PHARMACEUTICAL FORM, COMPOSITION AND PACKAGING

The solution for injection is clear, colorless to pale yellow.

1 syringe
enoxaparin sodium 2000 anti-Xa ME

0.2 ml - syringes (2) - blisters (1) - cardboard packs.
0.2 ml - syringes (2) - blisters (5) - cardboard packs.

PHARMACHOLOGIC EFFECT

The preparation of low molecular weight heparin (molecular weight about 4500 daltons). It is characterized by high activity against coagulation factor Xa (anti-Xa activity of about 100 IU / ml) and low activity against coagulation factor IIa (anti-IIa or antithrombin activity of about 28 IU / ml).

When using the drug in prophylactic doses, it slightly changes the activated partial thromboplastin time (APTT), has virtually no effect on platelet aggregation and on the level of fibrinogen binding to platelet receptors.

Plasma anti-IIa activity is approximately 10 times lower than anti-Xa activity. The average maximum anti-IIa activity is observed approximately 3-4 hours after s / c injection and reaches 0.13 IU / ml and 0.19 IU / ml after repeated administration of 1 mg / kg body weight with a double injection and 1.5 mg / kg body weight with a single dose introduction, respectively.

The average maximum plasma anti-Xa activity is observed 3-5 hours after s / c administration of the drug and is approximately 0.2, 0.4, 1.0 and 1.3 anti-Xa IU / ml after s / c administration of 20, 40 mg and 1 mg / kg and 1.5 mg/kg, respectively.

PHARMACOKINETICS

The pharmacokinetics of enoxaparin in these dosing regimens is linear.

Suction and distribution

After repeated s / c injections of enoxaparin sodium at a dose of 40 mg and at a dose of 1.5 mg / kg of body weight 1 time / day in healthy volunteers, Css is achieved by day 2, and AUC is on average 15% higher than after a single injection. After repeated s / c injections of enoxaparin sodium at a daily dose of 1 mg / kg of body weight 2 times / day, Css is achieved after 3-4 days, and AUC is on average 65% higher than after a single injection and the average values ​​​​of Cmax are 1.2 IU, respectively /ml and 0.52 IU/ml.

The bioavailability of enoxaparin sodium with s / c administration, estimated on the basis of anti-Xa activity, is close to 100%. Vd of enoxaparin sodium (according to anti-Xa activity) is approximately 5 liters and approaches the volume of blood.

Metabolism

Enoxaparin sodium is mainly biotransformed in the liver by desulfation and/or depolymerization to form inactive metabolites.

breeding

Enoxaparin sodium is a low clearance drug. After intravenous administration for 6 hours at a dose of 1.5 mg/kg of body weight, the average clearance of anti-Xa in plasma is 0.74 l/h.

Excretion of the drug is monophasic. T1 / 2 is 4 hours (after a single s / c injection) and 7 hours (after repeated administration of the drug). 40% of the administered dose is excreted in the urine, with 10% unchanged.

Pharmacokinetics in special clinical situations

There may be a delay in the excretion of enoxaparin sodium in elderly patients as a result of a decrease in renal function.

In patients with impaired renal function, there is a decrease in the clearance of enoxaparin sodium. In patients with minor (CC 50-80 ml / min) and moderate (CC 30-50 ml / min) impaired renal function after repeated s / c administration of 40 mg of enoxaparin sodium 1 time / day, there is an increase in anti-Xa activity, represented by AUC . In patients with severe renal impairment (CC less than 30 ml / min), with repeated subcutaneous administration of the drug at a dose of 40 mg 1 time / day, AUC in the equilibrium state is on average 65% higher.

In overweight patients with s / c administration of the drug, the clearance is somewhat less.

INDICATIONS

Prevention of venous thrombosis and thromboembolism, especially in orthopedics and general surgery;

Prevention of venous thrombosis and thromboembolism in patients with acute therapeutic diseases who are on bed rest (chronic heart failure III or IV functional class according to the NYHA classification, acute respiratory failure, acute infection, acute rheumatic diseases in combination with one of the risk factors for venous thrombosis);

Treatment of deep vein thrombosis with or without pulmonary embolism;

Treatment of unstable angina and non-Q wave myocardial infarction in combination with acetylsalicylic acid;

Prevention of thrombosis formation in the extracorporeal circulation system during hemodialysis.

DOSING MODE

The drug is administered s / c. The drug must not be administered intramuscularly!

For the prevention of venous thrombosis and thromboembolism, patients with moderate risk (abdominal surgery) are prescribed Clexane 20-40 mg (0.2-0.4 ml) s / c 1 time / day. The first injection is given 2 hours before surgery.

Patients at high risk (orthopedic surgery) are prescribed 40 mg (0.4 ml) s / c 1 time / day and the first dose is administered 12 hours before surgery or 30 mg (0.3 ml) s / c 2 times / day with start of administration 12-24 hours after surgery.

The duration of treatment with Clexane is 7-10 days. If necessary, therapy can be continued as long as the risk of developing thrombosis or embolism remains (for example, in orthopedics, Clexane is prescribed at a dose of 40 mg 1 time / day for 5 weeks).

For the prevention of venous thrombosis in patients with acute therapeutic conditions who are on bed rest, 40 mg is prescribed 1 time / day for 6-14 days.

For the treatment of deep vein thrombosis, 1 mg / kg s / c is administered every 12 hours (2 times / day) or 1.5 mg / kg 1 time / day. In patients with complicated thromboembolic disorders, the drug is recommended to be used at a dose of 1 mg / kg 2 times / day.

The duration of treatment averages 10 days. It is advisable to immediately start therapy with indirect anticoagulants, while Clexane therapy should be continued until a sufficient anticoagulant effect is achieved, i.e. INR should be 2.0-3.0.

With unstable angina and myocardial infarction without a Q wave, the recommended dose of Clexane is 1 mg / kg s / c every 12 hours. At the same time, acetylsalicylic acid is prescribed at a dose of 100-325 mg 1 time / day. The average duration of therapy is 2-8 days (until the patient's clinical condition stabilizes).

To prevent the formation of a thrombus in the extracorporeal circulation system during hemodialysis, the dose of Clexane is an average of 1 mg/kg of body weight. With a high risk of bleeding, the dose should be reduced to 0.5 mg/kg of body weight with a double vascular access or 0.75 mg/kg with a single vascular access.

In hemodialysis, the drug should be injected into the arterial site of the shunt at the beginning of the hemodialysis session. One dose, as a rule, is sufficient for a four-hour session, however, if fibrin rings are detected during longer hemodialysis, the drug can be additionally administered at the rate of 0.5-1 mg/kg of body weight.

In case of impaired renal function, it is necessary to adjust the dose of the drug depending on the CC. With CC less than 30 ml / min, Clexane is administered at the rate of 1 mg / kg of body weight 1 time / day for therapeutic purposes and 20 mg 1 time / day for prophylactic purposes. The dosage regimen does not apply to cases of hemodialysis. With CC more than 30 ml / min, dose adjustment is not required, however, laboratory monitoring of therapy should be carried out more carefully.

Rules for the introduction of the solution

It is desirable to carry out injections in the position of the patient lying down. Clexane is administered deep subcutaneously. When using pre-filled 20 mg and 40 mg syringes, do not remove air bubbles from the syringe before injection to avoid wasting the drug. Injections should be carried out alternately in the left or right upper lateral or lower lateral parts of the anterior abdominal wall.

The needle must be inserted vertically to its full length into the skin, holding the skin fold between the thumb and forefinger. The skin fold is released only after the injection is completed. Do not massage the injection site after drug administration.

SIDE EFFECT

Bleeding

With the development of bleeding, it is necessary to stop the drug, determine the cause and begin appropriate treatment.

In 0.01-0.1% of cases, hemorrhagic syndrome may develop, including retroperitoneal and intracranial bleeding. Some of these cases were fatal.

When using Clexane against the background of spinal / epidural anesthesia and postoperative use of penetrating catheters, cases of spinal cord hematoma (in 0.01-0.1% of cases) are described, which leads to neurological disorders of varying severity, including persistent or irreversible paralysis.

Thrombocytopenia

In the first days of treatment, a slightly pronounced transient asymptomatic thrombocytopenia may develop. In less than 0.01% of cases, immune thrombocytopenia may develop in combination with thrombosis, which can sometimes be complicated by organ infarction or limb ischemia.

Local reactions

After s / c injection, pain at the injection site may be observed, in less than 0.01% of cases - a hematoma at the injection site. In some cases, the formation of solid inflammatory infiltrates containing the drug is possible, which resolve after a few days, and drug withdrawal is not required. In 0.001% at the injection site, skin necrosis may develop, preceded by purpura or erythematous plaques (infiltrated and painful); in this case, the drug should be discontinued.

In 0.01-0.1% - skin or systemic allergic reactions. There have been cases of allergic vasculitis (less than 0.01%), requiring discontinuation of the drug in some patients.

Perhaps a reversible and asymptomatic increase in liver enzymes.

CONTRAINDICATIONS

Conditions and diseases in which there is a high risk of bleeding (threatening abortion, cerebral aneurysm or dissecting aortic aneurysm / with the exception of surgery /, hemorrhagic stroke, uncontrolled bleeding, severe enoxaparin- or heparin-induced thrombocytopenia);

Age up to 18 years (efficacy and safety not established);

Hypersensitivity to enoxaparin, heparin and its derivatives, including other low molecular weight heparins;

Use with caution in the following conditions: disorders of hemostasis (including hemophilia, thrombocytopenia, hypocoagulation, von Willebrand disease), severe vasculitis, peptic ulcer of the stomach and duodenum or other erosive and ulcerative lesions of the gastrointestinal tract, recent ischemic stroke, uncontrolled severe arterial hypertension, diabetic or hemorrhagic retinopathy, severe diabetes mellitus, recent or proposed neurological or ophthalmic surgery, spinal or epidural anesthesia (potential risk of hematoma), lumbar puncture (recent), recent childbirth, bacterial endocarditis (acute or subacute), pericarditis or pericardial effusion, renal and / or liver failure, intrauterine contraception, severe trauma (especially the central nervous system), open wounds with a large wound surface, simultaneous use of drugs that affect the hemostasis system.

The company does not have data on the clinical use of the drug Clexane in the following conditions: active tuberculosis, radiation therapy (recently performed).

PREGNANCY AND LACTATION

Clexane should not be used during pregnancy unless the intended benefit to the mother outweighs the potential risk to the fetus. There is no information that enoxaparin crosses the placental barrier in the II trimester, there is no information regarding the I and III trimesters of pregnancy.

When using Clexane during lactation, breastfeeding should be stopped.

SPECIAL INSTRUCTIONS

When prescribing the drug for the purpose of prevention, there was no tendency to increase bleeding. When prescribing the drug for therapeutic purposes, there is a risk of bleeding in older patients (especially in people over 80 years of age). Careful monitoring of the patient's condition is recommended.

Before starting therapy with this drug, it is recommended to cancel other drugs that affect the hemostatic system due to the risk of bleeding: salicylates, incl. acetylsalicylic acid, NSAIDs (including ketorolac); dextran 40, ticlopidine, clopidogrel, corticosteroids, thrombolytics, anticoagulants, antiplatelet agents (including glycoprotein IIb/IIIa receptor antagonists), unless required. If necessary, the combined use of Clexane with these drugs must be especially careful (careful monitoring of the patient's condition and relevant laboratory blood counts).

In patients with impaired renal function, there is a risk of bleeding as a result of an increase in anti-Xa activity. Because this increase increases significantly in patients with severe renal dysfunction (CC less than 30 ml / min), it is recommended to adjust the dose both for prophylactic and therapeutic use of the drug. Although dose adjustment is not required in patients with mild to moderate renal impairment (CC more than 30 ml / min), careful monitoring of the condition of such patients is recommended.

An increase in the anti-Xa activity of enoxaparin during its prophylactic administration in women weighing less than 45 kg and in men weighing less than 57 kg may lead to an increased risk of bleeding.

The risk of heparin-induced immune thrombocytopenia also exists with the use of low molecular weight heparins. If thrombocytopenia develops, it is usually detected between days 5 and 21 after initiation of enoxaparin sodium therapy. In this regard, it is recommended to regularly monitor the number of platelets before and during treatment with enoxaparin sodium. In the presence of a confirmed significant decrease in the number of platelets (by 30-50% compared with the baseline), it is necessary to immediately cancel enoxaparin sodium and transfer the patient to another therapy.

Spinal/epidural anesthesia

As with the use of other anticoagulants, cases of spinal cord hematoma are described when using Clexane against the background of spinal / epidural anesthesia with the development of persistent or irreversible paralysis. The risk of these phenomena is reduced when using the drug at a dose of 40 mg or lower. The risk increases with an increase in the dose of the drug, as well as with the use of penetrating epidural catheters after surgery, or with the concomitant use of additional drugs that have the same effect on hemostasis as NSAIDs. The risk also increases with traumatic exposure or repeated lumbar puncture.

To reduce the risk of bleeding from the spinal canal during epidural or spinal anesthesia, the pharmacokinetic profile of the drug must be taken into account. Placement or removal of a catheter is best done when the anticoagulant effect of enoxaparin sodium is low.

Installation or removal of the catheter should be carried out 10-12 hours after the use of prophylactic doses of Clexane in deep vein thrombosis. In cases where patients receive higher doses of enoxaparin sodium (1 mg / kg 2 times / day or 1.5 mg / kg 1 time / day), these procedures should be postponed for a longer period of time (24 hours). Subsequent administration of the drug should be carried out no earlier than 2 hours after removal of the catheter.

If the doctor prescribes anticoagulation therapy during epidural/spinal anesthesia, the patient must be especially carefully monitored continuously for any neurological signs and symptoms, such as: back pain, sensory and motor dysfunctions (numbness or weakness in the lower extremities), disorders bowel and/or bladder function. The patient should be instructed to immediately inform the doctor if the above symptoms occur. If signs or symptoms characteristic of a brainstem hematoma are detected, urgent diagnosis and treatment is necessary, including, if necessary, spinal decompression.

Heparin-induced thrombocytopenia

Clexane should be used with extreme caution in patients with a history of heparin-induced thrombocytopenia, with or without thrombosis.

The risk of heparin-induced thrombocytopenia may persist for several years. If the history suggests the presence of heparin-induced thrombocytopenia, then in vitro platelet aggregation tests are of limited value in predicting the risk of its development. The decision to prescribe Clexane in this case can only be made after consultation with the appropriate specialist.

Percutaneous coronary angioplasty

In order to reduce the risk of bleeding associated with invasive vascular manipulation in the treatment of unstable angina, the catheter should not be removed within 6-8 hours after s / c administration of Clexane. The next calculated dose should be administered no earlier than 6-8 hours after catheter removal. The injection site should be monitored for signs of bleeding and hematoma formation.

Artificial heart valves

Studies have not been conducted to reliably assess the efficacy and safety of Clexane in the prevention of thromboembolic complications in patients with artificial heart valves, so the use of the drug for this purpose is not recommended.

Laboratory tests

At doses used to prevent thromboembolic complications, Clexane does not significantly affect bleeding time and overall coagulation rates, as well as platelet aggregation or their binding to fibrinogen.

As the dose increases, the aPTT and clotting time may be prolonged. The increase in APTT and clotting time is not in a direct linear relationship with the increase in antithrombotic activity of the drug, so there is no need to monitor them.

Prevention of venous thrombosis and embolism in patients with acute therapeutic diseases who are on bed rest

In the event of an acute infection, acute rheumatic conditions, the prophylactic administration of enoxaparin sodium is justified only in the presence of risk factors for venous thrombosis (age over 75 years, malignant neoplasms, history of thrombosis and embolism, obesity, hormonal therapy, heart failure, chronic respiratory failure).

Influence on the ability to drive vehicles and control mechanisms

Clexane does not affect the ability to drive and use machines.

OVERDOSE

Symptoms. Accidental overdose with intravenous, extracorporeal or s / c administration can lead to hemorrhagic complications. When taken orally, even in large doses, absorption of the drug is unlikely.

Treatment: as a neutralizing agent, slow intravenous administration of protamine sulfate is indicated, the dose of which depends on the dose of Clexane administered. It should be taken into account that 1 mg of protamine neutralizes the anticoagulant effect of 1 mg of enoxaparin if Clexane was administered no more than 8 hours before the administration of protamine. 0.5 mg of protamine neutralizes the anticoagulant effect of 1 mg of Clexane if it was administered more than 8 hours ago or if a second dose of protamine is required. If more than 12 hours have passed after the administration of Clexane, then the administration of protamine is not required. However, even with the introduction of large doses of protamine sulfate, the anti-Xa activity of Clexane is not completely neutralized (by a maximum of 60%).

DRUG INTERACTIONS

With the simultaneous use of Clexane with drugs that affect hemostasis (salicylates / with the exception of unstable angina and non-ST elevation myocardial infarction /, other NSAIDs / including ketorolac /, dextran 40, ticlopidine, GCS for systemic use, thrombolytics, anticoagulants, antiplatelet agents / including antagonists of glycoprotein receptors IIb / IIIa /), the development of hemorrhagic complications is possible. If the use of such a combination cannot be avoided, enoxaparin should be used under close monitoring of blood coagulation parameters.

You should not alternate the use of enoxaparin sodium and other low molecular weight heparins, because. they differ from each other in the way of production, molecular weight, specific anti-Xa activity, units of measurement and doses. These drugs, therefore, have different pharmacokinetics, biological activity (anti-IIa activity and platelet interaction).

Pharmaceutical interaction

Clexane solution should not be mixed with other drugs.

TERMS AND CONDITIONS OF DISCOUNT FROM PHARMACIES
The drug is dispensed by prescription.

TERMS AND CONDITIONS OF STORAGE

List B. The drug should be stored out of the reach of children at a temperature not exceeding 25°C. Shelf life - 3 years.

In this article, you can read the instructions for using the drug Clexane. Reviews of site visitors - consumers of this medicine, as well as opinions of doctors of specialists on the use of Clexane in their practice are presented. A big request to actively add your reviews about the drug: did the medicine help or not help get rid of the disease, what complications and side effects were observed, perhaps not declared by the manufacturer in the annotation. Clexane analogues in the presence of existing structural analogues. Use for the treatment and prevention of thrombosis and embolism in adults, children, as well as during pregnancy and lactation.

Clexane- a preparation of low molecular weight heparin (molecular weight of about 4500 daltons: less than 2000 daltons - about 20%, from 2000 to 8000 daltons - about 68%, more than 8000 daltons - about 18%). Enoxaparin sodium (the active substance of Clexane) is obtained by alkaline hydrolysis of heparin benzyl ester, isolated from the mucous membrane of the small intestine of a pig. Its structure is characterized by a non-reducing 2-O-sulfo-4-enpyrazinosuronic acid moiety and a reducible 2-N,6-O-disulfo-D-glucopyranoside moiety. The enoxaparin structure contains about 20% (ranging from 15% to 25%) of the 1,6-anhydro derivative in the reducing fragment of the polysaccharide chain.

In a purified system, Clexane has high anti-10a activity (about 100 IU/ml) and low anti-2a or antithrombin activity (about 28 IU/ml). This anticoagulant activity acts through antithrombin 3 (AT-3) to provide anticoagulant activity in humans. In addition to anti-10a/2a activity, additional anticoagulant and anti-inflammatory properties of enoxaparin sodium have also been identified both in healthy people and patients, and in animal models. This includes AT-3-dependent inhibition of other coagulation factors such as factor 7a, activation of tissue factor pathway inhibitor (PTF) release, and reduced release of von Willebrand factor from the vascular endothelium into the circulation. These factors provide the anticoagulant effect of enoxaparin sodium in general.

When using the drug in prophylactic doses, it slightly changes the APTT, has virtually no effect on platelet aggregation and the level of fibrinogen binding to platelet receptors.

Plasma anti-2a activity is approximately 10 times lower than anti-10a activity. The average maximum anti-2a activity is observed approximately 3-4 hours after subcutaneous administration and reaches 0.13 IU / ml and 0.19 IU / ml after repeated administration of 1 mg / kg body weight with a double injection and 1.5 mg / kg body weight with a single injection, respectively. .

The average maximum anti-10a plasma activity is observed 3-5 hours after s / c administration of the drug and is approximately 0.2, 0.4, 1.0 and 1.3 anti-10a IU / ml after s / c administration of 20, 40 mg and 1 mg / kg and 1.5 mg/kg, respectively.

Compound

Enoxaparin sodium + excipients.

Pharmacokinetics

The pharmacokinetics of enoxaparin in these dosing regimens is linear. The bioavailability of enoxaparin sodium when administered subcutaneously, estimated on the basis of anti-10a activity, is close to 100%. Enoxaparin sodium is mainly biotransformed in the liver by desulfation and/or depolymerization to low molecular weight substances with very low biological activity. Excretion of the drug is monophasic. 40% of the administered dose is excreted by the kidneys, with 10% being unchanged.

There may be a delay in the excretion of enoxaparin sodium in elderly patients as a result of a decrease in renal function.

In patients with impaired renal function, there is a decrease in the clearance of enoxaparin sodium.

In overweight patients with subcutaneous administration of the drug, the clearance is somewhat less.

Indications

• prevention of venous thrombosis and embolism during surgical interventions, especially orthopedic and general surgical operations;
• prevention of venous thrombosis and thromboembolism in patients on bed rest due to acute therapeutic diseases (acute heart failure, chronic heart failure in the stage of decompensation of the 3 or 4 functional class according to the NYHA classification, acute respiratory failure, severe acute infection, acute rheumatic diseases in combination with one of the risk factors for venous thrombosis);
• treatment of deep vein thrombosis with or without thromboembolism of the pulmonary artery;
• prevention of thrombosis in the extracorporeal circulation system during hemodialysis (usually, with a session duration of not more than 4 hours);
• treatment of unstable angina and non-Q wave myocardial infarction in combination with acetylsalicylic acid;
• treatment of acute ST-segment elevation myocardial infarction in patients undergoing medical treatment or subsequent percutaneous coronary intervention.

Release form

Solution for injection 0.2 ml, 0.4 ml, 0.6 ml, 0.8 ml and 1 ml (injections in syringe ampoules).

Dosage form in the form of tablets does not exist.

Instructions for use, dosage and method of use (how to inject the drug correctly)

With the exception of special cases (treatment of ST-segment elevation myocardial infarction, medical or percutaneous coronary intervention and prevention of thrombus formation in the extracorporeal circulation system during hemodialysis), enoxaparin sodium is injected deeply SC. It is desirable to carry out injections in the position of the patient lying down. When using pre-filled 20 mg and 40 mg syringes, do not remove air bubbles from the syringe before injection to avoid loss of drug. Injections should be carried out alternately in the left or right anterolateral or posterolateral surface of the abdomen. The needle must be inserted vertically (not sideways) into the skin fold to its full length, collected and held until the injection is completed between the thumb and forefinger. The skin fold is released only after the injection is completed. Do not massage the injection site after drug administration.

The pre-filled disposable syringe is ready to use.

The drug must not be administered intramuscularly!

Prevention of venous thrombosis and embolism in surgical interventions, especially in orthopedic and general surgical operations

For patients with a moderate risk of developing thrombosis and embolism (general surgical operations), the recommended dose of Clexane is 20 mg subcutaneously once a day. The first injection is given 2 hours before surgery.

For patients with a high risk of thrombosis and embolism (general surgery and orthopedic surgery), the drug is recommended at a dose of 40 mg 1 time per day s / c, the first dose is administered 12 hours before surgery, or 30 mg 2 times a day s / c start of administration 12-24 hours after surgery.

The duration of treatment with Clexane is on average 7-10 days. If necessary, therapy can be continued as long as the risk of thrombosis and embolism persists (for example, in orthopedics Clexane is prescribed at a dose of 40 mg 1 time per day for 5 weeks).

Prevention of venous thrombosis and embolism in patients on bed rest due to acute therapeutic diseases

Treatment of deep vein thrombosis with or without pulmonary embolism

The drug is administered subcutaneously at the rate of 1.5 mg/kg body weight 1 time per day or at a dose of 1 mg/kg body weight 2 times a day. In patients with complicated thromboembolic disorders, the drug is recommended to be used at a dose of 1 mg / kg 2 times a day.

The duration of treatment averages 10 days. It is advisable to immediately start therapy with indirect anticoagulants, while Clexane therapy should be continued until a sufficient anticoagulant effect is achieved, i.e. MHO should be 2-3.

Prevention of thrombus formation in the extracorporeal circulation system during hemodialysis

The dose of Clexane is on average 1 mg/kg of body weight. With a high risk of bleeding, the dose should be reduced to 0.5 mg / kg body weight with a double vascular access or 0.75 mg with a single vascular access.

In hemodialysis, the drug should be injected into the arterial site of the shunt at the beginning of the hemodialysis session. One dose is usually sufficient for a 4-hour session, however, if fibrin rings are detected during longer hemodialysis, the drug can be additionally administered at the rate of 0.5-1 mg/kg of body weight.

Treatment of unstable angina and non-Q wave myocardial infarction

Clexane is administered at the rate of 1 mg/kg of body weight every 12 hours s/c, while the appointment of acetylsalicylic acid at a dose of 100-325 mg 1 time per day. The average duration of therapy is 2-8 days (until the patient's clinical condition stabilizes).

Treatment of ST-segment elevation myocardial infarction, medically or with percutaneous coronary intervention

Treatment begins with an intravenous bolus injection of enoxaparin sodium at a dose of 30 mg and immediately after it (within 15 minutes) Clexane is administered subcutaneously at a dose of 1 mg / kg (moreover, during the first two s / c injections, a maximum of 100 mg of enoxaparin can be administered sodium). Then all subsequent s / c doses should be administered every 12 hours at the rate of 1 mg / kg body weight (i.e., with a body weight of more than 100 kg, the dose may exceed 100 mg).

In persons 75 years of age and older, the initial intravenous bolus is not used. Clexane is injected s / c at a dose of 0.75 mg / kg every 12 hours (moreover, during the first two s / c injections, a maximum of 75 mg of enoxaparin sodium can be administered). Then all subsequent s / c doses should be administered every 12 hours at the rate of 0.75 mg / kg body weight (i.e., with a body weight of more than 100 kg, the dose may exceed 75 mg).

When combined with thrombolytics (fibrin-specific and fibrin-nonspecific), enoxaparin sodium should be administered in the range from 15 minutes before the start of thrombolytic therapy to 30 minutes after it. As soon as possible after the detection of acute myocardial infarction with ST segment elevation, acetylsalicylic acid should be started simultaneously and, if there are no contraindications, it should be continued for at least 30 days at doses of 75 to 325 mg daily.

Bolus administration of enoxaparin sodium should be carried out through a venous catheter and enoxaparin sodium should not be mixed or administered together with other drugs. In order to avoid the presence in the system of traces of other drugs and their interaction with enoxaparin sodium, the venous catheter should be flushed with a sufficient amount of 0.9% sodium chloride solution or dextrose before and after the intravenous bolus administration of enoxaparin sodium. Enoxaparin sodium can be safely administered with 0.9% sodium chloride solution and 5% dextrose solution.

For bolus administration of enoxaparin sodium at a dose of 30 mg in the treatment of acute myocardial infarction with ST segment elevation, excess amount of the drug is removed from glass syringes 60 mg, 80 mg and 100 mg so that only 30 mg (0.3 ml) remain in them. A dose of 30 mg can be directly injected into / in.

For intravenous bolus administration of enoxaparin sodium through a venous catheter, pre-filled syringes for subcutaneous administration of the drug 60 mg, 80 mg and 100 mg can be used. It is recommended to use 60 mg syringes, as this reduces the amount of drug removed from the syringe. Syringes 20 mg are not used, because. they do not have enough drug for a 30 mg bolus of enoxaparin sodium. 40 mg syringes are not used because there are no divisions on them and therefore it is impossible to accurately measure the amount of 30 mg.

In patients undergoing percutaneous coronary intervention, if the last subcutaneous injection of enoxaparin sodium was performed less than 8 hours before inflation of the balloon catheter inserted into the narrowing of the coronary artery, additional administration of enoxaparin sodium is not required. If the last s / c injection of enoxaparin sodium was carried out more than 8 hours before the inflation of the balloon catheter, an additional bolus of enoxaparin sodium at a dose of 0.3 mg / kg should be performed intravenously.

To improve the accuracy of an additional bolus injection of small volumes into a venous catheter during percutaneous coronary interventions, it is recommended to dilute the drug to a concentration of 3 mg / ml. It is recommended to dilute the solution immediately before use.

To prepare a solution of enoxaparin sodium with a concentration of 3 mg / ml using a pre-filled syringe of 60 mg, it is recommended to use a container with an infusion solution of 50 ml (i.e. with 0.9% sodium chloride solution or 5% dextrose solution). From the container with the infusion solution using a conventional syringe, 30 ml of the solution is removed and removed. Enoxaparin sodium (the contents of a syringe for s / c injection of 60 mg) is injected into the remaining 20 ml of the infusion solution in the container. The contents of the container with a diluted solution of enoxaparin sodium are gently mixed.

Side effect

• bleeding;
• retroperitoneal bleeding;
• intracranial bleeding;
• neuraxial hematomas;
• thrombocytopenia (including autoimmune thrombocytopenia);
• thrombocytosis;
• increased activity of hepatic transaminases;
• allergic reactions;
• hives;
• redness of the skin;
• hematoma and pain at the injection site;
• skin (bullous) rashes;
• inflammatory reaction at the injection site;
• skin necrosis at the injection site;
• anaphylactic and anaphylactoid reactions;
• hyperkalemia.

Contraindications

• conditions and diseases in which there is a high risk of bleeding (threatening abortion, cerebral aneurysm or dissecting aortic aneurysm (with the exception of surgery), hemorrhagic stroke, uncontrolled bleeding, severe enoxaparin- or heparin-induced thrombocytopenia);
• age up to 18 years (efficacy and safety have not been established);
• hypersensitivity to enoxaparin, heparin and its derivatives, including other low molecular weight heparins.

Use during pregnancy and lactation

Clexane should not be used during pregnancy unless the intended benefit to the mother outweighs the potential risk to the fetus. There is no information that enoxaparin sodium crosses the placental barrier in the 2nd trimester, there is no information on the 1st and 3rd trimesters of pregnancy.

When using Clexane during lactation, breastfeeding should be stopped.

Use in elderly patients

In persons 75 years of age and older, the initial intravenous bolus is not used. Enoxaparin sodium is injected s / c at a dose of 0.75 mg / kg every 12 hours (moreover, during the first two s / c injections, a maximum of 75 mg of enoxaparin sodium can be administered). Then all subsequent s / c doses are administered every 12 hours at the rate of 0.75 mg / kg of body weight (i.e., with a body weight of more than 100 kg, the dose may exceed 75 mg).

Use in children

Contraindicated in children and adolescents under 18 years of age (efficacy and safety not established).

special instructions

When prescribing the drug for the purpose of prevention, there was no tendency to increase bleeding. When prescribing the drug for therapeutic purposes, there is a risk of bleeding in older patients (especially in people over 80 years of age). Careful monitoring of the patient's condition is recommended.

It is recommended that the use of drugs that can disrupt hemostasis (salicylates, acetylsalicylic acid, non-steroidal anti-inflammatory drugs (NSAIDs), including ketorolac; dextran with a molecular weight of 40 kDa, ticlopidine, clopidogrel; glucocorticosteroids (GCS), thrombolytics, anticoagulants, antiplatelet agents, including glycoprotein antagonists 2b/3a receptors) was discontinued prior to initiation of enoxaparin sodium treatment unless strictly indicated. If combinations of enoxaparin sodium with these drugs are indicated, then careful clinical observation and monitoring of relevant laboratory parameters should be carried out.

In patients with impaired renal function, there is a risk of bleeding as a result of an increase in the anti-10a activity of enoxaparin sodium. In patients with severely impaired renal function (CK< 30 мл/мин) рекомендуется проводить коррекцию дозы как при профилактическом, так и терапевтическом назначении препарата. Хотя не требуется проводить коррекцию дозы у пациентов с легким и умеренным нарушением функции почек (КК 30-50 мл/мин или КК 50-80 мл/мин), рекомендуется проведение тщательного контроля состояния таких пациентов.

An increase in the anti-10a activity of enoxaparin sodium during its prophylactic administration in women weighing less than 45 kg and in men weighing less than 57 kg may lead to an increased risk of bleeding.

The risk of heparin-induced autoimmune thrombocytopenia also exists with the use of low molecular weight heparins. If thrombocytopenia develops, it is usually detected between days 5 and 21 after initiation of enoxaparin sodium therapy. In this regard, it is recommended to regularly monitor the number of platelets before starting treatment with the drug and during its use. In the presence of a confirmed significant decrease in the number of platelets (by 30-50% compared with the baseline), it is necessary to immediately cancel enoxaparin sodium and transfer the patient to another therapy.

Spinal/epidural anesthesia

As with the use of other anticoagulants, cases of the occurrence of neuraxial hematomas are described when using the drug Clexane against the background of spinal / epidural anesthesia with the development of persistent or irreversible paralysis. The risk of these phenomena is reduced when using the drug at a dose of 40 mg or lower. The risk increases with an increase in the dose of the drug, as well as with the use of penetrating epidural catheters after surgery, or with the concomitant use of additional drugs that have the same effect on hemostasis as NSAIDs. The risk also increases with traumatic exposure or repeated lumbar puncture or in patients with a history of previous spinal surgery or spinal deformity.

To reduce the risk of bleeding from the spinal canal during epidural or spinal anesthesia, the pharmacokinetic profile of the drug must be taken into account. Placement or removal of a catheter is best done when the anticoagulant effect of enoxaparin sodium is low.

Installation or removal of the catheter should be carried out 10-12 hours after the use of Clexane in prophylactic doses to prevent deep vein thrombosis. In cases where patients receive higher doses of enoxaparin sodium (1 mg/kg 2 times a day or 1.5 mg/kg 1 time a day), these procedures should be postponed for a longer period of time (24 hours). Subsequent administration of the drug should be carried out no earlier than 2 hours after removal of the catheter.

If the doctor prescribes anticoagulant therapy during epidural/spinal anesthesia, the patient must be especially carefully monitored continuously for any neurological signs and symptoms, such as: back pain, sensory and motor dysfunctions (numbness or weakness in the lower extremities), disorders bowel and/or bladder function. The patient should be instructed to immediately inform the doctor if the above symptoms occur. If signs or symptoms characteristic of a spinal cord hematoma are detected, urgent diagnosis and treatment is necessary, including, if necessary, spinal decompression.

Heparin-induced thrombocytopenia

Clexane should be used with extreme caution in patients with a history of heparin-induced thrombocytopenia, with or without thrombosis.

The risk of heparin-induced thrombocytopenia may persist for several years. If the history suggests the presence of heparin-induced thrombocytopenia, then platelet aggregation tests are of limited value in predicting the risk of its development. The decision to prescribe Clexane in this case can only be taken after consultation with the appropriate specialist.

Percutaneous coronary angioplasty

In order to reduce the risk of bleeding associated with invasive vascular manipulation in the treatment of unstable angina and non-Q wave myocardial infarction, the catheter should not be removed within 6-8 hours after s / c administration of Clexane. The next calculated dose should be administered no earlier than 6-8 hours after removal of the femoral artery introducer. It is necessary to monitor the site of invasion in order to detect signs of bleeding and hematoma formation in a timely manner.

Artificial heart valves

Studies have not been conducted to reliably assess the efficacy and safety of Clexane in the prevention of thromboembolic complications in patients with artificial heart valves. The use of the drug for this purpose is not recommended.

Laboratory tests

At doses used for the prevention of thromboembolic complications, Clexane does not significantly affect bleeding time and blood coagulation, as well as platelet aggregation or their binding to fibrinogen.

As the dose increases, the aPTT and clotting time may be prolonged. The increase in APTT and clotting time is not in a direct linear relationship with the increase in antithrombotic activity of the drug, so there is no need to monitor them.

Prevention of venous thrombosis and embolism in patients with acute therapeutic diseases who are on bed rest

In the event of an acute infection, acute rheumatic conditions, the prophylactic administration of enoxaparin sodium is justified only if the above conditions are combined with one of the following risk factors for venous thrombosis: age over 75 years, malignant neoplasms, history of thrombosis and embolism, obesity, hormonal therapy, heart failure , chronic respiratory failure.

Influence on the ability to drive vehicles and control mechanisms

Clexane does not affect the ability to drive vehicles and mechanisms.

drug interaction

Clexane should not be mixed with other drugs!

You should not alternate the use of enoxaparin sodium and other low molecular weight heparins, because. they differ from each other in the way of production, molecular weight, specific anti-10a activity, units of measurement and dosage. And, as a consequence, the drugs have different pharmacokinetics and biological activity (anti-2a activity, interaction with platelets).

With systemic salicylates, acetylsalicylic acid, non-steroidal anti-inflammatory drugs (NSAIDs) (including ketorolac), dextran with a molecular weight of 40 kDa, ticlopidine and clopidogrel, systemic glucocorticosteroids (GCS), thrombolytics or anticoagulants, other antiplatelet drugs (including glycoprotein 2b / 3a antagonists ) increases the risk of bleeding.

Analogues of the drug Kleksan

Structural analogues for the active substance:

• Anfibra;
• Gemapaksan;
• Enoxaparin sodium.

Analogues by pharmacological group (anticoagulants):

• Angioks;
• Angioflux;
• Antithrombin 3 human;
• Arikstra;
• Warfarex;
• Warfarin;
• Venabos;
• Venolife;
• Viatromb;
• Gemapaksan;
• Gepalpan;
• Heparin;
• Heparin ointment;
• Heparoid;
• Hepatrombin;
• Dolobene;
• Ellon gel;
• Calciparin;
• Klivarin;
• Xarelto;
• Lavenum;
• Lyoton 1000;
• Marevan;
• Nigepan;
• Pelentan;
• Piyavit;
• Pradax;
• Seprotin;
• Sincumar;
• Skinlight;
• Troxevasin Neo;
• Trombless;
• Thrombogel;
• Thrombophobic;
• Troparin;
• Phenylin;
• Fragmin;
• Fraxiparine;
• Fraxiparin Forte;
• Cibor;
• Exantha;
• Eliquis;
• Emeran;
• Enoxaparin sodium;
• Essaven.

In the absence of analogues of the drug for the active substance, you can follow the links below to the diseases that the corresponding drug helps with and see the available analogues for the therapeutic effect.

Instructions for medical use

medicinal product

Clexane Ò

Tradename

Clexane Ò

International non-proprietary name

Enoxaparin sodium

Dosage form

Solution for injection 2000 anti-Xa IU / 0, 2 ml, 2 single-dose pre-filled syringes with needle protection system

Injection solution 4000 anti-Xa IU / 0.4 ml, 10 single-dose pre-filled syringes with needle protection system

Injection solution 6000 anti-Xa IU / 0.6 ml, 2 single-dose pre-filled syringes with needle protection system

Solution for injection 8000 anti-Xa IU/0.8 ml, 10 single-dose pre-filled syringes with needle protection system

Compound

One syringe contains

active substance- enoxaparin sodium 20 mg (for a dosage of 2000 anti-Xa IU / 0.2 ml), 40 mg (for a dosage of 4000 anti-Xa IU / 0.4 ml), 60 mg (for a dosage of 6000 anti-Xa IU / 0, 6 ml), 80 mg (for a dosage of 8000 anti-Xa IU/0.8 ml

excipient- water for injections.

Description

Clear, colorless to pale yellow solution.

Pharmacotherapeutic group

Anticoagulants. Direct anticoagulants (heparin and its derivatives). Enoxaparin sodium.

ATX code B01AB05

Pharmacological properties

Pharmacokinetics

The pharmacokinetic parameters of enoxaparin were evaluated based on the temporal dynamics of plasma anti-X and anti-IIa activity at recommended doses (validated amidolytic methods) after single and repeated subcutaneous injections of the drug, and after a single intravenous injection.

Bioavailability

After subcutaneous administration, enoxaparin is rapidly and almost completely absorbed (about 100%). Peak plasma activity occurs between 3 and 4 hours after administration. This peak activity (expressed as anti-Xa IU) is 0.18 ± 0.04 (after 2,000 anti-Xa IU), 0.43 ± 0.11 (after 4,000 anti-Xa IU) in case of prophylactic therapy and 1.01±0.14 (after 10,000 anti-Xa IU) with medical therapy. Following an intravenous bolus dose of 3,000 anti-Xa IU followed by 100 anti-Xa IU/kg subcutaneously every 12 hours, there was a first peak in anti-Xa factor levels of 1.16 IU/mL (n=16), and an average exposure corresponding to 88% of the equilibrium concentration level. Equilibrium concentration is reached on the 2nd day of therapy. Within the recommended doses, the pharmacokinetics of enoxaparin is linear. Individual and interindividual variability is low. Following repeated subcutaneous injections of 4,000 anti-Xa IU once daily in healthy volunteers, an equilibrium state is reached on the second day with an average enoxaparin activity approximately 15% higher than after a single dose. The levels of activity of enoxaparin in the saturation stage are well predicted by the pharmacokinetics of a single dose. After multiple subcutaneous injections of 100 anti-Xa IU/kg twice daily, the saturation stage is reached on days 3-4 with an average exposure approximately 65% ​​higher than after a single dose and at maximum and minimum levels of anti-Xa activity, equal to approximately 1.2 and 0.52 anti-Xa IU/ml, respectively. Based on the pharmacokinetics of enoxaparin sodium, this difference in saturation stage is predictable and within the therapeutic range. Anti-IIa activity in blood plasma after subcutaneous administration is about 10 times lower than anti-Xa activity. The average maximum anti-IIa activity is observed approximately 3-4 hours after subcutaneous injection and reaches 0.13 anti-IIa IU / ml with repeated doses of 100 anti-Xa IU / kg twice a day. When co-administered enoxaparin and thrombolytic drugs, no pharmacokinetic interaction was observed.

Distribution

The volume of distribution of the anti-Xa activity of enoxaparin sodium is approximately 5 liters and approaches the blood volume.

Metabolism

Enoxaparin sodium is metabolized mainly in the liver (desulfation, depolymerization).

breeding

The half-life of anti-Xa activity observed after subcutaneous injection is higher for low molecular weight heparins (LMWHs) than for unfractionated heparins. Enoxaparin has a monophasic elimination with a half-life of about 4 hours after a single subcutaneous dose and about 7 hours after repeated dosing. In low molecular weight heparin (LMWH), the decrease in plasma activity of anti-IIa activity occurs faster than anti-Xa activity. Enoxaparin and its metabolites are excreted via the kidneys (unsaturated mechanism) and with bile. The renal clearance of fragments with anti-Xa activity is about 10% of the administered dose, and the total renal excretion of active and inactive components is 40% of the dose.

Patients at risk

Elderly patients

Since renal function in this population is physiologically reduced, excretion is delayed. This change does not affect the dosing or administration regimen for prophylactic therapy if the renal function of such patients remains within acceptable limits, that is, when it is only slightly reduced. Before starting treatment with LMWH, it is important to systematically assess renal function in patients over 75 years of age using the Cockcroft formula (see "Special Instructions" ).

Mild to moderate renal failure (i.e. creatinine clearance > 30 mL/min)

In some cases, it may be useful to monitor circulating anti-Xa factor activity to prevent overdose when enoxaparin is used as curative therapy (see section 4.4). "Special instructions").

Patients on hemodialysis

LMWH is injected into the arterial branch of the dialysis system at doses sufficient to prevent blood clotting in the system.

In general, pharmacokinetic parameters remain unchanged except in cases of overdose or in cases where the drug enters the general circulation and can cause high anti-Xa activity associated with end-stage renal disease.

Pharmacodynamics

Enoxaparin is a low molecular weight heparin in which the antithrombotic and anticoagulant actions of standard heparin are unrelated. It is characterized by higher anti-Xa activity than anti-IIa or antithrombin activity. The ratio between these two activities for enoxaparin is 3.6. In prophylactic doses, it does not significantly affect the activated partial thromboplastin time (APTT). At therapeutic doses, APTT can be increased by 1.5-2.2 times the reference time at peak activity. This elongation reflects the residual antithrombin effect.

Prophylactic therapy of venous thromboembolic disease in patients who are on bed rest due to acute illness

In a randomized, double-blind, comparative safety and efficacy study (MEDENOX), 2,000 anti-Xa IU/0.2 ml (20 mg/0.2 ml) and 4,000 anti-Xa IU/0.4 ml (40 mg /0.4 ml) of enoxaparin compared with placebo, the drug was administered subcutaneously once a day for 6-14 days to prevent venous thromboembolic disease in 1102 patients with a moderate risk of developing venous thromboembolic disease or in patients who were on bed rest for less than 3 days due to acute illness. These patients over 40 years of age had heart failure (NYHA class III or IV), acute respiratory failure indicative of chronic respiratory failure, acute infectious disease, or acute rheumatic disease associated with at least 1 other risk factor for venous thromboembolic disease (age over 75 years, cancer, history of venous thromboembolic disease, obesity, varicose veins, hormone therapy, chronic heart or respiratory failure).

This study did not include hospitalized patients at high risk of developing venous thromboembolic events (acute myocardial infarction; heart disease such as arrhythmia or valve disease requiring anticoagulant therapy; patients intubated or patients who had a stroke in the last 3 months).

The primary efficacy endpoint was the incidence of venous thromboembolic events at day 10 (±4) and was defined as the incidence of the following adverse events:

Deep vein thrombosis (DVT) documented by systematic phlebography (83.4% of patients examined) or Doppler ultrasound (16.6% of patients examined) in patients with symptomatic DVT

Symptomatic non-fatal pulmonary embolism confirmed by pulmonary angiography or helical CT scan

Or fatal pulmonary embolism

A significant reduction in the incidence of venous thromboembolic events was observed in 866 patients examined on day 10 (±4), 16/291 (5.5%) in the enoxaparin 4,000 anti-Xa IU/0.4 ml (40 mg/0 .4 ml) compared to 43/288 (14.9%) in the placebo group (p=0.0002). This effect was mainly due to a significant reduction in the total number of cases of DVT (proximal and distal), 16/291 (5.5%) in the enoxaparin 4000 IU anti-Xa / 0.4 ml (40 mg / 0.4 ml) group ) compared to 41/288 (14.2%) in the placebo group (p=0.0004). Deep vein thrombosis was mostly asymptomatic (only 6 cases of symptomatic DVT). Clinical beneficial effect was observed after 3 months.

Rehospitalization in the treatment of enoxaparin at a dose of 4000 IU anti-Xa / 0.4 ml (40 mg / 0.4 ml) was reported in 59% of patients.

With regard to the safety of the drug, hematomas or ecchymosis >5 cm at the injection site were significantly more common in the enoxaparin 4,000 IU anti-Xa/0.4 ml/day (40 mg/day) group than in the placebo group.

In this study, there was no significant difference in efficacy between enoxaparin 2000 IU anti-Xa/0.2 ml (20 mg/0.2 ml) and placebo.

Therapy of acute myocardial infarction with segment elevationSTin combination with thrombolytic drugs for patients in whom subsequent percutaneous coronary intervention is recommended or not recommended

In a large multicenter study, 20,479 patients with ST-segment elevation acute myocardial infarction treated with fibrinolytic therapy were randomized to receive either enoxaparin as an intravenous bolus of 3,000 IU of anti-Xa followed immediately by subcutaneous administration of 100 IU of anti-Xa. -Xa/kg, followed by 100 anti-Xa IU/kg subcutaneously every 12 hours, or unfractionated heparin by intravenous bolus at 60 IU/kg (maximum 4,000 IU) followed by continuous dosing adjusted according to parameter activated partial thromboplastin time. Subcutaneous administration of enoxaparin was carried out until discharge from the hospital or for a maximum of 8 days (in 75% of cases, at least 6 days). In half of the patients treated with heparin, the administration of the drug was carried out in less than 48 hours (in 89.5% of cases 36 hours or more). All patients were also treated with acetysalicylic acid for at least 30 days. The dose of enoxaparin has been adjusted for patients 75 years of age or older to 75 IU/kg as a subcutaneous injection every 12 hours, without an initial intravenous bolus injection.

In this blinded study, 4716 (23%) patients underwent percutaneous coronary intervention with antithrombotic therapy. Patients did not receive an additional dose of the drug if the last subcutaneous injection of enoxaparin was carried out less than 8 hours before balloon inflation; the patient received an intravenous bolus injection of 30 anti-Xa IU/kg if the last subcutaneous injection of enoxaparin was more than 8 hours before balloon inflation.

There was a significant reduction in the primary endpoint with enoxaparin [composite endpoint: recurrent myocardial infarction and death from any cause within 30 days of study entry: 9.9% in the enoxaparin group compared to 12% in the unfractionated heparin group (relative risk reduction by 17% (p<0,001)]. Частота рецидива инфаркта миокарда была значительно меньше в группе эноксапарина (3,4% в сравнении с 5%, p<0,001, уменьшение относительного риска на 31%). Частота летального исхода была меньше в группе эноксапарина, с отсутствием статистически значимого различия между группами терапии (6,9% в сравнении с 7,5%, p=0,11).

The beneficial effect of enoxaparin in the primary endpoint was consistent regardless of subgroup distribution (by age, sex, site of infarction, history of diabetes or myocardial infarction, type of thrombolytic agent, and interval between onset of clinical signs and initiation of therapy).

Enoxaparin showed a beneficial effect compared to unfractionated heparin on primary efficacy in patients who underwent coronary angioplasty within 30 days of study entry (10.8% vs. 13.9%, 23% relative risk reduction ) and also in patients who did not undergo coronary angioplasty (9.7% vs. 11.4%, 15% relative risk reduction).

The frequency of major bleeding within 30 days was significantly higher (p<0,0001) в группе эноксапарина (2,1%) в сравнении с группой гепарина (1,4%). Отмечалась более высокая частота желудочно-кишечного кровотечения в группе эноксапарина (0,5%) в сравнении с группой гепарина (0,1%), хотя частота внутричерепных кровотечений была схожей в обеих группах (0,8% при приеме эноксапарина в сравнении с 0,7% на фоне приема гепарина).

Analysis of the composite criteria for assessing the overall clinical benefit showed a statistically significant benefit (p<0,0001) эноксапарина над нефракционированным гепарином: уменьшение относительного риска на 14% в пользу эноксапарина (11% в сравнении с 12.8%) для составного критерия с учетом смертности, рецидива инфаркта миокарда, или массивного кровотечения [критерии тромболиза при инфаркте миокарда (TIMI) ] в течение 30 дней, и на 17% (10,1% в сравнении с 12.2%) для составного критерия с учетом смертности, рецидива инфаркта миокарда или внутричерепного кровотечения в течение 30 дней.

Indications for use

Solution for injection in syringes 2000 anti-Xa IU / 0.2 ml; 4000 anti-Xa IU/0.4 ml:

Prevention of venous thromboembolic disease in moderate or high risk surgery

Prevention of blood clotting in the extracorporeal circulation during hemodialysis (usually a procedure lasting 4 hours or less)

Solution for injection in syringes 4000 anti-Xa IU/0.4 ml:

Prevention of deep vein thrombosis in patients who are on bed rest due to an acute therapeutic illness, including:

Heart failure (NYHA class III or IV)

Acute respiratory failure

Episodes of acute infectious disease or acute rheumatic disease in combination with at least one of the risk factors for venous thromboembolism.

Treatment of established deep vein thrombosis with or without pulmonary embolism without severe clinical symptoms, except for pulmonary embolism, which may require treatment with a thrombolytic agent or surgery

Treatment of unstable angina and acute non-Q wave myocardial infarction in combination with acetylsalicylic acid

Treatment of acute ST-segment elevation myocardial infarction in combination with a thrombolytic agent for patients regardless of the likelihood of subsequent percutaneous coronary intervention (PCI).

Dosage and administration

This heparin is a low molecular weight heparin.

FOR SUBCUTANEOUS INTRODUCTION (with the exception of patients undergoing hemodialysis - for a solution in syringes of 2000 anti-Xa IU / 0.2 ml and 4000 anti-Xa IU / 0.4 ml).

FOR SUBCUTANEOUS INTRODUCTION (with the exception of patients with acute myocardial infarction, occurring with an increase in the ST segment, who require intravenous bolus administration - for a solution in syringes 6000 anti-Xa IU / 0.6 ml, 8000 anti-Xa IU / 0.8 ml) .

Clexane Ò is not subject to intramuscular injection. 1 ml solution for injection is equivalent to approximately 10,000 anti-Xa IU of enoxaparin.

Subcutaneous Injection Technique

Solution for injection in syringes 2000 anti-Xa IU / 0.2 ml; 4000 anti-Xa IU/0.4 ml: p The pre-filled syringe is ready for immediate use; there is no need to depress the plunger before injecting to remove air bubbles.

Solution for injection in syringes 6000 anti-Xa IU / 0.6 ml; 8000 anti-Xa IU/0.8 ml: the dose of Clexane to be administered should be adjusted according to the patient's body weight, and the excess volume should be removed before injection. If there is no excess volume, air bubbles do not need to be removed before administration.

Clexane should be administered subcutaneously, preferably with the patient in the supine position. Injections are administered alternately into the left, then into the right anterolateral or posterolateral wall of the abdomen.

The entire length of the needle should be inserted perpendicularly, and not at an angle, into the area of ​​skin sandwiched between the index and thumb fingers. During the injection, this area of ​​skin should be pinched between the fingers.

Clexane Ò in pre-filled syringes and in graduated pre-filled syringes is for single use only and comes with a post-injection needle protection system.

Remove the pre-filled syringe from the blister pack by tearing off the pack in the direction of the arrow indicated on the pack. Do not pull on the plunger as this may damage the syringe.

NOTE:

The safety system cannot be activated immediately after the entire contents of the syringe have been injected.

The safety system should only be activated after the needle has been removed from the patient's skin.

Do not change the needle cap after injection.

The security system does not need to be sterilized.

When the safety system is activated, a small splash of liquid may occur. For optimal safety, turn the system away from yourself and others when activating the system.

Intravenous (bolus) injection technique. ApplicationClexana 30 000 anti-xa IU/3ml in multi-use vialsfor the treatment of acute myocardial infarction with ST segment elevation:

Treatment begins with an intravenous bolus injection followed immediately by a subcutaneous injection. The starting dose is

3,000 IU (0.3 ml). The solution of the drug should be removed from the vial for multiple use using a graduated 1 ml syringe (insulin syringe). This dose of enoxaparin should be administered intravenously. The drug should not be mixed or administered together with other drugs. To avoid the presence of traces of other drugs in the system and their possible mixing with enoxaparin sodium, before and after the intravenous bolus administration of Clexane, the venous catheter should be flushed with a sufficient amount of sodium chloride or dextrose solution. It is safe to administer Clexane with 0.9% sodium chloride solution or 5% aqueous dextrose solution. In a hospital setting, the multiple-dose vial is subsequently used to administer the following doses:

The dose required for the first subcutaneous injection of 100 IU/kg, which is administered simultaneously with an intravenous bolus, then for a subsequent subcutaneous injection of the drug at the rate of 100 IU/kg every 12 hours

Dose of 30 IU/kg for intravenous bolus administration following percutaneous coronary intervention.

Throughout the entire period of treatment, regular monitoring of the platelet count is very important due to the risk of developing heparin-induced thrombocytopenia (HIT) (see "Special Instructions").

Preventive treatment of thromboembolic venous disease in surgery

As a rule, these recommendations are intended for surgical interventions performed under general anesthesia. When conducting spinal and epidural anesthesia, the benefit of preoperative administration of the drug should be compared with the theoretically increased risk of spinal hematoma (see "Special Instructions").

Dosing regimen: 1 injection daily.

Administered dose: d OZU is determined based on the individual risk characteristic of a given patient and the type of surgery.

Surgery involving moderate thrombogenic risk

Surgery involving moderate thrombogenic risk and in patients without high risk of thromboembolism, effective prophylaxis is achieved with daily injections of 2,000 anti-Xa IU (0.2 ml). The studied mode of administration provides for the introduction of the first injection 2 hours before surgery.

Surgery involving high thrombogenic risk

Hip and knee surgery: a dose of 4,000 anti-Xa IU (0.4 ml) is administered once a day. The studied dosing regimen was to administer the first injection of 4,000 anti-Xa IU (full dose) 12 hours before surgery, or the first injection of 2,000 anti-Xa IU (half dose) 2 hours before surgery.

Other situations: if there is an increased risk of venous thromboembolism due to the type of surgery (especially oncosurgery) and / or the individual patient (especially history of venous thromboembolism), a prophylactic dose equivalent to the dose prescribed for high-risk orthopedic surgery may be required such as hip or knee surgery.

Duration of treatment

Treatment of LMWH should be carried out along with the usual methods of support with compression stockings for the legs, until the patient fully restores the ability to actively move:

In general surgery, the duration of treatment with LMWH should be less than 10 days, if there is no risk of venous thromboembolism characteristic of this patient (see "Special Instructions")

Prophylactic treatment with 4,000 daily anti-Xa IU enoxaparin has been proven to be beneficial for 4-5 weeks after hip surgery.

If the risk of venous thromboembolism persists after the recommended duration of treatment, it may be necessary to prolong prophylactic therapy, in particular through the appointment of oral anticoagulants.

However, the clinical effect of long-term treatment with low molecular weight heparins or oral anticoagulants has not yet been evaluated.

Preventive care in medical institution

Assigned dose: dose of 40 mg, i.e. 4,000 anti-Xa IU/0.4 ml administered once a day by subcutaneous injection.

Duration of therapy: it has been proven that the treatment has an effect between the 6th and 14th day. At the moment, there are no data on efficacy and safety in relation to prophylactic therapy carried out for more than 14 days. If the risk of venous thromboembolism persists, continuation of prophylactic therapy, in particular oral anticoagulants, should be considered.

Prevention of blood coagulation in the extracorporeal circulation system / hemodialysis

Intravascular application(to the arterial line of the dialysis bed). Prevention of coagulation in the extrarenal cleansing system of patients undergoing repeated sessions of hemodialysis is achieved by introducing an initial dose of 100 anti-Xa IU/kg into the arterial line of the dialysis bed at the beginning of the procedure. This dose, administered as a single intravascular bolus injection, is only suitable for hemodialysis procedures of 4 hours or less. The dose may be subsequently adjusted to account for the high individual and interindividual variability. The maximum recommended dose is 100 anti-Xa IU/kg. During hemodialysis in patients with a high risk of bleeding (in particular, preoperative and postoperative dialysis) or with active bleeding, dialysis procedures can be performed using a dose of 50 anti-Xa IU / kg (dual access to vessels) or 75 anti-Xa IU / kg (one access to vessels).

Treatment of deep vein thrombosis (DVT) with or without pulmonary embolism without severe clinical symptoms

If DVT is suspected, the diagnosis should be confirmed promptly with appropriate investigations.

Dosing regimen: two injections per day, 12 hours apart.

Dose: for one injection is 100 anti-Xa IU/kg. Dosage of LMWH for body weights greater than 100 kg or less than 40 kg has not been evaluated. The effectiveness of treatment with LMWH may be slightly reduced in patients weighing more than 100 kg, and the risk of bleeding may be higher in patients weighing less than 40 kg. For such patients, special clinical monitoring should be carried out.

Duration of treatment in patients with DVT: treatment with LMWH should be rapidly replaced with oral anticoagulant treatment if there are no contraindications. The duration of treatment with LMWH should not exceed 10 days, including the time required to achieve the desired effect of oral anticoagulant, except in cases where this is difficult to achieve (see "Special Instructions"). Therefore, oral anticoagulant therapy should be started as soon as possible.

Treatment of unstable angina/non-Q wave myocardial infarction

A dose of 100 anti-Xa IU/kg of enoxaparin is administered by subcutaneous injection twice a day at 12-hour intervals in combination with acetylsalicylic acid (recommended doses: 75-325 mg orally, after a minimum loading dose of 160 mg). The recommended duration of therapy is about 2-8 days until the patient is clinically stable.

Treatment of acute ST-segment elevation myocardial infarction in combination with a thrombolytic agent for patients regardless of the likelihood of subsequent percutaneous coronary intervention

Following an initial intravenous bolus injection of 3,000 anti-Xa IU, a subcutaneous injection of 100 IU anti-Xa/kg is administered over 15 minutes, then every 12 hours (for the first 2 subcutaneous doses, a maximum of 10,000 anti-Xa IU).

The first dose of enoxaparin should be administered at any time between 15 minutes before and 30 minutes after the start of thrombolytic therapy (fibrin specific or not). The recommended duration of therapy is 8 days, or until the patient is discharged from the hospital if the hospital stay is less than 8 days.

Concomitant Therapy: Acetylsalicylic acid should be started as soon as possible after symptom onset, and the maintenance dose should be 75-325 mg daily for at least 30 days, unless otherwise indicated.

Patients with percutaneous coronary intervention:

If less than 8 hours have passed since the last subcutaneous injection of enoxaparin before the inflation of the balloon, no additional injection is required.

If more than 8 hours have elapsed from the last subcutaneous injection to balloon inflation, an intravenous bolus of 30 anti-Xa IU/kg of enoxaparin is required. To ensure the accuracy of the volumes to be administered, the drug is recommended to be diluted to 300 IU / ml (i.e. 0.3 ml of enoxaparin diluted in 10 ml) (see table below).

Injection volumes when dilution is performed for patients with percutaneous coronary intervention:

Patients aged 75 years and older: Those being treated for acute ST-segment elevation myocardial infarction should not administer the initial intravenous bolus injection. Every 12 hours, a dose of 75 anti-Xa IU/kg should be injected subcutaneously (only for the first two injections, a maximum of 7500 anti-Xa IU).

Side effects

Hemorrhagic symptoms associated mainly with the presence of concomitant risk factors: organic lesions, with a tendency to bleeding and some drug combinations (see "Contraindications" and "Drug Interactions"), age, renal failure, low body weight; hemorrhagic symptoms associated with non-compliance with therapeutic recommendations, especially regarding the duration of treatment and dose adjustment based on body weight (see "Special Instructions").

Hematoma, possible with subcutaneous injection at the injection site. The risk of forming such a hematoma increases if the recommendations on the technique of injection or the use of inappropriate injection material are not followed. Hard nodules that disappear within a few days may develop as a result of an inflammatory reaction and require discontinuation of therapy.

Thrombocytopenia 2 types:

Type I - the most common, usually moderate (>100,000/mm3), occurs early (before day 5) and does not require discontinuation of treatment

Type II is a rare severe immunoallergic thrombocytopenia (HIT). The frequency of this phenomenon is poorly understood (see "Special Instructions").

Increased platelet count is asymptomatic and reversible

Osteoporosis, the risk of development cannot be excluded with longer therapy, as with unfractionated heparin

Temporary elevation of transaminases

Rarely

Spinal hematoma after LMWH injection during spinal anesthesia, anesthesia or epidural anesthesia. These reactions led to damage to the nervous system of varying severity, including prolonged or permanent paralysis (see "Special Instructions").

Skin necrosis, most often at the injection site, which may be preceded by purpura or infiltrated, painful erythematous patches. In such cases, therapy should be discontinued immediately.

Skin or systemic allergic reactions leading in some cases to discontinuation of treatment

Very rarely

Vasculitis due to increased skin sensitivity

Hypereosinophilia occurring in isolated cases or in conjunction with skin reactions and resolved when treatment is discontinued.

In some cases

Hyperkalemia

Contraindications

Regardless of the dose (therapeutic or prophylactic), this drug should not be used in the following situations:

Hypersensitivity to enoxaparin, heparin or its derivatives, including other LMWHs

A history of severe, heparin-induced thrombocytopenia (HIT) type II caused by unfractionated or low molecular weight heparin (see "Special Instructions")

Bleeding or bleeding tendency associated with impaired hemostasis (possible exception to this contraindication may be disseminated intravascular coagulation syndrome, if it is not associated with heparin treatment (see "Special Instructions")

Organic lesion with a tendency to bleed

Clinically significant active bleeding

- Clexane30,000 anti-xaIU/3 ml: this drug is contraindicated in children under 3 years of age due to the content of benzyl alcohol.

At a therapeutic dose, this drug should not be used in the following situations:

intracerebral bleeding

Severe renal insufficiency, due to the lack of relevant data (defined on the basis of creatinine clearance of about 30 ml / min as assessed by the Cockcroft formula), except in isolated cases in patients on dialysis. Patients with severe renal insufficiency should take unfractionated heparin. For an accurate calculation according to the Cockcroft formula, it is necessary to use the data of the last measurement of body weight (see "Special Instructions")

Spinal or epidural anesthesia should never be performed in patients treated with LMWH.

At therapeutic doses, this drug is generally not recommended in the following situations:

Acute extensive ischemic stroke, with or without impaired consciousness. If the stroke is caused by an embolism, do not use enoxaparin in the first 72 hours after this event. The effectiveness of therapeutic doses of LMWH has not yet been established, regardless of the cause, prevalence or severity of clinical manifestations of cerebral infarction.

Acute infective endocarditis (excluding some embolic heart conditions)

Mild to moderate renal failure (creatinine clearance greater than 30 ml/min and less than 60 ml/min)

Simultaneous reception with the following drugs (see "Drug Interactions"):

NSAIDs (systemic use)

In prophylactic doses, this drug is generally not recommended in the following situations:

Severe renal failure (creatinine clearance of about 30 ml / min as assessed by the Cockcroft formula (see "Special Instructions")

In the first 24 hours after intracerebral bleeding

For elderly patients over the age of 65, while taking the following drugs (see "Drug Interactions"):

Acetylsalicylic acid in analgesic, antipyretic and anti-inflammatory doses

NSAIDs (systemic use)

Dextran 40 (parenteral)

Drug Interactions

Some drugs can cause hyperkalemia, such as potassium salts, potassium-sparing diuretics, ACE inhibitors (angiotensin converting enzyme inhibitors), angiotensin II receptor antagonists, non-steroidal anti-inflammatory drugs, heparin (low molecular weight or unfractionated), cyclosporine, tacrolimus and trimethoprim.

The development of hyperkalemia may depend on possible associated risk factors. The risk of hyperkalemia increases if the above drugs are used simultaneously.

For patients under 65 years of age at therapeutic doses of LMWH and for elderly patients (over 65 years of age) regardless of the dose of LMWH

Acetylsalicylic acid in analgesic, antipyretic and anti-inflammatory doses (by extrapolation and other salicylates): an increased risk of bleeding (suppression of platelet function by salicylates and damage to the mucous membrane of the gastrointestinal tract). A non-salicylate antipyretic analgesic (eg, paracetamol) should be used.

Non-steroidal anti-inflammatory drugs (systemic use): increased risk of bleeding (NSAIDs suppress platelet function and cause damage to the gastrointestinal mucosa). If concomitant use is unavoidable, careful clinical monitoring is required.

Dextran 40 (parenteral use): increased risk of bleeding (suppression of platelet function by Dextran 40).

Combinations requiring precautions

Oral anticoagulants: increased anticoagulant effect. When replacing heparin with an oral anticoagulant, clinical monitoring should be strengthened.

Combinations to consider

Platelet aggregation inhibitors (other than acetylsalicylic acid in analgesic, antipyretic and anti-inflammatory doses): abciximab, acetylsalicylic acid in antiplatelet doses for cardiac and neurological indications, beraprost, clopidogrel, eptifibatide, iloprost, ticlopidine, tirofiban: increased risk of bleeding.

Patients under 65 years of age on prophylactic doses of LMWH

Combinationsto be taken into account

The combined use of drugs that affect hemostasis to varying degrees increases the risk of bleeding. Therefore, regardless of the age of the patient, continuous clinical monitoring and, if necessary, laboratory tests should be carried out when prophylactic doses of LMWH are prescribed simultaneously with oral anticoagulants, inhibitors of platelet aggregation (abciximab, NSAIDs, acetylsalicylic acid at any dose, clopidogrel, eptifibatide, iloprost, ticlopidine, tirofoban) and thrombolytic agents.

special instructions

Warnings and Precautions

Although concentrations of various LMWHs are expressed in international anti-Xa units (IU), their effectiveness is not limited to their anti-Xa activity alone. It may not be safe to switch from one LMWH dosing regimen to another LMWH dosing regimen or to a dosing regimen for a drug based on a different synthetic polysaccharide due to the fact that different dosing regimens have been studied in different clinical studies. Thus, an individual approach and adherence to specific instructions for the use of each drug is recommended.

Clexane30,000 anti-xa IU/3 ml: This medicinal product contains 15 mg/ml benzyl alcohol. The drug can be toxic and cause an anaphylactic reaction in newborns and children under the age of 3 years.

Special Warnings

Risk of bleeding

It is necessary to observe the recommended dosing regimens (doses and duration of treatment). Failure to follow these recommendations may lead to the development of bleeding, in particular in high-risk patients (eg, elderly patients, patients with renal insufficiency).

Cases of severe bleeding have been reported in the following situations:

Elderly patients, in particular due to age-related decline in kidney function

Patients with renal insufficiency

Body weight below 40 kg

Simultaneous use of drugs that increase the risk of bleeding (see "Drug Interactions").

In all cases, it is important to conduct special monitoring for elderly patients and / or patients with renal insufficiency, as well as in case of treatment for more than 10 days.

In some cases, it may be useful to determine anti-Xa activity to detect drug accumulation (see "Precautions").

Risk of developing heparin-induced thrombocytopenia (HIT)

With the development of the following thrombotic complications in patients treated with LMWH (therapeutic or prophylactic dose):

Exacerbation of thrombosis after treatment

Pulmonary embolism

Acute lower limb ischemia

Or even myocardial infarction or ischemic stroke

the development of HIT should always be assumed and the number of platelets should be determined urgently (see "Special Instructions").

Application in pediatrics

Due to the lack of relevant data, the use of LMWH in pediatric practice is not recommended.

Mechanical prosthetic heart valves

The use of enoxaparin for the prevention of thromboembolic complications in patients with mechanical prosthetic heart valves has not been specifically studied. However, isolated cases of thrombosis have been reported in patients with mechanical prosthetic heart valves treated with enoxaparin for the prevention of thromboembolic complications.

Use in pregnant women

In a clinical study in pregnant women with mechanical prosthetic heart valves who received 100 anti-Xa IU/kg of enoxaparin twice daily to reduce the risk of thromboembolic complications, 2 of 8 women developed thrombosis, leading to valve block with death mother and fetus. Also, during post-marketing surveillance, isolated cases of valve thrombosis have been reported in pregnant women with mechanical prosthetic heart valves who received enoxaparin for the prevention of thromboembolic complications. Thus, the risk of developing thromboembolic complications for this group of patients may be higher.

Medical prevention

If an episode of acute infectious or rheumatic disease is present, prophylactic treatment is warranted only if at least one of the following risk factors for venous thromboembolism is present:

Age over 75

oncological disease

A history of venous thromboembolism

Obesity

hormone therapy

Heart failure

Chronic respiratory failure

There is only limited experience with the use of the drug for prophylaxis in patients over the age of 80 years weighing less than 40 kg.

Precautionary measures

Bleeding

Also, as is the case with all anticoagulants, bleeding may develop (see "Side Effects"). In the event of bleeding, its cause should be determined and appropriate treatment initiated.

Kidney function

Before initiating treatment with LMWH, it is important to assess renal function, particularly in patients 75 years of age and older, by determining creatinine clearance using the Cockcroft formula based on a recent body weight measurement:

For men, CC = (140-age) x weight/(0.814 x plasma creatinine), where age is in years, weight is in kg, and plasma creatinine is in µmol/L.

For women, this formula should be adjusted by multiplying the result by 0.85. If plasma creatinine is expressed in mg / ml, the indicator should be multiplied by 8.8.

In patients diagnosed with severe renal insufficiency (CC about 30 ml / min), the use of LMWH as a therapeutic therapy is contraindicated (see "Contraindications").

Laboratory tests

Monitoring of platelet counts in patients treated with LMWH and the risk of heparin-induced thrombocytopenia (i.e. HITIItype):

LMWH can cause HIT type II, severe immune-mediated thrombocytopenia, which can lead to the development of arterial or venous thromboembolism, which can be life-threatening or affect functional prognosis (see also "Side Effects"). For optimal detection of HIT, patients should be monitored as follows:

- surgery or recent trauma (within 3 months):

Regardless of the type of therapy prescribed - curative or prophylactic, it is necessary to systematically conduct laboratory tests for all patients, since the incidence of HIT is > 0.1%, or even > 1% in operations and injuries. As part of this analysis, the number of platelets is evaluated:

Before treatment with LMWH or at least 24 hours after initiation of therapy

Then 2 times a week for 1 month (maximum risk period)

Then, if therapy is continued, once a week until therapy is discontinued

- cases other than surgery or recent trauma (within 3 months):

Regardless of the type of therapy prescribed - curative or prophylactic, it is necessary to systematically conduct laboratory tests for the same reasons as in surgery and traumatology (see description above) in patients:

Previously treated with unfractionated heparin (UFH) or LMWH in the last 6 months, given that the incidence of HIT is >0.1%, or even >1%

With the presence of significant comorbidities, given the potential severity of HIT in these patients.

In other cases, taking into account the lower frequency of HIT (<0,1%), контроль числа тромбоцитов может быть снижен до:

Platelet counts at the start of therapy, or within 24 hours of starting therapy

Platelet counts in the presence of clinical symptoms with suspected HIT (any new episode of arterial and / or venous thromboembolism, any painful skin lesion at the injection site, any allergic or anaphylactic symptoms during therapy). Patients should be informed about the possibility of such symptoms and the need to report these symptoms to the doctor.

HIT may be suspected if the platelet count is below 150,000/mm3 or 150 giga/L) and/or there is a relative decrease in platelet count of 30-50% on 2 consecutive platelet count measurements. HIT generally develops 5-21 days after heparin therapy and (with a maximum incidence of approximately 10 days). This complication may develop much earlier in patients with a history of HIT; in some cases, such phenomena were observed after 21 days. Patients with this history should be systematically monitored and carefully questioned prior to initiating therapy. In all cases, the presence of HIT is a situation in which emergency treatment and the opinion of a specialist are required. A significant decrease in the number of platelets (30-50% compared to baseline) is a warning signal even before the numbers reach a critical level. With a decrease in the number of platelets, in all cases the following procedures should be performed:

1) immediate determination of the number of platelets in order to confirm the diagnosis

2) discontinuation of heparin treatment if the decrease in the number of platelets is confirmed or increases, judging by the results of the analysis, in the absence of other obvious reasons. Place blood samples in citrate tubes to perform tests in vitro for platelet aggregation and immunological tests. However, in such cases, immediate action should not be taken on the basis of tests in vitro for platelet aggregation or immunological tests due to the fact that only a few specialized laboratories can perform these tests, and the results are available at the earliest in a few hours. However, these tests are still necessary to diagnose complications, since the risk of thrombosis is very high with continued heparin therapy.

3) prevention or treatment of thrombotic complications associated with HIT. If continuation of anticoagulant therapy is considered important, heparin should be replaced by an antithrombotic drug of another group, for example, danaproide sodium or lepirudin, prescribed in therapeutic or prophylactic doses and on an individual basis. Replacement with oral anticoagulants is possible only after normalization of the platelet count due to the risk of recurrent thrombosis under the influence of oral anticoagulants.

Replacement of heparin with oral anticoagulants

Clinical surveillance and laboratory testing [prothrombin time expressed as international normalized ratio (INR)] should be strengthened to monitor the effect of oral anticoagulants. Due to the presence of an interval prior to the development of the maximum effect of an oral anticoagulant, heparin therapy should be carried out at a constant dose and for the time that will be necessary to maintain the INR in the desired therapeutic range for this indication according to the results of 2 consecutive tests.

Monitoring anti-factorxa-activities

Due to the fact that most of the clinical studies demonstrating the effectiveness of LMWH were conducted using a dose calculated based on body weight without specific laboratory monitoring, the suitability of laboratory tests for evaluating the effectiveness of treatment with LMWH has not been established. However, laboratory tests, such as those to monitor anti-Xa activity, may be useful in managing the risk of bleeding in some clinical conditions, often associated with the risk of overdose.

In connection with the prescribed doses, such cases relate mainly to the therapeutic indications of LMWH for use by patients:

Mild to moderate renal insufficiency (creatinine clearance approximately 30 ml/min to 60 ml/min calculated using Cockcroft's formula). Due to the fact that LMWH is predominantly excreted through the kidneys, in contrast to standard unfractionated heparin, any renal failure can lead to a relative overdose. Severe renal insufficiency is a contraindication for the use of LMWH at therapeutic doses (see "Contraindications")

Extremely large or low body weight (wasting or even cachexia, obesity)

With bleeding of unknown etiology

To detect possible accumulation of heparin during repeated administration, it is recommended, if necessary, to analyze blood for analysis at the peak of activity (based on available data), that is, approximately 4 hours after the 3rd injection, when the drug is administered subcutaneously twice a day. Repeated anti-Xa activity tests to determine blood heparin levels, for example, every 2-3 days, should be prescribed on an individual basis depending on the results of the previous test, and dose adjustment of LMWH should be considered. The observed anti-Xa activity varies for each LMWH and each dosing regimen.

Note: Based on available data, the mean (±SD) observed 4 hours after the 7th injection of enoxaparin administered at a dose of 100 anti-Xa IU/kg/injection twice daily was 1.20 ± 0 .17 anti-Xa IU/ml.

The same average was observed in clinical studies measuring anti-Xa activity performed by the chromogenic (amidolytic) method.

Activated partial thromboplastin time (APTT)

Some LMWH cause a moderate increase in aPTT. Since clinical significance has not been proven, this test is not needed to monitor treatment.

Spinal/epidural anesthesia in patients with prophylactic

treatment of LMWH

As with other anticoagulants, rare cases of spinal hematomas have been reported during concomitant administration of low molecular weight heparins during spinal or epidural anesthesia, causing prolonged or irreversible paralysis. The risk of spinal hematoma is higher with catheter-assisted epidural anesthesia than with spinal anesthesia. The risk of such rare disorders may increase in the case of prolonged use of epidural catheters in the postoperative period. If preoperative treatment with LMWH is needed (patients, long-term bedridden, trauma), and if the benefit of local/regional spinal anesthesia is carefully weighed, patients who receive preoperative LMWH injection may be anesthetized, provided that between heparin injection and spinal anesthesia for at least 12 hours. Careful neurological monitoring is recommended because of the risk of spinal hematoma. Prophylactic treatment of LMWH in almost all patients can be started 6-8 hours after anesthesia or catheter removal, providing neurological monitoring. Special care must be taken when administering the drug simultaneously with other drugs that affect hemostasis (especially non-steroidal anti-inflammatory drugs, acetylsalicylic acid).

Situations of particular risk

Monitoring of treatment should be strengthened in the following cases:

Liver failure

History of gastrointestinal ulcers or other organic changes prone to bleeding

Vascular disease of choriretin

Postoperative period after surgery on the brain or spinal cord

Lumbar puncture: the risk of intraspinal bleeding should be considered and should be deferred if possible

Simultaneous use of drugs that affect hemostasis (see "Drug Interactions")

Percutaneous coronary revascularization (PCR) procedures (for Clexane 6,000, 8,000, 10,000 and 30,000 anti-xaIU)

To reduce the risk of bleeding after percutaneous coronary intervention in the treatment of unstable angina, myocardial infarction without Q wave and acute myocardial infarction with ST segment elevation, it is recommended to strictly observe the recommended dose intervals of enoxaparin sodium. It is important to achieve hemostasis at the puncture site after RCC. If a protective device is used, the catheter can be withdrawn immediately. If the manual compression method is used, the catheter should be withdrawn 6 hours after the last subcutaneous/intravenous injection of enoxaparin sodium. If therapy is continued, the next dosing regimen should be administered no earlier than 6-8 hours after catheter removal. Evaluate for signs of bleeding or hematoma formation at the insertion site.

Pregnancy

In preclinical studies, no facts confirming the teratogenicity of enoxaparin have been identified. In the absence of any teratogenic effect in preclinical studies, a similar effect when using the drug in clinical studies is not expected. To date, carefully designed studies in two animal species have shown that substances that cause malformations in humans are also teratogenic in animals.

Preventive therapy during the first trimester and curative therapy

Currently available clinical data are insufficient to assess the possible teratogenic or fetotoxic effects of enoxaparin, administered prophylactically during the first trimester of pregnancy or therapeutic doses throughout pregnancy. Therefore, as a precautionary measure, enoxaparin is not recommended for prophylactic use during the first trimester or at therapeutic doses throughout pregnancy. If epidural anesthesia is planned, prophylactic heparin treatment should be discontinued, if possible, at least 12 hours before anesthesia. Epidural or spinal anesthesia should never be performed in the treatment of LMWH.

Prophylactic treatment during the 2nd and 3rd trimesters

To date, data from the clinical use of enoxaparin in a small number of pregnancies in the 2nd and 3rd trimesters does not indicate that the drug prescribed in prophylactic doses has any particular teratogenic or fetotoxic effect. However, more research is needed to evaluate the effects in these conditions.

Therefore, enoxaparin prophylaxis during the 2nd and 3rd trimesters can be done if needed. If epidural anesthesia is planned, prophylactic heparin treatment should be discontinued, if possible, at least 12 hours before anesthesia.

Lactation

Since gastrointestinal absorption is unlikely in neonates, enoxaparin treatment is not contraindicated in women who are breastfeeding.

Features of the influence of the drug on the ability to drive a vehicle or potentially dangerous mechanisms

Not installed.

Overdose

Symptoms: hemorrhagic complications in case of accidental overdose with subcutaneous administration of massive doses of LMWH. In the event of bleeding in some patients, treatment with protamine sulfate may be considered, taking into account the following factors:

The efficacy of this drug is much lower than that reported with unfractionated heparin overdoses.

Due to adverse reactions (especially anaphylactic shock), the benefit / risk ratio of protamine sulfate should be carefully weighed before prescribing the drug. Neutralization of Clexane is carried out by slow intravenous administration of protamine (as sulfate or hydrochloride).

The required dose of protamine depends on:

An administered dose of heparin (100 anti-heparin units of protamine neutralizes the activity of 100 anti-Xa IU LMWH) if enoxaparin sodium was administered within the last 8 hours

From the time elapsed since the introduction of heparin:

An infusion of 50 anti-heparin units of protamine per 100 anti-Xa IU of enoxaparin sodium can be administered if more than 8 hours have passed since the administration of enoxaparin sodium, or if a second dose of protamine is needed

There is no need to administer protamine if more than 12 hours have passed since the injection of enoxaparin.

However, it is not possible to completely neutralize anti-Xa activity. In addition, neutralization may be only temporary due to the pharmacokinetic characteristics of LMWH absorption, which may require dividing the total calculated dose of protamine into several injections (2-4) produced in a 24-hour period.

In general, no serious consequences are expected after taking LMWH even in large quantities (no reported cases) due to the very low absorption of this drug in the stomach and intestines.

Release form and packaging

0.2 ml or 0.6 ml solution in glass syringes with a needle protection system. 2 pre-filled syringes are placed in a plastic container. 1 container, together with instructions for medical use in the state and Russian languages, is placed in a cardboard box.