Integrilin

General characteristics. Structure:

Solution for in/in introductions transparent, colourless.

Active ingredient: эптифибатид 2 mg 20 mg

Excipients: citric acid monohydrate, sodium hydroxide (to рН 5.25), water for and.

Solution for in/in introductions transparent, colourless.

Active ingredient: эптифибатид 750 mkg 75 mg

Excipients: citric acid monohydrate, sodium hydroxide (to рН 5.25), water for and.

Pharmacological properties:

Antiagregantny drug, inhibitor of aggregation of thrombocytes. Blocker of glycoprotein IIb/IIIa of receptors of thrombocytes. Represents the synthetic cyclic heptapeptide containing 6 amino acids and the merkaptopropionilovy rest - dezaminotsisteinit. Is the inhibitor of aggregation of thrombocytes belonging to a class arginine-glycine-aspartate-mimetikov. Suppresses aggregation of thrombocytes, preventing linkng of fibrinogen, Villebrand's factor and other adhesive ligands with glycoprotein IIb/IIIa receptors of thrombocytes.

At in introduction эптифибатид causes suppression of aggregation of thrombocytes of ex vivo with use adenosine of diphosphate and other agonists inducing aggregation of thrombocytes which degree depends on a dose and concentration of drug. The effect of an eptifibatid is observed immediately later in/in introductions in a bolyusny dose of 180 mkg/kg. At in/in infusion in a dose of 2 mkg/kg/min. such mode will provide more than 80% of inhibition of aggregation of thrombocytes of ex vivo, at physiological concentration of calcium, at more than 80% of patients.

The inhibition of aggregation of thrombocytes is reversible; in 4 h after the infusion termination function of thrombocytes is recovered more than for 50% in comparison with initial level.

Eptifibatid does not exert noticeable impact on a prothrombin time and the activated partial tromboplastinovy time (APTT).

The greatest effect of Integrilin's use is expected at patients with high risk of development of a heart attack of a miokarad during the first 3-4 days after a stenocardia attack, including cases of performing the transdermal transluminal coronary angioplasty (TTCA).

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

Pharmacokinetics. The pharmacokinetics of an eptifibatid has linear and dozozavisimy character at jet introduction in a dose from 90 to 250 mkg/kg and infusion with a speed from 0.5 to 3 mkg/kg/min.

Absorption and distribution

At infusion of drug in a dose of 2 mkg/kg/min. average concentration of an eptifibatid in plasma is established within 1.5-2.2 mkg/ml at patients with diseases of coronary arteries, then decreases a little and reaches equilibrium values during 4-6 h Cmax in plasma is reached quicker if infusion is preceded by bolyusny introduction in a dose of 180 mkg/kg.

Extent of linkng of an eptifibatid with proteins of plasma of the person makes about 25%. Vd - 185-260 ml/kg.

Metabolism and removal

T1/2 of an eptifibatid makes of plasma about 2.5 h, clearance - 55-58 ml/kg/h. At healthy people the share of renal clearance from the general clearance makes about 50%. The most part of an eptifibatid is removed with urine in not changed look and in the form of metabolites. In plasma of the person the main metabolites are not found.

Indications to use:

— early prevention of a myocardial infarction at patients with unstable stenocardia or a myocardial infarction without tooth of Q noting the last painful attack during 24 h with changes on an ECG and/or increase in activity of cardiospecific enzymes;

— prevention of sudden closing of a vessel and the acute ischemic complications interfaced to it when performing the transdermal transluminal coronary angioplasty (TTCA).

Route of administration and doses:

Integrilin in the form of solution has to be applied to injections according to the schemes described below.

To adult patients (at the age of 18 years is also more senior) with unstable stenocardia or a myocardial infarction without Q tooth at once after establishment of the diagnosis the drug is administered in/in struyno in a dose of 180 mkg/kg, then begin continuous infusion with a speed of 2 mkg/kg/min. (at concentration of serumal creatinine less than 2 mg/dl) or 1 mkg/kg/min. (at concentration of serumal creatinine of 2-4 mg/dl) which is continued to 72 h, prior to operation of aortocoronary shunting or to an extract from a hospital in a zavismost from what occurs earlier. If at the same time to the patient begin to carry out ChTKA, then continue Integrilin's infusion during 20-24 h after intervention (the maximum general duration of introduction - 96 h). The patient with body weight more than 121 kg, Integrilin enter in the form of a bolus in a dose no more than 22.6 mg, in the form of infusion - no more than 15 mg/h (serumal creatinine less than 2 mg/dl) or 7.5 mg/h (serumal creatinine of 2-4 mg/dl).

When carrying out ChTKA just before the beginning of manipulation the drug is administered in/in struyno in a dose of 180 mkg/kg, then begin continuous drop administration of drug with a speed of 2 mkg/kg/min. (serumal creatinine less than 2 mg/dl) or 1 mkg/kg/min. (serumal creatinine of 2-4 mg/dl). In 10 min. after the first bolus enter 180 more mkg/kg in the form of a bolus. Infusion is continued during 18-24 h or to the patient's extract from a hospital if it occurs earlier. The minimum duration of administration of drug - 12 h. The patient with body weight more than 121 kg no more than 22.6 mg of Integrilin enter in the form of a bolus and no more than 15 mg/h (serumal creatinine less than 2 mg/dl) or 7.5 mg/h (serumal creatinine of 2-4 mg/dl) - in the form of infusion.

Integrilin's dose can be determined depending on the body weight of the patient by the following table:
 
Body weight        Bolus of 180 mkg/kg         Infusion of 2 mkg/kg/min.    Infusion of 1 mkg/kg/min.
patient (kg)    (bottle of 20 mg / 10 ml)  (bottle of 75 mg / 100 ml)   (bottle of 75 mg / 100 ml)
                         37-41 3.4                                                 ml 6 ml/h 3 ml/h
42-46                            4                                                 ml 7 ml/h 3.5 ml/h
                          47-53 4.5                                                  ml 8 ml/h 4 ml/h
54-59                            5                                                  ml 9 ml/h 4.5 ml/h
                         60-65 5.6                                               ml 10 ml/h 5 ml/h
                         66-71 6.2                                               ml 11 ml/h 5.5 ml/h
                         72-78 6.8                                               ml 12 ml/h 6 ml/h
                         79-84 7.3                                               ml 13 ml/h 6.5 ml/h
                         85-90 7.9                                                 ml 14 ml/h 7 ml/h
                          91-96 8.5                                                ml 15 ml/h 7.5 ml/h
97-103                          9                                                 ml 16 ml/h 8 ml/h
                      104-109 9.5                                               ml 17 ml/h 8.5 ml/h
110-115                     10.2                                              ml 18 ml/h 9 ml/h
116-121                     10.7                                              ml 19 ml/h 9.5 ml/h
more than 121                  11.3                                                ml 20 ml/h 10 ml/h

Patients with a renal failure with unstable stenocardia or the myocardial infarction without Q tooth which is demanding and not demanding ChTKA with easy renal failures (KK of ≥50 ml/min.) Integrilin can be appointed in standard doses. At patients with moderate renal failures (KK of ≥30 ml/min. and <50 ml/min.) Integrilin's dose for infusion has to make 1 mkg/kg/min. Clinical data concerning Integrilin's use for patients with heavy renal failures (KK <30 ml/min.) and the patients who are on a hemodialysis is not enough for the recommendation of use of drug for this category of patients.

Doses of acetylsalicylic acid and heparin at simultaneous use with Integrilin

At an acute coronary syndrome acetylsalicylic acid is appointed inside in an initial dose of 160-325 mg, then daily in the same dose.

Heparin for maintenance of AChTV within 50-70 sec. is entered a bolus, and then in the form of infusion in the following doses:

The body weight          of the patient Doz at introduction          by Doz's bolus at introduction in the form of infusion
more than 70                                                                         kg 5000 PIECES 1000 PIECES/h
less than 70                                                                         kg 60 PIECES/kg 12 PIECES/kg/h

If at the same time ChTKA is carried out, in addition enter heparin a bolus for maintenance of the activated coagulation time (ACT) within 200-300 sec. After end of ChTKA infusion of heparin is not recommended.

When carrying out ChTKA acetylsalicylic acid is appointed inside in a dose of 160-325 mg for 1-24 h prior to the beginning of ChTKA and further it is daily constant. Heparin enter at the beginning in the form of a bolus in a dose 60 PIECES/kg if the patient did not receive heparin during 6 h prior to the beginning of ChTKA. For maintenance of AVS within 200-300 sec. in addition enter heparin in the form of a bolus. After the termination ChTKA infusion of heparin is not recommended.

Rules of administration of solutions of Integrilin

Before introduction Integrilin's solution should be checked for existence of opacification or foreign particles; solution can be entered only at their absence. During introduction of protection of solution against light it is not required.

Integrilin it is possible to enter in one system with alteplazy, atropine, Dobutaminum, heparin, lidocaine, Meperidinum, metoprololy, midazolam, morphine, nitroglycerine, verapamil.

Integrilin it is impossible to enter in one system with furosemide.

Integrilin it is possible to enter in one system from 0.9% solution of sodium of chloride or its mix from 5% a dextrose. When using any of these solvents solution for introduction may contain also up to 60 mmol/l of potassium of chloride. Incompatibility with the materials used for production of systems for in/in introductions was not noted.

For bolyusny introduction Integrilin's solution should be gathered in the syringe from a bottle of 10 ml and to enter in/in struyno within 1-2 min.

Right after bolyusny introduction it is necessary to begin in/in drop infusion of drug. In the presence of the pump allowing to regulate infusion speed, the drug can be administered directly from a bottle of 100 ml, without diluting. In system for Integrilin's introduction from a bottle of 100 ml there has to be an air offtake; the needle for connection of system to a bottle should be entered strictly through the center of a stopper of a bottle.

The drug rest in a bottle is not subject to further use and it needs to be poured out.

Features of use:

Integrilin is intended for use only in the conditions of a hospital.

Bleedings

Integrilin is the antitrombotichesky means suppressing aggregation of thrombocytes; therefore all patients have to be carefully inspected for detection of possible bleedings, especially women, patients of advanced age, and also patients with low body weight.

The risk of bleeding is most high in the place of arterial access at patients to whom ChTKA is carried out. It is necessary to control carefully places of possible bleeding (including places of input of a catheter). It must be kept in mind a possibility of bleeding from a GIT and urinogenital ways, and also retroperitoneal bleedings.

If during treatment by Integrilin there is a situation demanding thrombolytic therapy or performing urgent aortocoronary shunting or intra aortal balloon counterpulsation, Integrilin it is necessary to cancel urgently.

If during treatment by Integrilin there is a need for urgent surgical intervention, infusion of drug should be stopped immediately. If the patient needs planned surgical intervention, infusion of drug should be stopped beforehand that function of thrombocytes was recovered to norm.

During Integrilin's use it is necessary to limit carrying out arterial and venous punctures, injections in oil, and also use of uric catheters, endotracheal tubes and nazogastralny probes. For in/in access it is not necessary to use the veins which are not subject to a compression (subclavial, jugular).

If at Integrilin's use there is serious bleeding which does not manage to be stopped by imposing of a compressing bandage, it is necessary to stop immediately introduction both Integrilin, and other unfractionated heparins.

Control over access to a femoral artery

At Integrilin's use the risk of bleeding is most high in a catheter injection site in a femoral artery when carrying out ChTKA. It is necessary to carry out a puncture of a femoral artery with care and to be convinced that a punktirovana only its front wall. Introdyyuser it is possible to remove from a femoral artery after recovery of coagulative function to norm (the activated blood clotting time - less than 180 sec., usually in 2-6 h after heparin cancellation). After removal of an introdyyuser it is necessary to carry out a hemostasis with the subsequent careful observation to an extract from a hospital.

Thrombocytopenia

Integrilin suppresses aggregation of thrombocytes, but does not influence their viability. At Integrilin's appointment thrombocytopenia cases, including acute heavy thrombocytopenia were observed. In clinical trials it was shown that the patients receiving placebo had a low frequency of development of thrombocytopenia and similar to that. It is necessary to monitorirovat quantity of thrombocytes during the 6-hour period after the beginning of use of Integrilin, and, further, not less than 1 throughout all time treatments, and also immediately, in case of signs of a tendency to development of unexpected bleeding. If at the patient decrease in quantity of thrombocytes lower than 100 000/mm3 is noted, then Integrilin's introduction and unfractionated heparin it is necessary to stop and carry out necessary medical actions. The decision on need of a transfusion of thrombocytes has to be based on clinical assessment, individually for each case. If at the patient in the anamnesis thrombocytopenia cases at use of other parenteral inhibitors of glycoprotein IIb/IIIa of receptors of thrombocytes were noted, then especially careful observation is necessary.

Patients with unstable stenocardia or a myocardial infarction without Q tooth

For patients with unstable stenocardia or a myocardial infarction without Q tooth with body weight more than 70 kg the recommended bolyusny dose makes 5000 PIECES, the subsequent continuous infusion of 1000 PIECES/h. For patients with body weight less than 70 kg the bolyusny dose makes 60 PIECES/kg, the subsequent infusion of 12 PIECES/kg/h of AChTV 50-70 sec. since at achievement of AChTV values more than 70 sec. the risk of bleeding can increase have to monitorirovatsya before achievement of values.

Increase in a bleeding time

At Integrilin's introduction perhaps reversible 5-fold increase in a bleeding time, this indicator is returned to initial level during 2-6 h after the termination of administration of drug.

Monitoring of laboratory indicators

When carrying out ChTKA at patients with unstable stenocardia or a myocardial infarction without tooth of Q it is necessary to control the activated blood clotting time (its values have to be within 300-350 sec.). At exceeding of value of the activated blood clotting time 300 sec., use of heparin it is necessary to stop and not to renew less than 300 sec. before decrease in value. Prior to Integrilin's use for identification of possible disturbances of a hemostasis definition of a prothrombin time, AChTV, concentration of creatinine in serum, numbers of thrombocytes, hemoglobin, a hematocrit is recommended. The last three indicators should be monitorirovat continuously during 6 h after the beginning of therapy, then at least 1 times / throughout therapy (or is more often in case of decrease in indicators). At decrease in number of thrombocytes lower than 100 000/mm3 it is necessary to carry out retests for a pseudo-thrombocytopenia exception; administration of heparin should be stopped. When carrying out ChTKA also definition of the activated blood clotting time is necessary.

Immunogenicity

The immune answer / development of antibodies to Intergrilin were observed in isolated cases at primary appointment and it is rare - at repeated purpose of drug. There is a limited experience of repeated appointment of Integrilin. In cases of resuming of treatment by Integrilin reduction of therapeutic effect is not expected.

Influence on ability to driving of motor transport and to control of mechanisms

Integrilin is intended for use in the conditions of a hospital. There are no data on cases of use of Integrilin for ambulatory patients.

Side effects:

The majority of undesirable reactions at Integrilin's use are connected with development of bleedings, cardiovascular disturbances.

Bleedings. At Integrilin's use small bleedings are observed very often (> 1/10) (13.1% - Integrilin, 7.6% - placebo). Small bleedings were shown by the spontaneous expressed hamaturia, a spontaneous hematemesis, a loss of blood with decrease in hemoglobin more than on 3 g/dl or more than on 4 g/dl in case localization of bleeding was not defined. Cases of bleeding were observed more often at the patients receiving at the same time heparin when carrying out ChTKA, at the same time the activated blood clotting time exceeded 350 sec. Massive bleedings were observed also very often (> 1/10), thus is more often in Integrilin's group, than in group of placebo (10.8% and 9.3%, respectively). Massive bleedings were shown by intracraneal hemorrhages, decrease in concentration of hemoglobin more than on 5 g/dl. Cases of development of heavy or zhizneugrozhayushchy bleedings at Integrilin's use were observed often (> 1/100, <1/10) (1.9% - Integrilin, 1.1% - placebo). Integrilin increases the need for a hemotransfusion a little (11.8 - Integrilin, 9.3% - placebo). In subgroup of the patients who transferred ChTKA, big bleedings were observed more often: in 9.7% at Integrilin's use and 4.6% in group of placebo.

Thrombocytopenia. In the research ESPRIT the frequency of cases of thrombocytopenia (number of thrombocytes less than 100 000/mm3 or decrease in their number by 50% and more from initial level) made 1.2% against 0.6% in group of placebo. In other researches the frequency of thrombocytopenia was at the level of placebo.

Other undesirable phenomena. Frequency of the serious undesirable phenomena which are not connected with bleeding (arterial hypotonia) at Integrilin's use does not differ from that at placebo use. Often (> 1/100, <1/10, were observed at ≥2% in all groups) there were reactions connected with a basic disease such as fibrillation of auricles, hypotension, congestive heart failure, cardiac standstill, shock, ventricular tachycardia / fibrillation.

According to the data obtained from post-marketing spontaneous messages the following undesirable reactions were observed.

From system of coagulation: very seldom - fatal bleeding (generally cerebral and intracranial bleedings), pulmonary bleeding, acute heavy thrombocytopenia, a hematoma, anemia.

From immune system: very seldom - anaphylactic reactions.

From skin and a hypodermic fatty tissue: very seldom - rash, reactions in an injection site, such as small tortoiseshell.

Changes of laboratory indicators is a consequence of the known pharmacological properties of Integrilin, for example, of inhibition of aggregation of thrombocytes. Thus, changes of the laboratory indicators characterizing bleeding (for example, a bleeding time), are observed often and are expected. There were no distinctions in the indicators characterizing function of a liver (ACT, ALT, bilirubin, ShchF) and function of kidneys (concentration of creatinine in plasma, residual nitrogen of urea) at Integrilin's use and at placebo use.

Interaction with other medicines:

Integrilin does not cause increase in risk of big and small bleedings at simultaneous use with warfarin and Dipiridamolum. At the patients important a prothrombin time 14.5 sec., receiving Integrilin along with warfarin increase in risk of development of bleedings was not noted.

The patients receiving thrombolytic drugs have limited these uses of Integrilin. There are no confirmed data testimonial of the fact that Integrilin increases risks of development of the big and small bleedings connected with a fabric plasminogen activator as at the patients who are exposed to ChTKA and at patients with an acute myocardial infarction. However, in clinical trials Integrilin increased risks of bleedings at appointment with Streptokinasa at patients with an acute myocardial infarction. In a research with participation of 181 patients with an acute myocardial infarction Integrilin (the dose of a bolyusny injection reached 180 mkg/kg, the subsequent infusion - to 2 mkg/kg/min. to 72 h) was appointed at the same time with Streptokinasa (1.5 mln units there are more than 60 min.). In case of the maximum speed of infusion (1.3 mkg/kg/min. and 2 mkg/kg/min.) Integrilin's use was associated with increase in frequency of cases of bleeding and the need for transfusions in comparison with monotherapy by Streptokinasa.

Special researches on studying of pharmacokinetic interaction of Integrilin with other drugs were not conducted. At conduct of clinical trials pharmacokinetic interaction between Integrilin and such drugs which are often used at patients by cardiovascular diseases as амлодипин, атенолол, atropine, captopril, cefazolin, diazepam, digoxin, diltiazem, дифенгидрамин, enalapril, fentanyl, furosemide, heparin, lidocaine, lisinopril, метопролол, midazolam, morphine, nitrates, nifedipine, warfarin was not revealed.

Contraindications:

— gastric or intestinal bleedings, serious genital and urological bleedings or other expressed pathological bleedings during the last 30 days;

— an acute disorder of cerebral circulation during the last 30 days or a hemorrhagic stroke in the anamnesis;

— intracranial diseases (neoplasia, arteriovenous malformation, aneurism);

— big surgical intervention or a severe injury within the last 6 weeks;

— hemorrhagic diathesis in the anamnesis;

— thrombocytopenia (<100 000/mm3);

— a prothrombin time more than 1.2 from control or MHO≥2;

— the expressed arterial hypertension (systolic the ABP is higher than 200 mm hg or diastolic the ABP is higher than 110 mm hg) against the background of anti-hypertensive therapy;

— renal failure of heavy degree (KK <30 ml/min.) or need of carrying out hemodialysis;

— clinically significant liver failure;

— the simultaneous or planned use of other IIb/IIIa inhibitor of receptors of thrombocytes for parenteral administration;

— hypersensitivity to any of drug components.

It is necessary to be careful at simultaneous use of Integrilin with other drugs influencing system of a hemostasis (trombolitikam, peroral anticoagulants, a dextran, adenosine, NPVS / including Sulfinpyrazonum/; the drugs containing prostacyclin; Dipiridamolum; тиклопидин also klopidogret).

The risk of developing of bleedings at a combination Integrilin's appointment and Streptokinasas used for treatment of an acute myocardial infarction increases.

Use of heparin is recommended in all cases, in the absence of contraindications to its use, for example, to the thrombocytopenia associated with reception of heparin in the anamnesis.

Integrilin's use along with low-molecular heparin due to the lack of clinical experience is not recommended.

Experience of use of Integrilin for patients with an abnormal liver function is very limited in this connection Integrilin such patients should appoint with care.

At patients with moderate renal failures (KK ≥ 30 ml/min. and <50 ml/min.) Integrilin's clearance decreases approximately by 50%, and its concentration in plasma respectively increase twice. There are not enough data for the recommendation of use of Integrilin for patients with heavy renal failures (KK <30 ml/min.) and the patients who are on a hemodialysis.

Safety and efficiency of use of Integrilin for children aged up to 18 years is not established in this connection use for this category of patients is not recommended.

 

Use of drug INTEGRILIN at pregnancy and feeding by a breast

There are no adequate data on Integrilin's use for pregnant women.

Researches on animals are not considered sufficient for judgment of Integrilin's influence on pregnancy, embryonic development, childbirth or post-natal development. The potential risk for the person is not studied. Integrilin should not be applied during pregnancy, except for emergency cases.

Data on whether Integrilin gets into breast milk, no. It is recommended to stop breastfeeding at Integrilin's use.

Use at abnormal liver functions
Experience of use of Integrilin for patients with an abnormal liver function is very limited in this connection Integrilin such patients should appoint with care.

Use at renal failures
Patients with a renal failure with unstable stenocardia or a myocardial infarction without tooth Oh, the demanding and not demanding ChTKA, with easy renal failures (KK of ≥50 ml/min.) Integrilin can be appointed in standard doses. At patients with moderate renal failures (KK of ≥30 ml/min. and <50 ml/min.) Integrilin's dose for infusion has to make 1 mkg/kg/min. Clinical data concerning Integrilin's use for patients with heavy renal failures (KK <30 ml/min.) and the patients who are on a hemodialysis is not enough for the recommendation of use of drug for this category of patients.

Use for children
Safety and efficiency of use of Integrilin for children aged up to 18 years is not established in this connection use for this category of patients is not recommended.

Overdose:

Information on Integrilin's overdose is very limited. Data on the serious violations connected with accidental overdose at jet or drop introduction, and also at exceeding of a cumulative dose no.

It was reported about 9 patients who within clinical trial of PURSUIT received the bolyusny dose and/or an infusional dose which more than twice exceeded recommended. At the same time it was observed the stopped bleedings at one of patients; to one patient aortocoronary shunting was carried out, and it observed only moderate bleeding; at one patient intracranial bleedings were not observed.

Potentially Integrilin's overdose can cause bleeding.

Treatment: as эптифибатид it is characterized by short T1/2 and high clearance, effect of drug can be quickly stopped by the introduction termination.

Storage conditions:

It is necessary to store drug in original packaging in the place protected from light at a temperature from 2 ° to 8 °C. To store in the place, unavailable to children. A period of validity - 3 years.

Issue conditions:

According to the recipe

Packaging:

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

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