Quadraparin-Solofarm solution for injection 10000 anti-XaIU/ml 0.6ml (6000 anti-XaIU) ampoules, 10pcs

Composition

1 syringe or ampoule (0.6 ml) contains:

Active ingredient: enoxaparin sodium 6000 anti-Xa IU (60 mg)

excipient: water for injection-up to 0.6 ml

Pharmacological action

Pharmacotherapy group

Direct-acting anticoagulant.

ATX code: B01AB05

Pharmacological properties

Enoxaparin sodium is a low molecular weight heparin with an average molecular weight of 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 depolymerization 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-enpyrazinosuric 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-IIa 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 in both human and 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.

Pharmacokinetics

Bioavailability and absorption

The absolute bioavailability of enoxaparin sodium with subcutaneous (subcutaneous) use, estimated on the basis of anti-Xa activity, is close to 100%.

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.

Intravenous bolus use of the drug at a dosage of 30 mg, accompanied by immediate subcutaneous use of the drug at a dosage of 1 mg / kg every 12 hours, provides the initial maximum anti-Xa activity at the level of 1.16 IU / ml (n=16), the average exposure of the drug in the blood is approximately 88% of the equilibrium state, which is reached on the second day of therapy.

The pharmacokinetics of enoxaparin sodium in these dosage regimens are linear. Variability within and between patient groups is low. After repeated subcutaneous use of 40 mg of enoxaparin sodium once a day and subcutaneous use of enoxaparin sodium at a dose of 1.5 mg/kg of body weight once a day in healthy volunteers, the equilibrium concentration is reached by the second day, and the area under the pharmacokinetic 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 curve (AUC) 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.

Anti-IIa activity in plasma is approximately 10 times lower than anti-Xa activity. The average maximum anti-IIa 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.

Distribution

The volume of distribution of anti-Xa activity of enoxaparin sodium is approximately 4.3 liters and is close to the volume of circulating blood.

Deduction

Enoxaparin 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 about 5 hours (after a single subcutaneous injection) and about 7 hours (after repeated use of the drug).

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

Special patient groups

Elderly patients (over 75 years of age): the pharmacokinetic profile of enoxaparin sodium does not differ in elderly patients and younger patients with normal renal function. However, as a result of decreased renal function with age, there may be a slowdown in the elimination of enoxaparin sodium in elderly patients.

Hepatic impairment: in a study involving patients with advanced cirrhosis treated with enoxaparin sodium at a dose of 4000 IU (40 mg) once a day, a decrease in maximum anti-Xa activity was associated with an increase in the severity of hepatic impairment (with a Child-Pugh score). This decrease was mainly due to a decrease in the level of AT-III, secondary to a decrease in AT-III synthesis in patients with impaired liver function.

Impaired renal function: decreased clearance of enoxaparin sodium was observed in patients with impaired renal function. After repeated subcutaneous use of 40 mg enoxaparin sodium once a day, anti-Xa activity is increased, represented by the area under the pharmacokinetic curve (AUC) in patients with mild renal impairment (creatinine clearance ≥50 and <80 ml/min) and moderate renal impairment (creatinine clearance ≥30 and < 80 ml / min). In patients with severe renal impairment (creatinine clearance less than 30 ml/min), the AUC at steady state is on average 65% higher with repeated subcutaneous use of 40 mg of the drug once a day.

Hemodialysis: The pharmacokinetics of enoxaparin sodium were comparable to those in the control population after a single intravenous dose of 25 IU,50 IU or 100 IU / kg (0.25,0.50 or 1.0 mg/kg), but the AUC was twice as high as in the control population.

Body weight: after repeated subcutaneous use at a dose of 1.5 mg / kg once a day, the average AUC of anti-Xa activity at equilibrium is slightly higher in overweight patients (BMI 30-48 kg/m2) compared to patients with normal average body weight, while the maximum anti-Xa activity in blood plasma does not increase. 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 40 mg of enoxaparin sodium, anti-Xa activity will be 52% 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

· Prevention of venous thrombosis and embolism in surgical interventions in patients at moderate and high risk, especially in orthopedic and General surgical procedures, including cancer;

· Prevention of venous thrombosis and embolism in patients on bed rest due to acute therapeutic diseases, including congestive heart failure and decompensation of chronic heart failure (III or class IV NYHA), respiratory failure, and in severe infections and rheumatic diseases with an increased risk of venous thrombosis (see section “Special instructions”);

· Treatment of deep vein thrombosis with pulmonary embolism or without pulmonary embolism, except in cases of pulmonary embolism requiring thromboembolic therapy or surgery;

· Prevention of clotting in the extracorporeal circulation during hemodialysis;

·  Acute coronary syndrome:

– treatment of unstable angina and non-ST-segment elevation myocardial infarction in combination with oral acetylsalicylic acid;

– treatment of acute ST-segment elevation myocardial infarction in patients undergoing medication or subsequent percutaneous coronary intervention (PCI).

Use during pregnancy and lactation

Pregnancy

There is no evidence that enoxaparin sodium penetrates the placental barrier during pregnancy.Since there are no adequate and well-controlled studies involving 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 exceptional cases, when there is an urgent need for its use, established by a doctor.

It is recommended to monitor the condition of patients for signs of bleeding or excessive anticoagulation, patients should be warned about the risk of bleeding.

There is no evidence of an increased risk of bleeding, thrombocytopenia, or osteoporosis in pregnant women, except in patients with artificial heart valves (see section “Special instructions”).

When planning an epidural, it is recommended to cancel enoxaparin sodium before performing it (see the section “Special instructions”).

Breast-feeding period

It is not known whether unchanged enoxaparin sodium is excreted in breast milk. Absorption of enoxaparin sodium in the gastrointestinal tract in a newborn is unlikely. The drug can be used during breastfeeding.

Contraindications

– hypersensitivity to enoxaparin sodium, heparin or its derivatives, including other low molecular weight heparins;

active clinically significant bleeding, as well as the conditions and diseases in which there is a high risk of bleeding, including recent hemorrhagic stroke, acute ulcer of the gastrointestinal tract (GIT), the presence of malignant neoplasms at high risk of bleeding, recent surgery on the brain and spinal cord, ophthalmic surgery, known or suspected presence of varicose veins of the esophagus, arteriovenous malformations, vascular aneurysms, vascular anomalies of the spinal cord and brain;

– spinal or epidural anesthesia or Loco-regional anesthesia, when enoxaparin sodium was used for the treatment in the previous 24 hours;

– immune-mediated heparin-induced thrombocytopenia (history) during the last 100 days, the presence of blood circulating antibodies antithrombocytic;

– children’s age up to 18 years since efficacy and safety in these patients has not been established (see section “Special instructions”).

With caution

Conditions where there is a potential risk of bleeding:

– hemostatic disorders (including hemophilia, thrombocytopenia, anticoagulation, von Willebrand disease, etc. ), severe vasculitis;

– ulcer of the stomach or duodenum, or other erosive and ulcerative lesions of the gastrointestinal tract in history;

– recent ischemic stroke;

– uncontrolled severe arterial hypertension;

– diabetic or hemorrhagic retinopathy;

– severe diabetes mellitus;

– recently moved or suspected neurological or ophthalmic surgery;

– carrying out spinal or epidural anesthesia (potential risk of bruising), a lumbar puncture (recent);

recent childbirth;

– bacterial endocarditis (acute or subacute);

– pericarditis or pericardial effusion;

renal and/or hepatic insufficiency;

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 without circulating antibodies in history (over 100 days).

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 myocardial infarction without Q wave dose of enoxaparin sodium is 1 mg/kg of body weight subcutaneously every 12 hours, and in case of myocardial infarction with ST-segment elevation was performed intravenous bolus of 30 mg followed by use of 1 mg/kg of body weight subcutaneously every 12 h.

the incidence of adverse reactions was determined in accordance with the who classification: very often (≥1/10); often (≥1/100 and <1/10); infrequently (≥1/1000 and <1/100); rare (≥1/10,000 and <1/1000); very rare (<1/10 000), the frequency unknown (cannot be estimated based on available data).

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 also 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 “Interaction with other drugs” and “Special Instructions”).

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 common – bleeding* in the prevention of venous thrombosis in surgical patients and in the treatment of deep vein thrombosis with or without thromboembolism.

Often – 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.

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

Rarely-retroperitoneal bleeding in the prevention of venous thrombosis in surgical patients and in the treatment of angina pectoris, myocardial infarction without Q wave.

Thrombocytopenia and thrombocytosis

Very often – thrombocytosis (the number of platelets in 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.

Often-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.

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

Very rarely – autoimmune 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.

Disorders of the blood and lymphatic system

Often – bleeding, thrombocytopenia, thrombocytosis.

Rarely-cases of autoimmune thrombocytopenia with thrombosis; in some cases, thrombosis was complicated by the development of an organ infarction or limb ischemia(see the section “Special instructions”, subsection “Monitoring the number of platelets in peripheral blood”).

Immune system disorders

Often include allergic reactions.

Liver and biliary tract disorders

Very often – 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.

Disorders of the skin and subcutaneous tissues

Often – urticaria, pruritus, erythema.

Infrequently-bullous dermatitis.

General disorders and disorders at the injection

site Often – 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.

Infrequently-irritation at the injection site, skin necrosis at the injection site.

Data obtained in the post-registration period

The following adverse reactions were observed with post-marketing use of the drug. These adverse reactions have been reported spontaneously.

Immune system disorders

Rarely – anaphylactic / anaphylactoid reactions, including shock.

Disorders of the nervous system

Often – headache.

Vascular disorders

Rarely, cases of spinal hematoma (or neuro-axial hematoma) have been reported with the use of enoxaparin sodium on the background of spinal/epidural anesthesia or spinal puncture. 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 or lymphatic system

Often – hemorrhagic anemia.

Rarely – eosinophilia.

Skin and subcutaneous tissue disorders

Rarely-alopecia; at the injection site may develop cutaneous vasculitis, skin necrosis, which is usually preceded by the appearance of purpura or erythematous papules (infiltrated and painful). In these cases, therapy with the drug 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.

Liver and biliary tract disorders

Infrequently – hepatocellular liver damage.

Rarely-cholestatic liver damage.

Musculoskeletal and connective tissue disorders

Rarely-osteoporosis with long-term therapy (more than three months).

Laboratory and instrumental data

Rarely-hyperkalemia.

Interaction

Enoxaparin sodium should not be mixed with other medications!

Not recommended combinations

Drugs that affect hemostasis (salicylates of systemic action, acetylsalicylic acid in doses that have an anti-inflammatory effect, non-steroidal anti-inflammatory drugs, including ketorolac, other thrombolytics (alteplase, reteplase, streptokinase, tenecteplase, urokinase)), it is recommended to cancel before starting therapy with enoxaparin sodium. If concomitant use with enoxaparin sodium is necessary, caution should be exercised and careful clinical monitoring and monitoring of appropriate laboratory parameters should be carried out.

Combinations that require caution

·  Other medications that affect hemostasis, such as:

– inhibitors of platelet aggregation, including acetylsalicylic acid in doses that have an antiplatelet effect (cardioprotection), clopidogrel, ticlopidine and antagonists of glycoprotein IIb/IIIa receptors, indicated in acute coronary syndrome, due to an increased risk of bleeding;

– dextran with a molecular weight of 40 kDa;

– systemic glucocorticosteroids.

* Medicines that increase the potassium content

When used concomitantly with drugs that increase the potassium content in the blood serum, clinical or laboratory monitoring should be carried out.

How to take, course of use and dosage

Subcutaneously, except in special cases (see the subsections “Prevention of thrombosis in the extracorporeal circulatory system during hemodialysis” and “Treatment of acute ST-segment elevation myocardial infarction, medical or percutaneous coronary intervention” below).

Prevention of venous thrombosis and embolism during surgical interventions in moderate and high-risk patients

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. If earlier preoperative prophylaxis is necessary (for example, in patients at high risk of developing thrombosis and thromboembolism awaiting delayed orthopedic surgery), the last injection should be made 12 hours before surgery and 12 hours after surgery.

The average duration of treatment with the drug 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.

For major orthopedic surgeries, it may be advisable to continue treatment after initial therapy by administering the drug at a dose of 40 mg once a day for five weeks.

For patients at high risk of venous thromboembolism who have undergone surgery, abdominal and pelvic surgery due to cancer, it may be advisable to increase the duration of use of the drug at a dose of 40 mg once a day for four weeks.

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

The recommended dose of the drug is 40 mg once a day, subcutaneously, for at least 6-14 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. The dosage regimen should be selected by the doctor based on an assessment of the risk of thromboembolism and the risk of bleeding. In patients without thromboembolic complications and with a low risk of venous thromboembolism, the drug is recommended to be administered subcutaneously at the rate of 1.5 mg/kg of body weight once a day. In all other patients, including those with obesity, symptomatic pulmonary embolism, cancer, recurrent venous thromboembolism and proximal thrombosis (in the iliac vein), 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 treatment with the drug should be continued until the therapeutic anticoagulant effect is achieved (INR values should be 2.0-3.0).

Prevention of thrombosis in the extracorporeal circulatory system during hemodialysis

The recommended dose of the drug 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, but 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.

There are no data available for patients using enoxaparin sodium for prevention or treatment and during hemodialysis sessions.

Treatment of unstable angina and non-ST-segment elevation myocardial infarction

The drug is administered at the rate of 1 mg/kg of body weight every 12 hours, subcutaneously, with simultaneous use of antiplatelet therapy. 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.

Acetylsalicylic acid is recommended for all patients who do not have contraindications, with an initial dose of 150-300 mg orally followed by a maintenance dose of 75-325 mg once a day.

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 it, 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 can not exceed 100 mg). 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 the drug is 8 days or until the patient is discharged from the hospital (if the period of hospitalization is less than 8 days).

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.

In patients aged 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 can not exceed 75 mg).

In patients undergoing percutaneous coronary intervention, if the last subcutaneous injection of enoxaparin sodium 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.

Features of drug use

The pre-filled disposable syringe is ready for use.

The drug should not be administered intramuscularly!

Subcutaneous use

Injections should preferably be performed in the patient’s “lying down” position. When using pre-filled 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 entire length of the needle should be inserted vertically (not laterally) into the skin fold, which is collected and held until the injection is completed between the thumb and index finger. The skin fold is released only after the injection is completed.

Do not massage the injection site after use of the drug.

Intravenous bolus use

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 larger glass syringes 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 30 mg,40 mg,50 mg,60 mg,70 mg,80 mg and 100 mg can be used. It is recommended to use syringes of 30 mg,40 mg,50 mg and 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 preparation for bolus use of 30 mg of enoxaparin sodium.

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 3 mg/ml enoxaparin sodium solution using a pre-filled 60 mg syringe, it is recommended to use a 50 ml infusion container (i. e. with 0.9% sodium chloride solution or 5% dectrose 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) × 0.1,

or using the table below.

Volumes that should be administered intravenously after dilution to a concentration of 3 mg / ml

Switching between enoxaparin sodium and oral anticoagulants

Switching between enoxaparin sodium and vitamin K antagonists (VKA)

To monitor the effect of AVK, it is necessary to observe a doctor and conduct laboratory tests [prothrombin time, represented as INR].

Since it takes time for the maximum effect of AVK to develop, enoxaparin sodium therapy should be continued at a constant dose for as long as it is necessary to maintain the INR values (according to two consecutive definitions) in the desired therapeutic range, depending on the indications.

For patients who are receiving AVA, discontinuation of AVA and use of the first dose of enoxaparin sodium should be performed after the INR has fallen below the limit of the therapeutic range.

Switching between enoxaparin sodium and direct-acting oral anticoagulants (POAC)

Discontinuation of enoxaparin sodium and use of POAC should be carried out 0-2 hours before the next scheduled use of enoxaparin sodium in accordance with the instructions for use of oral anticoagulants.

For patients receiving POAC, the first dose of enoxaparin sodium and discontinuation of direct-acting oral anticoagulants should be administered at the time corresponding to the next scheduled use of the POAC.

Use for spinal / epidural anesthesia or lumbar puncture

If anticoagulant therapy is used during epidural or spinal anesthesia/analgesia or lumbar puncture, neurological monitoring is necessary due to the risk of developing neuroaxial hematomas (see the section “Special instructions”).

The use of enoxaparin sodium in preventive doses

Catheter insertion or removal should be performed at least 12 hours after the last injection of a prophylactic dose of enoxaparin sodium.

When using a continuous technique, it is necessary to observe at least a 12-hour interval before removing the catheter.

In patients with creatinine clearance ≥15 and <30 ml/min, doubling the time to puncture or catheter insertion/removal to at least 24 hours should be considered.

Preoperative use of enoxaparin sodium 2 hours before the intervention in a dosage of 20 mg is incompatible with neuroaxial anesthesia.

The use of enoxaparin sodium in therapeutic doses

Catheter insertion or removal should be performed at least 24 hours after the last injection of the therapeutic dose of enoxaparin sodium (see section “Contraindications”).

When using a continuous technique, it is necessary to observe at least a 24-hour interval before removing the catheter.

In patients with creatinine clearance ≥15 and <30 ml/min, doubling the time to puncture or catheter insertion/removal to at least 48 hours should be considered.

Patients receiving enoxaparin sodium at doses of 0.75 mg / kg or 1 mg/kg body weight 2 times a day should not be given a second dose of the drug 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 (the risk of thrombosis and bleeding during the procedure, taking into account the presence of risk factors in patients). 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.

Dosage regimen for special patient groups

Children under 18 years of age

The safety and efficacy of enoxaparin sodium in children have not been established.

Elderly patients (over 75 years of age)

With the exception of treatment of ST-segment elevation myocardial infarction, no dose reduction of enoxaparin sodium is required for all other indications in elderly patients with no impaired renal function.

Patients with impaired renal function

Severe renal impairment (creatinine clearance ≥15 and

The use of enoxaparin sodium is not recommended in patients with end-stage chronic kidney disease (creatinine clearance

In patients with severe renal impairment (creatinine clearance ≥15 and

When using the drug in therapeutic doses, the following dosage adjustment is recommended::

When using the drug for preventive purposes, it is recommended to adjust the dosage regimen, as shown in the table below:

The recommended dosage adjustment is not used for hemodialysis.

Mild (creatinine clearance ≥50 and <80 ml/min) and moderate (creatinine clearance ≥30 and <50 ml/min) renal impairment

No dose adjustment is required, but patients should be under close medical supervision.

Patients with impaired liver function

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

Instructions for self-injection of enoxaparin sodium

1. Wash your hands and the area of skin (injection site) where you will inject the drug with soap and water. Dry them out.

2. Take a comfortable sitting or lying position and relax. Make sure that you can clearly see the place where you are going to inject the drug. It is optimal to use a lounge chair, a chaise longue or a bed covered with pillows for support.

3. Select the injection site on the right or left side of the abdomen. This area should be located at least 5 cm from the navel or around existing scars and bruises. Alternate the injection sites in the right and left sides of the abdomen, depending on where you injected the drug the previous time.

4. Wipe the injection site with a swab soaked in alcohol.

5. Carefully remove the cap from the syringe needle. Set aside the cap. The syringe is pre-filled and ready for use. Do not push the plunger to expel air bubbles before inserting the needle into the injection site. This can lead to the loss of the drug. After removing the cap, do not allow the needle to touch any objects. This is necessary to maintain the sterility of the needle.

Attention: If you have a needle protection label, follow the Instructions for using the needle protection label below.

6. Hold the syringe in one hand as you hold a pencil, and with the other hand, gently squeeze the alcohol-rubbed injection site between your thumb and index finger so as to form a skin fold. Hold the skin fold all the time while you inject the drug.

7. Hold the syringe so that the needle points down (vertically at an angle of 90°). Insert the entire length of the needle into the skin fold.

8. Press the plunger with your finger. This will ensure that the drug is injected into the subcutaneous adipose tissue of the abdomen. Hold the skin fold all the time while you inject the drug.

9. Remove the needle by pulling it back without deviating from its axis. Now you can stop holding the skin fold.

Attention: If there is a safety device, follow the Instructions for using the safety device given below.

10. To prevent bruising, do not rub the injection site after use of the drug.

11. Dispose of the used disposable syringe in the trash can.

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.

Instructions for using a protective label for the needle (if any)

Without opening the package, check the integrity of the syringe, as well as the absence of liquid in the contour cell package. If you have doubts about the integrity of the syringe or its tightness, take a different package.

Open the contour cell package.

Check the drug content in the syringe.

Instructions for using the safety device

Without opening the package, check the integrity of the syringe, as well as the absence of liquid in the contour cell package. If you have doubts about the integrity of the syringe or its tightness, take a different package.

Open the contour cell package.

Check the drug content in the syringe.

Overdose

Accidental overdose of the drug with intravenous, extracorporeal or subcutaneous use can lead to hemorrhagic complications. When taken orally, even in large doses, absorption of the drug is unlikely.

Anticoagulant effects can mainly be neutralized by slow intravenous use of protamine sulfate, the dose of which depends on the dose of the drug administered. One mg (1 mg) of protamine sulfate neutralizes the anticoagulant effect of one mg (1 mg) of the drug if enoxaparin sodium was administered no more than 8 hours before protamine use. 0.5 mg of protamine neutralizes the anticoagulant effect of 1 mg of the drug, if more than 8 hours have passed since the last dose was administered, or if a second dose of protamine is necessary. If 12 hours or more have passed since the introduction of enoxaparin sodium, the introduction of protamine is not required. However, even with the introduction of large doses of protamine sulfate, the anti-Xa activity of the drug is not completely neutralized (by a maximum of 60%).

Description

Transparent colorless or yellowish, or brownish-yellowish liquid.

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 the use of other anticoagulants, when the drug is administered, bleeding of any localization may develop (see the section “Side effects”). If bleeding develops, it is necessary to find its source and prescribe appropriate treatment.

Enoxaparin sodium, like other anticoagulants, should be used with caution in conditions with an increased risk of bleeding, such as::

· hemostatic disorders

· * a history of peptic ulcer disease· * a

recent ischemic stroke; *

severe arterial hypertension·

* diabetic retinopathy;

· neurosurgical or ophthalmic surgery;

· concomitant use of drugs that affect hemostasis (see the section “Interaction with other drugs”).

Bleeding in elderly patients

When using the drug in preventive 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 (see section “Pharmacokinetics” and section “Dosage and use”, subsection “Elderly patients”).

Concomitant use of other drugs that affect hemostasis

The use of drugs that affect hemostasis (salicylates of systemic action, including acetylsalicylic acid in doses that have an anti-inflammatory effect, nonsteroidal anti-inflammatory drugs, including ketorolac, other thrombolytics (alteplase, reteplase, streptokinase, tenecteplase, urokinase)) is recommended to be discontinued before starting treatment with 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 ≥15 and 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, and biological monitoring with measurement of anti-Xa activity may be considered (see sections “Pharmacokinetics” and “Dosage and use”, subsection “Patients with impaired renal function”).

The use of enoxaparin sodium is not recommended in patients with end-stage chronic kidney disease (creatinine clearance

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 (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, while this risk is higher in patients who have undergone heart surgery and patients with cancer. 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 the drug and during its use. The blood platelet count should be determined if there are symptoms that indicate GIT (a new episode of arterial and / or venous thromboembolic complications, painful skin damage at the injection site, an allergic or anaphylactic reaction during treatment). If these symptoms occur, you should inform your doctor.

If there is a confirmed significant decrease in platelet count (by 30-50% compared to baseline), enoxaparin sodium should be immediately discontinued and the patient should be transferred to another anticoagulant therapy without the use of heparins.

Spinal / epidural anesthesia

Cases of occurrence of neuroaxial hematomas during the use of the drug with 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 the use of higher doses of the drug, as well as with the use of permanent catheters after surgery, or with the simultaneous use of additional drugs that affect hemostasis, such as nonsteroidal anti-inflammatory drugs (see the section “Interaction with other 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 (see the section “Pharmacokinetics”). 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. It should also be taken into account that in patients with a creatinine clearance of 15-30 ml/min, the elimination of enoxaparin sodium slows down.

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

The use of enoxaparin sodium in patients with a history of heparin-induced thrombocytopenia within the last 100 days or in the presence of circulating antibodies is contraindicated (see the section “Contraindications”). Circulating antibodies can persist for several years.

Enoxaparin sodium should be used with extreme caution in patients with a history (more than 100 days) of heparin-induced thrombocytopenia without circulating antibodies. The decision to use enoxaparin sodium in this situation should be made only after evaluating the benefit/risk ratio and in the absence of heparin-free (non-heparin) therapy. alternative therapy.

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 drug use. This is necessary in order to achieve hemostasis at the catheter insertion site 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 the drug 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. Due to the lack of clinical data and the presence of ambiguous factors, including the underlying disease, it is difficult to assess such reports.

Pregnant women with mechanical artificial heart valves

The use of the drug 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 using enoxaparin sodium at a dose of 1 mg/kg of body weight 2 times 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 to prevent thrombosis.

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

Skin necrosis/cutaneous vasculitis

Skin necrosis and cutaneous vasculitis have been reported with low-molecular-weight heparins. If skin necrosis/cutaneous vasculitis develops, the drug should be discontinued.

Acute infectious endocarditis

The use of heparin is not recommended in patients with acute infectious endocarditis due to the risk of hemorrhagic stroke. If the use of the drug is considered absolutely necessary, the decision should be made only after a thorough individual assessment of the benefit-risk ratio.

Laboratory tests

In doses used for the prevention of thromboembolic complications, the drug does not significantly affect the bleeding time and blood clotting parameters, as well as platelet aggregation or their 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.

Hyperkalemia

Heparins can inhibit the secretion of aldosterone by the adrenal glands, which leads to the development of hyperkalemia, especially in patients with diabetes mellitus, chronic renal failure, previous metabolic acidosis, taking medications that increase the potassium content (see the section “Interaction with other medications”). Blood plasma potassium levels should be monitored regularly, especially in patients at risk.

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 only if the above conditions are combined with one of the following risk factors for venous thrombosis:

– age over 75 years;

– malignant neoplasms;

– thrombosis and embolism in the anamnesis;

– obesity;

– hormone therapy;

– heart failure;

– chronic respiratory failure.

Impaired liver function

Enoxaparin sodium should be used with caution in patients with impaired liver function due to an increased risk of bleeding. Dose adjustment based on monitoring of anti-Xa activity in patients with cirrhosis of the liver is unreliable and is not recommended.

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.

Keep out of reach of children.

Shelf

life is 3 years.

Do not use after the expiration date!

Active ingredient

Enoxaparin sodium

Conditions of release from pharmacies

By prescription

Dosage form

inhalation solution