsation, Integrilin is an urgent need to cancel.

If during treatment Integrilinom a need for emergency surgery, drug infusion should be stopped immediately. If the patient requires a planned surgery, infusion should be stopped in advance, to platelet function was restored to normal.

During the period of Integrilina necessary to limit the holding of arterial and venous punctures, i / m injection, and the use of urinary catheters, endotracheal tubes and nasogastric tubes. For I / O access, do not use a vein, not subject to compression (subclavian, jugular).

If serious bleeding occurs when the application Integrilina, which can not be stopped by applying a pressure bandage, should immediately stop the introduction of both Integrilina, and other unfractionated heparins.

In applying Integrilina bleeding risk is greatest at the site of the catheter into the femoral artery during PTCA. Caution is advised to carry out a puncture of the femoral artery, and make sure, that punctured only by its front wall. Introducer of the femoral artery can be removed after the restore function to normal coagulation (activated clotting time – less 180 sec, usually via 2-6 hours after withdrawal of heparin). After removal of the introducer sheath should be carried out, followed by thorough hemostasis supervision until hospital discharge.

Integrilin inhibits platelet aggregation, but it does not affect their viability. In appointing Integrilina cases of thrombocytopenia have been observed, including acute severe thrombocytopenia. Clinical studies have shown, that the incidence of thrombocytopenia was low and similar to that in patients, placebo. Platelet count should be monitored over a 6-hour period after initiation of Integrilina, and, further, no less 1 times / day throughout the treatment time, and immediately, in the event of signs of the trend in the development of unexpected bleeding. If the patient has decreased platelet counts below 100 000/mm³, the introduction Integrilina and unfractionated heparin should be discontinued and carry out the necessary remedial measures. A decision on the need for platelet transfusions should be based on clinical judgment, individually for each case. If the patient has a history of thrombocytopenia were cases when other parenteral inhibitors of glycoprotein IIb / IIIa platelet receptors, it should be particularly careful observation.

For patients with unstable angina or myocardial infarction without tooth Q body weight >70kg bolus dose is recommended 5000 ED, subsequent continuous infusion 1000 U / h. For patients weighing less than 70 kg bolus dose of 60 U / kg, subsequent infusion 12 ED / kg / h. APTT should be monitored until the values 50-70 sec, tk. when the APTT values ​​more 70 sec may increase the risk of bleeding.

With the introduction of Integrilina possible reversible 5-fold increase in bleeding time, This indicator returns to its original level within 2-6 h after the cessation of drug administration.

During the PTCA patients with unstable angina or myocardial infarction without tooth Q necessary to monitor the activated clotting time (its value should be within 300-350 sec). If exceeded, the activated clotting time 300 sec, heparin should be stopped and did not reopen until at least reduce the value 300 sec. Before the application Integrilina to detect possible violations of hemostasis is recommended that the definition of prothrombin time, APTT, serum creatinine concentration, platelet count, Hemoglobin, gematokrita. The last three indicators should be continuously monitored for 6 hours after the start of therapy, then at least 1 time / day throughout treatment (or more frequently if indicators of decline). By reducing the number of platelets below 100 000/mm³ should be retested to exclude pseudothrombocytopenia; heparin should be discontinued. In carrying out PTCA must also define the activated clotting time.

The immune response / development of antibodies to Intergrilinu observed in rare cases when the primary purpose and rarely – when re-appointment of the drug. There is limited experience reappointment Integrilina. In the event of a resumption of treatment Integrilinom not expected to reduce the therapeutic effect.

Effects on ability to drive vehicles and management mechanisms

Integrilin is intended for use in a hospital environment. No data on cases of Integrilina outpatients.

Overdose

Information on overdose is very limited Integrilina. Information about serious violations, associated with accidental overdose with inkjet or drip, and when exceeding cumulative doses, no.

reported 9 patients, that in a clinical study PURSUIT received a bolus dose and / or dose infusion, more than 2 times higher than the recommended. When this was not observed severe bleeding, none of the patients; one patient was performed coronary artery bypass grafting, and he has only a moderate bleeding observed; no patient was observed intracranial bleeding.

Potentially, an overdose can cause bleeding Integrilina.

Treatment: as eptifibatide has a short T_1/2 and high ground clearance, effect of the drug can be stopped quickly by cessation of.

Drug Interactions

Integrilin does not increase the risk of major and minor bleeding while the use of warfarin and dipyridamole. Patients, relevant prothrombin time 14.5 sec, receiving Integrilin concurrently with warfarin, not indicated an increased risk of bleeding.

There are limited data in patients use Integrilina, receiving thrombolytic agents. There is no confirmed data, testifying, that Integrilin increased the risk of large and small bleeding, associated with tissue plasminogen activator in patients, undergoing PTCA, and in patients with acute myocardial infarction. But, in clinical studies, Integrilin increased the risk of bleeding in the appointment with streptokinase in patients with acute myocardial infarction. In a study of 181 patients with acute myocardial infarction Integrilin (bolus dose reached 180 mg / kg, subsequent infusion – to 2 ug / kg / min to 72 no) administered simultaneously with streptokinase (1.5 million units more 60 m). In case the maximum rate of infusion (1.3 ug / kg / min, and 2 ug / kg / min) Integrilina application associated with increased incidence of bleeding and the need for transfusions, compared to a monotherapy streptokinase.

Special studies of pharmacokinetic interaction Integrilina with other drugs has not been. In clinical studies found no pharmacokinetic interaction between Integrilinom and such are often used in patients with cardiovascular disease drugs, how amlodipine, atenolol, atropyn, captopril, tsefazolyn, diazepam, Digoxin, diltiazem, difengidramin, Enalapril, Fentanyl, furosemid, Heparin, lidokain, Lisinopril, metoprolol, midazolam, morphine, nitrates, nifedipine, warfarin.

Conditions of supply of pharmacies

The drug is released under the prescription.

Conditions and terms

The preparation should be stored in their original packaging in a dark place at a temperature of from 2 ° to 8 ° C.. Keep out of the reach of children. Shelf life – 3 year.