Quadraparin-Solopharm, 1000 antiha me/ml 1 ml syringes 10 pcs

Pharmacotherapeutic group

A direct acting anticoagulant.

ATC 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%, 2000 to 8000 daltons, > 68%, more than 8000 daltons, < 18%. Enoxaparin sodium is obtained by alkaline depolymerization of heparin benzyl ester isolated from pig small intestine mucosa. Its structure is characterized by a nonreducible fragment of 2-O-sulfo-4-enpyrazino-suronic acid and a reducible fragment of 2-N,6-O-disulfo-D-gluco-pyranoside. The structure of enoxaparin sodium contains about 20% (between 15% and 25%) of the 1,6-anhydro derivative in the reducing fragment of the polysaccharide chain.

Pharmacodynamics

In a purified in vitro system, sodium enoxaparin 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 have also been identified in both human and animal models. These include AT-III dependent inhibition of other clotting factors such as factor VIIa, activation of tissue factor pathway inhibitor (TFP) release, and reduction of Willebrand factor release from the vascular endothelium into the bloodstream. These factors provide the anticoagulant effect of enoxaparin sodium in general.

The use of the drug in prophylactic doses slightly changes the activated partial thromboplastin time (APT), has almost 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 (p/k) administration, estimated on the basis of anti-Xa activity, is close to 100%.

The mean maximal plasma anti-Xa activity is observed 3-5 h after b/c administration of the drug and is approximately 0.2; 0.4; 1.0 and 1.3 anti-Xa IU/ml after b/c administration of 20 mg, 40 mg, 1 mg/kg and 1.5 mg/kg.

Intravenous bolus administration of 30 mg followed by immediate subcutaneous administration of 1 mg/kg every 12 h provides an initial maximum anti-Xa activity of 1.16 IU/ml (n=16), with mean blood exposure of approximately 88% of the equilibrium state reached by the second day of therapy.

The pharmacokinetics of enoxaparin sodium in the indicated dosing regimens is linear. The variability within and between patient groups is low. After repeated subcutaneous administration of 40 mg of enoxaparin sodium once daily and subcutaneous administration of 1.5 mg/kg body weight once daily in healthy volunteers the equilibrium concentration is reached by the second day, with the area under the pharmacokinetic curve being on average 15% higher than after a single injection. After repeated subcutaneous injections of enoxaparin sodium at a daily dose of 1 mg/kg body weight twice a day the equilibrium concentration is reached after 3-4 days, the area under the curve (AUC) is on average 65 % higher than after a single injection, and average values of maximum concentrations are 1.2 ME/ml and 0.52 ME/ml respectively.

The anti-IIa activity in plasma is about 10 times lower than the anti-Xa activity. Mean maximum anti-IIa activity is observed approximately 3-4 hours after subcutaneous administration and reaches 0.13 IU/ml and 0.19 IU/ml after repeated administration of 1 mg/kg body weight when administered twice and 1.5 mg/kg body weight when administered once, respectively.

Distribution

The volume of distribution of the anti-Xa activity of enoxaparin sodium is approximately 4.3 L and approximates the volume of circulating blood.

Elimination

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

The excretion of the drug is monophasic with a half-life (T_1/2) of about 5 hours (after a single subcutaneous administration) and about 7 hours (after multiple administration 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. Excretion through the kidneys of active drug fragments is approximately 10% of the administered dose, and total excretion of active and inactive fragments is approximately 40% of the administered dose.

Particular patient groups

Patients in the elderly (over 75 years): 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, slower excretion of enoxaparin sodium may be observed in elderly patients.

Liver dysfunction: In a study involving patients with advanced liver cirrhosis who received enoxaparin sodium at a dose of 4000 IU (40 mg) once daily, a decrease in maximum anti-Xa activity was associated with an increase in the severity of liver function impairment (as assessed by the Child-Pugh score). This decrease was mainly due to a decrease in AT-III levels secondary to a decrease in AT-III synthesis in patients with impaired liver function.

With impaired renal function: decreased clearance of enoxaparin sodium has been noted in patients with impaired renal function. After repeated subcutaneous administration of 40 mg of enoxaparin sodium once a day there is increase of anti-Xa activity represented by area under pharmacokinetic curve (AUC) in patients with mild (creatinine clearance ≥50 and <80 ml/min) and moderate renal dysfunction (creatinine clearance ≥30 and <50 ml/min). In patients with severe renal impairment (creatinine clearance less than 30 ml/min) the AUC at equilibrium is on average 65% higher with repeated subcutaneous administration of 40 mg of the drug once daily.

Hemodialysis: The pharmacokinetics of enoxaparin sodium were comparable to those in the control population after single intravenous doses 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 doses of 1.5 mg/kg once daily, mean AUC of anti-Xa activity at equilibrium was slightly higher in overweight patients (BMI 30-48 kg/m²) compared with patients with normal average body weight, whereas maximum plasma anti-Xa activity was not increased. In overweight patients with subcutaneous administration of the drug, the clearance is slightly lower. If no dose adjustment is made for patient weight, after a single subcutaneous injection of 40 mg of sodium enoxaparin, anti-Xa activity will be 52% higher in women with a body weight less than 45 kg and 27% higher in men with a body weight less than 57 kg compared with patients of normal average body weight.

Indications

· Prevention of venous thrombosis and embolism during surgical interventions in patients of moderate and high risk, especially during orthopedic and general surgical interventions, including oncology;

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

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

· Prevention of thrombus formation in the extracorporeal circulation system during hemodialysis;

Acute coronary syndrome:

– treatment of unstable angina and myocardial infarction without ST segment elevation in combination with oral administration of acetylsalicylic acid;

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

Pharmacological effect

Pharmacotherapeutic 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 – 68%, more than 8000 daltons – <18%. Enoxaparin sodium is obtained by alkaline depolymerization of heparin benzyl ester isolated from the mucous membrane of the small intestine of pigs. Its structure is characterized by a non-reducing 2-O-sulfo-4-enpyrazinosuronic acid moiety and a reducing 2-N,6-O-disulfo-D-glucopyranoside moiety. The structure of enoxaparin sodium contains about 20% (ranging from 15 to 25%) 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) to provide anticoagulant activity in humans. In addition to anti-Xa/IIa activity, additional anticoagulant and anti-inflammatory properties of enoxaparin sodium have also been identified both in humans and in animal models. This includes AT-III dependent inhibition of other coagulation factors such as factor VIIa, activation of tissue factor pathway inhibitor (TFP) release, and a decrease in the release of von Willebrand factor from the vascular endothelium into the circulation. These factors provide the anticoagulant effect of enoxaparin sodium in general.

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

Pharmacokinetics

Bioavailability and absorption

The absolute bioavailability of enoxaparin sodium after subcutaneous (SC) administration, assessed on the basis of anti-Xa activity, is close to 100%.

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

An intravenous bolus of 30 mg, followed by immediate subcutaneous administration of 1 mg/kg every 12 hours, provides an initial maximum anti-Xa activity of 1.16 IU/ml (n=16), the average drug exposure in the blood is approximately 88% of the equilibrium state, which is achieved on the second day of therapy.

The pharmacokinetics of enoxaparin sodium in the indicated dosage regimens is linear. Variability within and between patient groups is low. After repeated subcutaneous administration of 40 mg of enoxaparin sodium once daily and subcutaneous administration of enoxaparin sodium at a dose of 1.5 mg/kg body weight once daily in healthy volunteers, equilibrium concentrations are achieved by the second day, and the area under the pharmacokinetic curve is on average 15% higher than after a single administration. After repeated subcutaneous administrations of enoxaparin sodium at a daily dose of 1 mg/kg body weight twice a day, equilibrium concentrations are reached after 3-4 days, with the area under the curve (AUC) being on average 65% higher than after a single dose, and the average maximum concentrations being 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 administration and reaches 0.13 IU/ml and 0.19 IU/ml after repeated administration of 1 mg/kg body weight for a double dose and 1.5 mg/kg body weight for a single dose, respectively.

Distribution

The volume of distribution of anti-Xa activity of enoxaparin sodium is approximately 4.3 L and approaches the volume of circulating blood.

Removal

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

The elimination of the drug is monophasic with a half-life (T1/2) of about 5 hours (after a single subcutaneous injection) and about 7 hours (after repeated administration of the drug).

Enoxaparin sodium is primarily 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 between elderly patients and younger patients with normal renal function. However, as a result of decreased renal function with age, there may be a slower elimination of enoxaparin sodium in elderly patients.

Liver dysfunction: In a study of patients with advanced cirrhosis treated with enoxaparin sodium 4000 IU (40 mg) once daily, a decrease in maximum anti-Xa activity was associated with an increase in the severity of liver dysfunction (as assessed by the Child-Pugh score). This decrease was primarily due to decreased AT-III levels secondary to decreased AT-III synthesis in patients with hepatic impairment.

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

Hemodialysis: The pharmacokinetics of enoxaparin sodium were comparable to those in the control population after single intravenous doses of 25 IU, 50 IU, or 100 IU/kg (0.25, 0.50, or 1.0 mg/kg), but the AUC was two times higher than in the control population.

Body weight: After repeated subcutaneous dosages of 1.5 mg/kg once daily, the mean AUC of anti-Xa activity at steady state is slightly higher in overweight patients (BMI 30-48 kg/m2) compared with patients with normal average body weight, while the maximum anti-Xa activity in blood plasma does not increase. In patients with excess body weight, the clearance of the drug is slightly less when administered subcutaneously. If the dose is not adjusted for the patient’s body weight, then after a single subcutaneous injection of 40 mg of enoxaparin sodium, anti-Xa activity is 52% higher in women weighing less than 45 kg and 27% higher in men weighing less than 57 kg compared with patients with a normal average body weight.

Special instructions

General

Low molecular weight heparins are not interchangeable, as they differ in the manufacturing 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 interaction with platelets). 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 location may develop (see 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:

· hemostasis disorders;

history of peptic ulcer;

· recent ischemic stroke;

· severe arterial hypertension;

· diabetic retinopathy;

neurosurgical or ophthalmological surgery;

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

Bleeding in elderly patients

When using the drug 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 those aged 80 years and older), there is an increased risk of bleeding. It is recommended to carefully monitor the condition of such patients (see section “Pharmacokinetics” and section “Dosage and Administration”, subsection “Elderly Patients”).

Concomitant use of other drugs that affect hemostasis

The use of drugs that affect hemostasis (systemic salicylates, including acetylsalicylic acid in doses that have an anti-inflammatory effect, non-steroidal anti-inflammatory drugs, including ketorolac, other thrombolytics (alteplase, reteplase, streptokinase, tenecteplase, urokinase)) is recommended to be discontinued before starting treatment with enoxaparin sodium, unless their use is necessary. If combinations of enoxaparin sodium with these drugs are indicated, careful clinical observation and monitoring of relevant laboratory parameters should be carried out.

Kidney failure

In patients with impaired renal function, there is a risk of bleeding as a result of increased systemic exposure to enoxaparin sodium.

In patients with severe renal impairment (creatinine clearance ≥15 and <30 ml/min), there is a significant increase in the exposure of enoxaparin sodium, therefore dose adjustment is recommended for both prophylactic 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), close monitoring of such patients is recommended, and biological monitoring with measurement of anti-Xa activity may be considered (see sections “Pharmacokinetics” and “Dosage and Administration”, subsection “Patients with Impaired Renal Function”).

The use of enoxaparin sodium is not recommended for patients with end-stage chronic kidney disease (creatinine clearance <15 ml/min) due to the lack of data, except in cases of prevention of thrombus formation in the extracorporeal circulation system during hemodialysis.

Low body weight

There was an increase in the exposure of enoxaparin sodium when used prophylactically in women weighing less than 45 kg and in men weighing less than 57 kg, which may lead to an increased risk of bleeding. Careful monitoring of the condition of such patients is recommended.

Obese patients

Obese patients have an increased risk of developing thrombosis and embolism. The safety and effectiveness of the use of enoxaparin sodium in prophylactic doses in obese patients (BMI more than 30 kg/m2) has not been fully determined and there is no general consensus on dose adjustment. These patients should be closely monitored for the development of symptoms and signs of thrombosis and embolism.

Monitoring 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, and this risk is higher in patients who have undergone cardiac surgery and patients with cancer. If thrombocytopenia develops, it is usually detected between 5 and 21 days after initiation of enoxaparin sodium therapy. In this regard, it is recommended to regularly monitor the number of platelets in peripheral blood before starting treatment with the drug and during its use. The platelet count in the blood should be determined in the presence of symptoms indicating HIT (a new episode of arterial and/or venous thromboembolic complications, painful skin lesions 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 the initial value), it is necessary to immediately discontinue enoxaparin sodium and transfer the patient to another anticoagulant therapy without the use of heparins.

Spinal/epidural anesthesia

Cases of neuraxial hematomas occurring when using the drug during simultaneous spinal/epidural anesthesia with the development of long-term or irreversible paralysis have been described. The risk of these events is reduced when using the drug 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 indwelling catheters after surgery, or with the simultaneous use of additional drugs that affect hemostasis, such as non-steroidal anti-inflammatory drugs (see section “Interaction with other drugs”). The risk also increases 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 must be taken into account (see section “Pharmacokinetics”). Catheter insertion or removal is best done when the anticoagulant effect of enoxaparin sodium is low, but the exact time to achieve sufficient reduction in anticoagulant effect in different patients is unknown. It should be additionally taken into account that in patients with a creatinine clearance of 15-30 ml/min, the excretion of enoxaparin sodium slows down.

If anticoagulant therapy is used as prescribed by a physician during epidural/spinal anesthesia or lumbar puncture, the patient should be closely monitored for any neurological symptoms such as back pain, sensory and motor dysfunction (numbness or weakness in the lower extremities), bowel and/or bladder dysfunction. The patient should be instructed to immediately inform the doctor if the above symptoms occur. If symptoms consistent with a spinal cord hematoma are suspected, prompt diagnosis and treatment are necessary, 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 section “Contraindications”). Circulating antibodies may 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 assessing the benefit/risk ratio and in the absence of heparin-free (heparin-free) alternative therapy.

Percutaneous coronary angioplasty

To minimize the risk of bleeding associated with invasive vascular instrumentation 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 administrations. 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 sheath can be removed immediately. When using manual compression, the femoral artery sheath should be removed 6 hours after the last intravenous or subcutaneous injection of enoxaparin sodium. If treatment with enoxaparin sodium is continued, the next dose should be administered no earlier than 6-8 hours after removal of the femoral artery sheath. It is necessary to monitor the insertion site of the introducer to promptly identify signs of bleeding and hematoma formation.

Patients with mechanical artificial heart valves

The use of the drug for the prevention of thrombus formation in patients with mechanical artificial heart valves has not been sufficiently studied. There are isolated reports of the development of heart valve thrombosis in patients with mechanical artificial heart valves during therapy with enoxaparin sodium to prevent thrombosis. Due to the paucity of clinical data and the presence of confounding factors, including underlying disease, the evaluation of such reports is difficult.

Pregnant women with mechanical artificial heart valves

The use of the drug for the prevention of thrombus formation 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 using enoxaparin sodium at a dose of 1 mg/kg body weight 2 times a day to reduce the risk of thrombosis and embolism, 2 out of 8 women developed blood clots, which led to blocking of the heart valves and death of the mother and fetus.

There are isolated post-marketing reports of valvular thrombosis in pregnant women with mechanical prosthetic heart valves treated with enoxaparin for thrombotic prophylaxis.

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 the use of low molecular weight heparins. If skin necrosis/cutaneous vasculitis develops, use of the drug should be discontinued.

Acute infective endocarditis

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

Laboratory tests

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

As the dose increases, the aPTT and activated clotting time may prolong. The increase in aPTT and activated clotting time are not in a direct linear relationship with the increase in the anticoagulant activity of the drug, so there is no need to monitor them.

Hyperkalemia

Heparins can suppress 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, and taking medications that increase potassium levels (see section “Interaction with other drugs”). Plasma potassium levels should be regularly monitored, especially in high-risk patients.

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

In the event of the development of an acute infection or acute rheumatic conditions, the prophylactic use of enoxaparin sodium is justified only if the above conditions are combined with one of the following risk factors for venous thrombus formation:

– age over 75 years;

– malignant neoplasms;

– history of thrombosis and embolism;

– obesity;

– hormonal therapy;

– heart failure;

– chronic respiratory failure.

Liver dysfunction

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

Impact on the ability to drive vehicles and machinery

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

Active ingredient

Enoxaparin sodium

Composition

1 syringe or ampoule (1 ml) contains:

active ingredient: enoxaparin sodium 10000 anti-Xa ME (100 mg)

excipient: water for injection – up to 1.0 ml.

Pregnancy

Pregnancy

There is no information that enoxaparin sodium crosses the placental barrier during pregnancy. Since there are no adequate and well-controlled studies in pregnant women, and animal studies do not always predict the response to 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, as determined by a physician.

It is recommended that patients be monitored for signs of bleeding or excessive anticoagulation, and patients should be warned of the risk of bleeding.

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

When planning epidural anesthesia, it is recommended to discontinue enoxaparin sodium before it is performed (see section “Special Instructions”).

Breastfeeding period

It is not known whether unchanged enoxaparin sodium is excreted into breast milk. Absorption of enoxaparin sodium from 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 conditions and diseases in which there is a high risk of bleeding, including recent hemorrhagic stroke, acute gastrointestinal ulcer (GIT), the presence of a malignant neoplasm with a high risk of bleeding, recent surgery on the brain and spinal cord, ophthalmic surgery, known or suspected presence of esophageal varices, 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 treatment in the previous 24 hours;

– immune-mediated heparin-induced thrombocytopenia (history) within the last 100 days or the presence of circulating antiplatelet antibodies in the blood;

– children under 18 years of age, since the effectiveness and safety in this category of patients have not been established (see section “Special instructions”).

With caution

Conditions in which there is a potential risk of bleeding:

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

– a history of gastric or duodenal ulcers or other erosive and ulcerative lesions of the gastrointestinal tract;

– recent ischemic stroke;

– uncontrolled severe arterial hypertension;

– diabetic or hemorrhagic retinopathy;

– severe diabetes mellitus;

– recent or proposed neurological or ophthalmological surgery;

– spinal or epidural anesthesia (potential danger of hematoma development), spinal puncture (recently performed);

– recent birth;

– bacterial endocarditis (acute or subacute);

– pericarditis or pericardial effusion;

– renal and/or liver failure;

– intrauterine contraception (IUD);

– severe trauma (especially of the central nervous system), open wounds on large surfaces;

– simultaneous use of drugs that affect the hemostasis system;

– heparin-induced thrombocytopenia without a history of circulating antibodies (more than 100 days).

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

Side Effects

The study of the side effects of enoxaparin sodium was carried out in more than 15,000 patients participating in clinical studies, of which 1,776 patients – in the prevention of venous thrombosis and embolism during general surgery and orthopedic operations; in 1169 patients – for the prevention of venous thrombosis and embolism in patients on bed rest due to acute therapeutic 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 a Q wave; in 10,176 patients – in the treatment of myocardial infarction with ST segment elevation.

The mode of administration of enoxaparin sodium differed depending on the indication. For the prevention of venous thrombosis and embolism during general surgical and orthopedic operations or in patients on bed rest, 40 mg was administered subcutaneously once a day. For 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.

The incidence of adverse reactions was determined according to the WHO classification: very often (≥1/10); often (≥1/100 and <1/10); uncommon (≥1/1000 and <1/100); rare (≥1/10,000 and <1/1000); very rare (< 1/10,000), frequency unknown (cannot be calculated based on available data).

Vascular disorders:

Bleeding

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

As with the use of other anticoagulants, bleeding may occur when using enoxaparin sodium, especially in the presence of risk factors that contribute to the development of bleeding, during invasive procedures or the use of drugs that impair hemostasis (see sections “Interaction with other drugs” and “Special instructions”).

When describing bleeding below, the sign “*” means an indication of the following types of bleeding: hematoma, ecchymoses (except those developed at the injection site), wound hematomas, hematuria, nosebleeds, gastrointestinal bleeding.

Very common – bleeding* when preventing venous thrombosis in surgical patients and treating 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, myocardial infarction without a Q wave and myocardial infarction with ST segment elevation.

Uncommon: retroperitoneal bleeding and intracranial hemorrhage in patients treated for deep vein thrombosis with or without pulmonary embolism, as well as 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 a Q wave.

Thrombocytopenia and thrombocytosis

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

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

Uncommon – thrombocytopenia in the prevention of venous thrombosis in patients on bed rest and in the treatment of unstable angina, myocardial infarction without a Q wave.

Very rarely – autoimmune thrombocytopenia in the treatment of patients with acute myocardial infarction with ST segment elevation.

Other clinically significant adverse reactions, regardless of indication

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

Blood and lymphatic system disorders

Often – bleeding, thrombocytopenia, thrombocytosis.

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

Immune system disorders

Often – allergic reactions.

Disorders of the liver and biliary tract

Very often – an increase in the activity of liver enzymes, mainly an increase in the activity of transaminases, more than three times the upper limit of normal.

Skin and subcutaneous tissue disorders

Often – urticaria, skin itching, erythema.

Uncommon: bullous dermatitis.

General and administration site disorders

Often – hematoma at the injection site, pain at the injection site, swelling at the injection site, bleeding, hypersensitivity reactions, inflammation, formation of lumps at the injection site.

Uncommon: irritation at the injection site, skin necrosis at the injection site.

Data obtained during the post-registration period

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

Immune system disorders

Rarely – anaphylactic/anaphylactoid reactions, including shock.

Nervous system disorders

Often – headache.

Vascular disorders

Rarely, cases of spinal hematoma (or neuraxial hematoma) have been reported when using enoxaparin sodium during spinal/epidural anesthesia or spinal puncture. These reactions led to the development of neurological disorders of varying severity, including persistent or irreversible paralysis
(see section “Special instructions”).

Blood or lymphatic system disorders

Often – hemorrhagic anemia.

Rarely – eosinophilia.

Skin and subcutaneous tissue disorders

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

The formation of hard inflammatory nodules-infiltrates at the injection site of the drug is possible, which disappear after a few days and are not grounds for discontinuation of the drug.

Disorders of the liver and biliary tract

Uncommon: 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 drugs!

Combinations not recommended

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

Combinations requiring caution

· Other drugs that affect hemostasis, such as:

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

– dextran with a molecular weight of 40 kDa;

– systemic glucocorticosteroids.

Medicines that increase potassium levels

When used simultaneously with drugs that increase potassium levels in the blood serum, clinical and laboratory monitoring should be carried out.

Overdose

Accidental overdose of the drug during 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 be largely counteracted by slow intravenous administration of protamine sulfate, the dose of which depends on the dose of 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 the administration of protamine. 0.5 mg of protamine neutralizes the anticoagulant effect of 1 mg of the drug if more than 8 hours have passed since the administration of the latter or if a second dose of protamine is necessary. If 12 hours or more have passed after the administration of enoxaparin sodium, administration 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 (maximum 60%).

Storage conditions

At a temperature not exceeding 25 °C.

Keep out of the reach of children.

Shelf life

3 years. Do not use after the expiration date.

Manufacturer

Grotex LLC, Russia