Klexiparin 60mg/0.6ml 10 syringes

Composition Active substance: Enoxaparin sodium salt. 1 ml of solution contains: 10000 anti-Xa IU, equivalent to 100 mg of enoxaparin sodium salt. 2000 anti-Xa IU/0.2 ml, equivalent to 20 mg of enoxaparin sodium salt; 4000 anti-Xa IU/0.4 ml, equivalent to 40 mg of enoxaparin sodium salt; 6000 anti-Xa IU/0.6 ml, equivalent to 60 mg of enoxaparin sodium salt; 8000 anti-Xa IU/0.8 ml, equivalent to 80 mg of enoxaparin sodium salt; Excipient: Water for injection. Dosage form Solution for injection. Main physical and chemical properties: Clear, colorless or pale yellow liquid. Pharmacotherapeutic group Antithrombotic agent. Direct-acting anticoagulant. Heparin group. See blog: What is Clexiparine used for and when should it be taken? Mechanism of action Pharmacodynamics Enoxaparin - low molecular weight heparin, with antithrombotic and anticoagulant activity. It has a more pronounced anti-Xa activity than anti-IIa, and antithrombotic activity (the ratio for enoxaparin is 3.6). When used in prophylactic doses, enoxaparin does not significantly affect activated partial thromboplastin time (aPTT). When used in therapeutic doses, aPTT may be prolonged and exceed the time of maximum activity by 1.5-2 times. This prolongation is due to residual antithrombotic activity. Treatment of acute myocardial infarction with ST-segment elevation in combination with thrombolytic agents in patients undergoing subsequent coronary angioplasty, as well as in patients not undergoing this procedure. In a large multicenter clinical trial involving 20479 patients with acute myocardial infarction with ST-segment elevation, after fibrinolytic therapy, they were randomized into groups receiving either enoxaparin 3000 anti-Xa IU as an intravenous bolus injection, with subcutaneous injection of 100 anti-Xa IU/kg and then continuing subcutaneous injection of 100 anti-Xa IU/kg every 12 hours, or in the second group, receiving intravenous unfractionated heparin as a bolus injection of 60 IU/kg (maximum 4000 IU/kg) and then continuous infusion with dose adjustment controlled by aPTT. Subcutaneous injections of enoxaparin were administered until discharge from the hospital or for no more than 8 days after discharge (in 75% of cases - no more than 6 days). Half of the patients receiving heparin received the drug for at least 48 hours (in 89.5% of cases ≥36 hours). All patients also received acetylsalicylic acid for at least 30 days. The dose of enoxaparin in patients over 75 years of age was adjusted: 0.75 mg/kg (75 anti-Xa IU/kg) subcutaneously every 12 hours without an initial intravenous bolus injection. During the study, 4716 (23%) patients underwent coronary angioplasty against the background of antithrombotic therapy. Patients did not receive additional doses if less than 8 hours had passed since the last subcutaneous injection of enoxaparin until balloon inflation, or received a bolus intravenous injection of enoxaparin 0.3 mg/kg (30 anti-Xa IU/kg) if more than 8 hours had passed since the last subcutaneous injection of enoxaparin until balloon inflation. Enoxaparin significantly reduced the primary endpoints of the study (a composite endpoint including recurrent myocardial infarction and death from any cause within 30 days of study initiation: 9.9% in the enoxaparin group versus 12% in the unfractionated heparin group (relative risk reduction - 17% (p<0.001)). The incidence of recurrent myocardial infarction was significantly lower in the enoxaparin group (3.4% versus 5%, p<0.001, relative risk reduction - 31%). Mortality was lower in the enoxaparin group, although the difference between the groups was not statistically significant (6.9% versus 7.5%, p=0.11). The superiority of enoxaparin in terms of the primary endpoint was unquestionable regardless of subgroups (age, sex, localization of myocardial infarction, history of diabetes or myocardial infarction, type of thrombolytic administered, and time interval between onset of first clinical signs and initiation of treatment). Compared to unfractionated heparin, enoxaparin showed a significant advantage in the primary efficacy criterion, both in patients with coronary angioplasty within 30 days of study enrollment (10.8% versus 13.9%, relative risk reduction - 23%) and in patients without coronary angioplasty (9.7% versus 11.4%, relative risk reduction - 15%). The incidence of massive bleeding up to 30 days was significantly higher in the enoxaparin group (2.1%) compared to the heparin group (1.4%). The incidence of gastrointestinal bleeding was higher in the enoxaparin group (0.5%) than in the heparin group (0.1%), while the incidence of intracranial hemorrhage was similar in both groups (0.8% for enoxaparin and 0.7% for heparin). Analysis of composite endpoints assessing clinical benefit showed a statistically significant superiority of enoxaparin over unfractionated heparin (p<0.0001): a 14% relative risk reduction in favor of enoxaparin (11% versus 12.8%) for composite endpoints including death, recurrent myocardial infarction, and intracranial hemorrhage up to 30 days. Pharmacokinetics The pharmacokinetic parameters of the drug are assessed by changes in anti-Xa and anti-IIa activity over time in blood plasma within the recommended dose range. Bioavailability. After subcutaneous administration, enoxaparin is rapidly and almost completely (almost 100%) absorbed. Maximum activity in blood plasma is observed within 3 to 4 hours after administration. Maximum activity (expressed in anti-Xa IU) is 0.18±0.04 (after administration of 2000 anti-Xa IU), 0.43±0.11 (after administration of 4000 anti-Xa IU), and 1.01±0.14 (after administration of 10000 anti-Xa IU). The first peak level of anti-factor Xa - 1.16 IU/ml (n=16) and the average area under the pharmacokinetic curve - 88% is achieved with a bolus intravenous injection of 30 mg (0.3 ml; 3000 anti-Xa IU), followed by subcutaneous injections of 1 mg/kg (100 anti-Xa IU/kg) every 12 hours. Steady state is achieved on the second day of treatment. Enoxaparin pharmacokinetics are linear within the recommended dose range. Inter-individual and intra-individual variability is minimal. In healthy volunteers, with repeated subcutaneous administration of 40 mg (0.4 ml; 4000 anti-Xa IU) once daily, steady state is achieved on the second day, with average enoxaparin activity being 15% higher than after single administration. The stable level of enoxaparin activity is quite predictable with single dose administration. With repeated subcutaneous administration of 1 mg/kg (100 anti-Xa IU/kg) twice daily, steady state is achieved on the third to fourth day after administration, with average AUC being 65% higher than after single injection, and maximum and minimum anti-Xa activity being 1.2 and 0.52 anti-Xa IU/ml, respectively. This consistency of pharmacokinetic parameters of enoxaparin sodium salt is expected within the therapeutic dose range. After subcutaneous administration, anti-Xa activity in plasma is approximately 10 times lower than anti-IIa activity. Average maximum anti-Xa activity is observed approximately 3-4 hours after subcutaneous injection and is 0.13 anti-Xa IU/ml with repeated administration of 1 mg/kg (100 anti-Xa IU/kg) twice daily. Distribution. The volume of distribution of enoxaparin sodium salt based on anti-Xa activity is approximately 5 L and is almost equal to the circulating blood volume. Metabolism. Enoxaparin metabolism occurs mainly in the liver (via desulfation and depolymerization). Elimination from the body. After subcutaneous injection, the half-life of low molecular weight heparins based on anti-Xa activity is longer than that of unfractionated heparins. Enoxaparin elimination is monophasic, with a half-life of 4 hours after a single subcutaneous injection and 7 hours after repeated doses. Low molecular weight heparins are characterized by a faster decrease in anti-IIa activity in blood plasma than anti-Xa activity. Enoxaparin and its metabolites are excreted in urine and bile. Clearance of substances with anti-Xa activity is 10% of the administered dose, and the total excretion of active and inactive metabolites is 40%. High-risk groups Elderly patients. Due to the physiological decline in renal function in this age category, elimination is slowed. This does not affect the dosage and route of administration when the drug is used for prophylaxis. For patients over 75 years of age, systematic monitoring of renal function using the Cockcroft formula is important before starting treatment. Patients with mild to moderate renal insufficiency (creatinine clearance >30 ml/min). To avoid overdose, in some cases, monitoring of anti-Xa activity may be beneficial when using therapeutic doses of enoxaparin. Indications - Prevention of venous thromboembolism in surgical interventions with moderate or high thrombogenic risk; - Prevention of deep vein thrombosis in bedridden patients with acute therapeutic diseases: heart failure of NYHA class III and IV, acute respiratory failure, acute infectious or rheumatic diseases, in the presence of at least one additional risk factor for venous thromboembolism; - Prevention of thrombosis during hemodialysis in extracorporeal circulation systems (procedure lasts on average 4 hours); - Treatment of diagnosed deep vein thrombosis, with or without pulmonary embolism, and without severe clinical symptoms (except for pulmonary embolism requiring treatment with thrombolytic agents or surgery); - Treatment of unstable angina and acute myocardial infarction without Q wave in combination with acetylsalicylic acid; - Treatment of acute myocardial infarction with ST-segment elevation in combination with thrombolytic agents in patients who will subsequently undergo coronary angioplasty or do not require this procedure. Contraindications For doses: 2000 anti-Xa IU/0.2 ml, equivalent to 20 mg of enoxaparin sodium salt; 4000 anti-Xa IU/0.4 ml, equivalent to 40 mg of enoxaparin sodium salt; 6000 anti-Xa IU/0.6 ml, equivalent to 60 mg of enoxaparin sodium salt; 8000 anti-Xa IU/0.8 ml, equivalent to 80 mg of enoxaparin sodium salt; The drug is not used in the following cases: - Hypersensitivity to enoxaparin, heparin or its derivatives, including other low molecular weight heparins; - History of severe heparin-induced thrombocytopenia type II caused by unfractionated or low molecular weight heparin (see "Precautions"); - Hemorrhage or predisposition to bleeding associated with hemostasis disorders (this contraindication can be excluded if disseminated intravascular coagulation syndrome not associated with heparin treatment is observed (see "Precautions")); - Organic lesions of organs with a predisposition to bleeding; - Active bleeding of clinical significance; - Active peptic ulcer of the stomach and duodenum; - In patients receiving heparin for treatment, not prophylaxis, during planned surgical interventions, local anesthesia is not used. For doses: 2000 anti-Xa IU/0.2 ml, equivalent to 20 mg of enoxaparin sodium salt; 4000 anti-Xa IU/0.4 ml, equivalent to 40 mg of enoxaparin sodium salt; The drug is generally not recommended in the following cases: - Severe renal insufficiency (creatinine clearance <30 ml/min according to the Cockcroft formula, see "Precautions"); - First 24 hours after cerebral hemorrhage. In addition, these doses should preferably not be prescribed for prophylaxis in patients over 65 years of age in combination with drugs described in "Interactions with other drugs": 1. Acetylsalicylic acid in analgesic, antipyretic, and anti-inflammatory doses. 2. Non-steroidal anti-inflammatory drugs (systemic use). 3. Dextran 40 (parenteral use). For doses: 6000 anti-Xa IU/0.6 ml, equivalent to 60 mg of enoxaparin sodium salt; 8000 anti-Xa IU/0.8 ml, equivalent to 80 mg of enoxaparin sodium salt; The drug is not used in the following cases: - Cerebral hemorrhage. - Due to lack of data, the drug is not used in patients with severe renal insufficiency (creatinine clearance <30 ml/min according to the Cockcroft formula), except for patients on dialysis. Unfractionated heparin should be prescribed to patients with severe renal insufficiency. For calculations using the Cockcroft formula, the patient's weight is required (see "Precautions"). - Spinal or epidural anesthesia should not be used under any circumstances in patients treated with low molecular weight heparin. Use of the drug is not recommended in the following cases: - Acute extensive ischemic stroke of the brain, with or without loss of consciousness. If the stroke is embolic, enoxaparin should not be used within the first 72 hours; the efficacy of therapeutic doses of low molecular weight heparin has not yet been established, regardless of the cause, extent, or clinical manifestations of cerebral infarction; - Acute infectious endocarditis (except for some heart diseases caused by embolism); - Mild to moderate renal insufficiency (creatinine clearance 30-60 ml/min). In addition, the drug is generally not recommended for use in combination with the following agents (see "Interactions with other drugs"): 1. Acetylsalicylic acid in analgesic, antipyretic, and anti-inflammatory doses. 2. Non-steroidal anti-inflammatory drugs (systemic use). 3. Dextran 40 (parenteral use). Interactions with other drugs Certain drugs or therapeutic classes contribute to the development of hyperkalemia: potassium salts, potassium-sparing diuretics, angiotensin-converting enzyme inhibitors, angiotensin II inhibitors, non-steroidal anti-inflammatory drugs, heparins (low molecular weight or unfractionated heparins), cyclosporine and tacrolimus, trimethoprim. The development of hyperkalemia also depends on risk factors. The risk of its development increases if the above-mentioned agents are used simultaneously. Elderly patients (over 65 years of age). Undesirable combinations: With acetylsalicylic acid in analgesic, antipyretic, and anti-inflammatory doses (and other salicylates): increased risk of bleeding (inhibition of platelet function by salicylates and damage to the gastrointestinal mucosa). It is recommended to use antipyretic, analgesic drugs that are not salicylates (e.g., paracetamol). With non-steroidal anti-inflammatory drugs, including ketorolac (systemic use): increased risk of bleeding (inhibition of platelet function by NSAIDs and damage to the gastrointestinal mucosa). If simultaneous use cannot be avoided, constant clinical observation is necessary. With dextran 40 (parenteral use): increased risk of bleeding (inhibition of platelet function by dextran 40). Combinations requiring precautions: With oral anticoagulants: enhanced anticoagulant effect. When replacing heparin with an oral anticoagulant, increased clinical observation is necessary. Combinations to be considered: With platelet aggregation inhibitors (other than acetylsalicylic acid in analgesic, antipyretic, and anti-inflammatory doses; ASA): abciximab, acetylsalicylic acid in antiplatelet doses for cardiological and neurological indications, beraprost, clopidogrel, eptifibatide, iloprost, ticlopidine, tirofiban: increased risk of bleeding. Patients under 65 years of age. Combinations to be considered: The combined use of drugs acting on different phases of hemostasis increases the risk of bleeding. Therefore, regardless of the patient's age, constant clinical monitoring and laboratory tests, if necessary, should be performed when low molecular weight heparin in prophylactic doses is prescribed in combination with oral anticoagulants, platelet aggregation inhibitors (abciximab, ASA, acetylsalicylic acid in any dose, clopidogrel, systemic glucocorticosteroids, eptifibatide, iloprost, ticlopidine, tirofiban) and thrombolytic agents. Precautions The drug is not for intramuscular injection. Low molecular weight heparins are not interchangeable because they differ in molecular weight, specific anti-factor Xa activity, and dosage. Attention should be paid to and the specific instructions for use and recommended dosages for each low molecular weight heparin preparation should be followed. Precautions. Bleeding. As with anticoagulant therapy, bleeding can occur (see "Side Effects"). In case of bleeding, it is necessary to determine the cause and provide appropriate treatment. Renal function. It is very important to assess renal function before starting treatment with low molecular weight heparin, based on creatinine clearance calculated by the Cockcroft formula and the latest body weight data, including in patients over 75 years of age. For male patients: Creatinine clearance = (140-age)×body weight/0.814×serum creatinine, where age is in years, body weight in kg, and serum creatinine in mmol/L. For female patients, the formula needs to be adjusted and the result multiplied by 0.85. If serum creatinine is expressed in mg/ml, the result obtained must be multiplied by a factor of 8.8. Therapeutic doses of low molecular weight heparins are contraindicated in patients with diagnosed severe renal insufficiency (creatinine clearance approximately 30 ml/min) – (see "Contraindications"). Aldosterone secretion suppression. Heparin can suppress aldosterone secretion by the adrenal glands, especially in patients with diabetes mellitus, chronic renal insufficiency, pre-existing metabolic acidosis, elevated plasma potassium levels, and in patients taking potassium. The risk of hyperkalemia increases with the duration of therapy, but it is usually reversible. In patients at risk of this complication, plasma potassium levels should be determined before starting heparin treatment and regularly monitored thereafter, especially if treatment exceeds 7 days. Laboratory parameters. - Monitoring of platelet count. Heparin-induced thrombocytopenia (HIT). There is a risk of developing serious, sometimes thrombogenic, heparin-induced thrombocytopenia (also observed with unfractionated heparin and rarely with low molecular weight heparin) of immune origin - HIT type II (see "Side Effects"). Due to the existence of this risk, platelet count determination is necessary regardless of therapeutic indications and doses used. Platelet count determination is necessary before drug administration or no later than 24 hours after the start of treatment, then twice a week throughout the treatment period. If in some special cases (e.g., knee surgery, women in risk groups during the second and third trimesters of pregnancy (see "Pregnancy and Lactation")) the need for prolonged treatment is confirmed, platelet count analysis is performed twice a week during the first month of treatment (period of highest risk) and once a week until the end of treatment. Suspicion of HIT should arise if the platelet count does not exceed 150,000/mm3 and/or there is a 30-50% decrease in platelet count compared to the previous analysis. HIT usually develops within 5-21 days after the start of heparin treatment (more often on the tenth day). However, in case of a history of HIT, this complication can occur earlier. Isolated cases have been reported even after 21 days. Patients with such a history must be thoroughly interviewed before starting treatment. Furthermore, the risk of recurrence with repeated use of heparin remains for many years, and sometimes permanently (see "Contraindications"). In all cases, the development of HIT is an emergency and requires specialist consultation. Any significant decrease in platelet count (30-50% compared to baseline) is a warning sign, even if it has not yet reached critical levels. When platelet count decreases, the following measures are taken in all cases: 1. Immediate repeat platelet count analysis to confirm the results. 2. Discontinuation of heparin treatment if the results confirm a decrease in platelet count or even an increase, when no other cause is identified. For in vitro platelet aggregation tests and immunological studies, blood samples should be placed in tubes containing citrate solution. The need to initiate immediate measures is not based on the results of in vitro platelet aggregation tests and immunological studies, as they are often difficult to perform, are carried out in several specialized laboratories, and results are only available after several hours. However, these studies are necessary as they help in diagnosing complications or assessing the risk of thrombosis during long-term heparin treatment. 3. Prevention or treatment of HIT-related thromboembolic complications. If continued anticoagulant therapy is important, heparin should be replaced with an antithrombotic agent of a different chemical class, e.g., danaparoid sodium or hirudin, which are prescribed individually to patients in therapeutic or prophylactic doses. Transition to oral anticoagulants should occur only after the platelet count approaches normal levels, as there is a risk of worsening thrombosis with oral anticoagulants. - Replacement of heparin with oral anticoagulants. Intensive clinical monitoring and laboratory tests (prothrombin time, expressed as international normalized ratio) or control of effects induced by oral anticoagulants are necessary. Since it takes some time for the oral anticoagulant to reach its maximum effect, usual doses of heparin should be used during this period to maintain the prothrombin time within the required range in two consecutive analyses. - Monitoring of anti-factor Xa activity. Most clinical trials demonstrating the efficacy of low molecular weight heparins have been conducted using weight-based dosing and without specific laboratory monitoring. Therefore, the benefit of laboratory tests to assess the efficacy of low molecular weight heparins has not yet been established. However, monitoring of anti-Xa activity may be beneficial in some clinical situations to reduce the risk of bleeding, which is often associated with overdose. These situations mainly concern the use of therapeutic doses of low molecular weight heparins and occur in patients with the following nosologies: - Mild to moderate renal insufficiency (creatinine clearance approximately 30-60 ml/min according to the Cockcroft formula). Since, unlike unfractionated heparin, low molecular weight heparin is primarily excreted in the urine, a relative overdose may occur in any renal impairment. Severe renal insufficiency is a contraindication for treatment with low molecular weight heparin (see "Contraindications"). - Significant deviation from normal body weight (very low weight, cachexia, obesity); - Bleeding of unknown etiology. Laboratory monitoring is not recommended when low molecular weight heparin is prescribed in prophylactic doses, when the drug is used according to therapeutic recommendations (including duration of treatment) and during hemodialysis. To detect possible heparin accumulation with repeated drug administration, blood sampling is recommended during the period of highest drug activity (based on available data), i.e., approximately 4 hours after the third injection, if the drug is administered subcutaneously twice daily. The issue of repeated anti-Xa activity testing to determine heparin levels in the blood should be decided individually, based on previous results. Also, dose adjustment of heparin may be considered. Anti-Xa activity depends on the type of low molecular weight heparin and the dosing regimen. With enoxaparin 100 anti-Xa IU/kg twice daily injection, the average value (±standard deviation) observed 4 hours after the seventh injection was 1.2±0.17 anti-Xa IU/ml. This average value was determined in clinical trials where anti-Xa activity was studied using a chromogenic amidolytic method. - Monitoring of activated partial thromboplastin time (aPTT). Some low molecular weight heparins cause a moderate increase in aPTT. However, since the clinical significance of this test has not been established, its monitoring is not necessary. Spinal/epidural anesthesia in patients receiving low molecular weight heparin for prophylaxis. - Like other anticoagulants, low molecular weight heparins rarely cause spinal cord hematomas and prolonged or permanent paralysis during spinal/epidural anesthesia. The risk of spinal hematoma is higher with epidural anesthesia using a catheter than with spinal anesthesia. The risk of this rare event increases with prolonged use of epidural catheters postoperatively. If a physician decides to prescribe anticoagulants in the context of epidural/spinal anesthesia, particular and frequent monitoring for any signs and symptoms of neurological impairment, such as back pain, sensory and motor deficits (paralysis or weakness of the lower limbs), bowel and/or bladder dysfunction, is necessary. Patients should be instructed in advance to report any such symptoms to their doctor immediately. If signs and symptoms of spinal hematoma are suspected, urgent diagnosis and treatment measures, including intervention for spinal cord decompression, are necessary. - If low molecular weight heparin treatment is necessary in the preoperative period (long-term bedridden patients, trauma) and the benefits of local/regional spinal anesthesia have been well assessed, a minimum interval of 12 hours should be maintained between heparin injection and spinal anesthesia in these patients. Particular monitoring of the patient's neurological status is recommended, considering the risk of spinal hematoma. 6-8 hours after anesthesia or catheter removal, prophylactic low molecular weight heparin can be administered to almost all patients, with neurological status monitoring. Particular caution is required when treating with other drugs affecting hemostasis (including ASA, acetylsalicylic acid). Conditions carrying certain risks. Treatment requires special monitoring in the following conditions: - Liver failure; - Peptic ulcer disease of the gastrointestinal tract or other organic lesions with a probability of bleeding; - Vascular chorioretinal diseases; - Postoperative period after surgery on the brain and/or spinal cord; - Lumbar puncture, as there is a risk of internal bleeding in the spinal cord, so it is advisable to postpone the puncture; - Simultaneous use of other drugs affecting hemostasis (see "Interactions with other drugs"). Although the concentrations of different low molecular weight heparins are expressed in international units of anti-Xa activity (IU), their efficacy is not solely related to anti-Xa activity. Replacing the dosing regimen of one type of low molecular weight heparin with another type of heparin is dangerous, as each regimen has been tested and established through specific clinical trials. Therefore, extreme caution and adherence to instructions are necessary when using each drug. Precautions. Risk of bleeding. The recommended dosing regimen (dosage and duration of treatment) must be followed. Failure to follow recommendations can lead to bleeding, especially in high-risk patients (elderly patients and patients with renal insufficiency). Serious bleeding has been observed: - In elderly patients, including those with age-related changes and deterioration of renal function; - In patients with renal insufficiency; - In cases of weight less than 40 kg; - When therapy lasts longer than recommended (10 days); - In case of non-compliance with therapeutic recommendations, including duration of treatment and dose adjustment according to weight; - When taken simultaneously with other drugs (see "Interactions with other drugs"). Enoxaparin injections, like other anticoagulants, require caution in conditions with a risk of bleeding, such as hemostasis disorders, history of peptic ulcer, recent ischemic stroke, uncontrolled arterial hypertension, diabetic retinopathy, recent neurosurgical or ophthalmological surgery. In all cases, monitoring of the condition of elderly patients and/or patients with renal insufficiency is necessary, as well as if treatment lasts longer than 10 days. To detect drug accumulation, determination of anti-Xa activity may be beneficial in some cases (see "Special Instructions"). Risk of developing heparin-induced thrombocytopenia (HIT). If a patient receiving low molecular weight heparin (therapeutic or prophylactic dose) develops a thromboembolic complication: - Worsening of thrombosis during treatment; - Phlebitis; - Pulmonary embolism; - Acute limb ischemia; - Or even myocardial infarction or ischemic stroke, the possibility of HIT development should always be considered and platelet count should be determined immediately (see "Precautions"). Coronary artery revascularization procedures. To reduce the risk of bleeding in patients undergoing coronary angioplasty for unstable angina, non-ST-segment elevation myocardial infarction, or acute ST-segment elevation myocardial infarction, recommended intervals between enoxaparin injections must be observed. After coronary angioplasty, achieving hemostasis at the injection site is important. When using special devices to close the vessel (hemostatic devices), the introducer must be removed immediately. In case of manual compression, the introducer should be removed 6 hours after the last subcutaneous/intravenous administration of enoxaparin. If enoxaparin treatment is continued, the next injection should be given at least 6-8 hours after removal of the introducer. Continuous monitoring of the skin puncture site is necessary to detect signs of bleeding or hematoma. Presence of artificial mechanical heart valves. Specific studies on the use of enoxaparin for the prevention of thromboembolic complications in patients with artificial mechanical heart valves have not been conducted. However, thrombosis has been reported in isolated cases in patients with prosthetic heart valves on enoxaparin therapy for the prevention of thromboembolic complications. Pregnant women. In clinical trials involving pregnant women with artificial heart valves who received enoxaparin 100 anti-Xa IU/kg twice daily to reduce the risk of thromboembolic complications, thrombosis occurred in 2 out of 8 cases, leading to valve obstruction and maternal and fetal death. Isolated cases of thrombosis in pregnant women have been reported in post-marketing surveillance in patients in the same group. Therefore, the risk of thromboembolic complications in these patients may be higher. Bleeding in elderly patients. When used in prophylactic doses, elderly patients do not show a tendency towards bleeding. Elderly patients (especially those over 80 years of age) are at high risk of bleeding when therapeutic doses are used. During the treatment of acute myocardial infarction with ST-segment elevation, the incidence of bleeding was observed in patients aged 65-75 years, indicating that these patients belong to a special risk group for bleeding. Special clinical monitoring is recommended. Renal insufficiency. Patients with renal insufficiency experience increased exposure to enoxaparin, which increases the risk of bleeding. Since the effect of enoxaparin is significantly increased in patients with severe renal insufficiency (creatinine clearance <30 ml/min), correction of therapeutic and prophylactic doses is recommended. However, dose adjustment is not recommended for moderate (creatinine clearance 30-50 ml/min) and mild (creatinine clearance 50-80 ml/min) renal insufficiency, although clinical monitoring is necessary. Data are limited in patients with acute myocardial infarction with ST-segment elevation and creatinine levels >220 and 175 µmol/L (women and men). Low body weight. In women (<45 kg) and men (<57 kg) with low body weight, increased exposure to enoxaparin was observed with prophylactic doses (dose not adjusted for body weight), which increases the risk of bleeding. Therefore, constant clinical monitoring of these patients is necessary. Monitoring. Risk assessment and clinical monitoring are the best ways to prevent potential bleeding risk. Routine monitoring of anti-Xa activity is not necessary, but monitoring of anti-Xa activity is considered in patients receiving low molecular weight heparin who are at risk of bleeding (e.g., patients with renal insufficiency, elderly patients, and patients with low body weight) or who are bleeding. Laboratory tests. At doses used for the prevention of venous thromboembolism, enoxaparin does not significantly affect bleeding times or general analyses, nor platelet aggregation or fibrinogen binding to platelets. At high doses, a prolongation of activated partial thromboplastin time (aPTT) and activated clotting time (ACT) may be observed. The increase in aPTT and ACT is not linearly correlated with the increase in enoxaparin's antithrombotic activity, therefore it is not a reliable indicator for monitoring enoxaparin activity. Pregnancy and lactation For doses: 2000 anti-Xa IU/0.2 ml, equivalent to 20 mg of enoxaparin sodium salt; 4000 anti-Xa IU/0.4 ml, equivalent to 40 mg of enoxaparin sodium salt; Pregnancy. Prophylactic treatment in the first trimester. There is insufficient clinical data to assess the teratogenic and fetotoxic effects of enoxaparin when used for prophylaxis in the first trimester of pregnancy. Therefore, enoxaparin should preferably not be prescribed for prophylaxis in the first trimester of pregnancy. If epidural anesthesia is planned, prophylactic treatment with heparin should be discontinued at least 12 hours before anesthesia. Prophylactic treatment in the second and third trimesters. Based on limited clinical data, teratogenic and fetotoxic effects are not known when enoxaparin is used for prophylaxis in the second and third trimesters. However, additional studies are needed for confirmation. Therefore, the prescription of enoxaparin for prophylaxis in the second and third trimesters should only be considered if necessary. If epidural anesthesia is planned, prophylactic treatment with heparin should be discontinued at least 12 hours before anesthesia. For doses: 6000 anti-Xa IU/0.6 ml, equivalent to 60 mg of enoxaparin sodium salt; 8000 anti-Xa IU/0.8 ml, equivalent to 80 mg of enoxaparin sodium salt; Existing clinical data do not allow to determine the ability of therapeutic doses of enoxaparin to cause developmental defects and fetotoxicity during pregnancy. Therefore, for safety reasons, the use of therapeutic doses of enoxaparin during pregnancy is not recommended. Spinal and epidural anesthesia are contraindicated in patients treated with low molecular weight heparin. Breastfeeding. Since enoxaparin ingested with milk cannot be absorbed in the infant's gastrointestinal tract, treatment of breastfeeding mothers with enoxaparin is not contraindicated. Effect on ability to drive and use machinery The drug does not affect the ability to drive vehicles and operate machinery. However, potential side effects should be considered (see "Side Effects"). Overdose Accidental overdose with a large dose of low molecular weight heparin administered subcutaneously can cause hemorrhagic complications. In some patients with bleeding, protamine sulfate may be used, considering the following factors: - The efficacy of protamine is significantly lower than its efficacy in overdose of unfractionated heparins; - Considering the side reactions (including anaphylactic shock), the risk/benefit ratio must be carefully assessed. Heparin neutralization is achieved by slow intravenous administration of protamine (sulfate or hydrochloride). The required dose of protamine depends on several factors: - Dose of heparin administered (100 antiheparin units of protamine neutralize 100 anti-Xa IU activity of low molecular weight heparin) if no more than 8 hours have passed since enoxaparin administration; - Time elapsed since heparin administration: - A slow infusion of 50 antiheparin units of protamine per 100 anti-Xa IU of enoxaparin sodium may be necessary if more than 8 hours have passed since enoxaparin administration or if a second dose of protamine is needed; - If more than 12 hours have passed since enoxaparin sodium injection, protamine administration is not necessary. These recommendations apply to patients with normal renal function receiving repeated doses. However, complete neutralization of anti-Xa activity cannot be achieved. Moreover, due to the peculiarities of low molecular weight heparin absorption, neutralization may be temporary, and therefore, the total dose of protamine may need to be divided into several injections (2-4) over 24 hours. Severe complications are unlikely when low molecular weight heparin is ingested, even in large doses (no such cases have been registered), as only a small amount of the drug is absorbed from the stomach and intestines. Dosage and administration 1 mg (0.01 ml) of enoxaparin sodium salt corresponds to approximately 100 IU of anti-Xa activity. Clexiparine should be administered subcutaneously for prophylactic and therapeutic purposes, except in the following cases: - Use of the drug for anticoagulation during hemodialysis; - Treatment of acute myocardial infarction with ST-segment elevation in patients requiring intravenous bolus administration. Intramuscular administration of Clexiparine is contraindicated. The drug is recommended for adult patients only. Subcutaneous injection technique. Pre-filled syringes supplied by the manufacturer are ready for immediate use. Depending on the patient's weight, Clexiparine dose adjustment is allowed if necessary. In such cases, the unnecessary amount of drug should be expelled from the syringe before injection. If it is not necessary to remove an unnecessary amount of liquid from the syringe, expelling air bubbles from the syringe before injection is not necessary. Subcutaneous injection of Clexiparine should preferably be performed with the patient in a lying position. The drug should be injected into the subcutaneous fat tissue of the left or right upper or lower abdomen, at different sites for each injection. The needle should be inserted vertically along its entire length into the skin fold formed between the thumb and index finger, not at an angle to it. The skin fold is released only after the injection is completed. Do not rub the injection site after drug administration. Intravenous (bolus) injection technique/ Use of Clexiparine in the treatment of acute myocardial infarction with ST-segment elevation. Treatment begins with an intravenous bolus injection, followed immediately by a subcutaneous injection. For intravenous bolus injection, from a pre-filled graduated Clexiparine syringe containing 40 mg (0.4 ml; 4000 anti-Xa IU), 60 mg (0.6 ml; 6000 anti-Xa IU), or 80 mg (0.8 ml; 8000 anti-Xa IU), the excess amount of drug must be removed so that 30 mg (0.3 ml; 3000 anti-Xa IU) remains in the syringe. This dose of Clexiparine should be administered into the infusion line of intravenous solutions. Mixing or simultaneous administration with other drugs is not allowed. To avoid mixing with residues of other drugs and consequently with Clexiparine, the system must be flushed with a sufficient amount of 0.9% sodium chloride or 5% glucose solution before and after intravenous bolus injection of Clexiparine. Clexiparine administration is safe with 0.9% sodium chloride or 5% glucose solution. In hospital settings, Clexiparine is used: - Dose of 1 mg/kg (100 anti-Xa IU/kg) for the first subcutaneous injection, which should be given immediately after the intravenous bolus injection, as well as subsequent doses of 1 mg/kg (100 anti-Xa IU/kg) administered subcutaneously every 12 hours; - Dose of 0.3 mg/kg (30 anti-Xa IU/kg) for intravenous bolus injection in patients undergoing subsequent coronary angioplasty. Throughout the treatment period, constant monitoring of platelet count is necessary due to the risk of developing heparin-induced thrombocytopenia. Prevention of venous thromboembolism in surgical interventions with moderate or high thrombogenic risk. As a rule, these recommendations apply to surgical interventions under general anesthesia. During spinal and epidural anesthesia, the benefit of enoxaparin administration before surgery and the theoretical high risk of spinal hematoma development must be assessed in advance (see "Precautions"). - Administration schedule. Clexiparine is administered subcutaneously once daily. - Dose. The dose is determined for each patient based on risk assessment and type of surgical intervention. Surgical operations with moderate risk of thrombosis. In surgical operations with moderate risk of thrombosis, and in patients with low risk of thromboembolism, effective prophylaxis is achieved with daily administration of Clexiparine 20 mg (0.2 ml; 2000 anti-Xa IU). The dosing regimen established by studies takes into account the first injection 2 hours before surgery. Surgical operations with high risk of thrombosis. Hip and knee replacement surgery. The dose of Clexiparine is 40 mg (0.4 ml 4000 anti-Xa IU) once daily. The established dosing regimen includes the first injection of 4000 anti-Xa IU (total dose) 12 hours before surgery or the first injection of 2000 anti-Xa IU (half of the total dose) 2 hours before surgery. Other cases. If, depending on the type of surgical intervention (especially in oncological surgery) and/or the patient's history (if there have been cases of venous thromboembolism), there is a high risk of thromboembolism, the prophylactic dose is determined in the same amount as for high-risk orthopedic surgery, such as hip and knee replacement surgery. Duration of treatment. During treatment with low molecular weight heparin, elastic bandages should be used on the legs until the patient can move fully and actively: - In general surgical interventions, treatment with low molecular weight heparin lasts up to 10 days as long as there is a risk of venous thromboembolism (see "Precautions"); - Therapeutic benefit of prophylactic treatment with enoxaparin 4000 anti-Xa IU/day for 4-5 weeks after knee replacement surgery has been established; - If the risk of venous thromboembolism persists within the recommended duration of treatment, the issue of continuing prophylactic therapy, including the use of oral anticoagulants, should be considered. It should be noted that no studies have been conducted on the clinical benefit of long-term treatment with low molecular weight heparins or oral anticoagulants. Prevention of deep vein thrombosis in bedridden patients with acute therapeutic diseases. The recommended dose of Clexiparine is 40 mg (0.4 ml; 4000 anti-Xa IU) subcutaneously once daily. Clexiparine is administered for at least 6 days, duration of treatment - no more than 14 days. If the risk of venous thromboembolism persists, long-term prophylactic treatment with oral anticoagulants is necessary. Prevention of thrombosis during hemodialysis in extracorporeal circulation systems. The drug is administered intravenously (into the arterial catheter or dialysis circuit). In patients undergoing repeated dialysis sessions, prevention of blood clotting in the extracorporeal circuit is carried out at the beginning of the session by administering an initial dose of Clexiparine 100 anti-Xa IU/kg into the arterial catheter or dialysis circuit. The dose is administered intravenously as a single bolus injection. The anticoagulant effect of this dose is usually sufficient for a dialysis procedure lasting on average 4 hours or less. Further dose adjustment may be made considering individual variations in response. The maximum recommended dose is 100 anti-Xa IU/kg. In patients on hemodialysis at high risk of bleeding (especially in the pre- or postoperative period) or with active bleeding, 50 anti-Xa IU/kg (for bilateral access) or 75 anti-Xa IU/kg (for unilateral access) may be used during the dialysis procedure. Treatment of diagnosed deep vein thrombosis, with or without pulmonary embolism, and without severe clinical symptoms. In case of any suspicion of deep vein thrombosis, it must be immediately confirmed by appropriate diagnostic methods. Dosage. Clexiparine is administered subcutaneously twice daily at 100 anti-Xa IU/kg every 12 hours. For patients weighing over 100 kg and under 40 kg, the dose adjustment of low molecular weight heparin has not been studied. Low molecular weight heparin may be less effective in patients weighing over 100 kg and may increase the risk of bleeding in patients weighing under 40 kg. Therefore, constant monitoring of the clinical condition of these patients is necessary. Duration of treatment for deep vein thrombosis. During treatment with low molecular weight heparin, it is advisable to switch to oral anticoagulants as soon as possible, if there are no contraindications. The duration of treatment should not exceed 10 days, including the time to achieve steady state with oral anticoagulants, unless it is difficult to achieve steady state. Therefore, treatment with oral anticoagulants should be started as soon as possible. Treatment of unstable angina and acute myocardial infarction without Q wave. The recommended single dose of Clexiparine is 1 mg/kg (100 anti-Xa IU/kg) subcutaneously every 12 hours; acetylsalicylic acid is administered orally concurrently (recommended dose: 75 to 325 mg orally after an initial dose of 160 mg). Duration of treatment - at least 2-8 days, until the patient achieves a clinically stable condition. Treatment of acute myocardial infarction with ST-segment elevation in combination with thrombolytic agents in patients who will subsequently undergo coronary angioplasty or do not require this procedure. The initial intravenous bolus injection of Clexiparine is given at a dose of 30 mg (0.3 ml; 3000 anti-Xa IU). This is followed by subcutaneous injection of 1 mg/kg (100 anti-Xa IU/kg) over 15 minutes, then every 12 hours (the maximum total dose for the first two subcutaneous injections is 10000 anti-Xa IU). The first dose of Clexiparine is administered 15 minutes before or at any time between 30 minutes after the start of thrombolytic therapy. The recommended duration of treatment is 8 days or until the patient is discharged from the hospital, if hospitalization is less than 8 days. Concomitant therapy: acetylsalicylic acid should be administered as soon as possible after the onset of symptoms and continued at a dose of 75-325 mg for at least 30 days, unless otherwise indicated. Patients undergoing coronary angioplasty: - If at least 8 hours have passed since the last subcutaneous injection of Clexiparine until balloon inflation, no additional administration of the drug is necessary; - If more than 8 hours have passed since the last subcutaneous injection of Clexiparine until balloon inflation, an intravenous bolus injection of Clexiparine 0.3 mg/kg (30 anti-Xa IU/kg) is required. To ensure accuracy of the injection fluid volume, it is recommended to dilute the drug to 300 anti-Xa IU/ml (0.3 ml (3000 anti-Xa IU dissolved in 10 ml of solvent (0.9% sodium chloride or 5% glucose solution))) (see table). Injection solution volumes when diluted for patients undergoing coronary angioplasty. Body weight, kg Required dose, anti-Xa IU Volume required for injection, with dilution to 300 IU/ml (i.e., 0.3 ml of Clexiparine (3000 anti-Xa IU) diluted in 10 ml of solvent), ml 45 1350 4.5 50 1500 5 55 1650 5.5 60 1800 6 65 1950 6.5 70 2100 7 75 2250 7.5 80 2400 8 85 2550 8.5 90 2700 9 95 2850 9.5 100 3000 10 In patients over 75 years of age with acute myocardial infarction with ST-segment elevation, the initial intravenous bolus injection is not administered. They receive a subcutaneous dose of Clexiparine 0.75 mg/kg (75 anti-Xa IU/kg) every 12 hours (maximum total dose for the first 2 injections only is 75 mg (7500 anti-Xa IU)). Children. Due to lack of relevant data, the use of low molecular weight heparins in pediatric practice is not recommended. Side effects Significant hemorrhagic complications have been reported, some with fatal outcomes. Intracranial and retroperitoneal hemorrhages have been observed. Hemorrhagic complications (bleeding) such as hematoma, ecchymosis at the injection site, wound hematoma, hematuria, epistaxis, and gastrointestinal bleeding have also been reported. Hemorrhagic manifestations are mainly associated with: - Concomitant risk factors: organic lesions with a predisposition to bleeding and certain drug combinations (see "Contraindications" and "Interactions with other drugs"), age, renal insufficiency, low body weight; - Non-compliance with therapeutic recommendations, including deviations in duration of treatment or dose adjustment according to weight (see "Precautions"). Cases of spinal hematoma have been reported, associated with the administration of low molecular weight heparin during spinal anesthesia, analgesia, or epidural anesthesia. These adverse reactions caused neurological impairments of varying severity, including prolonged and permanent paralysis (see "Precautions"). Hematoma formation at the injection site may occur after subcutaneous injection. Pain and various reactions at the injection site have been reported - irritation, swelling, hypersensitivity, inflammation, and nodule formation. The risks of the latter increase if injection technique is not followed or inappropriate instruments are used for injection. Inflammatory nodules at the injection site, which disappear within a few days, are a result of inflammation. However, this does not require discontinuation of therapy. Thrombocytopenia has been reported. There are two types: - Type I - a more common form, usually mild (platelet count >100,000/mm3), appears early (within 5 days) and does not require discontinuation of treatment; - Type II - a less common severe form of immunoallergic thrombocytopenia - heparin-induced thrombocytopenia (HIT) with thrombosis; in some cases, thrombosis complicated by organ infarction or limb ischemia. Its prevalence is poorly studied (see "Precautions"). Asymptomatic and reversible increase in platelet levels may occur. Necrosis of the skin has been reported with the use of heparins, which may be preceded by purpura and infiltrated, painful erythematous spots. In such cases, immediate discontinuation of treatment is necessary. Systemic allergic reactions (anaphylactic/anaphylactoid reactions) or skin reactions (urticaria, itching, erythema, bullous rash) have been observed, which in some cases required discontinuation of treatment. Similar to unfractionated heparins, prolonged treatment with Clexiparine may lead to osteoporosis. Unfractionated heparins can cause hypoaldosteronism, which in turn leads to an increase in plasma potassium levels. Clinically significant hyperkalemia may occur, especially in patients with chronic renal insufficiency and diabetes mellitus. A transient increase in transaminase levels may occur. Several cases of hyperkalemia are known. Vasculitis has been observed, associated with increased skin sensitivity. Hypereosinophilia has been observed, independently and in conjunction with skin reactions, requiring discontinuation of treatment. Shelf life and storage conditions The shelf life of the drug is 2 years. Do not use the drug after the expiry date indicated on the packaging. Store in the original packaging at a temperature not exceeding 25°C. Do not freeze. Keep out of reach of children! Incompatibility - Do not mix with other drugs during injection. Dosage form 0.2 ml, 0.4 ml, 0.6 ml or 0.8 ml in a syringe. 1 syringe in a blister. 1, 2 or 10 blisters (drug with activity 2000 anti-Xa IU, 4000 anti-Xa IU, 6000 anti-Xa IU) and 1 or 2 blisters (drug with activity 8000 anti-Xa IU) are placed in a carton with instructions. 2 syringes in a blister. 1 or 5 blisters (drug with activity 2000 anti-Xa IU, 4000 anti-Xa IU, 6000 anti-Xa IU) and 1 blister (drug with activity 8000 anti-Xa IU) are placed in a carton with instructions. Conditions for dispensing from pharmacies Pharmaceutical product group II, dispensed by prescription form #3.