Enixum 5000 anti-Ha IU/0.5 ml 0.5 ml, 10 pcs.

Enoxaparies sodium is a low molecular weight heparin. The average molecular weight is about 4500 daltons: less than 2000 daltons – < 20%, from 2000 to 8000 daltons – > 68%, more than 8000 daltons – < 18%. Enoxaparies sodium is obtained by alkaline hydrolysis of heparin benzine ester isolated from the mucous membrane of pig small intestine. Its structure is characterized by a nonreducible fragment of 2-0-sulfo-4-enpyrazinosuronic acid and a reducible fragment of 2-14.6-0-disulfo-0-glucopyranoside.

The structure of enoxaparin sodium contains about 20% (ranging from 15% to 25%) of the 1.6- anhydron derivative in the reducing fragment of the polysaccharide chain.

Pharmacodynamics

In vitro enoxaparyl sodium has high activity against factor Ha clotting (anti-Xa activity approximately 100 IU/ml) and low activity against factor Na clotting (antp IIa or anti-thrombin activity approximately 28 IU/ml). This anticoagulant activity is mediated by antithrombin III (AT-III). In addition to anti-Xa/IIa activity, additional anticoagulant and anti-inflammatory properties of enoxaparpene sodium have also been identified in both human and animal models, which include AT-III-dependent inhibition of other clotting factors such as factor Vila, activation of tissue factor pathway inhibitor 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.

When used in prophylactic doses, sodium epoxaparin slightly changes the activated partial thromboplastin time (APT). It has almost no effect on platelet aggregation and on the degree of binding of fibrinogen to platelet receptors.

The anti-IIa activity in plasma is about 10 times lower than the anti-Xa activity.

The mean maximum anti-IIa activity is observed about 3-4 h 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. Mean maximum plasma anti-Xa activity is observed 3-5 h 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 and 1 mg/kg and 1.5 mg/kg, respectively

.

Indications

– prevention of venous thrombosis and embolism in surgical interventions, especially in orthopedic and general surgical operations;

– 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), acute respiratory failure; acute infectious diseases; acute stages of rheumatic diseases combined with a risk factor for venous thrombosis (see “Special Indications));

– treatment of deep vein thrombosis, which is accompanied or not accompanied by pulmonary embolism;

– treatment of unstable angina and myocardial infarction without Q-wave in combination with acetylsalicylic acid;

– prophylaxis against thrombosis in the extracorporeal circulatory system during hemodialysis (usually with a session duration of 4 hours or less);

The treatment of acute ST-segment elevation myocardial infarction in patients undergoing medication-assisted or subsequent percutaneous coronary intervention.

Active ingredient

Composition

How to take, the dosage

The needle should be inserted vertically (not laterally) into the full length skin fold, gathered and held between the thumb and forefinger until the injection is complete. The skin fold, release only after the injection is completed. The injection site should not be massaged after the injection.

The pre-filled disposable syringe is ready for use.

The product must not be injected intramuscularly!

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

In patients with a moderate risk of thrombosis and embolism (general surgical procedures), the recommended dose is 20 mg once daily subcutaneously. The first injection is given 2 hours before the surgical intervention.

In patients with high risk of thrombosis and embolism (general surgical and orthopedic operations), the drug is recommended in a dose of 40 mg once daily subcutaneously; the first dose is given 12 hours before the surgical intervention, or 30 mg 2 times daily with the beginning of the injection 12-24 hours after surgery.

The peculiarities of the drug administration during spinal/epidural anesthesia as well as during percutaneous coronary angioplasty are described in section “Special Precautions”.

Prevention of venous thrombosis and embolism in bedridden patients due to acute medical conditions

The recommended dose of enoxaparin sodium is 40 mg once daily subcutaneously for 6 to 14 days.

The treatment of deep vein thrombosis with or without pulmonary embolism

Enixum® is administered subcutaneously at a rate of 1.5 mg/kg once daily or at a dose of 1 mg/kg twice daily. In patients with complicated thromboembolic disorders the drug is recommended in a dose of 1 mg/kg twice daily.

The duration of treatment is on average 10 days. It is advisable to initiate therapy with oral anticoagulants immediately, while therapy with sodium enoxaparin should be continued until sufficient anticoagulant effect is achieved, i.e. INR should be 2.0-3.0. If necessary, control of anticoagulant effect should be assessed by anti-Xa activity.

The treatment of unstable angina and myocardial infarction without Q-wave in combination with acetylsalicylic acid

Enixum® is administered at a rate of 1 mg/kg body weight every 12 h subcutaneously, while acetylsalicylic acid is given simultaneously in an oral dose of 100-325 mg once daily.

The average duration of treatment is 2-8 days (until the patient’s clinical condition stabilizes).

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

. Treatment begins with an intravenous bolus injection of 30 mg of enoxaparin sodium and is immediately followed (within 15 minutes) by a subcutaneous dose of 1 mg/kg (with a maximum of 100 mg of enoxaparin sodium in the first two subcutaneous injections). Thereafter, all subsequent subcutaneous doses are administered every 12 hours at a rate of 1 mg/kg (i.e., if body weight exceeds 100 kg, the dose may exceed 100 mg).

To perform a 30 mg bolus injection of enoxaparin sodium in the treatment of acute ST-segment elevation myocardial infarction, the 60 mg, 80 mg and 100 mg glass syringes should be discarded so that only 30 mg (0.3 ml) remains. The 30 mg dose can be given directly intravenously.

Pre-filled 60 mg, 80 mg and 100 mg hypodermic syringes may be used for intravenous bolus injection of enoxaparin sodium via a venous catheter. The 60 mg syringe is recommended because it reduces the amount of drug removed from the syringe. The 20 mg syringe is not used because it does not contain enough preparation for a 30 mg bolus of enoxaparin sodium. The 40 mg syringe is not used because it has no graduations and therefore cannot accurately measure the 30 mg.

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

In order to improve the accuracy of additional bolus injection of small volumes into the venous catheter during percutaneous coronary interventions, it is recommended to dilute the drug to a concentration of 3 mg/ml. Dilution of the solution is recommended immediately prior to administration.

To obtain a 3 mg/ml solution of enoxaparin sodium using a pre-filled syringe, it is recommended to use a container with infusion solution from which a portion of the solution is extracted to the desired volume using a normal syringe. Enoxaparin sodium (contents of the hypodermic syringe) is injected into the remaining infusion solution in the container.

The volume of the pre-filled syringe

The amount of infusion solution left in the container

0.3 ml

10 ml

0.6 ml

20 ml

The contents of the container with the diluted enoxaparin sodium solution are mixed gently. The required volume of the diluted enoxaparin sodium solution is extracted for injection using a syringe, which is calculated according to the formula:

Volume of diluted solution = Patient body weight (kg) x 0.1 or using the table below.

Volumes to be administered intravenously after dilution

Patient body weight (kg)

Required dose (0.3 mg/kg) [mg]

45

13.5

4.5

50

15

5

55

16.5

5.5

1.5 mg subcutaneously once daily

1 mg/kg subcutaneously once daily

Treatment of acute ST-segment elevation myocardial infarction in patients < 75 years old

Once: 30 mg bolus intravenous injection plus 1 mg/kg subcutaneously; followed by a subcutaneous injection of 1 mg/kg twice daily (maximum 100 mg for each of the first two subcutaneous injections)

Once: 30 mg bolus intravenous plus 1 mg/kg subcutaneously; followed by 1 mg/kg subcutaneously once daily (maximum

100 mg for the first subcutaneous injection)

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Treatment of acute myocardial infarction with ST-segment elevation in patients >75 years old

0.75 mg/kg subcutaneously 1 mg/kg subcutaneously twice daily without initial bolus injection (maximum 75 mg for each of the first two subcutaneous injections)

1 mg/kg subcutaneously once daily without initial bolus injection (maximum 100 mg for the first subcutaneous injection)

The following dosing regimen adjustment is recommended when using the drug for prophylactic purposes

The usual dosing regimen

The dosing regimen for severe renal failure

40 mg subcutaneously once daily

20 mg subcutaneously once daily

20 mg subcutaneously once daily

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20 mg subcutaneously once daily

The recommended dosing adjustment is not applicable for hemodialysis.

In mild (creatinine clearance 50-80 mL/min) and moderate (creatinine clearance 30-50 mL/min) renal failure, no dose adjustment is required, but more careful laboratory monitoring of therapy should be performed.

Patients with hepatic impairment

In the absence of clinical studies, caution should be exercised when using enoxaparin sodium in patients with hepatic impairment.

Interaction

Enixum should not be mixed with other drugs in the same syringe.

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, 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 the use of each drug belonging to the class of low molecular weight heparins.

Bleeding

As with the use of other anticoagulants, the use of Enixum® may cause bleeding of any localization (see “Side effects”). In case of bleeding it is necessary to find its source and prescribe an appropriate treatment.

Contraindications

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

– active major bleeding, as well as conditions and diseases with a high risk of bleeding: threatened abortion, cerebral vascular aneurysm, or dissecting aortic aneurysm (unless surgery is performed for this reason). Recent hemorrhagic stroke, uncontrolled bleeding, thrombocytopenia in combination with a positive in vitro test for antiplatelet antibodies in the presence of enoxaparin sodium;

– it is not recommended to use sodium enoxaparin to prevent thrombosis in pregnant women with mechanical artificial heart valves (insufficient clinical experience of use);

– age under 18 years (effectiveness and safety not established).

Conditions in which there is a potential risk of bleeding:

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

– gastric or duodenal ulcer or other

– gastrointestinal erosive-ulcerative lesions in the anamnesis;

– recent ischemic stroke;

– uncontrolled severe arterial hypertension;

– diabetic or hemorrhagic retinopathy;

– severe diabetes mellitus;

– recent or suspected neurologic or ophthalmic surgery;

– performing spinal or epidural anesthesia (potential risk of hematoma), spinal tap (recent):

– recent childbirth;

– bacterial endocarditis (acute or subacute):

– pericarditis or pericardial effusion;

– renal and/or liver failure;

– intrauterine contraception (IUD);

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

– concomitant administration of drugs that affect the hemostatic system;

– heparin-induced thrombocytopenia (history) in combination with or without thrombosis.

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

Side effects

Side effects were classified by frequency as follows: very frequent (>1/10), frequent (>1/100 to < 1/10), infrequent (>1/1000 to < 1/100), rare (>1/10000 to < 1/1000), very rare (< 1/10000).

Bleeding

Bleeding may occur, especially in the presence of associated risk factors: organic changes with propensity for bleeding, age, renal insufficiency, low body weight, and some combinations of drugs (see “Interactions with other drugs”). If bleeding develops, the drug administration should be stopped, the cause of bleeding should be determined and an appropriate therapy should be started.

Very common are bleeding during prophylaxis of venous thrombosis, in surgical patients and treatment of deep vein thrombosis with or without thromboembolism.

Frequent – Bleeding in prophylaxis of venous thrombosis in bed-ridden patients and in treatment of angina pectoris, myocardial infarction without Q wave and myocardial infarction with ST-segment elevation.

Infrequent – retroperitoneal bleeding and intracranial bleeding in patients treated for deep vein thrombosis with or without thromboembolism and ST-segment elevation myocardial infarction.

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

When using enoxaparin sodium against the background of spinal/epidural anesthesia and postoperative use of penetrating catheters, rare cases of neuroaxial hematomas resulting in neurological disorders of varying severity, including long-term persistent or irreversible paralysis, have been described (see “Special Precautions”).

Thrombocytopenia and thrombocytopenia are very common in the prevention of venous thrombosis in surgical patients and in the treatment of deep vein thrombosis with or without thromboembolism.

Frequent – thrombocytopenia. In prophylaxis of venous thrombosis in surgical patients and treatment of deep vein thrombosis with or without thromboembolism, and in ST-segment elevation myocardial infarction.

Infrequent – thrombocytopenia in prophylaxis of venous thrombosis in bed-ridden patients and in treatment of angina pectoris, myocardial infarction without Q-wave.

Very rare – autoimmune thrombocytopenia in ST-segment elevation myocardial infarction.

In rare cases, the development of autoimmune thrombocytopenia in combination with thrombosis has been reported. In some of them, thrombosis has been complicated by organ infarction or limb ischemia (see section “Special Indications”).

Other

Very often – increased activity of “hepatic” transaminases.

Often – allergic reactions, urticaria, itching, redness of the skin, bruising and pain at the injection site.

Infrequent – skin (bullous rashes), inflammatory reaction at the injection site, skin necrosis at the injection site.

Rarely – anaphylactic and anaphylactoid reactions, hyperkalemia. Necrosis of the skin may develop at the injection site preceded by purpura or erythematous painful papules. In these cases the drug therapy should be discontinued. Solid inflammatory nodules-infiltrates may form at the injection site of the drug, which disappear after a few days and are not a reason for discontinuation of the drug.

Overdose

Symptoms: hemorrhagic complications of accidental overdose during subcutaneous injection of enoxaparin sodium. In case of accidental ingestion of even large doses, absorption of the drug is unlikely.

Treatment: neutralize the effect of enoxaparin sodium by slow intravenous (IV) administration of protamine sulfate. 1 mg of protamine sulfate will neutralize the anticoagulant effect of 1 mg of enoxaparin sodium if the drug is administered no more than 8 hours before administration of protamine sulfate.

The 0.5 mg of protamine sulfate will neutralize the anticoagulant effect of 1 mg of enoxaparin sodium if administered more than 8 h before or if a second dose of protamine sulfate must be administered.

If, however, 12 hours or more have elapsed since the administration of enoxaparin sodium, administration of protamine sulfate is not necessary. However, even when large doses of protamine sulfate are administered, the anti-Xa activity of sodium enoxaparin is not completely neutralized (maximum 60%).

Pregnancy use

There are currently insufficient clinical data to determine the possible teratogenic or fetotoxic effects of enoxaparin sodium when administered prophylactically during pregnancy. Enixum® should not be used during pregnancy unless the potential benefit to the mother outweighs the possible risk to the fetus.

A spinal or epidural anesthesia should not be performed during treatment with the drug.

If epidural anesthesia is planned, preventive treatment with Enoxaparin sodium should be discontinued, if possible, at least 12 hours before the anesthesia. Enoxaparin sodium is not recommended for use in pregnant women with prosthetic heart valves.

Breastfeeding should be discontinued during treatment with Enoxaparin sodium.

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