Clexane® 300

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT CLEXANE® 300 (CLEXANE® 300)

Composition:

Active substance: enoxaparin;

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

Excipients: benzyl alcohol**, water for injections.

*Sodium enoxaparin is a biological substance obtained by alkaline depolymerization of the benzyl ester of heparin derived from the intestinal mucosa of pigs.

**Benzyl alcohol is an excipient with a known effect.

Pharmaceutical form. Solution for injection.

Main physicochemical characteristics: 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 mechanisms contribute to the overall antithrombotic effect of enoxaparin sodium.

When used for prophylaxis, enoxaparin sodium does not substantially affect the activated partial thromboplastin time (aPTT). When used for treatment, aPTT may be prolonged by 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) following orthopedic surgery. In a double-blind study on extended prophylaxis after 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 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 occurred.

Efficacy data are presented in Table 1.

Table 1.

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

Extended prophylaxis of DVT following surgery for cancer. In a double-blind, multicenter study, safety and efficacy of a 4-week versus a 1-week regimen of prophylactic enoxaparin sodium were compared in 332 patients undergoing planned abdominal or pelvic surgery for cancer. 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. Bilateral venography was performed between days 25 and 31, or earlier if symptoms of VTE occurred. Patients were followed for 3 months. Prophylactic use of enoxaparin sodium for 4 weeks after abdominal or pelvic cancer surgery significantly reduced the rate of venographically confirmed thrombosis compared to a 1-week 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 the rates of bleeding or other complications during the double-blind phase or the follow-up period.

Prophylaxis of venous thromboembolic complications in medical patients with acute illnesses associated with limited mobility.

In a double-blind, multicenter, parallel-group study, enoxaparin sodium at doses of 2000 IU (20 mg) or 4000 IU (40 mg) once daily subcutaneously was compared with placebo for the prevention of DVT in medical patients with severely limited mobility (defined as walking distance < 10 meters within ≤ 3 days) due to 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 risk factor for VTE (age ≥ 75 years, active cancer, prior VTE, obesity, varicose veins, hormonal therapy, chronic heart or respiratory insufficiency).

Overall, 1102 patients were enrolled in the study, and 1073 patients received the study treatment. Treatment duration ranged from 6 to 14 days (median duration was 7 days). Enoxaparin sodium administered at 4000 IU (40 mg) once daily subcutaneously 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 rate 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 events 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 PE, were randomized to receive in-hospital treatment either with 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 investigational treatment. All patients also received sodium warfarin (dose adjusted according to prothrombin time with the aim of achieving an INR value 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 sodium warfarin. Both enoxaparin sodium regimens were equivalent to standard heparin therapy in reducing the risk of recurrent venous thromboembolic events (DVT and/or PE). Efficacy data are presented in Table 3.

Table 3.

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

In a large-scale, multicenter study, 3171 patients enrolled during the acute phase of unstable angina and non-Q-wave myocardial infarction were randomized to receive either enoxaparin sodium 100 IU/kg (1 mg/kg) every 12 hours or unfractionated heparin (UFH) intravenously with dose adjustment based on aPTT levels, both in combination with acetylsalicylic acid (100−325 mg once daily). 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 up for 30 days. Compared with heparin, enoxaparin sodium 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 endpoint 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 bruising occurred more frequently.

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

In a large-scale, multicenter study, 20,479 STEMI patients eligible for fibrinolytic therapy were randomized to receive either enoxaparin sodium as a single intravenous bolus of 3000 IU (30 mg), followed by subcutaneous administration at 100 IU/kg (1 mg/kg) and subsequent subcutaneous dosing at 100 IU/kg (1 mg/kg) every 12 hours, or intravenous unfractionated heparin (UFH) for 48 hours with dose adjustment based on aPTT levels. All patients also received acetylsalicylic acid for at least 30 days. The enoxaparin sodium dosing regimen was adjusted for patients with severe renal impairment and elderly patients (≥ 75 years). Subcutaneous enoxaparin sodium injections were continued until hospital discharge or for a maximum of 8 days, whichever occurred earlier.

Percutaneous coronary intervention (PCI) was performed in 4716 patients, with antithrombotic support provided by the study drugs in a blinded manner. Thus, patients receiving enoxaparin sodium underwent PCI while continuing enoxaparin sodium (without switching to the comparator drug), using a regimen studied in prior trials: no additional enoxaparin sodium bolus was administered if the last subcutaneous dose had been given less than 8 hours before balloon inflation; an intravenous bolus of enoxaparin sodium 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, enoxaparin sodium 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 enoxaparin sodium group vs. 12.0% in the UFH group], representing a 17% relative risk reduction (p < 0.001).

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

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

The incidence of major bleeding at 30 days was significantly higher (p < 0.0001) in the enoxaparin sodium group (2.1%) compared to the heparin group (1.4%). Gastrointestinal bleeding occurred more frequently in the enoxaparin sodium group (0.5%) compared to the heparin group (0.1%), while the rates of intracranial hemorrhage were similar in both groups (0.8% with enoxaparin sodium vs. 0.7% with heparin).

The positive effect of enoxaparin sodium on the primary endpoint observed during the first 30 days was maintained throughout the 12-month follow-up period.

Hepatic impairment. According to literature data, administration of enoxaparin sodium 4000 IU (40 mg) in patients with liver cirrhosis (Child-Pugh class B−C) is safe and effective for prevention of portal vein thrombosis. However, it should be noted that the studies described in the literature may have certain limitations. Caution is advised in patients with hepatic impairment, as they are more prone to bleeding (see section "Special precautions for use"), and no formal dose-finding studies have been conducted in patients with liver cirrhosis (Child-Pugh class A, B, or C).

Pharmacokinetics.

General characteristics.

The pharmacokinetic parameters of enoxaparin sodium were primarily evaluated based on plasma anti-Xa activity, as well as anti-IIa activity, within the recommended dose range after single and multiple subcutaneous administrations and after single intravenous administration. Quantitative determination of pharmacokinetic anti-Xa and anti-IIa activities was performed using validated amidolytic methods.

Absorption. Absolute bioavailability of enoxaparin sodium after subcutaneous injection, assessed by anti-Xa activity, approaches 100%.

Various doses, dosage forms, and administration regimens may be used.

The mean peak plasma anti-Xa activity is observed within 3−5 hours after subcutaneous injection and reaches approximately 0.2, 0.4, 1.0, and 1.3 IU/mL of anti-Xa activity after single subcutaneous doses of 2000 IU, 4000 IU, 100 IU/kg, and 150 IU/kg (20 mg, 40 mg, 1 mg/kg, and 1.5 mg/kg), respectively.

After intravenous bolus administration of 3000 IU (30 mg), followed immediately by subcutaneous dosing of 100 IU/kg (1 mg/kg) every 12 hours, the initial peak plasma anti-Xa activity was 1.16 IU/mL (n = 16), and the mean exposure corresponded to 88% of steady-state levels. Steady state was achieved by day 2 of treatment.

After multiple subcutaneous administration at regimens of 4000 IU (40 mg) once daily and 150 IU/kg (1.5 mg/kg) once daily in healthy volunteers, steady state was reached by day 2, with mean exposure approximately 15% higher than after single-dose administration. After multiple subcutaneous administration at 100 IU/kg (1 mg/kg) twice daily, steady state was achieved between days 3 and 4, with mean exposure approximately 65% higher than after single-dose administration, and mean peak and trough anti-Xa activity levels of approximately 1.2 and 0.52 IU/mL, respectively.

Injection volume and dose concentration within the range of 100−200 mg/mL did not affect pharmacokinetic parameters in healthy volunteers.

Within the recommended dose range, the pharmacokinetics of enoxaparin sodium are linear.

Intra- and inter-individual variability is low. No accumulation was observed after multiple subcutaneous administrations.

Anti-IIa activity in plasma after subcutaneous administration is approximately 10-fold lower than anti-Xa activity. The mean peak anti-IIa activity occurs approximately 3−4 hours after subcutaneous injection, reaching 0.13 IU/mL and 0.19 IU/mL after multiple dosing at 100 IU/kg (1 mg/kg) twice daily and 150 IU/kg (1.5 mg/kg) once daily, respectively.

Distribution. The volume of distribution of anti-Xa activity of enoxaparin sodium is approximately 4.3 liters, close to the volume of circulating blood.

Biotransformation. Enoxaparin sodium is primarily metabolized in the liver via desulfation and/or depolymerization, forming compounds with lower molecular weight and significantly reduced biological activity.

Elimination. Enoxaparin sodium is a drug with low clearance, with a mean anti-Xa activity clearance from plasma of 0.74 L/h after a 6-hour infusion at 150 IU/kg (1.5 mg/kg).

Elimination is monophasic, with a half-life ranging from approximately 5 hours after single subcutaneous administration to about 7 hours after multiple administrations.

Renal clearance of active fragments accounts for approximately 10% of the administered dose, while total renal excretion of active and inactive fragments accounts for 40% of the dose.

Special patient groups.

Elderly patients. Population pharmacokinetic analysis indicates that the pharmacokinetic profile of enoxaparin sodium in elderly patients does not differ from that in younger patients if renal function is not impaired.

However, since renal function may decline with age, lower elimination of enoxaparin sodium may be observed in elderly patients (see sections "Special precautions for use" and "Dosage and administration").

Hepatic impairment. In a study involving patients with severe liver cirrhosis receiving enoxaparin sodium 4000 IU (40 mg) once daily, a reduction in peak anti-Xa activity was associated with increasing severity of hepatic dysfunction (assessed by Child-Pugh classification). This reduction was primarily explained by decreased ATIII levels, secondary to reduced ATIII synthesis in patients with hepatic impairment.

Renal impairment. A linear relationship was observed between plasma anti-Xa activity clearance and creatinine clearance at steady state, indicating reduced enoxaparin sodium clearance in patients with renal impairment. Exposure to anti-Xa activity, expressed as AUC (area under the concentration-time curve), increased marginally at steady state in patients with mild renal impairment (creatinine clearance 50−80 mL/min) and moderately increased in those with moderate renal impairment (creatinine clearance 30−50 mL/min) after multiple subcutaneous doses of 4000 IU (40 mg) once daily. In patients with severe renal impairment (creatinine clearance < 30 mL/min), steady-state AUC significantly increased by an average of 65% after multiple subcutaneous administration of 4000 IU (40 mg) once daily (see sections "Special precautions for use" and "Dosage and administration").

Hemodialysis. The pharmacokinetics of enoxaparin sodium during hemodialysis were similar to those in the control group after single intravenous doses of 25 IU, 50 IU, or 100 IU/kg (0.25, 0.50, or 1.0 mg/kg), although AUC levels were twice as high compared to the control group.

Body weight. After multiple subcutaneous administration of 150 IU/kg (1.5 mg/kg) once daily, mean steady-state AUC of anti-Xa activity was marginally higher in healthy volunteers with obesity (BMI 30−48 kg/m²) compared to the non-obese control group, while peak plasma anti-Xa activity did not increase. In obese individuals, lower clearance was observed after subcutaneous administration when corrected for body weight.

When administered without dose adjustment for body weight, after single subcutaneous administration of 4000 IU (40 mg), anti-Xa activity exposure was 52% higher in women with low body weight (< 45 kg) and 27% higher in men with low body weight (< 57 kg) compared to control subjects with normal body weight (see section "Special precautions for use").

Pharmacokinetic interactions. No pharmacokinetic interactions were observed between enoxaparin sodium and thrombolytic agents when administered concomitantly.

Preclinical safety data. Apart from the anticoagulant effects of enoxaparin sodium, no signs of adverse effects were observed when the drug was administered at 15 mg/kg/day in 13-week toxicity studies after subcutaneous administration in rats and dogs, and at 10 mg/kg/day in 26-week toxicity studies after subcutaneous and intravenous administration in rats and monkeys.

Enoxaparin sodium showed no mutagenic activity in in vitro studies, including the Ames test, mouse lymphoma cell direct mutation assay, and no clastogenic activity in in vitro chromosomal aberration analysis in human lymphocytes and in vivo chromosomal aberration analysis in rat bone marrow.

Studies in pregnant rats and rabbits receiving subcutaneous enoxaparin at doses up to 30 mg/kg/day revealed no evidence of teratogenic effects or fetotoxicity. Enoxaparin sodium was shown to have no effect on fertility or reproductive function in male and female rats when administered subcutaneously at doses up to 20 mg/kg/day.

Clinical characteristics.

Indications.

The drug is indicated for use in adults for:

• Prophylaxis of venous thromboembolic complications in surgical patients with moderate to high risk, particularly 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 clot 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 past 100 days or 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 regional block anesthesia if sodium enoxaparin has been administered for treatment within the previous 24 hours (see section "Special precautions").
• Hypersensitivity to benzyl alcohol.
• Due to the presence of benzyl alcohol (see section "Composition"), sodium enoxaparin in multidose vials should not be administered to newborns and premature infants (see sections "Special precautions" and "Use during pregnancy or breastfeeding").

Interaction with other medicinal products and other forms of interaction.

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, unless such agents are absolutely indicated. If combination therapy is indicated, sodium enoxaparin should be administered with careful clinical and laboratory monitoring as necessary.

These include:

• systemic salicylates, acetylsalicylic acid at anti-inflammatory doses, and non-steroidal 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 requiring cautious concomitant use.

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 dose (cardioprotection), 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 under close 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, particular attention must be paid to the instructions for medical use specific to each proprietary medicinal product, and these instructions must be strictly followed.

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

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

Sodium enoxaparin should be used with extreme caution in patients with a history (> 100 days) of immune-mediated HIT in the absence of circulating antibodies. The decision to use sodium enoxaparin in such cases should be made only after careful benefit-risk assessment and after considering the possibility of using alternative non-heparin anticoagulant treatments (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 individual case evaluation, and close monitoring is recommended.

The use of LMWHs also carries a risk of antibody-mediated HIT, which typically develops between the 5th and 21st day after initiation of sodium enoxaparin therapy.

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

Therefore, platelet counts should be determined before initiating sodium enoxaparin therapy and regularly monitored 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 must 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 count (30–50% from baseline) occurs, sodium enoxaparin must be discontinued immediately and the patient switched to an alternative non-heparin anticoagulant.

Bleeding events. As with other anticoagulants, bleeding or hemorrhage of any localization may occur. If bleeding occurs, 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;
• recent 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. At doses used for prevention of venous thromboembolism, sodium enoxaparin has no significant effect on bleeding time, general coagulation parameters, platelet aggregation, or fibrinogen binding to platelets.

At higher doses, activated partial thromboplastin time (aPTT) and activated clotting time (ACT) may increase. Since there is no linear correlation between increases in aPTT and ACT and enhanced antithrombotic activity of sodium enoxaparin, these parameters are unreliable and should not be used to monitor the activity of sodium enoxaparin.

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 neuraxial 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. Such events are rare when sodium enoxaparin is used at a dose of 4000 IU (40 mg) once daily or at lower doses. The risk is higher with postoperative continuous epidural catheters, concomitant use of other medicinal products affecting hemostasis (e.g., non-steroidal anti-inflammatory drugs), 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 spinal/epidural 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, although the exact time to achieve sufficiently low anticoagulant effect in individual patients is unknown. Additional consideration should be given to the prolonged elimination of sodium enoxaparin in patients with creatinine clearance of 15–30 mL/min (see section "Dosage and administration").

If the physician decides to use anticoagulant therapy during spinal/epidural anesthesia/analgesia or lumbar puncture, frequent monitoring for neurological symptoms such as midline back pain, sensory or motor disturbances (numbness or weakness in lower limbs), or bowel and/or bladder dysfunction is required. Patients should be instructed to immediately report any of these symptoms to their physician. If spinal hematoma is suspected, appropriate diagnostic and therapeutic measures must 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 must 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), recommended intervals between doses of sodium enoxaparin must be strictly observed. 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 6 hours after the last intravenous or subcutaneous injection of sodium enoxaparin. If treatment with sodium enoxaparin needs to be continued, the next scheduled dose should be administered no earlier than 6–8 hours after removal of the introducer. The catheter insertion site should be monitored for early detection 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 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 factors potentially increasing risk, including underlying disease and insufficient clinical data, limits evaluation 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 study where pregnant women with mechanical heart valves received sodium enoxaparin (100 IU/kg [1 mg/kg] twice daily) to reduce the risk of thromboembolism, 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 dose ranges, 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 for ST-segment elevation myocardial infarction (STEMI), careful clinical monitoring is recommended, and dose reduction may be considered (see sections "Pharmacokinetics" and "Dosage and administration").

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 "Pharmacokinetics" and "Dosage and administration").

Sodium enoxaparin is not recommended for use in patients with end-stage renal disease (creatinine clearance < 15 mL/min) due to lack of adequate data in this population, except for 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 sodium enoxaparin is recommended for both therapeutic and prophylactic use due to significantly increased exposure (see section "Dosage and 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. In women with low body weight (< 45 kg) and men with low body weight (< 57 kg), increased exposure to sodium enoxaparin administered at prophylactic doses (without body weight adjustment) has been observed, 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 (BMI > 30 kg/m²) have not been sufficiently studied, and there is currently no consensus on dose adjustment 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 medicinal products 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.

Benzyl alcohol. This medicinal product contains 15 mg of benzyl alcohol per 1 mL. Benzyl alcohol may cause allergic reactions. The use of medicinal products containing benzyl alcohol as a preservative in neonates has been associated with fatal cases of "gasping syndrome" (see section "Contraindications"). Benzyl alcohol may also cause toxic and anaphylactoid reactions in infants and children under 3 years of age. The minimal amount of benzyl alcohol at which toxicity may occur is unknown.

Patients sensitive to sodium

For patients receiving a daily dose exceeding 210 mg, it should be noted that a single 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 closely monitored for skin reactions. If signs or symptoms suggestive of such reactions occur, enoxaparin should be discontinued immediately and alternative therapy 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 evidence of fetotoxicity or teratogenicity (see section "Preclinical safety data"). Data from animal experiments 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 should be warned about the risk of hemorrhagic events. Overall, available data indicate 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, discontinuation of sodium enoxaparin therapy is recommended prior to the procedure (see section "Special precautions for use").

Since benzyl alcohol can cross the placenta, it is recommended to use a formulation of the drug that does not contain benzyl alcohol.

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

Oral absorption of sodium enoxaparin is unlikely; therefore, 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

Sodium enoxaparin has no or negligible influence on the ability to drive or operate machinery.

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 (scale).

• For patients at moderate risk of thromboembolic events, the recommended dose of sodium enoxaparin is 2000 IU (20 mg) once daily administered by subcutaneous (s.c.) injection. Preoperative initiation of sodium enoxaparin at a dose of 2000 IU (20 mg) 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 has significantly reduced mobility.

• For patients at high risk of thromboembolic events, the recommended dose of sodium enoxaparin is 4000 IU (40 mg) once daily, preferably administered by subcutaneous (s.c.) injection 12 hours before surgery. If prophylactic use of sodium enoxaparin needs to be initiated more than 12 hours before surgery (e.g., high-risk patient awaiting delayed orthopedic surgery), the last injection should be given no later than 12 hours before surgery, and prophylactic dosing should be resumed 12 hours after surgery.
• Patients undergoing major orthopedic surgery should receive extended thromboprophylaxis—up to 5 weeks.
• Patients at high risk of venous thromboembolism undergoing abdominal or pelvic surgery for oncological diseases should receive extended thromboprophylaxis—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 s.c. 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 s.c. as 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 regimen of 150 IU/kg (1.5 mg/kg) once daily is recommended for uncomplicated patients at low risk of recurrent VTE. The regimen of 100 IU/kg (1 mg/kg) twice daily should be prescribed for all other patients, including those with obesity, symptomatic PE, cancer, recurrent VTE, or proximal venous thrombosis (iliac vein).

Sodium enoxaparin is typically administered for an average of 10 days. If necessary, oral anticoagulants should be initiated (see "Transition from sodium enoxaparin to 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) twice daily administered by s.c. injection for 5–10 days, followed by 150 IU/kg (1.5 mg/kg) once daily by s.c. injection for 6 months. The benefits of continuous anticoagulant therapy should be re-evaluated after 6 months of treatment.

Prophylaxis of clot 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 injected 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 form, 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 s.c. 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 already on 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 (i.v.) bolus of 3000 IU (30 mg) plus a s.c. dose of 100 IU/kg (1 mg/kg), followed by s.c. administration of 100 IU/kg (1 mg/kg) every 12 hours (maximum 10,000 IU [100 mg] for each of the first two s.c. doses). Concomitant antiplatelet therapy, such as oral acetylsalicylic acid (75–325 mg once daily), should be administered unless contraindicated. 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 initiation of fibrinolytic therapy.
• Dosage specifics for patients aged ≥75 years are provided below ("Elderly patients").
• For patients undergoing PCI, if the last s.c. dose of sodium enoxaparin was administered less than 8 hours before balloon inflation, no additional doses are required. If the last s.c. dose was administered more than 8 hours before balloon inflation, an i.v. 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 the pediatric population have not yet been established.

Since the medicinal product CLEXANE® 300 contains benzyl alcohol, it is not administered to premature infants and newborns (see section "Contraindications"). Due to the risk of fatal toxic reactions, it should not be used in infants and children under 3 years of age.

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

For treatment of acute STEMI, elderly patients (≥75 years) should not receive the initial i.v. bolus. Treatment should be initiated with a dose of 75 IU/kg (0.75 mg/kg) s.c. every 12 hours (maximum 7500 IU [75 mg] for each of the first two s.c. doses), followed by continued administration of 75 IU/kg (0.75 mg/kg) s.c. for subsequent doses. Dosage specifics for elderly patients with renal impairment are provided in the subsection "Renal impairment" and section "Special precautions".

Hepatic impairment. Currently, only limited data are 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 precautions").

Renal impairment (see sections "Special precautions" and "Pharmacokinetics").

Severe renal impairment. 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 prophylaxis of clot formation in the extracorporeal circulation 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 required.

Route of administration.

KLEKSAN® 300 must not be administered intramuscularly.

For the prevention of venous thromboembolic complications following surgery, treatment of VTE and PE, long-term treatment of VTE and PE in patients with active cancer, and treatment of unstable angina and NSTEMI, sodium enoxaparin should be administered via subcutaneous (s.c.) injection.

• For the treatment of acute STEMI, administration of the drug should begin with a single intravenous (i.v.) bolus injection followed immediately by s.c. 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.

When using multidose vials, it is recommended to use an insulin syringe or equivalent to ensure accurate withdrawal of the required volume of the drug.

Technique for subcutaneous injection.

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

The injection should be alternately administered into the left and right anterolateral or posterolateral abdominal walls.

The needle should be inserted vertically, in its full length, into a skin fold gently held between the thumb and index finger. The skin fold must be held throughout the injection until completion. The injection site should not be massaged after administration.

If the patient is self-administering, it is recommended to follow the instructions provided in the package leaflet included in the drug’s packaging.

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 i.v. bolus injection followed immediately by s.c. administration.

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

Sodium enoxaparin should be administered via an i.v. infusion system. It must not be mixed or co-administered with other medicinal products. To avoid potential mixing of sodium enoxaparin with other drugs, the selected i.v. access should be flushed with an adequate amount of 0.9% sodium chloride solution or 5% dextrose solution before and after the i.v. bolus administration of sodium enoxaparin to clear the administration port of other drugs. Sodium enoxaparin may be safely administered with 0.9% sodium chloride solution or 5% aqueous dextrose solution.

Initial bolus: 3000 IU (30 mg). The dose of 3000 IU (30 mg) may be administered directly i.v.

Additional bolus in patients undergoing PCI when the last s.c. dose was administered more than 8 hours before balloon inflation. For patients undergoing PCI, an additional i.v. bolus of 30 IU/kg (0.3 mg/kg) should be administered if the last s.c. dose was given more than 8 hours prior to 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 6000 IU (60 mg) of sodium enoxaparin and a 50 mL infusion bag (i.e., normal saline (0.9%) or 5% dextrose solution) as follows: withdraw 30 mL from the infusion bag using a syringe and discard the withdrawn fluid. Then, transfer the entire contents of the pre-filled syringe containing 6000 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 i.v. 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) × 0.1] or by using Table 7. Dilution should be performed immediately before drug administration.

Table 7

Volume to be administered via the i.v. 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 circulation during hemodialysis.

Transition from sodium enoxaparin to oral anticoagulants.

Transition between sodium enoxaparin and vitamin K antagonists (VKAs). Clinical monitoring and laboratory tests [prothrombin time expressed as international normalized ratio (INR)] should be intensified to monitor the effect of VKAs.

Since there is a certain period required for VKAs to reach their maximum effect, administration of sodium enoxaparin at a constant dose should be continued for as long as necessary to maintain the INR within the target therapeutic range for the corresponding indication, based on results of two consecutive tests.

For patients currently receiving VKAs, VKAs 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). For 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.

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

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

Prophylactic doses. A minimum interval of at least 12 hours without puncture procedures should elapse between the last injection of prophylactic-dose sodium enoxaparin and insertion of the needle or catheter.

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

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

Initial administration of sodium enoxaparin 2000 IU (20 mg) two hours before surgery does not apply when performing neuroaxial anesthesia.

Therapeutic doses. A minimum interval of at least 24 hours without puncture procedures should elapse between the last injection of therapeutic-dose sodium enoxaparin and insertion of the needle or catheter (see also section "Contraindications").

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

In patients with creatinine clearance of [15–30] mL/min, consideration should be given to doubling the time to 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 omit 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 or after catheter removal. This time interval should be based on the benefit-risk assessment, which should take into account both thrombosis risk and bleeding risk for this procedure, considering the risk factors present in the individual patient.

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

The drug Clexane® 300 contains benzyl alcohol and should not be used in neonates and preterm newborns (see section "Contraindications").

Overdose.

Symptoms and signs. Accidental overdose of sodium enoxaparin following intravenous, extracorporeal, or subcutaneous administration may lead to hemorrhagic complications. After oral intake, even of relatively high doses, absorption of sodium enoxaparin is unlikely.

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 preceding 8 hours.
• Infusion of protamine 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 may not be necessary 12 hours after sodium enoxaparin injection.

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 salts).

Side effects.

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. Specifically, there were 1,776 cases of drug use for the prevention of deep vein thrombosis after orthopedic or abdominal surgery in patients at increased risk of thromboembolic complications; 1,169 cases of drug use for the prevention of deep vein thrombosis in patients with acute medical conditions and very limited mobility; 559 cases of drug use for the treatment of deep vein thrombosis with or without pulmonary embolism; 1,578 cases of drug use for the treatment of unstable angina and non-Q-wave myocardial infarction; and 10,176 cases of drug use for the 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 the prevention 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 the 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 at a dose of 150 IU/kg (1.5 mg/kg) subcutaneously once daily. In clinical trials where the drug was used for the treatment of unstable angina and non-Q-wave myocardial infarction, doses were 100 IU/kg (1 mg/kg) subcutaneously every 12 hours. In the clinical trial where the drug was used for the 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" and "Description of selected adverse reactions" below).

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

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 the 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 heparin-induced thrombocytopenia with thrombosis; in some of these cases, thrombosis was complicated by organ infarction or limb ischemia (see section "Special precautions").

Disorders of the immune system.

Common: allergic reaction.

Rare: anaphylactic/anaphylactoid reactions, including shock*.

Disorders of the nervous system.

Common: headache*.

Vascular disorders.

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

Hepatobiliary disorders.

Very common: increased levels of liver enzymes (mainly 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 representing 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.

Rare: osteoporosis* after prolonged therapy (more than 3 months).

General disorders and administration site reactions.

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

Uncommon: local irritation, skin necrosis at injection site.

Investigations.

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

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 significant clinical event, if it was associated with a hemoglobin decrease ≥ 2 g/dL, or if it 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 "Interaction with other medicinal products and other forms of interaction" and "Special precautions").

Table 8

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

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

Table 9

Thrombocytopenia and thrombocytosis (see section "Special precautions for use". Platelet count monitoring)

c Increase in platelet count > 400 x 10⁹/L.

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

The use of medicinal products containing benzyl alcohol as a preservative in neonates has been associated with fatal cases of "gasping syndrome" (see section "Contraindications").

Benzyl alcohol may also cause toxic and anaphylactoid reactions in infants and children under 3 years of age (see section "Special warnings and precautions for use").

Reporting of suspected adverse reactions.

Reporting suspected adverse reactions after authorization of the medicinal product is important. It allows ongoing monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals and patients are encouraged to report any suspected adverse reactions and lack of efficacy of the medicinal product via the automated pharmacovigilance information system at: https://aisf.dec.gov.ua.

Shelf life. 2 years.

Shelf life after opening of the vial – no more than 28 days.

Storage conditions. Keep out of the reach of children. Store in the original packaging 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 those specified in the section "Dosage and administration".

Packaging. No. 1: 1 multidose vial of 3 mL in a cardboard box.

Prescription status. Prescription only.

Manufacturer.

1. FARMAR HEALTH CARE SERVICES MADRID, S.A.U.
2. Sanofi-Aventis Deutschland GmbH.

Manufacturer's address.

1. Avenida Leganes, 62, Alcorcón 28923 Madrid, Spain.
2. Bruningstrasse 50, Industriepark Höchst, 65926 Frankfurt am Main, Germany.

Marketing Authorization Holder.

LLC "Sanofi-Aventis Ukraine", Ukraine.