Enixum, 4000 anti-ha me/0.4ml 0.4 ml 10 pcs

• Prevention of venous thrombosis and embolism in surgical interventions, especially in orthopedic and general surgical procedures;
• 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.Prevention of venous thrombosis and embolism in bedridden patients due to acute medical conditions, including acute heart failure and decompensation of chronic heart failure (NYHA class III or IV), acute respiratory failure; acute infectious diseases; acute stages of rheumatic diseases combined with a risk factor for venous thrombosis (see “Special Instructions. “
• treatment of deep vein thrombosis with or without pulmonary embolism;
• prevention of thrombosis in extracorporeal circulation during hemodialysis (usually with a session duration of 4 hours or less);
• treatment of unstable angina and myocardial infarction without Q-wave in combination with acetylsalicylic acid;
• treatment of acute ST-segment elevation myocardial infarction in patients undergoing drug treatment or subsequent percutaneous coronary intervention.

Indications

prevention of venous thrombosis and embolism during surgical interventions, especially during orthopedic and general surgical operations, 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 “Special Instructions”);
treatment of deep vein thrombosis with or without pulmonary embolism, except in cases of pulmonary embolism requiring thrombolytic 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.

Pharmacological effect

Pharmacodynamics

Enoxaparin sodium is a low molecular weight heparin. Average molecular weight is about 4500 Da: less than 2000 Da – 68%, more than 8000 Da – <18%. Enoxaparin sodium is obtained by alkaline hydrolysis 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 part of the polysaccharide chain.

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/III activity, additional anticoagulant and anti-inflammatory properties of enoxaparin sodium have also been identified in both humans and animal models, which include AT-III-dependent inhibition of other coagulation factors such as factor VIIa, activation of tissue factor pathway inhibitor release, and reduction of von Willebrand factor release from the vascular endothelium into the circulation. These factors provide the anticoagulant effect of enoxaparin sodium in general.

When used in prophylactic doses, enoxaparin sodium slightly changes the aPTT and has virtually no effect on platelet aggregation and the degree of fibrinogen binding to platelet receptors.

Pharmacokinetics

Special instructions

General

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

Bleeding

As with the use of other anticoagulants, when using the drug Enixum®, bleeding of any location may develop (see “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 “Interaction”).

Bleeding in elderly patients

When using enoxaparin sodium in prophylactic doses in elderly patients, there was no increase in the risk of bleeding. When using enoxaparin sodium in therapeutic doses in elderly patients (especially those aged 80 years and older), there is an increased risk of bleeding. Close monitoring of the condition of such patients is recommended (see “Pharmacokinetics” and “Dosage and Administration”, Elderly).

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, NSAIDs, including ketorolac, other thrombolytics (altenlase, reteplase, streptokinase, tenecteplase, urokinase) is recommended to be discontinued before starting treatment with enoxaparin sodium, unless their use is necessary. If their simultaneous use with enoxaparin sodium, 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 (Cl creatinine < 15–30 ml/min), there is a significant increase in exposure to enoxaparin sodium, therefore dose adjustment is recommended for both prophylactic and therapeutic use of the drug and biological monitoring of anti-Xa activity may be considered. Although no dose adjustment is required in patients with mild to moderate renal impairment (Cl creatinine 30–50 or 50–80 ml/min), close monitoring of such patients is recommended (see Pharmacokinetics and Dosage and Administration, Renal Impairments). The use of enoxaparin sodium is not recommended in patients with end-stage chronic kidney disease (Cl creatinine < 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 exposure to enoxaparin sodium when used prophylactically in women weighing less than 45 kg and 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 (HIT) also exists with the use of low molecular weight heparins. 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 platelet count in peripheral blood before starting treatment with Enixum® 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 baseline), 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 have been described when using enoxaparin sodium during simultaneous spinal/epidural anesthesia with the development of long-term or irreversible paralysis.

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 enoxaparin sodium, as well as with the use of indwelling catheters after surgery, or the simultaneous use of additional drugs that affect hemostasis, such as NSAIDs (see section “Interactions”). 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 “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 creatinine Cl 15–30 ml/min, the excretion of enoxaparin sodium is slowed 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 spinal cord decompression if necessary.

GIT

The use of enoxaparin sodium in patients with a history of HIT within the last 100 days or in the presence of circulating antibodies is contraindicated (see 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 HIT 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 the administration of Enixum®. This is necessary in order to achieve hemostasis 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 IV or SC 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 enoxaparin sodium 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 the administration of enoxaparin sodium for the prevention of thrombus formation. 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 enoxaparin sodium for the prevention of thrombus formation in pregnant women with mechanical artificial heart valves has not been sufficiently studied. In a clinical study in pregnant women with mechanical artificial heart valves, when using enoxaparin sodium at a dose of 1 mg/kg 2 times a day to reduce the risk of thrombosis and embolism, 2 out of 8 women developed a blood clot, which led to blocking of the heart valves and death of the mother and fetus.

There have been isolated post-marketing reports of valvular thrombosis in pregnant women with mechanical prosthetic heart valves treated with enoxaparin sodium for thrombotic prophylaxis. Pregnant women with mechanical artificial heart valves are at 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, enoxaparin sodium 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 is 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 “Interactions”). 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; hormone 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.

Influence on the performance of potentially hazardous activities that require special attention and speed of reactions. No effect.

Active ingredient

Enoxaparin sodium

Composition

Solution for injection
1 amp./1 syringe (0.4 ml)
active ingredient:
enoxaparin sodium
4000 anti-Xa IU (40 mg*)
excipient: water for injection – up to 0.4 ml

Pregnancy

Our own preclinical studies did not show a teratogenic effect of the drug Enixum® on the fetus.

Clinical studies have not been conducted in pregnant women. There is no information that enoxaparin sodium crosses the placental barrier during the second trimester of pregnancy in humans. There is no relevant information regarding the first and third trimesters of pregnancy. Since there are no adequate and well-controlled studies in pregnant women, and animal studies do not always predict the response to enoxaparin sodium administration during pregnancy in humans, the use of Enixum® is possible only in cases where the potential benefit to the mother outweighs the possible risk to the fetus. It is recommended that patients be monitored for signs of bleeding or excessive anticoagulation and patients should be advised 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 “Special Instructions”).

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

It is not known whether enoxaparin sodium is excreted unchanged into breast milk. Absorption of enoxaparin sodium from the gastrointestinal tract in a newborn is unlikely. However, as a precaution, breastfeeding women receiving Enixum® treatment should be advised to discontinue breastfeeding.

Contraindications

hypersensitivity to enoxaparin sodium, heparin or its derivatives, including other low molecular weight heparins;
active major bleeding, as well as conditions and diseases in which there is a high risk of bleeding, including recent hemorrhagic stroke, acute gastrointestinal ulcer, presence of a malignant neoplasm with a high risk of bleeding, recent brain and spinal cord surgery, ophthalmic surgery, known or suspected presence of esophageal varices, arteriovenous malformations, vascular aneurysms, vascular abnormalities 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, because efficacy and safety in this category of patients have not been established (see “Special Instructions”).

With caution: conditions in which there is a potential risk of bleeding – hemostasis disorders (including hemophilia, thrombocytopenia, hypocoagulation, von Willebrand disease), 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; performing spinal or epidural anesthesia (potential danger of developing a hematoma), spinal puncture (recently performed); recent birth; bacterial endocarditis (acute or subacute); pericarditis or pericardial effusion; renal and/or liver failure; intrauterine contraception; severe trauma (especially the central nervous system), open wounds on large surfaces; simultaneous use of drugs that affect the hemostatic system; heparin-induced thrombocytopenia without a history of circulating antibodies (more than 100 days).

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

Side Effects

The side effects of enoxaparin sodium were studied in more than 15,000 patients participating in clinical studies, of which 1,776 patients were studied 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 DVT with or without PE; in 1578 patients – in the treatment of unstable angina and myocardial infarction without a Q wave; y 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 s.c. was administered once a day. When treating DVT with or without PE, patients received enoxaparin sodium at the rate of 1 mg/kg body s.c. every 12 hours or 1.5 mg/kg s.c. once daily.

In the treatment of unstable angina and myocardial infarction without a Q wave, the dose of enoxaparin sodium was 1 mg/kg subcutaneously every 12 hours, and in the case of myocardial infarction with ST-segment elevation, an intravenous bolus of 30 mg was administered followed by 1 mg/kg subcutaneously every 12 hours. The incidence of adverse reactions was determined in accordance with the WHO classification very often (≥1/10); often (≥1/100, <1/10); uncommon (≥1/1000, <1/100); rare (1/10000, <1/1000); very rare (< 1/10000); frequency unknown (cannot be calculated from available data).

From the side of blood vessels

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 Hb content by 2 g/L or more, required transfusion of 2 or more units of blood components, and if it was retroperitoneal or intracranial). Some of these cases were fatal.

As with other anticoagulants, bleeding may occur when using enoxaparin sodium, especially in the presence of risk factors that contribute to the development of bleeding, invasive procedures, or the use of drugs that impair hemostasis (see “Special instructions” and “Interaction”). 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 often – bleeding* when preventing venous thrombosis in surgical patients and treating DVT with or without pulmonary embolism; 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; infrequently – retroperitoneal bleeding and intracranial hemorrhage in patients during the treatment of DVT with or without PE, as well as during the treatment of myocardial infarction with ST segment elevation; rarely – retroperitoneal bleeding in the prevention of venous thrombosis in surgical patients and in the treatment of unstable angina and 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 treatment of DVT with or without PE; 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 DVT with or without PE, 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 and 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.

From the blood and lymphatic system: 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 “Special Instructions”, Monitoring the number of platelets in peripheral blood.)

Immune system disorders: often – allergic reactions.

From the liver and biliary tract: very often – increased activity of liver enzymes, mainly increased activity of transaminases, more than 3 times the ULN.

From the skin and subcutaneous tissues: often – urticaria, skin itching, 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; uncommon – irritation at the injection site, skin necrosis at the injection site.

Data obtained after the drug entered the market

The following adverse reactions have been reported with post-marketing use of enoxaparin sodium. These adverse reactions have been spontaneously reported.

From the immune system: rarely – anaphylactic/anaphylactoid reactions, including shock.

From the nervous system: often – headache.

Vascular: rarely – cases of spinal hematoma (or neuraxial hematoma) have been reported when using enoxaparin sodium against 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 “Special Instructions”).

From the blood or lymphatic system: often – hemorrhagic anemia; rarely – eosinophilia.

From the skin and subcutaneous tissues: 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, therapy with enoxaparin sodium 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.

From the liver and biliary tract: infrequently – hepatocellular liver damage; rarely – cholestatic liver damage.

Disorders of the musculoskeletal system and connective tissue: rarely – osteoporosis with long-term therapy (more than 3 months).

Laboratory and instrumental data: rarely – hyperkalemia.

Interaction

Enoxaparin sodium should not be mixed with other drugs!

Not recommended combinations

Drugs affecting hemostasis (systemic salicylates, acetylsalicylic acid in doses that have an anti-inflammatory effect, NSAIDs, fibrinolytics (alteplase, reteplase, streptokinase, tenecteplase, urokinase) are recommended to be discontinued before starting therapy with enoxaparin sodium. If simultaneous use with enoxaparin sodium is necessary, caution should be exercised and careful clinical observation and monitoring of relevant laboratory parameters.

Combinations requiring caution

1. Other drugs that affect hemostasis, such as:

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

– dextran with a molecular weight of 40 kDa;

– system GKS.

2. 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

Symptoms: hemorrhagic complications in case of accidental overdose with intravenous, extracorporeal or subcutaneous administration of enoxaparin sodium. When taken orally, even large doses, absorption of the drug is unlikely.

Anticoagulant effects can be largely counteracted by slow IV administration of protamine sulfate

Treatment: neutralize the effect of enoxaparin sodium by slow intravenous administration of protamine sulfate, the dose of which depends on the dose of the drug administered. 1 mg of protamine sulfate neutralizes the anticoagulant effect of 1 mg of enoxaparin sodium (see information on the use of protamine salts) 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 it is necessary to administer a 2nd dose of protamine. 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 enoxaparin sodium is not completely neutralized (maximum by 60%).

Storage conditions

At a temperature not exceeding 25 °C. Do not freeze.

Shelf life

2 years.

Manufacturer

PharmFirma Sotex, Russia