Enixum Injection solution 4000 anti-HaIU/0.4ml 0.4ml ampoules, 10pcs

Composition

1 syringe (0.4 ml) contains as an Active ingredient enoxaparin sodium 4000 anti-Xa IU (40 mg); excipients: water for injection-up to 0.4 ml

Pharmacological action

Pharmacotherapy group: direct-acting anticoagulant. ATX code: 01 AB 05 Pharmacological propertiespharmacodynamicaenoxaparin sodium is a low-molecular-weight heparin. The average molecular weight is about 4,500 daltons. In a purified in vitro system, enoxaparin sodium has high activity against coagulation factor Xa (anti-Xa activity of approximately 100 IU / ml) and low activity against coagulation factor IIa (anti-IIa or antithrombin activity of approximately 28 IU / ml). The anticoagulant activity of enoxaparin is mediated by antithrombin III. When used in prophylactic doses, enoxaparin sodium slightly changes the activated partial thromboplastin time (APTT), has virtually no effect on platelet aggregation and on the level of fibrinogen binding to platelet receptors. The anti-IIa activity of enoxaparin in plasma is approximately 10 times lower than the anti-Xa activity. The average maximum anti-IIa activity is observed approximately 3-4 hours after subcutaneous use and reaches 0.13 IU / ml and 0.19 IU / ml after repeated use of 1 mg/kg of body weight-with a double use and 1.5 mg/kg of body weight – with a single use, respectively. The average maximum anti-Xa plasma activity is observed 3-5 hours after subcutaneous use of the drug and is approximately 0.2; 0.4; 1.0 and 1.3 anti-Xa IU / ml after subcutaneous use of 20,40 mg and 1 mg / kg and 1.5 mg/kg, respectively. Pharmacokineticspharmacokinetics of enoxaparin sodium in these dosage regimens is linear. Variability within and between patient groups is low. After repeated subcutaneous use of 40 mg of enoxaparin sodium once a day and subcutaneous use of enoxaparin sodium at a dose of 1.5 mg/kg once a day in healthy volunteers, the equilibrium concentration is reached by day 2, and the area under the pharmacokinetic curve is on average 15% higher than after a single use. After repeated subcutaneous use of enoxaparin sodium at a daily dose of 1 mg/kg twice a day, the equilibrium concentration is reached in 3-4 days, and the area under the pharmacokinetic curve is on average 65% higher than after a single use and the average values of maximum concentrations (Cmax) are, respectively,1.2 IU / ml and 0.52 IU/ml. The bioavailability of enoxaparin sodium with subcutaneous use, estimated on the basis of anti-Xa activity, is close to 100%. The volume of distribution of anti-Xa activity of enoxaparin sodium is approximately 5 liters and approaches the volume of blood. Enoxaparin sodium is a low-clearance drug. After intravenous use for 6 hours at a dose of 1.5 mg/kg of body weight, the average plasma clearance of anti-Xa is 0.74 l / h. Enoxaparin sodium is mainly metabolized in the liver by desulfation and / or depolymerization to form low-molecular-weight substances with very low biological activity. Elimination of the drug is monophasic with a half-life (T1 / 2) of 4 hours (after a single subcutaneous injection) and 7 hours (after repeated use 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: Elimination is delayed due to a physiological decrease in renal function. This change does not affect the dosage and mode of use during preventive therapy, if the renal function of such patients remains within acceptable limits, that is, slightly reduced. Before starting treatment with low-molecular-weight heparins in patients over 75 years of age, it is necessary to conduct a systematic examination of renal function. Patients with impaired renal function The clearance of enoxaparin sodium decreases in patients with reduced renal function. In patients with severe renal insufficiency (creatinine clearance less than 30 ml/min), repeated subcutaneous use increases the area under the pharmacokinetic curve at equilibrium by 65%. Patients undergoing hemodialysis Enoxaparin sodium is administered into the arterial branch of the dialysis system in doses sufficient to prevent coagulation in the system. In general, the pharmacokinetic parameters remain unchanged except in cases of overdose, in which the drug enters the general bloodstream and can induce high anti-Xa activity associated with end-stage renal failure. Overweight patients and overweight people with subcutaneous use of the drug have a slightly lower clearance. If no dose adjustment is made 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 with a body weight of less than 45 kg and 27% higher in men with a body weight of less than 57 kg compared to patients with a normal average body weight.

Indications

• Prevention of venous thrombosis and embolism in surgical interventions, especially in orthopedic and General surgical operations;
• prevention of venous thrombosis and embolism in patients who are on bed rest due to the acute therapeutic diseases, including congestive heart failure and decompensation of chronic heart failure (III or class IV NYHA), acute respiratory failure; acute infectious diseases; acute stage of rheumatic diseases in combination with one of the risk factors of venous thrombosis (see “Special instructions”);
• the treatment of deep vein thrombosis, accompanied or not accompanied by pulmonary thromboembolism;
• prevention of clotting in the extracorporeal circulation during hemodialysis (usually, if the duration of the session is not more than 4 hours);
• the treatment of unstable angina and myocardial infarction without Q wave in combination with acetylsalicylic acid;
• treatment of acute myocardial infarction with ST-segment elevation in patients subject to medical treatment or subsequent percutaneous coronary intervention.

Contraindications

• Hypersensitivity to enoxaparin sodium, heparin or its derivatives, including other low molecular weight heparins;
• conditions and diseases in which there is a high risk of bleeding: threatened abortion, aneurysm of cerebral vessels or an aortic dissection (excluding surgery);
• hemorrhagic stroke;
• uncontrolled bleeding;
• enoxaparin and heparin-induced thrombocytopenia;
• not recommended in pregnant women with artificial heart valves;
• the age of 18 years (effectiveness and safety not established).

With care

• hemostatic disorders (including hemophilia, thrombocytopenia, anticoagulation, von Willebrand disease, etc. ), severe vasculitis;
• peptic ulcer of the stomach or duodenum, or other erosive and ulcerative lesions of the gastrointestinal tract;
• recent ischemic stroke;
• severe uncontrolled hypertension;
• or diabetic hemorrhagic retinopathy;
• severe diabetes mellitus;
• recent or suspected neurological or ophthalmic surgery;
• the conduct of spinal or epidural anesthesia (potential risk of bruising), lumbar puncture (recent);
• recent childbirth;
• bacterial endocarditis (acute or subacute);
• pericarditis or pericardial effusion;
• renal and/or hepatic failure;
• intrauterine contraception (IUD);
• severe trauma (especially the Central nervous system (CNS)), open wounds on large surfaces;
• concomitant use of drugs affecting hemostasis.

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

Side effects

WHO classification of adverse drug reactions by frequency of occurrence:  Very frequent-1/10 appointments (≥ 10%) Frequent – 1/100 appointments (≥ 1%, but Infrequent-1/1000 appointments (≥ 0.1%, but Rare-1/10000 appointments (≥ 0.01%, but Very rare-less than 1/10000 appointments (Frequency not known – cannot be determined based on available data. Bleeding may occur, especially in the presence of concomitant risk factors: organic changes with a tendency to bleed, age, renal failure, low body weight, and certain drug combinations (see “Interactions with other drugs”). In clinical trials, major bleeding events (leading to clinically significant complications and/or accompanied by a decrease in hemoglobin by 2 g/l or more and / or requiring transfusion of 2 or more doses of blood components) with enoxaparin developed in 4.2% of patients, and in some of these cases were fatal. Possible spot hemorrhages (petechiae), ecchymosis.Very frequent – bleeding in the prevention of venous thrombosis during surgical interventions and in the treatment of deep vein thrombosis with or without pulmonary embolism. Frequent-bleeding in the prevention of venous thrombosis in patients on bed rest due to acute therapeutic diseases and in the treatment of unstable angina and non-Q-wave myocardial infarction. Infrequent-retroperitoneal bleeding or intracranial hemorrhage in the treatment of deep vein thrombosis with or without pulmonary embolism. Rare-retroperitoneal bleeding in the prevention of venous thrombosis in surgical patients and in the treatment of unstable angina and non-Q-wave myocardial infarction In case of bleeding, it is necessary to cancel the drug use, determine the cause of bleeding and start appropriate therapy. When using enoxaparin sodium on the background of spinal/epidural anesthesia and postoperative use of penetrating catheters, cases of neuroaxial hematomas (in 0.01-0.1% of cases) have been described, which led 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, slightly pronounced transient asymptomatic thrombocytopenia may develop. Very frequent – thrombocytosis in the prevention of venous thrombosis during surgical interventions and in the treatment of deep vein thrombosis with or without pulmonary embolism. Frequent-thrombocytopenia in the prevention of venous thrombosis during surgical interventions and in the treatment of deep vein thrombosis with or without pulmonary embolism Non-frequent-thrombocytopenia in the prevention of venous thrombosis in patients who are on bed rest due to acute therapeutic diseases and in the treatment of unstable angina and myocardial infarction without Q wave. In very rare cases (less than 0.01%), autoimmune thrombocytopenia may develop in combination with thrombosis, which is sometimes complicated by organ infarction or limb ischemia. Allergic reactio Nscast – urticaria, itching, redness of the skin. Rare – anaphylactic and anaphylactoid reactions, allergic vasculitis. Skin disorders and reactions at the injection site are frequent – hematoma, pain at the injection site. Rare – bullous dermatitis. Very rare-skin necrosis preceded by the appearance of purpura or infiltrated and painful erythematous plaques. In these cases, therapy with the drug should be discontinued. In some cases, hard inflammatory nodules may form at the injection site-infiltrates containing the drug, which disappear after a few days and are not a reason for discontinuing the drug. From the cardiovascular system Rare-thrombosis of artificial heart valves (usually with inadequate dosage)Changes in laboratory parameters Very frequent – asymptomatic and reversible increase in the activity of “hepatic” transaminases (AST and ALT > 3 times higher than the upper limit of normal values). Rare – hypoaldosteronism, hyperkalemia (especially in patients with chronic renal failure and diabetes mellitus, metabolic acidosis). Other Prolonged treatment increases the risk of developing osteoporosis.

Interaction

Do not mix Enixum® with other medications in the same syringe.

Do not alternate the use of enoxaparin sodium with other low-molecular-weight heparins, as they differ from each other in the method of production, molecular weight, specific anti-Xa activity, units of measurement and dosage. As a result, low-molecular-weight heparin preparations are characterized by different pharmacokinetics and biological activity (anti-IIa activity, interaction with platelets).

Anisum® is not recommended in combination with:

• salicylates and acetylsalicylic acid in doses that provide analgesic, antipyretic and anti-inflammatory effects: increased risk of bleeding (due to inhibition of platelet function under the action of salicylates and damage to the mucous membrane of the stomach and duodenum);
• NSAIDs (non-steroidal anti-inflammatory drugs) for systemic use: increased risk of bleeding (inhibition of platelet function under the action of NSAIDs and damage to the mucous membrane of the stomach and duodenum). If simultaneous use cannot be avoided, careful clinical monitoring of the patient’s condition should be carried out;
• dextran (parenteral use): increased risk of bleeding (inhibition of platelet function due to dextran 40).

Hyperkalemia may occur when used concomitantly with potassium salts, potassium-sparing diuretics, angiotensin converting enzyme inhibitors, angiotensin II antagonists, cyclosporins, tacrolimus and trimethoprim.

The anticoagulant effect of enoxaparin sodium is enhanced when used concomitantly with oral anticoagulants.

When used concomitantly with platelet aggregation inhibitors (acetylsalicylic acid in antiplatelet doses for cardiological and neurological diseases, clopidogrel, absiximab, ticlopidine, eptifibatide, tirofiban, beraprost, iloprost), the risk of bleeding increases.

How to take, course of use and dosage

Enixum® is administered subcutaneously (deep), in special cases in the arterial circuit during a hemodialysis session and intravenously. The drug should not be administered intramuscularly!

Overdose

Symptoms: hemorrhagic complications in case of accidental overdose with subcutaneous use of enoxaparin sodium. When taken orally, even large doses of the drug are unlikely to be absorbed. Treatment: neutralize the effect of enoxaparin sodium by slow intravenous (iv) use of protamine sulfate (or hydrochloride). Before using protamine sulfate, due to the possibility of side effects (in particular, anaphylactic shock), it is necessary to carefully weigh the benefit/risk ratio. 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 use of protamine sulfate. 0.5 mg of protamine sulfate neutralizes the anticoagulant effect of 1 mg of enoxaparin sodium, if it was administered more than 8 hours ago or if a second dose of protamine sulfate is necessary. If 12 or more hours have elapsed since the introduction of enoxaparin sodium, the introduction of protamine sulfate is not required. However, even with high doses of protamine sulfate, the anti-Xa activity of enoxaparin sodium is not completely neutralized (by a maximum of 60%).

Special instructions

When prescribing the drug for preventive purposes, there was no tendency to increase bleeding. When prescribing the drug for medical purposes, there is a risk of bleeding in older patients (especially over 80 years of age). Careful monitoring of the patient’s condition is recommended. Before starting therapy, it is recommended to cancel other medications that affect the hemostatic system due to the risk of bleeding (salicylates, acetylsalicylic acid, NSAIDs, including ketorolac, dextran 40, ticlopidine, clopidogrel, glucocorticosteroids, thrombolytics, anticoagulants, antiplatelet agents, including glycoprotein IIb/IIIa receptor antagonists), except when their use is strictly indicated. If it is necessary to combine the use of enoxaparin sodium with these drugs, it is necessary to carefully monitor the patient’s condition and monitor the appropriate laboratory parameters. Patients with impaired renal function are at risk of developing bleeding as a result of increased anti-Xa activity of enoxaparin sodium. Due to the fact that anti-Xa activity significantly increases in patients with severe renal impairment (creatinine clearance less than 30 ml/min), it is recommended to adjust the dose, both with prophylactic and therapeutic use of enoxaparin sodium in such patients. Patients with mild to moderate renal impairment (creatinine clearance 50-80 ml/min or 30-50 ml/min, respectively) do not need to adjust the dose, but their condition should be carefully monitored. With a single subcutaneous injection of enoxaparin sodium at a dose of 40 mg, anti-Xa activity increases by 52% in women with a body weight of less than 45 kg and by 27% in men with a body weight of less than 57 kg compared to individuals with normal body weight. The risk of heparin-induced immune thrombocytopenia also exists when using low-molecular-weight heparins. If thrombocytopenia develops, its signs are usually detected between 5 and 21 days after the start of enoxaparin sodium therapy. In this regard, the platelet count should be regularly monitored before and during the use of the drug. If there is a confirmed significant decrease in platelet count (by 30-50% compared to baseline), Enixum® should be immediately discontinued and the patient should be transferred to another therapy. Spinal / epidural anaesthetismas with the use of other anticoagulants, cases of neuroaxial hematomas have been described when using enoxaparin sodium against the background of spinal / epidural anaesthesia with the development of persistent or irreversible paralysis. The risk of these events is reduced when enoxaparin sodium is administered at a dose of 40 mg or lower. The risk increases with an increase in the dose of the drug, as well as with the use of penetrating epidural catheters after surgery, or with the concomitant use of additional drugs that have the same effect on hemostasis as NSAIDs (see”Interaction with other medicinal products”). The risk also increases with traumatic or repeated spinal puncture, as well as in patients with a history of spinal surgery or spinal deformity. To reduce the risk of bleeding from the spinal canal during epidural or spinal anesthesia, the pharmacokinetic profile of the drug should be taken into account (see “Pharmacological properties”). Catheter insertion or removal is best performed when the anticoagulant effect of enoxaparin sodium is low. Insertion or removal of the catheter should be performed 10-12 hours after the use of prophylactic doses of enoxaparin sodium for deep vein thrombosis. In cases where patients receive higher doses of enoxaparin sodium (1 mg/kg twice daily or 1.5 mg/kg once daily), these procedures should be postponed for a longer period of time (24 hours). Subsequent use of the drug should be carried out no earlier than 2 hours after removal of the catheter. If the patient is prescribed anticoagulant therapy during spinal / epidural anesthesia, especially careful constant monitoring of the patient is necessary to detect any neurological symptoms, such as: back pain, impaired sensory and motor functions (numbness or weakness in the lower extremities), impaired bowel and/or bladder function. The patient should be instructed to inform the doctor immediately if the symptoms described above occur. If symptoms characteristic of a brain stem hematoma are detected, urgent diagnosis and treatment is necessary, including, if necessary, spinal cord decompression. Heparin-induced thrombocytopenia With extreme caution, Enixum® should be prescribed to patients with a history of possible thrombocytopenia caused by heparin, with or without thrombosis. The risk of heparin-induced thrombocytopenia may persist for several years. If a history of heparin-induced thrombocytopenia is suspected, in vitro platelet aggregation tests are of limited value in predicting the risk of developing it. The decision on the appointment of enoxaparin sodium in this case can be made only after consultation with the appropriate specialist. Percutaneous coronary angioplasty To reduce the risk of bleeding associated with percutaneous coronary angioplasty (PCA) in the treatment of unstable angina and non-Q-wave myocardial infarction, the recommended intervals between use of Enixum® and catheter removal should be strictly adhered to. In order to reduce the risk of bleeding associated with percutaneous coronary angioplasty (PCA) in the treatment of unstable angina and non-Q-wave myocardial infarction, the recommended intervals between use of Enixum® and catheter extraction should be strictly adhered to. It is necessary to achieve hemostasis at the site of peripheral artery puncture after PCA. If a closure device is used, the catheter can be removed immediately after the procedure is completed. If manual compression is used, the catheter should not be removed within 6 hours after the last subcutaneous injection of enoxaparin sodium. If it is necessary to continue therapy, the next calculated dose of enoxaparin sodium should be administered no earlier than 6-8 hours after catheter removal. The injection site should be monitored to detect signs of bleeding and hematoma formation in a timely manner. Artificial heart valves Studies on the efficacy and safety of enoxaparin sodium in preventing thromboembolic complications in patients with artificial heart valves have not been conducted. Prophylactic doses of enoxaparin sodium are insufficient to prevent artificial valve thrombosis. There have been cases of thrombosis of prosthetic heart valves in pregnant women with the use of enoxaparin sodium in therapeutic doses. The use of Enixum® in this category of patients cannot be recommended (see the section “Contraindications”). Laboratory tests At doses used for the prevention of thromboembolic complications, Enixum® does not significantly affect the bleeding time and total coagulation parameters, as well as platelet aggregation or their binding to fibrinogen. Increasing the dose of enoxaparin sodium may prolong APTT (activated partial thromboplastin time) and blood clotting time. The increase in these parameters is not directly linear with the increase in the antithrombotic activity of enoxaparin sodium, 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 case of acute infection, acute rheumatic conditions, the preventive appointment of enoxaparin sodium is justified only if the above conditions are combined with one of the following risk factors for venous thrombosis:age 75 years and older, malignancies, history of thrombosis and embolism, obesity, hormone therapy, heart failure, chronic respiratory failure. Effects on the performance of potentially dangerous activities that require special attention and responsiveness There are no data indicating a negative effect of enoxaparin sodium on the ability to drive vehicles and engage in other potentially dangerous activities that require increased concentration of attention and speed of psychomotor reactions.

Storage conditions

At a temperature not exceeding 25 °C. Do not freeze it. Keep out of reach of children.

Shelf

life is 2 years.

Active ingredient

Enoxaparin sodium

Conditions of release from pharmacies

By prescription

Dosage form

solution for injection