Enixum 8000 anti-Ha IU/0.8 ml, 10 pcs.

Enoxaparin sodium is a low molecular weight heparin. The average molecular weight is about 4500 Da: less than 2000 Da – <20%, 2000 to 8000 Da – >68%, more than 8000 Da – <18%. Enoxaparin sodium is obtained by alkaline hydrolysis of heparin benzyl ether isolated from pig small intestinal mucosa. Its structure is characterized by a nonreducible fragment of 2-O-sulfo-4-enpyrazinosuronic acid and a reducible fragment of 2-N,6-O-disulfo-D-glucopyranoside. The structure of enoxaparin sodium contains about 20% (in the range of 15 to 25%) of the 1,6-anhydro derivative in the reducing fragment of the polysaccharide chain.

In vitro, enoxaparin sodium has high activity against factor Xa clotting (anti-Xa activity of approximately 100 IU/ml) and low activity against factor IIa clotting (anti-IIa or antithrombin activity of approximately 28 IU/ml). This anticoagulant activity is mediated by antithrombin III. 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, which include AT-III-dependent inhibition of other clotting factors such as factor VIIa, 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, enoxaparin sodium slightly changes the PTC and has almost no effect on platelet aggregation and 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. Mean maximal anti-IIa activity is observed approximately 3-4 h after p/q administration and reaches 0.13 and 0.19 IU/ml after repeated administration of 1 mg/kg with double administration and 1.5 mg/kg with single administration, respectively.

The mean maximum plasma anti-Xa activity is observed 3-5 h after a p/k injection of the drug and is approximately 0.2; 0.4; 1 and 1.3 anti-Xa IU/ml after a p/k injection of 20, 40 mg and 1 and 1.5 mg/kg, respectively.

Indications

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

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), acute respiratory failure; acute infectious diseases; acute stage of rheumatic diseases in combination with one of the risk factors for venous thrombus formation (see “Special Instructions”);

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

prevention of thrombus formation in the extracorporeal circulatory system during hemodialysis (usually with a session duration of no more than 4 hours);

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

Treatment of acute ST-segment elevation myocardial infarction in patients undergoing medical treatment or subsequent percutaneous coronary intervention.

Pharmacological effect

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 vitro, enoxaparin sodium has high activity against coagulation factor Xa (anti-Xa activity approximately 100 IU/ml) and low activity against coagulation factor IIa (anti-IIa or antithrombin activity approximately 28 IU/ml). This anticoagulant activity is mediated by antithrombin III. In addition to anti-Xa/IIa 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 the release of tissue factor pathway inhibitor, and a decrease in the release of von Willebrand factor from the vascular endothelium into the bloodstream. 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.

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 and 0.19 IU/ml after repeated administration of 1 mg/kg with a double dose and 1.5 mg/kg with a single dose, respectively.

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 and 1.3 anti-Xa IU/ml after subcutaneous administration of 20, 40 mg and 1 and 1.5 mg/kg, respectively.

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.

Bleeding in elderly patients

When using enoxaparin sodium in prophylactic doses in elderly patients, there was no tendency to increase 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

It is recommended that the use of drugs affecting hemostasis (salicylates, including acetylsalicylic acid, NSAIDs, including ketorolac, dextran with a molecular weight of 40 kDa, ticlopidine, clopidogrel, corticosteroids, thrombolytics, anticoagulants, antiplatelet agents, including antagonists of glycoprotein IIb/IIIa receptors) should be discontinued before starting treatment enoxaparin sodium, except when 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 severely impaired renal function (Cl creatinine less than 30 ml/min), there is a significant increase in the exposure of enoxaparin sodium, therefore it is recommended to adjust the dose, both for prophylactic and therapeutic use of the drug. Although no dose adjustment is required in patients with mild to moderate renal impairment (Cl creatinine 30–50 or 50–80 ml/min), careful monitoring of the condition of such patients is recommended (see Pharmacokinetics and Dosage and Administration, Renal Insufficiency).

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 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. If there is a confirmed significant decrease in the platelet count (by 30–50% compared to the initial value), it is necessary to immediately discontinue enoxaparin sodium and transfer the patient to another therapy.

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 enoxaparin sodium is used 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 with the simultaneous use of additional drugs that affect hemostasis, such as NSAIDs (see “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.

Insertion or removal of the catheter should be carried out at least 12 hours after the administration of lower doses of Enixum® (20 mg once a day, 30 mg once or twice a day, 40 mg once a day) and at least 24 hours after administration of higher doses of Enixum® (0.75 mg/kg twice a day, 1 mg/kg twice a day, 1.5 mg/kg/day). At these time points, the anti-Xa activity of enoxaparin sodium is still detectable, and time delays do not guarantee that the development of a neuraxial hematoma can be avoided.

Patients receiving enoxaparin sodium in doses of 0.75 mg/kg 2 times a day or 1 mg/kg 2 times a day, with this dosing regimen (twice daily), should not administer a second dose in order to increase the interval before inserting or replacing the catheter. Similarly, consideration should be given to delaying the next dose of enoxaparin sodium for at least 4 hours, based on an assessment of the benefit/risk ratio (risk of thrombosis and bleeding during the procedure, taking into account the patient’s risk factors). However, it is not possible to give clear recommendations on the timing of the next dose of enoxaparin sodium after catheter removal. It should be taken into account that in patients with creatinine Cl less than 30 ml/min, the elimination of enoxaparin sodium is slowed down. Therefore, in this category of patients, doubling the time from catheter removal should be considered: at least 24 hours for lower doses of enoxaparin sodium (30 mg/day) and at least 48 hours for higher doses (1 mg/kg/day).

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

Enixum® should be used with extreme caution in patients with a history of heparin-induced thrombocytopenia with or without thrombosis.

The risk of developing heparin-induced thrombocytopenia may persist for several years. If the history suggests the presence of heparin-induced thrombocytopenia, then in vitro platelet aggregation tests are of limited value in predicting the risk of its development. The decision to use Enixum® in this case can only be made after consultation with an appropriate specialist.

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. The evaluation of these reports is limited by the presence of competing factors that contribute to the development of thrombosis of prosthetic heart valves, including the underlying disease, and by the paucity of clinical data.

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 blockage 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.

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.

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.

Use in pediatrics

The safety and effectiveness of enoxaparin sodium in children under 18 years of age have not been established.

Influence on the performance of potentially hazardous activities that require special attention and speed of reactions. There is no data indicating a negative effect of enoxaparin sodium on the ability to drive vehicles and engage in other potentially hazardous activities that require increased concentration and speed of psychomotor reactions.

Active ingredient

Enoxaparin sodium

Composition

Active ingredient:

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 – threatened abortion, cerebral aneurysm or dissecting aortic aneurysm (except in cases of surgical intervention for this purpose);

recent hemorrhagic stroke;

uncontrolled bleeding;

thrombocytopenia in combination with a positive in vitro test for antiplatelet antibodies in the presence of enoxaparin sodium;

children under 18 years of age (efficacy and safety 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 (history) with or without thrombosis.

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

Side Effects

Side effects were classified by frequency as follows: very often – ≥1/10; often – ≥1/100–<1/10; uncommon - ≥1/1000–<1/100; rarely - ≥1/10000–<1/1000; very rarely - <1/10000.

Bleeding: Bleeding may occur, especially in the presence of associated risk factors – organic changes with a tendency to bleeding, age, renal failure, low body weight and certain drug combinations (see “Interactions”). If bleeding develops, it is necessary to discontinue the drug, establish the cause of the bleeding and begin appropriate therapy. Very often – bleeding during the prevention of venous thrombosis during surgery and the treatment of deep vein thrombosis with or without thromboembolism; often – bleeding in the prevention of venous thrombosis in patients on bed rest due to acute therapeutic diseases, and in the treatment of angina and myocardial infarction without a Q wave and myocardial infarction with ST segment elevation; uncommon – retroperitoneal bleeding and intracranial bleeding in patients treated for deep vein thrombosis with or without thromboembolism, as well as myocardial infarction with ST segment elevation; rarely – retroperitoneal bleeding in the prevention of venous thrombosis in surgical patients and in the treatment of angina pectoris and myocardial infarction without a Q wave. When using enoxaparin sodium against the background of spinal/epidural anesthesia and postoperative use of penetrating catheters, rare cases of the formation of neuraxial hematomas have been described, leading to neurological disorders of varying severity, including long-term or irreversible paralysis (See “Special Instructions”).

Thrombocytopenia and thrombocytosis: during the first days after the start of therapy, mild transient asymptomatic thrombocytopenia may develop. Very often – thrombocytosis in the prevention of venous thrombosis during surgery and the treatment of deep vein thrombosis with or without thromboembolism; often – thrombocytopenia. For the prevention of venous thrombosis during surgery and the treatment of deep vein thrombosis with or without thromboembolism, as well as for myocardial infarction with ST segment elevation; infrequently – thrombocytopenia in the prevention of venous thrombosis in patients on bed rest and in the treatment of angina pectoris, myocardial infarction without a Q wave; very rarely – autoimmune thrombocytopenia during myocardial infarction with ST segment elevation. In rare cases, the development of autoimmune thrombocytopenia in combination with thrombosis has been reported. In some of them, thrombosis was complicated by organ infarction or limb ischemia (see “Special Instructions”).

Other: very often – increased activity of liver transaminases; often – allergic reactions, urticaria, itching, redness of the skin, hematoma and pain at the injection site; uncommon – skin (bullous rashes), inflammatory reaction at the injection site, skin necrosis at the injection site; rarely – anaphylactic and anaphylactoid reactions, hyperkalemia. Skin necrosis may develop at the injection site, preceded by the appearance of purpura or erythematous painful papules. 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.

Interaction

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

When used simultaneously with other drugs that affect hemostasis (salicylates, including acetylsalicylic acid, NSAIDs, including ketorolac, dextran with a molecular weight of 40 kDa, ticlopidine, clopidogrel, systemic corticosteroids, thrombolytics or anticoagulants, other antiplatelet drugs, including antagonists of glycoprotein IIb/IIIa receptors), the risk of bleeding increases.

Overdose

Symptoms: hemorrhagic complications due to accidental overdose with subcutaneous administration of enoxaparin sodium. When taken orally, even large doses, absorption of the drug is unlikely.

Treatment: neutralize the effect of enoxaparin sodium by slow intravenous administration of protamine sulfate (or hydrochloride). Before using protamine sulfate, due to the possibility of side effects (in particular anaphylactic shock), the benefit/risk ratio must be carefully weighed.

1 mg of protamine sulfate neutralizes the anticoagulant effect of 1 mg of enoxaparin sodium if the drug was administered no more than 8 hours before the administration of protamine sulfate.

0.5 mg protamine sulfate neutralizes the anticoagulant effect of 1 mg enoxaparin sodium if it was administered more than 8 hours ago or if a second dose of protamine sulfate is necessary.

If 12 hours or more have passed after the administration of enoxaparin sodium, the administration of protamine sulfate 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%).

Functional features

The pharmacokinetics of enoxaparin sodium at therapeutic doses is linear. Variability within and between patient groups is low. After a single subcutaneous administration of Enixum® at a dose of 1 mg/kg, Cmax is (0.49±0.07) IU/ml, Tmax is (3.19+1.08) h, AUC0–24=(4.44+0.91) IU ml/h. According to the literature, after repeated subcutaneous administration of enoxaparin sodium at a dose of 40 mg once a day and subcutaneous administration of enoxaparin sodium at a dose of 1.5 mg/kg once a day, Css is achieved by the 2nd day, and AUC is on average 15% higher than after a single administration. After repeated subcutaneous injections of enoxaparin sodium at a daily dose of 1 mg/kg 2 times a day, Css is achieved after 3–4 days, and AUC is on average 65% higher than after a single administration. The bioavailability of enoxaparin sodium after subcutaneous administration, assessed on the basis of anti-Xa activity, is close to 100%.

The Vd of anti-Xa activity of enoxaparin sodium is approximately 5 L and is close to the blood volume.

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

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

The elimination of the drug is monophasic with T1/2 – 4 hours (after a single subcutaneous injection) and 7 hours (after repeated administration of the drug).

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.

Elderly patients. Excretion is slowed down due to a physiological decrease in renal function. This change does not affect the dosing and administration regimen of prophylactic therapy if the renal function of such patients remains within acceptable limits, i.e. decreased slightly.

Renal dysfunction. The clearance of enoxaparin sodium is reduced in patients with reduced renal function. A decrease in the clearance of enoxaparin sodium was noted in renal failure. After repeated subcutaneous administration of 40 mg of enoxaparin sodium once a day, there is an increase in anti-Xa activity, represented by AUC, in mild (creatinine clearance 50–80 ml/min) and moderate (creatinine clearance 30–50 ml/min) renal failure. In patients with severe renal failure (creatinine Cl 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 a day.

Overweight patients. In people with excess body weight, with subcutaneous administration of the drug, the clearance is slightly less. 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 will be 50% higher in women weighing less than 45 kg and 27% higher in men weighing less than 57 kg compared with patients with normal average body weight.

Storage conditions

At a temperature not exceeding 25 °C (do not freeze).

Keep out of the reach of children.

Shelf life

2 years.

Do not use after the expiration date stated on the package.

Manufacturer

PharmFirma Sotex, Russia