Enoxaparin-Binergia solution for injection 10000 anti-HaIU/ml 0.4ml ampoules, 10pcs

Composition

1 syringe or ampoule (1.0 ml) contains:

Active ingredient:

enoxaparin sodium 10000 anti-XaIU (100 mg*);

excipient: water for injection-up to 1.0 ml.

* Weight is calculated based on the content of enoxaparin sodium used (theoretical activity 100 anti-Xa IU / mg).

Pharmacological action

Pharmacotherapeutic group: Direct-acting anticoagulant

ATX Code: B 01 AB 05

Pharmacological properties

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

Pharmacodynamics

In a purified in vitro system, enoxaparin sodium has high anti-Xa activity (approximately 100 IU / ml) and low anti-Pa or antithrombin activity (approximately 28 IU/ml). This anticoagulant activity acts through antithrombin III (AT-III), providing anticoagulant activity in humans. In addition to anti-Xa / IIa activity, additional anticoagulant and anti-inflammatory properties of enoxaparin sodium were also revealed both in healthy people and patients, as well as in animal models. This includes AT-III dependent inhibition of other clotting factors, such as factor VIIa, activation of the release of the tissue factor pathway inhibitor (PTF), and reduction of the release of von Willebrand factor from the vascular endothelium into the bloodstream. These factors contribute to the overall anticoagulant effect of enoxaparin sodium.

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

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

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

Pharmacokinetics

The pharmacokinetics of enoxaparin sodium in these dosage regimens are linear.

Suction and distribution

After repeated subcutaneous use of enoxaparin sodium at a dose of 40 mg and at a dose of 1.5 mg/kg body weight once a day in healthy volunteers, the equilibrium concentration is reached by the second day, and the area under the concentration-time curve is on average 15% higher than after a single use. After repeated subcutaneous use of enoxaparin sodium at a daily dose of 1 mg/kg body weight twice a day, the equilibrium concentration is reached in 3-4 days, and the area under the concentration-time curve is on average 65% higher than after a single use and the average values of maximum concentrations are 1.2 IU / ml and 0.52 IU/ml, respectively. The bioavailability of enoxaparin sodium with subcutaneous use, estimated on the basis of anti-Xa activity, is close to 100%. The volume of distribution of enoxaparin sodium (according to anti-Xa activity) is approximately 5 liters and approaches the volume of blood.

Metabolism

Enoxaparin sodium is biotransformed mainly in the liver by desulfation and / or depolymerization to form low-molecular-weight substances with very low biological activity.

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

Elimination of the drug is monophasic with a half-life (T_1/2) of 4 hours (after a single subcutaneous injection) and 7 hours (after repeated use of the drug). Renal excretion of active fragments of the drug is approximately 10% of the administered dose, and the total excretion of active and inactive fragments is approximately 40% of the administered dose.

Pharmacokinetics in special patient groups

It is possible to delay the rate of elimination of enoxaparin sodium in elderly patients as a result of decreased renal function.

In patients with reduced renal function, there is a decrease in the clearance of enoxaparin sodium. In patients with mild (creatinine clearance 50-80 ml/min) and moderate (creatinine clearance 30-50 ml/min) renal impairment, after repeated subcutaneous use of 40 mg of enoxaparin sodium once a day, anti-Xa activity increases, represented by the area under the pharmaceutical curve.

In patients with severe renal impairment (creatinine clearance less than 30 ml / min) with repeated subcutaneous use of the drug at a dose of 40 mg once a day, the area under the pharmaceutical curve at steady state is on average 65% higher.

In overweight patients, subcutaneous use of the drug has a slightly lower clearance. If no dose adjustment is made for the patient’s body weight, then after a single subcutaneous injection of enoxaparin sodium at a dose of 40 mg, anti-Xa activity will be 50% higher in women with a body weight of less than 45 kg and 27% higher in men with a body weight of less than 57 kg compared to patients with a normal average body weight.

Indications

• prophylaxis of venous thrombosis and embolism in surgical interventions, especially in orthopedic and General surgical operations;
• prevention of venous thrombosis and thromboembolism in patients on bed rest due to acute internal diseases (congestive heart failure, chronic heart failure decompensation III or IV functional class 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 embolism pulmonary embolism;
• treatment of unstable angina and myocardial infarction without Q wave in combination with acetylsalicylic acid;
• treatment of acute myocardial infarction with ST-segment elevation in patients subject to medical treatment or subsequent percutaneous coronary intervention;
• prevention of clotting in the extracorporeal blood circulation during hemodialysis (usually in session no more than 4 hours).

Use during pregnancy and lactation

Pregnancy

There is no evidence that enoxaparin sodium penetrates the placental barrier during the second trimester of pregnancy in humans. There is no relevant information regarding the first and third trimesters of pregnancy.

Since there are no adequate and well-controlled studies in pregnant women, and animal studies do not always predict a response to the introduction of enoxaparin sodium during pregnancy in humans, it should be used during pregnancy only in cases where there is an urgent need for use established by a doctor.

Breast-feeding period

It is not known whether unchanged enoxaparin sodium is excreted in human breast milk. Absorption of enoxaparin sodium in the gastrointestinal tract in a newborn is unlikely. However, as a precautionary measure, breastfeeding women treated with enoxaparin sodium should be advised to discontinue breastfeeding.

Contraindications

• hypersensitivity to enoxaparin sodium, heparin or its derivatives, including other low molecular weight heparins;
• large active bleeding, as well as the conditions and diseases in which there is a high risk of bleeding: threatened abortion, aneurysm of cerebral vessels or dissecting aneurysm of the aorta (except surgery for this reason), recent hemorrhagic stroke, uncontrolled bleeding, thrombocytopenia in combination with positive test in vitro for antiplatelet antibody in the presence of enoxaparin sodium;
• age to 18 years (efficacy and safety not established).

With caution

Conditions where there is a potential risk of bleeding:

• hemostatic disorders (including hemophilia, thrombocytopenia, anticoagulation, von Willebrand disease, etc. ), severe vasculitis;
• peptic ulcer of the stomach or duodenum, other erosive and ulcerative lesions of the gastrointestinal tract (GIT) in history;
• recent ischemic stroke;
• severe uncontrolled hypertension; diabetic or hemorrhagic retinopathy; severe diabetes mellitus;
• recent or suspected neurological or ophthalmic surgery;
• the conduct of spinal or epidural anesthesia (potential risk of bruising), lumbar puncture (recent);
• recent childbirth;
• bacterial endocarditis (acute or subacute);
• pericarditis or pericardial effusion;
• renal and/or hepatic failure;
• intrauterine contraception (IUD);
• severe trauma (especially of the Central nervous system), open wounds on large surfaces;
• concomitant use of drugs affecting hemostasis; heparin-induced thrombocytopenia (history) in combination with or without thrombosis.

There are no data on the clinical use of enoxaparin sodium in the following diseases: active tuberculosis, radiation therapy (recently transferred).

Side effects

Study the side effects of enoxaparin sodium was carried out in more than 15,000 patients participating in clinical trials, of which, in 1776 patients in the prevention of venous thrombosis and embolism in surgical and orthopedic surgery; in 1169 patients in the prevention of venous thrombosis and embolism in patients on bed rest due to acute internal diseases; in 559 patients in the treatment of deep vein thrombosis with pulmonary embolism or without pulmonary embolism; in 1578 patients in the treatment of unstable angina and myocardial infarction without Q wave; have 10176 patients in the treatment of myocardial infarction with ST-segment elevation.

The mode of use of enoxaparin sodium differed depending on the indications.

In the prevention of venous thrombosis and embolism in general surgical and orthopedic operations or in patients on bed rest,40 mg was administered subcutaneously once a day.

In the treatment of deep vein thrombosis with or without pulmonary embolism, patients received enoxaparin sodium at the rate of 1 mg/kg body weight subcutaneously every 12 hours or 1.5 mg/kg body weight subcutaneously once a day.

In the treatment of unstable angina and non-Q-wave myocardial infarction, the dose of enoxaparin sodium was 1 mg / kg body weight subcutaneously every 12 hours, and in the case of ST-segment elevation myocardial infarction, an intravenous bolus of 30 mg was administered followed by 1 mg/kg body weight subcutaneously every 12 hours.

Adverse reactions were classified by frequency as follows: very frequent (≥1/10), frequent (≥1/100 – <1/10), infrequent (≥1/1000 – <1/100), rare (≥1/10000 – <1/1000), very rare (

Vascular disorders

Bleeding issues

In clinical studies, bleeding was the most common adverse reaction. These included large bleeding events that were observed in 4.2% of patients (bleeding was considered large if it was accompanied by a decrease in hemoglobin content by 2 g/l or more, required transfusion of 2 or more doses of blood components, and if it was retroperitoneal or intracranial). Some of these cases were fatal.

As with other anticoagulants, bleeding may occur when enoxaparin sodium is used, especially if there are risk factors that contribute to the development of bleeding, when performing invasive procedures or using drugs that disrupt hemostasis (see the sections “Special instructions” and “Interactions with other drugs”).

When describing bleeding below, the ” * ” sign indicates the following types of bleeding: hematoma, ecchymosis (except for those that developed at the injection site), wound hematomas, hematuria, nosebleeds, gastrointestinal bleeding.

Very clean-bleeding* in the prevention of venous thrombosis in surgical patients and in the treatment of deep vein thrombosis with or without pulmonary embolism.

Frequent-bleeding* in the prevention of venous thrombosis in patients on bed rest, and in the treatment of unstable angina, non-Q-wave myocardial infarction, and ST-segment elevation myocardial infarction.

Infrequent-retroperitoneal bleeding and intracranial hemorrhage in patients with deep vein thrombosis with or without pulmonary embolism, as well as in the treatment of ST-segment elevation myocardial infarction.

Rare-retroperitoneal bleeding in the prevention of venous thrombosis in surgical patients and in unstable angina and non-Q-wave myocardial infarction.

Thrombocytopenia and thrombocytosis

Very frequent – thrombocytosis (the number of platelets in the peripheral blood is more than 400×109/l) in the prevention of venous thrombosis in surgical patients and in the treatment of deep vein thrombosis with or without pulmonary embolism.

Frequent-thrombocytosis in the treatment of patients with acute ST-segment elevation myocardial infarction. Thrombocytopenia in the prevention of venous thrombosis in surgical patients and in the treatment of deep vein thrombosis with or without pulmonary embolism, as well as in acute ST-segment elevation myocardial infarction.

Infrequent-thrombocytopenia in the prevention of venous thrombosis in patients on bed rest, and in the treatment of unstable angina and non-Q-wave myocardial infarction.

Very rare – immuno-allergic thrombocytopenia in the treatment of patients with acute ST-segment elevation myocardial infarction.

Other clinically significant adverse reactions regardless of indications

The adverse reactions presented below are grouped by organ-system classes, given with an indication of the frequency of their occurrence determined above and in order of decreasing their severity.

• Immune system disorders
• are Frequent: allergic reactions.
• Rare ones: anaphylactic and anaphylactoid reactions.

Liver and biliary tract disorders

• Very frequent ones: an increase in the activity of” liver ” enzymes, mainly an increase in the activity of transaminases, more than three times higher than the upper limit of normal.

Skin and subcutaneous tissue disorders

• are frequent: urticaria, pruritus, erythema.
• Infrequent ones: bullous dermatitis.

General disorders and disorders at the injection

• site are frequent: hematoma at the injection site, pain at the injection site, swelling at the injection site, bleeding, hypersensitivity reactions, inflammation, formation of seals at the injection site.
• Infrequent ones: irritation at the injection site, skin necrosis at the injection site.

Laboratory and instrumental data: Rare ones: hyperkalemia.

Data obtained in the post-registration period

The following adverse reactions were reported during post-marketing use of enoxaparin sodium. These adverse reactions were spontaneously reported and their frequency was defined as “frequency unknown” (cannot be determined from available data).

Immune system disorders: Anaphylactic / anaphylactoid reactions, including shock.

Nervous system disorders: Headache.

Vascular disorders: When using enoxaparin sodium on the background of spinal/epidural anesthesia or spinal puncture, cases of spinal hematoma (or neuroaxial hematoma) have been reported. These reactions led to the development of neurological disorders of varying severity, including persistent or irreversible paralysis (see the section “Special instructions”).

Disorders of the blood and lymphatic system: Hemorrhagic anemia. Cases of immune-allergic thrombocytopenia with thrombosis; in some cases, thrombosis was complicated by the development of organ infarction or limb ischemia (see the section “Special instructions”, subsection “Monitoring the number of platelets in peripheral blood”).

Eosinophilia.

Skin and subcutaneous tissue disorders: At the injection site, cutaneous vasculitis, skin necrosis may develop, which is usually preceded by the appearance of purpura or erythematous papules (infiltrated and painful). In these cases, enoxaparin sodium therapy should be discontinued. It is possible to form solid inflammatory nodules-infiltrates at the injection site of the drug, which disappear after a few days and are not a reason for discontinuing the drug.

Alopecia.

Liver and biliary tract disorders: Hepatocellular liver damage. Cholestatic liver damage.

Musculoskeletal and connective tissue disorders: Osteoporosis with long-term therapy (more than three months).

Interaction

Enoxaparin sodium should not be mixed with other medications!When used concomitantly with drugs that affect hemostasis (systemic salicylates, acetylsalicylic acid, nonsteroidal anti-inflammatory drugs (including ketorolac), dextran with a molecular weight of 40 kDa, ticlopidine and clopidogrel, systemic glucocorticosteroids, thrombolytics or anticoagulants, other antiplatelet drugs (including glycoprotein IIb/IIIa antagonists)), increases the risk of bleeding.

How to take, course of use and dosage

Except in special cases, enoxaparin sodium is administered deep subcutaneously. Injections should preferably be performed in the patient’s “lying down” position. When using pre-filled 20 mg and 40 mg syringes, do not remove air bubbles from the syringe before injection to avoid drug loss.Injections should be performed alternately in the left or right anterolateral or posterolateral surface of the abdomen. The needle must be inserted vertically (not laterally) into the entire length of the skin fold, which is collected and held between the thumb and index finger until the injection is completed. The skin fold is released only after the injection is completed. Do not massage the injection site after use of the drug. The pre-filled disposable syringe is ready for use.

The drug should not be administered intramuscularly!

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

In patients with a moderate risk of developing thrombosis and embolism (for example, abdominal surgery), the recommended dose of the drug is 20 mg once a day subcutaneously. The first injection should be given 2 hours before surgery.

Patients with a high risk of developing thrombosis and embolism (for example, during orthopedic operations, surgical operations in oncology, patients with additional risk factors not related to surgery, such as congenital or acquired thrombophilia, malignancy, bed rest for more than three days, obesity, a history of venous thrombosis, varicose veins of the lower extremities, pregnancy), the drug is recommended at a dose of 40 mg once a day subcutaneously, with the first dose administered 12 hours before surgery, or at a dose of 30 mg twice a day with the start of use 12-24 hours after surgery.

The average duration of treatment with enoxaparin sodium is 7-10 days. If necessary, therapy can be continued as long as there is still a risk of developing thrombosis and embolism, and until the patient switches to outpatient mode.

In orthopedic operations, it may be advisable to continue treatment after the initial therapy by injecting the drug at a dose of 40 mg once a day for 3 weeks.

Features of using the drug during spinal / epidural anesthesia, as well as during coronary revascularization procedures.

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

The recommended dose of enoxaparin sodium is 40 mg once daily subcutaneously for at least 6 days. Therapy should be continued until the patient is completely switched to outpatient mode (maximum for 14 days).

Treatment of deep vein thrombosis with or without pulmonary embolism

The drug is administered subcutaneously at the rate of 1.5 mg / kg of body weight once a day or 1 mg / kg of body weight twice a day. In patients with complicated thromboembolic disorders, the drug is recommended to be used at a dose of 1 mg/kg twice a day. The average duration of treatment is 10 days.

Indirect anticoagulant therapy should be initiated immediately, and enoxaparin sodium treatment should be continued until the therapeutic anticoagulant effect is achieved (the INR (International Normalized Ratio) value should be 2.0-3.0).

Prevention of thrombosis in the extracorporeal circulatory system during hemodialysis

The recommended dose of enoxaparin sodium is on average 1 mg / kg of body weight.

If there is a high risk of bleeding, the dose should be reduced to 0.5 mg / kg of body weight with double vascular access or to 0.75 mg with single vascular access.

During hemodialysis, enoxaparin sodium should be injected into the arterial section of the shunt at the beginning of the hemodialysis session. One dose is usually 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.

Treatment of unstable angina and non-Q wave myocardial infarction

Enoxaparin sodium is administered at the rate of 1 mg/kg of body weight every 12 hours, subcutaneously, with simultaneous use of acetylsalicylic acid at a dose of 100-325 mg once a day.

The average duration of therapy is at least 2 days and continues until the patient’s clinical condition stabilizes. Usually, the drug use lasts from 2 to 8 days.

Treatment of acute ST-segment elevation myocardial infarction, by medication or by percutaneous coronary intervention

Treatment begins with a single intravenous bolus injection of enoxaparin sodium at a dose of 30 mg. Immediately after this, enoxaparin sodium is administered subcutaneously at a dose of 1 mg/kg of body weight. Next, the drug is administered subcutaneously at 1 mg / kg of body weight every 12 hours (maximum 100 mg of enoxaparin sodium for each of the first two subcutaneous injections, then 1 mg/kg of body weight for the remaining subcutaneous doses, that is, with a body weight of more than 100 kg, a single dose may exceed 100 mg).

In patients 75 years and older, the initial intravenous bolus is not used.

The drug is administered subcutaneously at a dose of 0.75 mg / kg every 12 hours (maximum 75 mg of enoxaparin sodium for each of the first two subcutaneous injections, then 0.75 mg/kg of body weight for the remaining subcutaneous doses, that is, with a body weight of more than 100 kg, a single dose may exceed 75 mg).

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

The recommended duration of treatment with enoxaparin sodium is 8 days or until the patient is discharged from the hospital (if the period of hospitalization is less than 8 days).

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

For bolus use of 30 mg of enoxaparin sodium in the treatment of acute ST-segment elevation myocardial infarction, an excess amount of the drug is removed from glass syringes of 60 mg,80 mg or 100 mg so that only 30 mg (0.3 ml) remains in them. A dose of 30 mg can be directly administered intravenously.

For intravenous bolus use of enoxaparin sodium through a venous catheter, pre-filled syringes for subcutaneous use of the drug 60 mg,80 mg or 100 mg can be used. It is recommended to use syringes of 60 mg, as this reduces the amount of drug removed from the syringe. 20 mg syringes are not used, as they do not contain enough drug for intravenous bolus use of 30 mg of enoxaparin sodium. Syringes of 40 mg are not used, as they do not have divisions and therefore it is impossible to accurately measure the amount of 30 mg.

In patients undergoing percutaneous coronary intervention, if the last subcutaneous injection was performed less than 8 hours before inflating the balloon catheter inserted into the site of narrowing of the coronary artery, additional use of enoxaparin sodium is not required. If the last subcutaneous injection of enoxaparin sodium was performed more than 8 hours before inflating the balloon catheter, an additional intravenous bolus of enoxaparin sodium should be administered at a dose of 0.3 mg / kg.

To increase the accuracy of additional intravenous bolus use 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. Dilution of the solution is recommended immediately before use.

To obtain a solution of enoxaparin sodium with a concentration of 3 mg / ml using a pre-filled 60 mg syringe, it is recommended to use a container with an infusion solution of 50 ml (that is, with 0.9% sodium chloride solution or 5% dextrose solution).30 ml of the solution is extracted and removed from the container with the infusion solution using a conventional syringe. Enoxaparin sodium (the contents of the hypodermic syringe 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 carefully mixed. For use with a syringe, the required volume of diluted enoxaparin sodium solution is extracted, which is calculated by the formula:Volume of diluted solution = Patient’s body weight (kg) x 0.1;or using the table below.

Table 1. Volumes to be administered intravenously after dilution

Dosage regimen for special patient groups

Elderly patients

With the exception of treatment of ST – segment elevation myocardial infarction (see above), no dose reduction of enoxaparin sodium is required for all other indications in elderly patients who do not have impaired renal function.

Patients with impaired renal function

Severe renal impairment (creatinine clearance less than 30 ml / min)

The dose of enoxaparin sodium is reduced in accordance with the tables below, as these patients show an increase in systemic exposure (duration of action) of the drug.

When using the drug for therapeutic purposes, the following dosage adjustment is recommended::

When using the drug for preventive purposes in patients with a moderate risk of developing thromboembolic complications, it is recommended to adjust the dosage regimen shown in the table below.

The recommended dosage adjustment is not used for hemodialysis.

In patients with mild (creatinine clearance 50-80 ml/min) and moderate (creatinine clearance 50-50 ml/min) renal impairment, no dose adjustment is required, but patients should be carefully monitored by a doctor.

Patients with impaired liver function

Due to the lack of clinical studies, enoxaparin sodium should be used with caution in patients with impaired liver function.

Instructions for self-use of enoxaparin sodium injection

When using the drug, strictly follow the recommendations given in these instructions, as well as the instructions of a doctor or pharmacist. If you have any questions, contact your doctor or pharmacist.

Overdose

Symptoms: accidental overdose with intravenous, extracorporeal or subcutaneous use 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 use of protamine sulfate is indicated, the dose of which depends on the dose of enoxaparin sodium administered. It should be taken into account that 1 mg of protamine sulfate neutralizes the anticoagulant effect of 1 mg of enoxaparin sodium, if the drug was administered no more than 8 hours before the use of protamine sulfate. 0.5 mg of protamine sulfate neutralizes the anticoagulant effect of 1 mg of enoxaparin sodium, if more than 8 hours have passed since the last dose was administered, or if a second dose of protamine sulfate is necessary. If 12 hours or more have elapsed since the introduction of enoxaparin sodium, the introduction of protamine sulfate is not required. However, even with high doses of protamine sulfate. The anti-Xa activity of enoxaparin sodium is not completely neutralized (by a maximum of 60%).

Description

Clear, colorless to pale yellow solution.

Special instructions

General information

Low-molecular-weight heparins are not interchangeable, as they differ in the production process, molecular weight, specific anti-Xa activity, dosage units and dosage regimen, which are associated with differences in their pharmacokinetics and biological activity (antithrombin activity and platelet interaction). Therefore, it is necessary to strictly follow the recommendations for use for each drug belonging to the class of low-molecular-weight heparins.

Bleeding

As with other anticoagulants, the use of enoxaparin sodium may cause bleeding of any localization. If bleeding develops, it is necessary to find its source and prescribe appropriate treatment.

Bleeding in elderly patients

When using enoxaparin sodium in prophylactic doses in elderly patients, there was no increase in the risk of bleeding.

When using the drug in therapeutic doses in elderly patients (especially at the age of 80 years and older), there is an increased risk of bleeding. Careful monitoring of these patients is recommended.

Concomitant use of other drugs that affect hemostasis

It is recommended that the use of drugs that affect hemostasis (salicylates, including acetylsalicylic acid, nonsteroidal anti-inflammatory drugs, including ketorolac; dextran with a molecular weight of 40 kDa, ticlopidine, clopidogrel; glucocorticosteroids, thrombolytics, anticoagulants, antiplatelet agents, including glycoprotein IIb/IIIa receptor antagonists) be discontinued before starting treatment enoxaparin sodium, except in cases where their use is necessary. If combinations of enoxaparin sodium with these drugs are indicated, then careful clinical monitoring and monitoring of appropriate laboratory parameters should be carried out.

Kidney failure

Patients with impaired renal function are at risk of developing bleeding as a result of increased systemic exposure to enoxaparin sodium. In patients with severe renal impairment (creatinine clearance less than 30 ml / min), there is a significant increase in exposure to enoxaparin sodium, so it is recommended to adjust the dose for both preventive and therapeutic use of the drug. Although no dose adjustment is required in patients with mild to moderate renal impairment (creatinine clearance 30-50 ml / min or 50-80 ml / min), careful monitoring of these patients is recommended.

Low body weight

There was an increase in exposure to enoxaparin sodium with its preventive use in women with a body weight of less than 45 kg and in men with a body weight of less than 57 kg, which may lead to an increased risk of bleeding. Careful monitoring of these patients is recommended.

Obese patients

Obese patients have an increased risk of developing thrombosis and embolism. The safety and efficacy of enoxaparin sodium in prophylactic doses in obese patients (body mass index (BMI) greater than 30 kg/m2) is not fully defined and there is no consensus on dose adjustment. These patients should be closely monitored for the development of symptoms and signs of thrombosis and embolism.

Controlling the number of platelets in peripheral blood

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

Spinal / epidural anesthesia

Cases of occurrence of neuroaxial hematomas with enoxaparin sodium and simultaneous spinal/epidural anesthesia with the development of long-term or irreversible paralysis are described. The risk of these events is reduced when the drug is administered at a dose of 40 mg or lower. The risk increases with higher doses of enoxaparin sodium, as well as with the use of permanent catheters after surgery, or with the simultaneous use of additional drugs. hemostasis-related medications, such as nonsteroidal anti-inflammatory drugs. The risk is also increased with traumatic or repeated spinal puncture, or in patients with a history of spinal surgery or spinal deformity.

To reduce the possible risk of bleeding associated with the use of enoxaparin sodium and epidural or spinal anesthesia/analgesia, the pharmacokinetic profile of the drug should be taken into account.

Catheter insertion or removal is best performed when the anticoagulant effect of enoxaparin sodium is low, but the exact time to achieve a sufficient reduction in the anticoagulant effect in different patients is unknown.

Catheter insertion or removal should be performed at least 12 hours after use of lower doses of enoxaparin sodium (20 mg once a day,30 mg once or twice a day,40 mg once a day) and at least 24 hours after use of higher doses of enoxaparin sodium (0.75 mg/kg of body weight twice a day,1 mg/kg of body weight twice a day,1.5 mg/kg of body weight once a day).

At these time points, the anti-Xa activity of the drug still continues to be detected, and time delays are not a guarantee that the development of a neuroaxial hematoma can be avoided. Patients receiving enoxaparin sodium at doses of 0.75 mg / kg of body weight twice a day or 1 mg/kg of body weight twice a day, with this (twice a day) dosage regimen, should not be given a second dose in order to increase the interval before installing or replacing the catheter.

Similarly, consideration should be given to delaying the next dose of the drug for at least 4 hours, based on an assessment of the benefit/risk ratio (risk of thrombosis and bleeding during the procedure, taking into account the presence of risk factors in patients). However, it is not possible to give clear recommendations on the time of use of the next dose of enoxaparin sodium after catheter removal. It should be noted that in patients with a creatinine clearance of less than 30 ml/min, the elimination of enoxaparin sodium slows down. Therefore, in this category of patients, doubling the time from catheter removal should be considered: at least 24 hours for lower doses of enoxaparin sodium (30 mg once daily) and at least 48 hours for higher doses (1 mg/kg body weight per day).

If the doctor prescribes anticoagulant therapy during epidural / spinal anesthesia or lumbar puncture, the patient should be constantly monitored for any neurological symptoms, such as back pain, impaired sensory and motor functions (numbness or weakness in the lower extremities), impaired bowel and/or bladder function. The patient should be instructed to inform the doctor immediately if the symptoms described above occur. If symptoms that are characteristic of a spinal cord hematoma are suspected, urgent diagnosis and treatment are required, including, if necessary, spinal cord decompression.

Heparin-induced thrombocytopenia

Enoxaparin sodium should be used with extreme caution in patients who have a history of heparin-induced thrombocytopenia with or without thrombosis. The risk of heparin-induced thrombocytopenia may persist for several years. If a history of heparin-induced thrombocytopenia is suspected, then in vitro platelet aggregation tests are of limited importance in predicting the risk of its development. The decision on the use of enoxaparin sodium in this case can be made only after consultation with the appropriate specialist.

Percutaneous coronary angioplasty

In order to minimize the risk of bleeding associated with invasive vascular instrumental manipulation in the treatment of unstable angina and non-Q-wave myocardial infarction and acute ST-segment elevation myocardial infarction, these procedures should be performed at intervals between the use of enoxaparin sodium. This is necessary in order to achieve hemostasis after percutaneous coronary intervention.

If a closure device is used, the femoral artery introducer can be removed immediately. When applying manual compression, the femoral artery introducer should be removed 6 hours after the last intravenous or subcutaneous injection of enoxaparin sodium. If treatment with enoxaparin sodium continues, the next 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 introduction of the introducer in order to detect signs of bleeding and hematoma formation in a timely manner.

Patients with mechanical artificial heart valves

The use of enoxaparin sodium for the prevention of thrombosis in patients with mechanical artificial heart valves has not been sufficiently studied. There have been isolated reports of cardiac valve thrombosis in patients with mechanical artificial heart valves treated with enoxaparin sodium to prevent thrombosis. Evaluation of these reports is limited due to the presence of competing factors contributing to the development of artificial heart valve thrombosis, including the underlying disease, and due to insufficient clinical data.

Pregnant women with mechanical artificial heart valves

The use of enoxaparin sodium for the prevention of thrombosis in pregnant women with mechanical artificial heart valves has not been sufficiently studied.In a clinical study of pregnant women with mechanical artificial heart valves, when enoxaparin sodium was administered at a dose of 1 mg/kg of body weight twice a day to reduce the risk of thrombosis and embolism,2 out of 8 women developed blood clots that led to blockage of the heart valves and death of the mother and fetus.

There are isolated post-marketing reports of heart valve thrombosis in pregnant women with mechanical artificial heart valves treated with enoxaparin sodium to prevent thrombosis.

Pregnant women with mechanical artificial heart valves have a high risk of developing thrombosis and embolism.

Laboratory tests

In doses used for the prevention of thromboembolic complications, enoxaparin sodium does not significantly affect the bleeding time and blood clotting parameters, as well as platelet aggregation or binding to fibrinogen.

When the dose is increased, the APTT and activated blood clotting time may be prolonged. The increase in APTT and activated clotting time are not directly linearly related to the increase in anticoagulant 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 case of acute infection, acute rheumatic conditions, prophylactic use of enoxaparin sodium is justified 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;• hormone therapy;• heart failure;• chronic respiratory failure.

Application in pediatrics

The safety and efficacy of enoxaparin sodium in children under 18 years of age have not been established.

Influence on the ability to drive vehicles and mechanisms

Enoxaparin sodium does not affect the ability to drive vehicles and mechanisms.

Storage conditions

At a temperature not exceeding 25 °C. Do not freeze it. Keep out of reach of children.

Shelf

life is 3 years. Do not use after the expiration date indicated on the package.

Active ingredient

Enoxaparin sodium

Conditions of release from pharmacies

By prescription

Dosage form

solution for injection