Clexane

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT KLEKSAN® (CLEXANE®)

Composition:

Active substance: enoxaparin;

1 ml of solution contains 10,000 anti-Xa IU, equivalent to 100 mg of enoxaparin sodium*;

1 pre-filled syringe contains 8000 anti-Xa IU/0.8 ml, equivalent to 80 mg of enoxaparin sodium*;

Excipient: water for injections.

* Enoxaparin sodium is a biological substance obtained by alkaline depolymerization of the benzyl ether of heparin derived from porcine intestinal mucosa.

Pharmaceutical form. Solution for injection.

Main physicochemical properties: colorless or pale yellow, clear solution.

Pharmacotherapeutic group. Antithrombotic agents. Heparin group.

ATC code B01AB05.

Pharmacological Properties.

Pharmacodynamics.

Enoxaparin is a low molecular weight heparin (LMWH) with an average molecular weight of approximately 4500 daltons, in which the antithrombotic and anticoagulant activities of standard heparin are dissociated. The active substance is presented as the sodium salt.

In a purified in vitro system, enoxaparin sodium exhibits high anti-Xa activity (approximately 100 IU/mg) and low anti-IIa (or antithrombin) activity (approximately 28 IU/mg), resulting in a ratio of 3.6. These anticoagulant activities are mediated through antithrombin III (ATIII), which underlies the antithrombotic effects in humans.

In addition to anti-Xa/IIa activity, additional antithrombotic and anti-inflammatory properties of enoxaparin have been identified in healthy volunteers and patients, as well as in experimental models within preclinical studies. These include ATIII-dependent inhibition of other coagulation factors, such as factor VIIa, induction of endogenous release of tissue factor pathway inhibitor (TFPI), and reduction of von Willebrand factor (vWF) release from vascular endothelium into the circulation. These factors contribute to the overall antithrombotic effect of enoxaparin sodium.

When used for prophylaxis, enoxaparin sodium does not significantly affect the activated partial thromboplastin time (aPTT). When used for treatment, aPTT may be prolonged 1.5–2.2 times compared to the control value at peak drug activity.

Clinical Efficacy and Safety.

Prevention of venous thromboembolic complications associated with surgical procedures.

Long-term prevention of venous thromboembolism (VTE) after orthopedic surgery. In a double-blind study on extended prophylaxis following hip replacement surgery, 179 patients without any venous thromboembolic complications who initially received enoxaparin sodium 4000 IU (40 mg) subcutaneously (s.c.) during hospitalization were randomized after hospital discharge to receive either enoxaparin sodium 4000 IU (40 mg) (n = 90) once daily s.c. or placebo (n = 89) for 3 weeks. The incidence of deep vein thrombosis (DVT) during extended prophylaxis was statistically significantly lower in the enoxaparin sodium group compared to the placebo group; no cases of pulmonary embolism (PE) were recorded. No major bleeding events were observed.

Efficacy data are presented in Table 1.

Table 1.

In another double-blind study, 262 patients without any venous thromboembolic events (VTE), undergoing elective hip replacement surgery and initially receiving enoxaparin sodium 4000 IU (40 mg) subcutaneously during hospitalization, were randomized to receive either enoxaparin sodium 4000 IU (40 mg) (n = 131) once daily subcutaneously or placebo (n = 131) after hospital discharge for 3 weeks. Similar to the results of the first study, the incidence of VTE during extended prophylaxis was statistically significantly lower in the enoxaparin sodium group compared to placebo, both in terms of total VTE (enoxaparin sodium − 21 [16%] versus placebo − 45 [34.4%]; p = 0.001) and proximal deep vein thrombosis (DVT) (enoxaparin sodium − 8 [6.1%] versus placebo − 28 [21.4%]; p < 0.001). There were no differences in the frequency of major bleeding between the enoxaparin sodium and placebo groups.

Extended prophylaxis of DVT following oncological surgery. In a double-blind, multicenter study, safety and efficacy of a 4-week versus a 1-week prophylactic regimen of enoxaparin sodium were compared in 332 patients undergoing planned abdominal or pelvic surgery for malignant diseases. Patients received enoxaparin sodium (4000 IU [40 mg] subcutaneously) daily for 6–10 days, after which they were randomized to receive either enoxaparin sodium or placebo for an additional 21 days. Between days 25 and 31, or earlier if VTE symptoms occurred, bilateral venography was performed. Patients were followed for 3 months. Prophylactic use of enoxaparin sodium for 4 weeks after abdominal or pelvic oncological surgery significantly reduced the frequency of venographically confirmed thrombosis compared to a 1-week prophylaxis regimen. The incidence of VTE at the end of the double-blind phase was 12.0% (n = 20) in the placebo group and 4.8% (n = 8) in the enoxaparin sodium group; p = 0.02. This difference persisted over 3 months [13.8% vs. 5.5% (n = 23 vs. 9), p = 0.01]. No differences between groups were observed in terms of bleeding frequency or other complications during the double-blind phase or the subsequent follow-up period.

Prevention of venous thromboembolic complications in medical patients with acute illnesses expected to cause limited mobility.

In a double-blind, multicenter, parallel-group study, enoxaparin sodium at a dose of 2000 IU (20 mg) or 4000 IU (40 mg) once daily subcutaneously was compared to placebo for the prevention of DVT in medical patients with severely limited mobility (defined as walking distance < 10 meters within ≤ 3 days) due to an acute illness. The study included patients with heart failure (NYHA functional class III or IV), acute respiratory insufficiency or complicated chronic respiratory insufficiency, or acute infection, or acute rheumatic disease, provided they had at least one VTE risk factor (age ≥ 75 years, malignancy, previous VTE, obesity, varicose veins, hormonal therapy, chronic heart or respiratory insufficiency).

Overall, 1102 patients were enrolled in the study, and 1073 patients received the investigational treatment. Treatment lasted 6–14 days (median duration was 7 days). When administered at a dose of 4000 IU (40 mg) once daily subcutaneously, enoxaparin sodium significantly reduced the incidence of VTE compared to placebo. Efficacy data are presented in Table 2.

Table 2.

After approximately 3 months of patient enrollment in the study, the incidence of VTE in the group receiving enoxaparin sodium at a dose of 4000 IU (40 mg) remained statistically significantly lower compared to the placebo group.

The overall frequency of bleeding and the frequency of major bleeding were 8.6% and 1.1%, respectively, in the placebo group, 11.7% and 0.3% in the group receiving enoxaparin sodium at a dose of 2000 IU (20 mg), and 12.6% and 1.7% in the group receiving enoxaparin sodium at a dose of 4000 IU (40 mg).

Treatment of deep vein thrombosis, with or without pulmonary embolism.

In a multicenter, parallel-group study, 900 patients with acute DVT of the lower limbs, with or without pulmonary embolism (PE), were randomized to receive in-hospital treatment with either enoxaparin sodium at a dose of 150 IU/kg (1.5 mg/kg) once daily subcutaneously; or enoxaparin sodium at a dose of 100 IU/kg (1 mg/kg) every 12 hours subcutaneously; or heparin as an intravenous bolus (5000 IU) followed by continuous intravenous infusion (to achieve an aPTT of 55 to 85 seconds). Overall, 900 patients were randomized in the study, all of whom received the study treatment. All patients also received warfarin sodium (dose adjusted according to prothrombin time with the aim of achieving an INR of 2.0 to 3.0), which was initiated within 72 hours after starting enoxaparin sodium or standard heparin therapy and continued for 90 days. Enoxaparin sodium or standard heparin therapy was administered for at least 5 days and until the target INR was achieved with warfarin sodium. Both enoxaparin sodium regimens were equivalent to standard heparin therapy in reducing the risk of recurrent venous thromboembolism (DVT and/or PE). Efficacy data are presented in Table 3.

Table 3.

The frequency of major bleeding was 1.7% in the group receiving sodium enoxaparin 150 IU/kg (1.5 mg/kg) once daily, 1.3% in the group receiving sodium enoxaparin 100 IU/kg (1 mg/kg) twice daily, and 2.1% in the heparin group.

Long-term treatment of deep vein thrombosis and pulmonary embolism, as well as prevention of their recurrence in patients with active cancer

In clinical studies with a limited number of patients, the recurrence rate of VTE in patients receiving enoxaparin once daily or twice daily for 3–6 months was comparable to that in patients receiving warfarin. Effectiveness under real-world conditions was evaluated in a cohort of 4,451 patients with symptomatic VTE and active cancer from the multinational RIETE registry of patients with VTE and other thrombotic conditions. Of these, 3,526 patients received subcutaneous enoxaparin for 6 months and 925 patients received subcutaneous tinzaparin or dalteparin. Among the 3,526 patients receiving enoxaparin treatment, 891 received 1.5 mg/kg once daily as both initial and long-term treatment up to 6 months (once daily), 1,854 received 1.0 mg/kg twice daily as both initial and long-term treatment up to 6 months (twice daily), and 687 received 1.0 mg/kg twice daily as initial treatment followed by 1.5 mg/kg once daily (twice daily, then once daily) as long-term treatment up to 6 months. The mean and median durations of treatment before dose regimen change were 17 days and 8 days, respectively. There was no significant difference in the rate of VTE recurrence between the two treatment groups (see Table 4), with enoxaparin meeting the predefined non-inferiority criterion of 1.5 (adjusted HR 0.817, 95% CI 0.499–1.336). There was no statistically significant difference between the two treatment groups in terms of relative risk of major bleeding (fatal or non-fatal) or all-cause mortality (see Table 5).

Table 4

Efficacy and safety outcomes in the RIETECAT study

Below is a brief summary of the results for each treatment regimen used in the RIETECAT study in patients who received treatment for 6 months.

Table 5

Results at 6 months of treatment in patients receiving different treatment regimens

* All data with 95% CI.

Treatment of unstable angina and non-ST-segment elevation myocardial infarction.

In a large, multicenter study, 3,171 patients enrolled during the acute phase of unstable angina and non-Q-wave myocardial infarction were randomized to receive, in combination with acetylsalicylic acid (100−325 mg once daily), either sodium enoxaparin at a dose of 100 IU/kg (1 mg/kg) every 12 hours, or unfractionated heparin (UFH) intravenously with dose adjustment based on aPTT levels. Patients received in-hospital treatment for a minimum of 2 days and up to 8 days until clinical stabilization, revascularization procedures, or hospital discharge. Patients were followed for up to 30 days. Compared with heparin, sodium enoxaparin significantly reduced the composite incidence of angina, myocardial infarction, and death from 19.8% to 16.6% (relative risk reduction of 16.2%) by day 14. This reduction in the composite incidence was maintained at 30 days (from 23.3% to 19.8%; relative risk reduction of 15%).

No statistically significant differences were observed in the incidence of major bleeding, although injection site bleeding occurred more frequently.

Treatment of acute ST-segment elevation myocardial infarction (STEMI).

In a large, multicenter study, 20,479 patients with STEMI eligible for fibrinolytic therapy were randomized to receive either sodium enoxaparin as a single intravenous bolus of 3,000 IU (30 mg) followed by 100 IU/kg (1 mg/kg) subcutaneously and subsequent administration of 100 IU/kg (1 mg/kg) subcutaneously every 12 hours, or intravenous UFH for 48 hours with dose adjustment based on aPTT levels. All patients also received acetylsalicylic acid for at least 30 days. The dosing regimen of sodium enoxaparin was adjusted for patients with severe renal impairment and for elderly patients (≥75 years). Subcutaneous injections of sodium enoxaparin were continued until hospital discharge or for a maximum of 8 days, whichever came first.

Percutaneous coronary intervention (PCI) was performed in 4,716 patients, with antithrombotic support provided using the study drugs in a blinded manner. Thus, for patients receiving sodium enoxaparin, PCI was performed while continuing sodium enoxaparin (without switching to the comparator drug), according to a regimen studied in previous trials: no additional enoxaparin was administered if the last subcutaneous dose had been given less than 8 hours before balloon inflation; an intravenous bolus of sodium enoxaparin at 30 IU/kg (0.3 mg/kg) was administered if the last subcutaneous dose had been given more than 8 hours before balloon inflation.

Compared with UFH, sodium enoxaparin significantly reduced the incidence of the primary endpoint—a composite of all-cause mortality and recurrent myocardial infarction—during the first 30 days after randomization [9.9% in the sodium enoxaparin group vs. 12.0% in the UFH group], with a 17% relative risk reduction (p < 0.001).

The benefits of sodium enoxaparin treatment, evident across multiple efficacy measures, were apparent within 48 hours, when a 35% relative risk reduction in recurrent myocardial infarction was observed compared to UFH treatment (p < 0.001).

The positive effect of sodium enoxaparin on the primary endpoint was consistent across all key subgroups, including subgroups defined by age, sex, infarct location, history of diabetes, prior myocardial infarction, type of fibrinolytic agent used, and time to initiation of study treatment.

Statistically significant advantages of sodium enoxaparin treatment over UFH were observed in patients who underwent PCI within 30 days after randomization (23% relative risk reduction) and in those managed medically (15% relative risk reduction, p = 0.27 for interaction).

The incidence of the composite endpoint including death, recurrent myocardial infarction, or intracranial hemorrhage (a measure of net clinical benefit) at 30 days was significantly lower (p < 0.0001) in the sodium enoxaparin group (10.1%) compared to the UFH group (12.2%), corresponding to a 17% relative risk reduction in favor of sodium enoxaparin treatment.

The incidence of major bleeding at 30 days was significantly higher (p < 0.0001) in the sodium enoxaparin group (2.1%) compared to the UFH group (1.4%). The rate of gastrointestinal bleeding was higher in the sodium enoxaparin group (0.5%) than in the UFH group (0.1%), while the incidence of intracran游戏副本

Clinical characteristics.

Indications.

The medicinal product is indicated for use in adults for:

• Prophylaxis of venous thromboembolic complications in surgical patients with moderate and high risk, especially in patients undergoing orthopedic or general surgical procedures, including surgery for oncological diseases.
• Prophylaxis of venous thromboembolic complications in medical patients with acute illnesses (such as acute heart failure, respiratory failure, severe infections, or rheumatic diseases) and reduced mobility who are at increased risk of venous thromboembolism.
• Treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE), except in cases of PE where thrombolytic therapy or surgical intervention may be required.
• Long-term treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE), as well as prevention of their recurrence in patients with active phase of oncological disease.
• Prevention of thrombus formation in the extracorporeal circulation during hemodialysis.
• In acute coronary syndrome:
  • for treatment of unstable angina and non-ST-segment elevation myocardial infarction (NSTEMI), in combination with oral acetylsalicylic acid;
  • for treatment of acute ST-segment elevation myocardial infarction (STEMI), including in patients planned for pharmacological treatment or subsequent percutaneous coronary intervention (PCI).

Contraindications.

Sodium enoxaparin is contraindicated in patients with the following conditions:

• Hypersensitivity to sodium enoxaparin, heparin or its derivatives, including other low molecular weight heparins, or to any of the excipients (see section "Composition").
• History of immune-mediated heparin-induced thrombocytopenia (HIT) within the last 100 days in the presence of circulating antibodies (see also section "Special precautions").
• Active clinically significant bleeding and conditions with a high risk of bleeding, including recent hemorrhagic stroke, gastrointestinal ulcer, presence of malignant tumor with high bleeding risk, recent surgery on the brain, spinal cord or eyes, known or suspected esophageal varices, arteriovenous malformations, vascular aneurysms, or serious congenital defects of intraspinal or intracerebral vessels.
• Spinal or epidural anesthesia or locoregional anesthesia if sodium enoxaparin has been used for treatment within the previous 24 hours (see section "Special precautions").

Interaction with other medicinal products and other types of interactions.

Concomitant use with the following medicinal products is not recommended.

Medicinal products affecting hemostasis (see section "Special precautions"). Some agents affecting hemostasis should be discontinued prior to initiation of sodium enoxaparin treatment, except when such agents are absolutely indicated. If such combination is indicated, sodium enoxaparin should be administered with careful clinical and laboratory monitoring.

These include:

• salicylates for systemic use, acetylsalicylic acid at anti-inflammatory doses, and nonsteroidal anti-inflammatory drugs (NSAIDs), including ketorolac;
• other thrombolytics (e.g., alteplase, reteplase, streptokinase, tenecteplase, urokinase) and anticoagulants (see section "Method of administration and dosage").

Medicinal products that should be used concomitantly with caution.

The following medicinal products may be used concomitantly with sodium enoxaparin with caution.

• Other medicinal products affecting hemostasis, such as:
• platelet aggregation inhibitors, including acetylsalicylic acid used at antiplatelet (cardioprotective) doses, clopidogrel, ticlopidine, and glycoprotein IIb/IIIa antagonists indicated in acute coronary syndrome, due to the risk of bleeding;
• dextran 40;
• systemic glucocorticoids.
• Medicinal products that increase potassium levels. Medicinal products that increase serum potassium levels may be prescribed concomitantly with sodium enoxaparin with careful clinical and laboratory monitoring (see sections "Special precautions" and "Adverse reactions").

Special precautions for use.

General warnings.

Sodium enoxaparin must not be used interchangeably (unit for unit) with other low-molecular-weight heparins (LMWHs). These medicinal products differ in their manufacturing processes, molecular weights, specific anti-Xa and anti-IIa activities, units of activity, dosing regimens, and clinical efficacy and safety. These differences result in variations in pharmacokinetics and biological activity (e.g., antithrombotic activity, platelet interactions).

Therefore, it is essential to pay close attention to the instructions for medical use specific to each branded product and strictly follow them.

History of heparin-induced thrombocytopenia (HIT) (> 100 days).

The use of sodium enoxaparin is contraindicated in patients with a history of immune-mediated HIT within the past 100 days or in those with circulating antibodies (see section "Contraindications"). Circulating antibodies may persist for several years.

Sodium enoxaparin should be used with extreme caution in patients with a history of immune-mediated HIT (> 100 days) in the absence of circulating antibodies. The decision to use sodium enoxaparin in such cases should be made only after a careful benefit-risk assessment and after considering alternative non-heparin anticoagulant therapies (e.g., danaparoid sodium or lepirudin).

Platelet monitoring.

In cancer patients with platelet counts below 80 × 10⁹/L, anticoagulant therapy may be considered only after careful individual assessment, and close monitoring is recommended.

There is also a risk of antibody-mediated HIT when using LMWHs, which typically develops between days 5 and 21 after initiation of sodium enoxaparin therapy.

The risk of HIT is higher in patients who have undergone surgery, particularly after cardiac surgery, and in patients with malignancies.

Therefore, it is recommended to determine platelet counts before starting sodium enoxaparin therapy and to monitor them regularly during treatment.

If clinical symptoms suggestive of HIT occur (any new episode of arterial and/or venous thromboembolism, any painful skin lesion at the injection site, or any allergic or anaphylactoid reactions during treatment), platelet counts should be determined. Patients should be informed about the possibility of such symptoms and instructed to report them to their physician immediately.

In clinical practice, if a confirmed significant decrease in platelet levels (30−50% from baseline) occurs, sodium enoxaparin should be discontinued immediately, and the patient should be switched to an alternative non-heparin anticoagulant therapy.

Bleeding events.

As with other anticoagulants, bleeding or hemorrhage of any localization may occur. In case of bleeding, the source should be investigated and appropriate treatment initiated.

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

• coagulation disorders; history of peptic ulcer;
• recent ischemic stroke;
• severe arterial hypertension;
• recent onset of diabetic retinopathy;
• surgery on the nervous system or eyes;
• concomitant use of medicinal products affecting hemostasis (see section "Interaction with other medicinal products and other forms of interaction").

Laboratory tests.

Sodium enoxaparin, when used at doses for prevention of venous thromboembolism, has no significant effect on bleeding time, general coagulation parameters, platelet aggregation, or fibrinogen binding to platelets.

When higher doses are used, activated partial thromboplastin time (aPTT) and activated clotting time (ACT) may increase. However, since there is no linear correlation between the increase in aPTT and ACT and the antithrombotic activity of sodium enoxaparin, these parameters are unreliable and should not be used for monitoring enoxaparin activity.

Use during spinal/epidural anesthesia or lumbar puncture.

Spinal/epidural anesthesia or lumbar puncture should not be performed within 24 hours after administration of therapeutic doses of sodium enoxaparin (see also section "Contraindications").

Cases of neuroaxial hematomas have been reported with concomitant use of sodium enoxaparin and procedures involving spinal/epidural anesthesia or spinal puncture, leading to long-term or irreversible paralysis. These events are rare when sodium enoxaparin is used at a dose of 4000 IU (40 mg) once daily or at lower doses. The risk of such events is higher when postoperative continuous epidural catheters are used, with concomitant use of other drugs affecting hemostasis (e.g., nonsteroidal anti-inflammatory drugs), with traumatic or repeated epidural or spinal punctures, or in patients with a history of spinal surgery or spinal deformities.

To reduce the potential risk of bleeding associated with concomitant use of sodium enoxaparin and procedures involving epidural or spinal anesthesia/analgesia or lumbar puncture, the pharmacokinetic profile of sodium enoxaparin should be considered (see section "Pharmacokinetics"). Placement or removal of an epidural catheter or performance of lumbar puncture should ideally be performed when the anticoagulant effect of sodium enoxaparin is low; however, the exact time at which a sufficiently low anticoagulant effect is achieved in each individual patient is unknown. It should also be noted that elimination of sodium enoxaparin is prolonged in patients with creatinine clearance of 15−30 mL/min (see section "Posology and method of administration").

If the physician decides to use anticoagulant therapy during epidural or spinal anesthesia/analgesia or lumbar puncture, frequent monitoring is required to detect any neurological symptoms, such as midline back pain, sensory or motor disturbances (numbness or weakness in the lower limbs), or bowel and/or bladder dysfunction. Patients should be instructed to report any of these symptoms immediately. If a spinal hematoma is suspected, appropriate diagnostic and therapeutic measures should be initiated immediately, including consideration of spinal cord decompression, even though such treatment may not prevent adverse neurological outcomes.

Skin necrosis / cutaneous vasculitis. Cases of skin necrosis and cutaneous vasculitis have been reported during treatment with low-molecular-weight heparins; in such cases, the drug should be discontinued immediately.

Percutaneous coronary interventions. To minimize the risk of bleeding after invasive vascular procedures in the treatment of unstable angina, non-ST-segment elevation myocardial infarction (NSTEMI), and acute ST-segment elevation myocardial infarction (STEMI), the recommended intervals between doses of sodium enoxaparin must be strictly followed. Achieving hemostasis at the puncture site after percutaneous coronary intervention (PCI) is essential. If a vascular closure device is used, the introducer can be removed immediately after the procedure. If manual compression is used, the introducer should be removed at least 6 hours after the last intravenous or subcutaneous injection of sodium enoxaparin. If treatment with sodium enoxaparin is to be continued, the next scheduled dose should not be administered earlier than 6−8 hours after removal of the introducer. The puncture site should be monitored for signs of bleeding or hematoma formation.

Acute infective endocarditis. The use of heparin in patients with acute infective endocarditis is generally not recommended due to the risk of cerebral hemorrhage. If such use is considered absolutely necessary, the decision should be made only after a careful individual benefit-risk assessment.

Mechanical heart valves. The use of sodium enoxaparin for thromboprophylaxis in patients with mechanical heart valves has not been adequately studied. Isolated cases of mechanical heart valve thrombosis have been reported in patients receiving sodium enoxaparin for thromboprophylaxis. The presence of risk factors, including underlying disease and limited clinical data, complicates the assessment of these cases. Some of these cases occurred in pregnant women, resulting in maternal and fetal death.

Pregnant women with mechanical heart valves. The use of sodium enoxaparin for thromboprophylaxis in pregnant women with mechanical heart valves has not been adequately studied. In a clinical trial where pregnant women with mechanical heart valves received sodium enoxaparin (100 IU/kg [1 mg/kg] twice daily) to reduce the risk of thromboembolic events, two out of eight women developed blood clots leading to valve obstruction and maternal and fetal death. Post-marketing reports have included isolated cases of valve thrombosis in pregnant women with mechanical heart valves receiving sodium enoxaparin for thromboprophylaxis. Pregnant women with mechanical heart valves may have an increased risk of thromboembolic events.

Elderly patients. When used at prophylactic doses, no increased bleeding tendency has been observed in elderly patients. However, elderly patients (especially those aged 80 years or older) may have an increased risk of hemorrhagic complications when therapeutic doses are used. For patients aged over 75 years receiving treatment with the drug for ST-segment elevation myocardial infarction (STEMI), careful clinical monitoring is recommended, and dose reduction may be considered (see sections "Posology and method of administration" and "Pharmacokinetics").

Renal impairment. In patients with renal impairment, exposure to sodium enoxaparin is increased, which raises the risk of bleeding. Careful clinical monitoring is recommended for such patients, and biological monitoring via anti-Xa activity measurement may be considered (see sections "Posology and method of administration" and "Pharmacokinetics").

Sodium enoxaparin is not recommended for use in patients with end-stage renal disease (creatinine clearance < 15 mL/min) due to the lack of adequate data in this population, except for the prevention of thrombus formation in the extracorporeal circulation during hemodialysis.

For patients with severe renal impairment (creatinine clearance 15−30 mL/min), dose adjustment of the drug is recommended for both therapeutic and prophylactic use due to significantly increased exposure to sodium enoxaparin (see section "Posology and method of administration").

Dose adjustment is not recommended for patients with moderate (creatinine clearance 30−50 mL/min) or mild (creatinine clearance 50−80 mL/min) renal impairment.

Hepatic impairment. Sodium enoxaparin should be used with caution in patients with hepatic impairment due to an increased risk of bleeding. Dose adjustment based on anti-Xa activity monitoring is unreliable in patients with liver cirrhosis and is not recommended (see section "Pharmacokinetics").

Low body weight. Increased exposure to sodium enoxaparin has been observed in women with low body weight (< 45 kg) and men with low body weight (< 57 kg) when prophylactic doses (without weight adjustment) are used, potentially increasing the risk of bleeding. Therefore, careful clinical monitoring is recommended for such patients (see section "Pharmacokinetics").

Obese patients. Obese patients have an increased risk of thromboembolic events. The safety and efficacy of prophylactic doses of the drug in obese patients (body mass index [BMI] > 30 kg/m²) have not been sufficiently studied, and there is currently no consensus on whether dose adjustment is necessary for this patient group. These patients should be closely monitored for possible symptoms of thromboembolism.

Hyperkalemia. Heparins may suppress aldosterone secretion in the adrenal glands, leading to hyperkalemia (see section "Adverse reactions"), particularly in patients with diabetes mellitus, chronic renal insufficiency, pre-existing metabolic acidosis, or those receiving drugs known to increase potassium levels (see section "Interaction with other medicinal products and other forms of interaction"). Plasma potassium levels should be monitored periodically, especially in patients at increased risk.

Traceability. Low-molecular-weight heparins are biological medicinal products. To improve traceability, healthcare professionals are recommended to record the brand name and batch number of the administered product in the patient's documentation.

Patients sensitive to sodium.

Patients receiving doses exceeding 210 mg/day should be aware that one dose of this medicinal product contains more than 24 mg of sodium, equivalent to 1.2% of the WHO recommended maximum daily intake of sodium (2 g for an adult).

Acute generalized exanthematous pustulosis (AGEP).

Acute generalized exanthematous pustulosis (AGEP) has been reported with an "unknown" frequency in association with enoxaparin treatment. Patients should be informed about the symptoms of AGEP, and careful monitoring for skin reactions should be performed. If symptoms suggestive of these reactions occur, enoxaparin should be discontinued immediately, and alternative treatment should be considered if necessary.

Use during pregnancy or breastfeeding.

Pregnancy. There is no evidence in humans that enoxaparin crosses the placental barrier during the second and third trimesters of pregnancy. Information regarding the first trimester is currently lacking.

Animal studies have shown no signs of fetotoxicity or teratogenicity (see section "Preclinical safety data"). Data from experimental animals indicate that placental transfer of enoxaparin is minimal.

Sodium enoxaparin should be administered to pregnant women only if clearly needed, as determined by the physician.

Pregnant women receiving sodium enoxaparin should be closely monitored for signs of bleeding or excessive anticoagulant effect, and they should be warned about the risk of hemorrhagic events. Overall, available data suggest no evidence of increased risk of bleeding, thrombocytopenia, or osteoporosis in such patients compared to non-pregnant women, except for the risk observed in pregnant women with mechanical heart valves (see section "Special precautions for use").

If epidural anesthesia is planned, it is recommended to discontinue sodium enoxaparin treatment prior to the procedure (see section "Special precautions for use").

Breastfeeding. It is unknown whether unchanged enoxaparin is excreted in human breast milk. In rats during lactation, transfer of enoxaparin or its metabolites into milk is very low.

Since oral absorption of sodium enoxaparin is unlikely, it may be used during breastfeeding.

Fertility. Clinical data on the effect of sodium enoxaparin on fertility are currently lacking. Animal studies have not demonstrated any effect of the drug on fertility (see section "Preclinical safety data").

Ability to affect reaction speed when driving or operating machinery.

The effect of sodium enoxaparin on the ability to drive or operate machinery is absent or negligible.

Method of Administration and Dosage.

Dosage.

Prophylaxis of venous thromboembolic complications in surgical patients with moderate and high risk. Individual thromboembolic risk in patients can be assessed using a validated risk stratification model (score).

• For patients with moderate risk of thromboembolic events, the recommended dose of sodium enoxaparin is 2000 IU (20 mg) once daily administered by subcutaneous (SC) injection. Preoperative initiation of sodium enoxaparin at a dose of 2000 IU (20 mg) given 2 hours before surgery has been shown to be effective and safe in surgical procedures associated with moderate risk.

In patients at moderate risk, prophylactic treatment with sodium enoxaparin should continue for a period of at least 7–10 days, regardless of recovery status (e.g., mobility). Prophylaxis should be continued until the patient no longer exhibits significantly reduced mobility.

• For patients with high risk of thromboembolic events, the recommended dose of sodium enoxaparin is 4000 IU (40 mg) once daily, preferably administered by subcutaneous (SC) injection 12 hours before surgery. If prophylactic administration of sodium enoxaparin needs to be initiated more than 12 hours before surgery (e.g., a high-risk patient awaiting delayed orthopedic surgery), the last preoperative dose should be administered no later than 12 hours before surgery, and prophylactic treatment should be resumed 12 hours after surgery.
• For patients undergoing major orthopedic surgery, prolonged thromboprophylaxis is recommended—up to 5 weeks.
• For high-risk patients undergoing abdominal or pelvic surgery for oncological diseases, prolonged thromboprophylaxis is recommended—up to 4 weeks.

Prophylaxis of venous thromboembolism (VTE) in medical patients. The recommended dose of sodium enoxaparin is 4000 IU (40 mg) once daily administered by SC injection.

Prophylactic treatment with sodium enoxaparin should be continued for a period of at least 6–14 days, depending on recovery status (e.g., mobility). The benefit of treatment beyond 14 days has not yet been established.

Treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE). Sodium enoxaparin should be administered SC as either a single daily injection of 150 IU/kg (1.5 mg/kg) or as two daily injections of 100 IU/kg (1 mg/kg) twice daily.

The dosing regimen should be selected by the physician based on individual assessment, including evaluation of thromboembolic and bleeding risks. The once-daily regimen of 150 IU/kg (1.5 mg/kg) is recommended for uncomplicated patients at low risk of recurrent VTE. The twice-daily regimen of 100 IU/kg (1 mg/kg) should be prescribed for all other patients, including those with obesity, symptomatic PE, cancer, recurrent VTE, or proximal venous thrombosis (e.g., iliac vein thrombosis).

Sodium enoxaparin is typically administered for an average of 10 days. If necessary, oral anticoagulants should be initiated (see "Switching between sodium enoxaparin and oral anticoagulants" at the end of this section).

For long-term treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE), as well as prevention of their recurrence in patients with active cancer, the physician must carefully assess the risks of thromboembolism and bleeding.

The recommended dose is 100 IU/kg (1 mg/kg) administered twice daily by SC injection for 5–10 days, followed by 150 IU/kg (1.5 mg/kg) once daily by SC injection for 6 months. The benefits of continuous anticoagulant therapy should be re-evaluated after 6 months of treatment.

Prophylaxis of thrombus formation during hemodialysis. The recommended dose of sodium enoxaparin is 100 IU/kg (1 mg/kg). In patients at high risk of bleeding, the dose should be reduced to 50 IU/kg (0.5 mg/kg) with dual vascular access or to 75 IU/kg (0.75 mg/kg) with single vascular access.

During hemodialysis, sodium enoxaparin should be administered into the arterial limb of the circuit at the beginning of the dialysis session. This dose is generally sufficient for a 4-hour dialysis session. However, if fibrin rings occur, for example, during longer-than-usual sessions, an additional dose of 50–100 IU/kg (0.5–1 mg/kg) may be administered.

There are no data on the use of sodium enoxaparin in patients for prophylaxis or treatment during hemodialysis sessions.

Acute coronary syndrome: treatment of unstable angina and non-ST-segment elevation myocardial infarction (NSTEMI), and acute ST-segment elevation myocardial infarction (STEMI).

• For treatment of unstable angina and NSTEMI, the recommended dose of sodium enoxaparin is 100 IU/kg (1 mg/kg) administered every 12 hours by SC injection, in combination with antiplatelet therapy. Treatment should be initiated for at least 2 days and continued until clinical stabilization of the patient. The usual duration of treatment is 2 to 8 days.
• All uncomplicated patients should receive oral acetylsalicylic acid with an initial loading dose of 150–300 mg (for patients not previously taking acetylsalicylic acid) and a maintenance dose of 75–325 mg/day long-term, regardless of treatment strategy.
• For treatment of acute STEMI, the recommended dose of sodium enoxaparin is a single intravenous (IV) bolus of 3000 IU (30 mg) plus a dose of 100 IU/kg (1 mg/kg) SC, followed by SC administration of 100 IU/kg (1 mg/kg) every 12 hours (maximum 10,000 IU [100 mg] for each of the first two SC doses). Appropriate antiplatelet therapy, such as oral acetylsalicylic acid (75–325 mg once daily), should be administered concomitantly, in the absence of contraindications. The recommended duration of treatment is 8 days or until hospital discharge, whichever occurs earlier. When used in combination with thrombolytic therapy (fibrin-specific or non-fibrin-specific), sodium enoxaparin should be administered between 15 minutes before and 30 minutes after the start of fibrinolytic therapy.
• Dosage specifics for patients aged ≥75 years are described below ("Elderly Patients").
• For patients undergoing percutaneous coronary intervention (PCI), if the last SC dose of sodium enoxaparin was administered less than 8 hours before balloon inflation, no additional doses are required. If the last SC dose was administered more than 8 hours before balloon inflation, an IV bolus of 30 IU/kg (0.3 mg/kg) of sodium enoxaparin should be administered.

Pediatric patients. The safety and efficacy of sodium enoxaparin in pediatric patients have not been established.

Elderly patients. For all indications except ST-segment elevation myocardial infarction (STEMI), dose reduction in elderly patients is not required, except in cases of renal impairment (see below "Renal Impairment" and section "Special Warnings and Precautions").

For treatment of acute STEMI in elderly patients (≥75 years), the initial IV bolus should not be administered. Treatment should begin with a dose of 75 IU/kg (0.75 mg/kg) SC every 12 hours (maximum 7500 IU [75 mg] for each of the first two SC doses), followed by continued administration of 75 IU/kg (0.75 mg/kg) SC for subsequent doses. Dosage specifics for elderly patients with renal impairment are described below in the subsection "Renal Impairment" and in the section "Special Warnings and Precautions."

Hepatic impairment. Limited data are currently available on the use of the drug in patients with hepatic impairment (see sections "Pharmacodynamics" and "Pharmacokinetics"); therefore, caution should be exercised in this patient population (see section "Special Warnings and Precautions").

Renal impairment (see sections "Special Warnings and Precautions" and "Pharmacokinetics").

Severe renal impairment. Sodium enoxaparin is not recommended for patients with end-stage renal disease (creatinine clearance < 15 mL/min) due to lack of adequate data in this population, except for prophylaxis of thrombus formation in the extracorporeal circuit during hemodialysis.

Table 6

Dosage for patients with severe renal impairment

(creatinine clearance 15–30 mL/min)

The recommended dose adjustment does not apply to the use of the drug for hemodialysis.

• Mild and moderate renal impairment. Although dose adjustment is not recommended for patients with mild (creatinine clearance 50–80 mL/min) or moderate (creatinine clearance 30–50 mL/min) renal impairment, careful clinical monitoring of such patients is necessary.

Route of administration. The drug CLEXANE® must not be administered intramuscularly.

For the prevention of venous thromboembolic complications after surgery, treatment of DVT and PE, long-term treatment of DVT and PE in patients with active cancer, and treatment of unstable angina and NSTEMI, sodium enoxaparin should be administered by subcutaneous injection.

• For the treatment of acute STEMI, the drug should be initiated with a single intravenous (IV) bolus injection, followed immediately by subcutaneous administration.
• For the prevention of clot formation in the extracorporeal circulation during hemodialysis, the drug is administered into the arterial line of the dialysis circuit.

Single-use pre-filled syringe, ready for use

Technique of subcutaneous injection.

Administration of the drug should preferably be performed with the patient lying down. Sodium enoxaparin is administered by deep subcutaneous injection.

To avoid loss of drug when using pre-filled syringes, air bubbles should not be expelled from the syringe before injection. If dose adjustment according to patient body weight is required, graduated pre-filled syringes should be used, allowing the desired volume to be obtained by removing the excess prior to injection. Please note that in some cases it may not be possible to achieve the exact dose due to the syringe graduation marks, and the volume should then be rounded to the nearest graduation mark.

The drug should be administered alternately into the left and right anterolateral or posterolateral abdominal wall.

The needle should be inserted fully, perpendicularly, into a skin fold gently held between the thumb and index finger. The skin fold should be held until the injection is completed. The injection site should not be massaged after administration.

The safety system of pre-filled syringes with a needle protection system is activated at the end of the injection.

If the patient is self-administering the drug, they should be advised to follow the instructions for self-injection of CLEXANE® using a syringe with a needle protection system.

Intravenous (bolus) injection (only when the drug is used for the indication of acute ST-segment elevation myocardial infarction (STEMI)).

For the treatment of acute STEMI, administration of the drug should begin with a single intravenous (IV) bolus injection, followed immediately by subcutaneous administration.

For IV injection, either a multidose vial or a pre-filled syringe may be used.

Sodium enoxaparin should be administered through an IV infusion system. It must not be mixed or administered simultaneously with other medicinal products. To avoid potential mixing of sodium enoxaparin with other drugs, the selected IV access should be flushed with an adequate amount of 0.9% sodium chloride solution or dextrose (glucose) solution before and after the IV bolus administration of sodium enoxaparin to clear the administration port of other drugs. Sodium enoxaparin can be safely administered with 0.9% sodium chloride solution or 5% aqueous dextrose (glucose) solution.

Initial bolus 3,000 IU (30 mg). To administer the initial bolus of 3,000 IU (30 mg) using a graduated pre-filled syringe, the excess volume should be removed from the syringe so that only 3,000 IU (30 mg) remains. The dose of 3,000 IU (30 mg) can then be administered directly intravenously.

Additional bolus in the case of PCI when the last subcutaneous dose was administered more than 8 hours before balloon inflation. For patients undergoing PCI, an additional IV bolus of 30 IU/kg (0.3 mg/kg) is required if the last subcutaneous dose was administered more than 8 hours before balloon inflation.

To ensure accurate administration of such a small volume, it is recommended to dilute the drug to a concentration of 300 IU/mL (3 mg/mL).

To prepare a solution of 300 IU/mL (3 mg/mL), it is recommended to use a pre-filled syringe containing 6,000 IU (60 mg) of sodium enoxaparin and a 50 mL infusion bag (i.e., 0.9% normal saline or 5% dextrose solution) as follows: withdraw 30 mL from the infusion bag using a syringe and discard the withdrawn fluid. Then inject the entire contents of the pre-filled syringe containing 6,000 IU (60 mg) of sodium enoxaparin into the remaining 20 mL in the infusion bag. Gently mix the contents of the bag.

Withdraw the required volume of the diluted solution using a syringe for administration into the IV infusion system.

After dilution, the volume to be administered can be calculated using the following formula: [Volume of diluted solution (mL) = Patient's body weight (kg) x 0.1] or by using Table 7. Dilution should be performed immediately before drug administration.

Table 7.

Volume to be administered via the IV infusion system after dilution of the drug to a concentration of 300 IU (3 mg)/mL.

Administration into the arterial segment of the dialysis circuit. The drug is administered into the arterial line of the dialysis circuit to prevent clot formation in the extracorporeal blood circulation during hemodialysis.

Transition from sodium enoxaparin to oral anticoagulants.

Transition from sodium enoxaparin to vitamin K antagonists (VKA). Clinical monitoring and laboratory tests [prothrombin time expressed as the International Normalized Ratio (INR)] should be intensified to monitor the effect of VKA.

Since there is a certain time interval before VKA reaches its maximum effect, administration of sodium enoxaparin should be continued at a constant dose for as long as necessary to maintain the INR within the target therapeutic range for the respective indication, based on results of two consecutive tests.

In patients currently receiving VKA, VKA should be discontinued and the first dose of sodium enoxaparin should be administered when the INR decreases to a level below the therapeutic range.

Transition from sodium enoxaparin to direct oral anticoagulants (DOACs) and vice versa. In patients currently receiving sodium enoxaparin, sodium enoxaparin should be discontinued and DOAC therapy should be initiated 0–2 hours (depending on the instructions for medical use of each DOAC) before the next scheduled dose of sodium enoxaparin is due.

In patients currently receiving DOACs, the first dose of sodium enoxaparin should be administered at the time when the next dose of DOAC was due.

Use of the drug in spinal/epidural anesthesia or lumbar puncture. If the physician decides that anticoagulants are necessary during spinal/epidural anesthesia or lumbar puncture, careful neurological monitoring is recommended due to the risk of developing neuroaxial hematoma (see section "Special precautions").

Use of prophylactic doses. A puncture-free interval of at least 12 hours should be maintained between the last injection of prophylactic-dose sodium enoxaparin and insertion of a needle or catheter.

For procedures with prolonged access, a similar interval of at least 12 hours should be maintained before catheter removal.

In patients with creatinine clearance of [15–30] mL/min, consideration should be given to doubling the time to perform puncture/catheter insertion or removal to at least 24 hours.

Initial administration of sodium enoxaparin 2,000 IU (20 mg) two hours before surgery does not apply when neuroaxial anesthesia is performed.

Use of therapeutic doses. A puncture-free interval of at least 24 hours should be maintained between the last injection of therapeutic-dose sodium enoxaparin and insertion of a needle or catheter (see also section "Contraindications").

For procedures with prolonged access, a similar interval of at least 24 hours should be maintained before catheter removal.

In patients with creatinine clearance of [15–30] mL/min, consideration should be given to doubling the time to perform puncture/catheter insertion or removal to at least 48 hours.

Patients receiving the drug according to a twice-daily regimen (i.e., 75 IU/kg [0.75 mg/kg] twice daily or 100 IU/kg [1 mg/kg] twice daily) should skip the second dose of sodium enoxaparin to ensure an adequate time interval before catheter insertion or removal.

At these time points, anti-Xa activity of the drug is still detectable, and adherence to these time intervals does not guarantee prevention of neuroaxial hematoma.

Therefore, sodium enoxaparin should not be administered for at least 4 hours after spinal/epidural puncture and after catheter removal. This time interval should be based on the benefit-risk assessment, taking into account both the risk of thrombosis and the risk of bleeding for this procedure, considering the patient's individual risk factors.

Instructions for self-administration of the drug CLIXAN® in a pre-filled syringe with needle safety system ERIS or PREVENTIS

The automatic needle safety system helps reduce the risk of pain and bruising at the injection site.

The drug CLIXAN® is an injection solution in pre-filled syringes with a needle safety system to prevent accidental needlestick injury after injection.

1. Wash hands with soap and water. Dry them.
2. Select an area on the right or left side of the abdomen. This area should be at least 5 centimeters away from the navel (toward the sides).

1. Rotate injection sites by alternating between the right and left sides of the abdomen, depending on where the previous injection was administered. Clean the injection site with an alcohol swab.

1. Carefully remove the cap from the needle attached to the CLIXAN® syringe. Discard this cap. The syringe is pre-filled and ready for use. DO NOT press the plunger before administering the injection to expel air bubbles. This may result in loss of medication. After removing the cap, do not allow the needle to touch anything to ensure it remains clean (sterile).

1. Hold the syringe in your hand like a pencil, and with the other hand gently pinch the cleaned area of the abdomen between the index finger and thumb to form a skin fold. It is essential to hold the skin fold throughout the entire injection.

1. Hold the syringe so that the needle is pointing downward (perpendicular at a 90° angle). Insert the needle fully into the skin fold.

1. Press the syringe plunger with the index finger. Be sure to continue holding the skin fold throughout the injection.
2. Withdraw the needle straight back and release the skin fold.
3. When using CLIXAN® in a pre-filled syringe with the ERIS needle safety system, the needle will automatically be covered by a protective sheath.
4. When using CLIXAN® in a pre-filled syringe with the PREVENTIS needle safety system, after withdrawing the needle from the injection site, keep your finger on the plunger. Direct the needle downward and away from yourself and others, then press the plunger fully until it stops to activate the safety mechanism. The protective sheath will automatically cover the needle, and a clicking sound will confirm activation of the safety system.
5. Immediately dispose of the syringe in an appropriate sharps container.

Note: The ERIS or PREVENTIS needle safety systems can only be activated when the syringe is completely emptied.

To avoid bruising, do not rub the injection site after administering the drug.

Children. The safety and efficacy of sodium enoxaparin in pediatric patients have not yet been established.

Overdose.

Symptoms. Accidental overdose of sodium enoxaparin due to intravenous, extracorporeal, or subcutaneous administration may lead to hemorrhagic complications. Oral intake, even of relatively high doses, is unlikely to result in absorption of sodium enoxaparin.

Treatment. The anticoagulant effects of the drug can be largely neutralized by slow intravenous administration of protamine. The dose of protamine depends on the administered dose of sodium enoxaparin:

• 1 mg of protamine neutralizes the anticoagulant effect of 100 IU (1 mg) of sodium enoxaparin if sodium enoxaparin was administered within the previous 8 hours.
• Protamine infusion at a dose of 0.5 mg per 100 IU (1 mg) of sodium enoxaparin may be used if sodium enoxaparin was administered more than 8 hours prior to protamine administration or if a second dose of protamine is required.
• Administration of protamine more than 12 hours after sodium enoxaparin may not be necessary.

However, even with high doses of protamine, the anti-Xa activity of sodium enoxaparin is never completely neutralized (maximum approximately 60%) (see Instructions for medical use of protamine sulfate).

Adverse reactions.

General description of the drug safety profile. Enoxaparin sodium has been studied in more than 15,000 patients who received enoxaparin sodium in clinical trials. Among them were 1,776 cases of drug use for prophylaxis of deep vein thrombosis after orthopedic or abdominal surgery in patients at increased risk of thromboembolic complications, 1,169 cases of drug use for prophylaxis of deep vein thrombosis in patients with acute medical conditions and very limited mobility, 559 cases of drug use for treatment of deep vein thrombosis with or without pulmonary embolism, 1,578 cases of drug use for treatment of unstable angina and non-Q-wave myocardial infarction, and 10,176 cases of drug use for treatment of acute ST-segment elevation myocardial infarction.

Dosing regimens of enoxaparin sodium in these clinical trials varied depending on the indication. The dose of enoxaparin sodium for prophylaxis of deep vein thrombosis after surgery or in patients with acute medical conditions and very limited mobility was 4,000 IU (40 mg) subcutaneously once daily. For treatment of deep vein thrombosis with or without pulmonary embolism, patients received enoxaparin sodium either at a dose of 100 IU/kg (1 mg/kg) subcutaneously every 12 hours, or 150 IU/kg (1.5 mg/kg) subcutaneously once daily. In clinical trials where the drug was used for treatment of unstable angina and non-Q-wave myocardial infarction, doses were 100 IU/kg (1 mg/kg) subcutaneously every 12 hours, and in the clinical trial where the drug was used for treatment of acute ST-segment elevation myocardial infarction, the enoxaparin sodium regimen included an intravenous bolus of 3,000 IU (30 mg) followed by subcutaneous administration of the drug at a dose of 100 IU/kg (1 mg/kg) every 12 hours.

In clinical trials, the most frequently reported adverse reactions were hemorrhagic events, thrombocytopenia, and thrombocytosis (see section "Special precautions for use" and "Description of selected adverse reactions" below).

Acute generalized exanthematous pustulosis (AGEP) has been reported during treatment with enoxaparin (see section "Special precautions for use").

The safety profile of enoxaparin for long-term treatment of DVT and PE in patients with active cancer is similar to its safety profile for treatment of DVT and PE.

Tabulated list of adverse reactions. Other adverse reactions observed in clinical trials and reported during the post-marketing period (* indicates adverse reactions reported during the post-marketing period) are described in detail below.

Frequency was defined as follows: very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1,000 to < 1/100); rare (≥ 1/10,000 to < 1/1,000); very rare (< 1/10,000); frequency not known (cannot be estimated from available data). Within each "System-Organ-Class" category, adverse reactions are listed in order of decreasing severity.

Disorders of the blood and lymphatic system.

Common: hemorrhagic events, hemorrhagic anemia*, thrombocytopenia, thrombocytosis.

Rare: eosinophilia*, cases of immune-mediated thrombocytopenia with thrombosis; in some of these cases, thrombosis was complicated by organ infarction or limb ischemia (see section "Special precautions for use").

Immune system disorders.

Common: allergic reaction.

Rare: anaphylactic/anaphylactoid reactions, including shock*.

Nervous system disorders.

Common: headache*.

Vascular disorders.

Rare: spinal hematoma* (or neuraxial hematoma). These reactions led to neurological disorders of varying severity, including permanent or irreversible paralysis (see section "Special precautions for use").

Hepatobiliary disorders.

Very common: increased liver enzyme levels (primarily transaminases more than 3 times the upper limit of normal).

Uncommon: hepatocellular liver injury*.

Rare: cholestatic liver injury*.

Skin and subcutaneous tissue disorders.

Common: urticaria, pruritus, erythema.

Uncommon: bullous dermatitis.

Rare: alopecia*, skin vasculitis*, skin necrosis*, which usually occurs at the injection site (these events are typically preceded by purpura or erythematous, infiltrated, and painful plaques). Injection site nodules* (inflammatory nodules appearing as non-cystic "pockets" of enoxaparin). These resolve within several days and do not require discontinuation of the drug.

Frequency not known: acute generalized exanthematous pustulosis (AGEP).

Musculoskeletal and connective tissue disorders, bone disorders.

Rare: osteoporosis* after long-term therapy (more than 3 months).

General disorders and administration site conditions.

Common: hematoma at injection site, pain at injection site, other reaction at injection site (e.g., swelling, bruising, hypersensitivity, inflammation, mass, pain, or other reactions).

Uncommon: local irritation, skin necrosis at injection site.

Investigations.

Rare: hyperkalemia* (see sections "Special precautions for use" and "Interaction with other medicinal products and other forms of interaction").

Description of selected adverse reactions.

Hemorrhagic events. Serious hemorrhagic events were observed and recorded in no more than 4.2% of patients (surgical patients). Some of these cases were fatal. In surgical patients, hemorrhagic complications were considered serious if the hemorrhagic event caused a clinically significant event or was associated with a hemoglobin decrease ≥ 2 g/dL or required transfusion of 2 or more standard units of blood products. Retroperitoneal and intracranial hemorrhages were always considered serious.

As with other anticoagulants, hemorrhagic events may occur in the presence of concomitant risk factors such as: organic lesions with a risk of bleeding, invasive procedures, or concomitant use of medicinal products affecting hemostasis (see sections "Special precautions for use" and "Interaction with other medicinal products and other forms of interaction").

Table 8

a Such as hematoma, ecchymosis (except at the injection site), wound hematoma, hematuria, epistaxis, and gastrointestinal hemorrhage.

b Frequency based on a retrospective study in a registry including 3526 patients (see section "Pharmacodynamics").

Table 9

Thrombocytopenia and thrombocytosis* (see section "Special precautions". Monitoring of platelet count)*

c Increase in platelet count > 400 G/L.

Paediatric population. The safety and efficacy of sodium enoxaparin in children have not yet been established (see section "Dosage and administration").

Reporting of suspected adverse reactions.

Reporting suspected adverse reactions after marketing authorization is important. It allows continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare and pharmaceutical professionals, as well as patients or their legal representatives, should report all suspected adverse reactions and lack of efficacy through the automated pharmacovigilance information system at: https://aisf.dec.gov.ua.

Shelf life. 3 years.

Storage conditions. Keep out of reach and sight of children. Store at a temperature not exceeding 25 °C. Do not freeze.

Incompatibilities.

Subcutaneous injection. Do not mix with other medicinal products.

Intravenous (bolus) injection (exclusively for treatment of acute ST-segment elevation myocardial infarction). Sodium enoxaparin should not be mixed with other medicinal products except as specified in the section "Dosage and administration".

Packaging.

No. 2: 0.8 mL in a syringe-dose with needle protection system ERIS; 2 syringe-doses in a blister; 1 blister in a cardboard box;

No. 2: 0.8 mL in a syringe-dose with needle protection system PREVENTIS; 2 syringe-doses in a blister; 1 blister in a cardboard box;

No. 2: 0.8 mL in a syringe-dose without needle protection system; 2 syringe-doses in a blister; 1 blister in a cardboard box.

Prescription status. Prescription only.

Manufacturer. SANOFI WINTHROP INDUSTRIE.

Manufacturer's address.

180 rue Jean Jaurès, 94700 MAISON-ALFORT, France.

or

1051 Boulevard Industriel, 76580 LE THILLE, France.

Marketing Authorization Holder. LLC "Sanofi-Aventis Ukraine".