Enixum, 6000 anti-ha me/0.6 mL 0.6 mL 10 pcs

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Indications

– Prevention of venous thrombosis and embolism in surgical interventions in moderate- and high-risk patients, especially in orthopedic and general surgical interventions, including cancer.

– Prevention of venous thrombosis and embolism in bedridden patients due to acute therapeutic conditions, including acute heart failure and decompensation of chronic heart failure (NYHA class III or IV), respiratory failure, and in severe infections and rheumatic diseases at increased risk of venous thrombosis (see section “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 thrombosis 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;

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Active ingredient

Enoxaparin sodium

Composition

1 syringe (0.6 ml) contains:

The active ingredient:

enoxaparin sodium 60 mg

Associates:

water for injection – up to 0.6 ml.

How to take, the dosage

Subcutaneously, except in special cases.

Prevention of venous thrombosis and embolism in surgical procedures in moderate to high risk patients

Patients at moderate risk of thrombosis and embolism (e.g., abdominal surgery) have a recommended dose of Enixum® 20 mg once daily subcutaneously. The first injection should be given 2 hours before the surgical intervention.

. In patients at high risk of thrombosis and embolism (e.g., orthopedic surgery, oncologic surgery, patients with additional non-surgical risk factors such as congenital or acquired thrombophilia malignant neoplasm, bed rest for more than three days, obesity, venous thrombosis in anamnesis, varicose veins of lower limbs, pregnancy) the drug is recommended in a dose of 40 mg once a day subcutaneously, with the first dose administered 12 hours before the surgical intervention. If earlier preoperative prophylaxis is necessary (e.g., in patients at high risk of thrombosis and thromboembolism awaiting delayed orthopedic surgery) the last injection should be given 12 hours before surgery and 12 hours after surgery.

The duration of treatment with Enixum is 7-10 days on average. If necessary, therapy may be continued as long as the risk of thrombosis and embolism persists and until the patient is switched to an outpatient regimen.

In major orthopedic surgeries, it may be appropriate to continue treatment after initial therapy with Enixum® at a dose of 40 mg once daily for five weeks.

In patients at high risk of venous thromboembolism who have undergone surgery, abdominal and pelvic surgery because of cancer, it may be advisable to increase the duration of Enixum® administration in a dose of 40 mg once daily for four weeks.

Prevention of venous thrombosis and embolism in patients on bed rest due to acute medical conditions

The recommended dose of Enixum® is 40 mg once daily, subcutaneously, for 6-14 days. The therapy should be continued until the patient is fully ambulatory (maximum 14 days).

The treatment of deep vein thrombosis with or without pulmonary embolism

The drug is administered subcutaneously at a rate of 1.5 mg/kg body weight once daily or 1 mg/kg body weight twice daily. The dosing regimen should be chosen by a physician on the basis of assessing the risk of thromboembolism and the risk of bleeding.

In patients without thromboembolic complications and at low risk of venous thromboembolism, the drug is recommended to be given subcutaneously at a rate of 1.5 mg/kg body weight once daily.

In all other patients, including patients with obesity, symptomatic pulmonary embolism, cancer, recurrent venous thromboembolism and proximal thrombosis (in the iliac vein), the drug is recommended at a dose of 1 mg/kg twice daily.

The duration of treatment is on average 10 days. It is recommended to start immediately the therapy with indirect anticoagulants and continue Enixum® therapy until therapeutic anticoagulant effect is achieved (INR value [International Normalized Ratio] should be 2.0-3.0).

Prevention of thrombosis in extracorporeal circulation during hemodialysis

The recommended dose of Enixum® is on average 1 mg/kg body weight. If the risk of bleeding is high, the dose should be reduced to 0.5 mg/kg body weight for dual vascular access or 0.75 mg/kg for single vascular access.

In hemodialysis, Enixum® should be administered to the arterial shunt site at the beginning of the hemodialysis session. One dose is usually sufficient for a four-hour session; however, if fibrin rings are detected during a longer hemodialysis session, additional drug may be administered at a rate of 0.5-1 mg/kg of body weight. No data are available for patients using enoxaparin sodium for prophylaxis or treatment and during hemodialysis sessions.

Treatment of unstable angina and myocardial infarction without ST-segment elevation

Enixum® is administered at a rate of 1 mg/kg body weight every 12 hours, subcutaneously, with concomitant use of antiplatelet therapy. Average therapy duration is at least 2 days and lasts until patient’s clinical condition stabilizes. The drug usually lasts from 2 to 8 days.

Acetylsalicylic acid is recommended for all patients with no contraindications, with an initial dose of 150-300 mg orally followed by a maintenance dose of 75-325 mg once daily.

The treatment of acute ST-segment elevation myocardial infarction, drug or percutaneous coronary intervention

The treatment begins with a single intravenous bolus injection of Enoxaparin sodium at a dose of 30 mg. Immediately thereafter, enoxaparin sodium is administered subcutaneously in a dose of 1 mg/kg of body weight. The drug is then administered subcutaneously at 1 mg/kg of body weight every 12 hours (maximum 100 mg of sodium enoxaparin for each of the first two subcutaneous injections, then 1 mg/kg of body weight for the remaining subcutaneous doses, that is, if the body weight exceeds 100 kg, the single dose may not exceed 100 mg).

As soon as possible after detection of acute myocardial infarction with ST-segment elevation, patients should be simultaneously prescribed acetylsalicylic acid and, if there are no contraindications, administration of acetylsalicylic acid (in doses of 75-325 mg) should be continued daily for at least 30 days.

The recommended duration of treatment with Enixum® is 8 days or until discharge from hospital (if hospitalization is less than 8 days).

When combined with thrombolytics (fibrin-specific and fibrin-unspecific), enoxaparin sodium should be administered between 15 min before and 30 min after thrombolytic therapy.

In patients 75 years of age and older, initial intravenous bolus administration 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 body weight for the remaining subcutaneous doses, that is, if the body weight exceeds 100 kg, the single dose cannot exceed 75 mg).

In patients undergoing percutaneous coronary intervention, if the last subcutaneous injection of enoxaparin sodium was given less than 8 hours before the balloon catheter inserted into the coronary artery constriction was inflated, no additional injection of enoxaparin sodium is required. If the last subcutaneous injection of sodium enoxaparin was given more than 8 hours before the balloon catheter was inflated, an additional intravenous bolus injection of sodium enoxaparin at a dose of 0.3 mg/kg should be given.

Interaction

Enoxaparin sodium must not be mixed with other medications!

Unrecommended combinations

Therapies affecting hemostasis (systemic salicylates, acetylsalicylic acid in anti-inflammatory doses, non-steroidal anti-inflammatory drugs (NSAIDs) including ketorolac, other thrombolytics (alteplase, reteplase. streptokinase, tenecteplase, urokinase)) it is recommended to cancel before the start of 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 performed.

Combinations requiring caution

– Other drugs affecting hemostasis, such as:

• platelet aggregation inhibitors, including acetylsalicylic acid at doses with antiaggregant effects (cardioprotection), clopidogrel, ticlopidine, and glycoprotein IIb/IIIa antagonists indicated for acute coronary syndrome due to increased risk of bleeding;
• dextran with a molecular weight of 40 kDa;
• systemic glucocorticosteroids.

– Drugs that increase potassium content

Clinical and laboratory monitoring should be performed when concomitant use with drugs that increase serum potassium content.

Special Instructions

General

Low molecular weight heparins are not interchangeable, since they differ in manufacturing process, molecular weight, specific anti-Xa activity, dosing units and dosing regimen, with associated 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 other anticoagulants, the administration of enoxaparin sodium may cause bleeding of any localization. If bleeding develops, the source of bleeding must be found and appropriate treatment administered.

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

• disorders of hemostasis;
• a history of peptic ulcer disease;
• recurrent ischemic stroke;
• severe arterial hypertension;diabetic retinopathy;
• neurosurgical or ophthalmic surgery; and concomitant use of drugs that affect hemostasis.

Bleeding in elderly patients

When enoxaparin sodium is used in prophylactic doses in elderly patients, no increased risk of bleeding has been noted.

When using the drug in therapeutic doses in elderly patients (especially those aged 80 years and older) there is an increased risk of bleeding. Close monitoring of these patients is recommended.

Simultaneous use of other drugs that affect hemostasis

. The use of drugs that affect hemostasis (systemic salicylates, including acetylsalicylic acid in doses with anti-inflammatory effect, NSAIDs, including ketorolac, other thrombolytics (alteplase, reteplase, streptokinase, tenecteplase, urokinase)) is recommended to be cancelled before starting treatment with Enoxaparin sodium, unless their use is necessary. If their concomitant use with enoxaparin sodium is indicated, close clinical observation and monitoring of relevant laboratory parameters should be performed.

Renal failure

In patients with impaired renal function, there is an increased risk of bleeding due to increased systemic exposure to enoxaparin sodium.

In patients with severe renal dysfunction (CKR 15-30 ml/min), a significant increase in exposure of enoxaparin sodium is noted, so dose adjustments are recommended for both prophylactic and therapeutic use of the drug. Although there is no need to perform dose adjustment in patients with mild (CKR 30-50 ml/min) and moderate (CKR 50-80 ml/min) renal dysfunction, close monitoring of such patients is recommended, and biological monitoring with measurement of anti-Xa activity may be considered.

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

Low body weight

There has been increased exposure to enoxaparin sodium when used prophylactically in women with a body weight less than 45 kg and in men with a body weight less than 57 kg, which may lead to an increased risk of bleeding. Close monitoring of such patients is recommended.

Patients with obesity

Patients with obesity have an increased risk of 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 general consensus on dose adjustment. It is recommended that patients be monitored for signs and symptoms of thrombosis and embolism.

Peripheral blood platelet count monitoring

The risk of antibody-mediated heparin-induced thrombocytopenia (AIT) also exists with low molecular weight heparins, with a higher risk in patients who have undergone heart surgery and patients with cancer. If thrombocytopenia develops, it is usually detected between days 5 and 21 after initiation of therapy with enoxaparin sodium.

In this regard, it is recommended that peripheral blood platelet counts be monitored regularly before and during treatment with Enoxaparin sodium. The blood platelet count should be determined in the presence of symptoms indicating GIT (new episode of arterial and/or venous thromboembolic complications, painful skin lesions at the injection site, allergic or anaphylactic reactions during treatment). If the above symptoms occur, the attending physician should be informed.

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

Spinal/epidural anesthesia

There have been cases of neuroaxial hematomas when using enoxaparin sodium concomitantly with spinal/epidural anesthesia with the development of long-standing or irreversible paralysis. The risk of these phenomena is reduced when using the drug at a dose of 40 mg or lower. The risk increases when using higher doses of enoxaparin sodium, as well as when using permanent catheters after surgery, or when concomitant use of additional drugs that affect hemostasis, such as NSAIDs. The risk also increases with traumatic or repeated spinal tap 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 considered. Catheter placement or removal is best performed when the anticoagulant effect of enoxaparin sodium is low, but the exact time to achieve sufficient reduction of anticoagulant effect in different patients is unknown. Additionally, note that in patients with a CK of 15-30 mL/min, excretion of enoxaparin sodium is delayed.

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

Heparin-induced thrombocytopenia

The use of enoxaparin sodium in patients with a history of heparin-induced thrombocytopenia within the past 100 days or in the presence of circulating antibodies is contraindicated. Circulating antibodies may persist for several years.

Enoxaparin sodium should be used with particular 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 a benefit/risk assessment and in the absence of heparin-free alternative therapy.

Prescope coronary angioplasty

In order to minimize the risk of bleeding associated with invasive vascular instrumentation in the treatment of unstable angina and myocardial infarction without Q-wave and acute myocardial infarction with ST-segment elevation, these procedures should be performed in intervals between drug administrations. This is necessary to achieve hemostasis at the catheter insertion site after percutaneous coronary intervention. If a femoral artery intraductor device is used, the femoral artery intraductor can be removed immediately.

If manual (manual) compression is used, the femoral artery intromedullary tube should be removed 6 hours after the last intravenous or subcutaneous injection of enoxaparin sodium. If treatment with sodium enoxaparin is continued, the next dose should not be administered before 6-8 h after removal of the femoral artery intraductor. The site of insertion of the intraductor should be monitored to detect timely signs of bleeding and hematoma formation.

Patients with mechanical artificial heart valves

The use of enoxaparin sodium for prophylaxis of thrombosis in patients with mechanical artificial heart valves has not been well studied. There have been isolated reports of heart valve thrombosis in patients with mechanical artificial heart valves on therapy with Enoxaparin sodium for prophylaxis of thrombosis. Because of insufficient clinical data and ambiguous factors, including underlying disease, it is difficult to evaluate such reports.

Pregnant women with mechanical artificial heart valves

The use of sodium enoxaparin for prophylaxis of thrombosis in pregnant women with mechanical artificial heart valves has not been well studied. In a clinical study involving pregnant women with mechanical artificial heart valves, when enoxaparin sodium was used at a dose of 1 mg/kg body weight twice daily to reduce the risk of thrombosis and embolism, 2 of 8 women developed thrombi that led to heart valve blockage and death to mother and fetus.

There have been anecdotal postmarketing reports of heart valve thrombosis in pregnant women with mechanical artificial heart valves treated with enoxaparin to prevent thrombus formation.

Pregnant women with mechanical artificial heart valves may have an increased risk of thrombosis and embolism.

Skin necrosis/skin vasculitis

The development of skin necrosis and skin vasculitis has been reported with the use of low molecular weight heparins. If skin necrosis/skin vasculitis develops, the use of the drug should be discontinued.

The use of heparin is not recommended in patients with acute infective 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 careful individual evaluation of the benefit-risk ratio.

Laboratory tests

In doses used for prevention of thromboembolic complications, enoxaparin sodium has no significant effect on bleeding time and clotting parameters, as well as on platelet aggregation or their binding to fibrinogen.

Additional dose increases may lengthen the ACTV and activated clotting time. Increase of ACTV and activated clotting time are not in direct linear relation to increase of anticoagulant activity of the drug, so there is no need to monitor them.

Hyperkalemia

Heparins may inhibit aldosterone secretion by the adrenal glands, resulting in the development of hyperkalemia, especially in patients with diabetes, chronic renal failure, prior metabolic acidosis, taking medications that increase potassium content. Plasma potassium levels should be monitored regularly, especially in patients in the risk group.

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

In case of acute infection, acute rheumatic conditions, prophylactic use of enoxaparin sodium is warranted only if the above conditions are combined with one of the following risk factors for venous thrombosis:

• age greater than 75 years;
• malignant neoplasms;
• a history of thrombosis and embolism;
• hormone therapy;
• heart failure;
• chronic respiratory failure.

Hepatic impairment

Sodium Enoxaparin should be used with caution in patients with hepatic impairment due to increased risk of bleeding. Dose adjustment based on monitoring of anti-Xa activity in patients with cirrhosis is unreliable and is not recommended.

Contraindications

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Side effects

The side effects of enoxaparin sodium have been studied in more than 15,000 patients who participated in clinical trials, including 1,776 patients in the prevention of venous thrombosis and embolism in general surgery and orthopedic surgery; 1,169 patients in the prevention of venous thrombosis and embolism in bed-ridden patients due to acute therapeutic conditions; in 559 patients, in the treatment of deep vein thrombosis with or without pulmonary embolism; in 1578 patients, in the treatment of unstable angina and myocardial infarction without a Q wave; in 10176 patients, in the treatment of ST-segment elevation myocardial infarction.

The mode of administration of enoxaparin sodium differed depending on the indication. In the prevention of venous thrombosis and embolism in general surgery and orthopedic surgery or in patients on bed rest, 40 mg was administered subcutaneously once daily.

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

In the treatment of unstable angina and myocardial infarction without Q-wave, the dose of enoxaparin sodium was 1 mg/kg body weight subcutaneously every 12 hours, and in case of myocardial infarction with ST-segment elevation, an intravenous bolus of 30 mg followed by 1 mg/kg body weight subcutaneously every 12 hours was administered.

The incidence of adverse reactions was determined in accordance with the classification of the World Health Organization: Very common (≥ 1/10); common (≥ 1/100 and < 1/10); infrequent (≥ 1/1000 and < 1/100); rare (≥ 1/10000 and < 1/1000); very rare (< 1/10000), frequency unknown (cannot be calculated from available data).

Vascular disorders

Bleeding

In clinical trials, 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 of 2 g/L or more, required a transfusion of 2 or more doses of blood components, or if it was retroperitoneal or intracranial). Some of these cases were fatal.

As with other anticoagulants, bleeding is possible with the use of enoxaparin sodium, especially in the presence of risk factors that contribute to bleeding, during invasive procedures or when using drugs that disrupt hemostasis.

In the description of bleeding below, the sign “*” means to indicate the following types of bleeding: hematoma, ecchymoses (except those developed at the injection site), wound hematomas, hematuria, nasal bleeding, gastrointestinal bleeding.

Very common: bleeding* during prophylaxis of venous thrombosis in surgical patients and treatment of deep vein thrombosis with or without pulmonary embolism.

Often: Bleeding* in prophylaxis of venous thrombosis in bed-ridden patients and in treatment of unstable angina pectoris, myocardial infarction without Q wave and ST-segment elevation myocardial infarction.

Infrequent: retroperitoneal bleeding and intracranial hemorrhage in patients treated for deep vein thrombosis with or without pulmonary embolism and for treatment of ST-segment elevation myocardial infarction.

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

Thrombocytopenia and thrombocytosis

Very common: Thrombocytosis (peripheral blood platelet count greater 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 ST-segment elevation myocardial infarction.

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

Infrequent: thrombocytopenia in prophylaxis of venous thrombosis in patients on bed rest and in treatment of unstable angina and myocardial infarction without Q-wave.

Very rare: autoimmune thrombocytopenia in the treatment of patients with acute ST-segment elevation myocardial infarction.

Other clinically significant adverse reactions, regardless of indication

The adverse reactions presented below are grouped by systemic organ class, given by the frequency of occurrence defined above and in decreasing order of 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 organ infarction or limb ischemia.

Disorders of the immune system:

often: allergic reactions.

Liver and biliary tract disorders:

very common: increased activity of “liver” enzymes, mainly increased activity of transaminases, more than three times the upper limit of normal.

Skin and subcutaneous tissue disorders:

often: urticaria, skin itching, erythema.

infrequent: bullous dermatitis.

General disorders and disorders at the injection site:

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

Infrequent: irritation at the injection site, necrosis of the skin at the injection site.

Data obtained after the drug was placed on the market

The following adverse reactions have been reported in the post-marketing use of enoxaparin sodium. There have been spontaneous reports of these adverse reactions.

Disorders of the immune system:

Rarely: anaphylactic/anaphylactoid reactions, including shock.

Nervous system disorders:

often: headache.

vascular disorders:

seldom: cases of spinal hematoma (or neuroaxial hematoma) have been reported when using enoxaparin sodium against the background of spinal/epidural anesthesia or spinal tap. These reactions led to the development of neurological disorders of varying severity, including persistent or irreversible paralysis.

Disorders of the blood or lymphatic system:

often: hemorrhagic anemia;

rarely: eosinophilia

Skin and subcutaneous tissue disorders:

rarely: alopecia; cutaneous vasculitis, skin necrosis may develop at the injection site, 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 solid inflammatory nodules-infiltrates at the site of injection of the drug is possible, which disappear after a few days and are not a reason for discontinuation of the drug.

Hepatic and biliary tract disorders:

infrequent: hepatocellular liver damage;

rare: cholestatic liver damage.

Muscular and connective tissue disorders:

seldom: osteoporosis with prolonged therapy (more than three months).

Laboratory and instrumental findings:

rarely: hyperkalemia.

Overdose

An accidental overdose of enoxaparin sodium with intravenous, extracorporeal or subcutaneous administration may lead to hemorrhagic complications. Absorption is unlikely when administered orally, even in large doses.

Anticoagulant effects can mainly be neutralized by slow intravenous administration of protamine sulfate, the dose of which depends on the dose administered. One mg (1 mg) of protamine sulfate will neutralize the anticoagulant effect of one mg (1 mg) of enoxaparin sodium (see information on the use of protamine salts) if enoxaparin sodium was administered no more than 8 h before protamine was given. 0.5 mg protamine will neutralize the anticoagulant effect of 1 mg of the drug if more than 8 hours have elapsed since the last injection or if a second dose of protamine must be administered. If enoxaparin sodium has been administered for 12 hours or more, no protamine administration is required. However, even with high doses of protamine sulfate, the anti-Xa activity of sodium enoxaparin is not completely neutralized (maximum 60%).

Similarities

Clexane