Flenox®

INSTRUCTIONS for medical use of the medicinal product FLENOX® (FLENOX)

Composition:

Active substance: enoxaparin sodium;

1 ml of solution contains 10000 anti-Xa IU of enoxaparin sodium;

Excipients: benzyl alcohol, water for injections.

Pharmaceutical form. Solution for injection.

Main physicochemical properties: clear, colorless or slightly yellow liquid.

Pharmacotherapeutic group.

Antithrombotic agents. Heparin group. Enoxaparin.

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 are dissociated from those of standard heparin. 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, further antithrombotic and anti-inflammatory properties of enoxaparin have been identified in healthy volunteers and patients, as well as in experimental models during 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 has little effect on 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 the time of maximum 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, long-term prophylaxis study following hip replacement surgery, 179 patients who had no venous thromboembolic complications during initial hospitalization and who had received enoxaparin sodium 4000 IU (40 mg) subcutaneously (s.c.) during hospital stay were randomized after 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 long-term 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 venous thromboembolism undergoing elective hip replacement surgery and initially receiving enoxaparin sodium 4000 IU (40 mg) subcutaneously during hospitalization were randomized to receive, after hospital discharge, either enoxaparin sodium 4000 IU (40 mg) (n = 131) once daily subcutaneously 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%], placebo — 45 [34.4%]; p = 0.001) and proximal DVT (enoxaparin sodium — 8 [6.1%], placebo — 28 [21.4%]; p < 0.001). No differences in the frequency of major bleeding were observed between the enoxaparin sodium and placebo groups.

Extended prophylaxis of DVT after 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 frequency of venographically confirmed thromboses 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 and 9), p = 0.01]. No differences between groups were observed in terms of bleeding rates or other complications during the double-blind period 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 VTE 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 failure or complicated chronic respiratory insufficiency, or acute infection or acute rheumatic disease, provided they had at least one VTE risk factor (age ≥ 75 years, cancer, prior VTE, obesity, varicose veins, hormonal therapy, chronic heart or respiratory failure).

Overall, 1102 patients were enrolled in the study, and 1073 patients received the study treatment. Treatment duration was 6–14 days (median duration was 7 days). Enoxaparin sodium administered at a dose of 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 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 incidence of bleeding and the incidence 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 (s.c.), or enoxaparin sodium at a dose of 100 IU/kg (1 mg/kg) every 12 hours s.c., or heparin as an intravenous (i.v.) bolus (5000 IU) followed by continuous 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 International Normalized Ratio (INR) of 2.0 to 3.0), which was initiated within 72 hours after the start of 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 thromboembolism (DVT and/or PE). Efficacy data are presented in Table 3.

Table 3.

The incidence 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.

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

In a large multicenter study, 3171 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 100 IU/kg (1 mg/kg) every 12 hours or intravenous unfractionated heparin (UFH) with dose adjustment based on aPTT levels. Patients received inpatient treatment for a minimum of 2 days and a maximum of 8 days until clinical stabilization, revascularization procedures, or hospital discharge. Patients were followed up for 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 endpoint was maintained at 30 days (from 23.3% to 19.8%; relative risk reduction of 15%).

There were no statistically significant differences in the incidence of major bleeding, although injection site hemorrhages occurred more frequently.

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

In a large multicenter study, 20,479 STEMI patients eligible for fibrinolytic therapy were randomized to receive either sodium enoxaparin as a single intravenous bolus of 3000 IU (30 mg), followed by subcutaneous administration of 100 IU/kg (1 mg/kg) and subsequent subcutaneous dosing of 100 IU/kg (1 mg/kg) every 12 hours, or 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 occurred earlier.

Percutaneous coronary intervention (PCI) was performed in 4716 patients with blinded antithrombotic support using the study drugs. Thus, patients receiving sodium enoxaparin underwent PCI while continuing sodium enoxaparin (without switching to the comparator drug), using a regimen studied in prior 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 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 versus 12.0% in the UFH group], representing a 17% relative risk reduction (p < 0.001).

The benefits of sodium enoxaparin treatment, evident across multiple efficacy endpoints, were apparent by 48 hours, with a 35% relative risk reduction in recurrent myocardial infarction 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 drug 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 heparin group (1.4%). The sodium enoxaparin group had a higher incidence of gastrointestinal bleeding (0.5%) compared to the heparin group (0.1%), while the incidence of intracranial hemorrhage was similar in both groups (0.8% with sodium enoxaparin versus 0.7% with heparin).

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

Hepatic impairment. According to scientific literature, administration of sodium enoxaparin 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, the studies reported in the literature may have certain limitations. Caution should be exercised 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.

Pharmacokinetic parameters of sodium enoxaparin were primarily evaluated based on plasma anti-Xa activity and its effect on 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 assays.

Absorption. Absolute bioavailability of sodium enoxaparin 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 occurs 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 administration 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 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 of 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 activities 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 sodium enoxaparin are linear.

Intra- and inter-subject variability is low. No accumulation occurs after multiple subcutaneous administrations.

Plasma anti-IIa activity 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 administration of 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 sodium enoxaparin is approximately 4.3 liters, close to the volume of circulating blood.

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

Elimination. Sodium enoxaparin is a drug with low clearance, with a mean anti-Xa activity clearance of 0.74 L/h after a 6-hour infusion at a dose of 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, and total renal excretion of both active and inactive fragments accounts for 40% of the dose.

Special patient groups.

Elderly patients. Population pharmacokinetic analysis indicates that the pharmacokinetic profile of sodium enoxaparin 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 rates of sodium enoxaparin may be observed in elderly patients (see section "Dosage and administration").

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

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

Hemodialysis. The pharmacokinetics of sodium enoxaparin 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), but AUC was 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, subcutaneous administration resulted in lower clearance after correction for body weight.

When administered without dose adjustment for body weight, after single subcutaneous administration of 4000 IU (40 mg), exposure to anti-Xa activity 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 interaction was observed between sodium enoxaparin and thrombolytic agents when administered concomitantly.

Preclinical safety data. Apart from the anticoagulant effects of sodium enoxaparin, 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.

Sodium enoxaparin 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 human lymphocyte chromosome aberration analysis and in vivo rat bone marrow chromosome aberration analysis.

Studies in pregnant rats and rabbits receiving subcutaneous enoxaparin at doses up to 30 mg/kg/day showed no evidence of teratogenic effects or fetotoxicity. Sodium enoxaparin was shown not to affect fertility or reproductive function in male and female rats after subcutaneous administration at doses up to 20 mg/kg/day.

Clinical characteristics.

Indications.

The medicinal product is indicated for use in adults:

• For prophylaxis of venous thromboembolic complications in surgical patients with moderate or high risk, especially in patients undergoing orthopedic or general surgical procedures, including those related to oncological diseases.
• For prophylaxis of venous thromboembolic complications in medical patients with acute conditions (such as acute heart failure, respiratory failure, severe infections, or rheumatic diseases) and reduced mobility, who are at increased risk of venous thromboembolism.
• For treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE), except in cases of PE where thrombolytic therapy or surgical intervention may be required.
• For prevention of clot formation in 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 medical therapy 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 for use").
• Active clinically significant bleeding or conditions with a high risk of bleeding, including recent hemorrhagic stroke, gastrointestinal ulcer, presence of malignant neoplasm 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 used for treatment within the preceding 24 hours (see section "Special precautions for use").
• Hypersensitivity to benzyl alcohol.

Due to the presence of benzyl alcohol (see section "Composition"), the medicinal product in vial presentation should not be used in preterm infants and newborns. It may cause toxic and allergic reactions in infants and children under 3 years of age (see sections "Special precautions for use" and "Pediatric use").

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 for use"). Some agents affecting hemostasis should be discontinued prior to initiation of sodium enoxaparin therapy, unless their use is absolutely indicated. If such combination is indicated, sodium enoxaparin should be administered with careful clinical and laboratory monitoring.

These include:

• systemic salicylates, 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 "Dosage and administration").

Medicinal products requiring caution when used concomitantly.

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 risk of bleeding);
• dextran 40;
• systemic glucocorticoids.
• Medicinal products that increase serum potassium levels. These medicinal products may be prescribed concomitantly with sodium enoxaparin under careful clinical and laboratory monitoring (see sections "Special precautions for use" and "Adverse reactions").

Special precautions for use

Enoxaparin sodium 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, interaction with platelets).

Therefore, it is essential to pay close attention to the prescribing information specific to each branded medicinal product and strictly adhere to it.

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

The use of enoxaparin sodium 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.

Enoxaparin sodium 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 enoxaparin sodium in such cases should be made only after a careful benefit-risk assessment and after considering the possibility of using alternative non-heparin anticoagulant agents (e.g., danaparoid sodium or lepirudin).

Platelet monitoring.

There is also a risk of antibody-mediated HIT during LMWH therapy, which typically develops between the 5th and 21st day after initiation of enoxaparin sodium treatment.

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

Therefore, platelet counts should be determined before starting enoxaparin sodium therapy and monitored regularly during treatment.

If clinical signs 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 measured. Patients should be informed about these potential symptoms and advised to report them immediately to their physician.

In clinical practice, if a confirmed significant decrease in platelet count (30–50% from baseline) is observed, enoxaparin sodium must be discontinued immediately and the patient should be switched to an alternative non-heparin anticoagulant agent.

Hemorrhagic complications.

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

Enoxaparin sodium, like any other anticoagulant, should be used with caution in conditions that increase the 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, enoxaparin sodium 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 increases in aPTT or ACT and enhanced antithrombotic activity of enoxaparin sodium, these parameters are unreliable and should not be used to monitor enoxaparin sodium activity.

Use during spinal/epidural anesthesia or lumbar puncture.

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

Cases of neuraxial hematomas have been reported with concomitant use of enoxaparin sodium and spinal/epidural anesthesia or lumbar puncture, leading to long-term or permanent paralysis. These events are rare when enoxaparin sodium is used at a regimen of 4000 IU (40 mg) once daily or at lower doses. The risk of such complications is higher when postoperative indwelling epidural catheters are used, with concomitant use of other medicinal products affecting hemostasis (e.g., nonsteroidal anti-inflammatory drugs), after traumatic or repeated epidural or spinal procedures, and in patients with a history of spinal surgery or spinal deformity.

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

If the physician decides to use anticoagulant therapy during epidural/spinal anesthesia/analgesia or lumbar puncture, careful monitoring for neurological symptoms such as midline back pain, sensory or motor disturbances (numbness or weakness in the lower limbs), or bowel and/or bladder dysfunction is required. Patients should be instructed to report immediately any of these symptoms. If spinal hematoma is suspected, immediate diagnostic and therapeutic measures should be initiated, 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 interventional 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 enoxaparin sodium doses 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 6 hours after the last intravenous or subcutaneous dose of enoxaparin sodium. If enoxaparin sodium treatment 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 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 a careful individual benefit-risk assessment.

Mechanical heart valves. The use of enoxaparin sodium 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 enoxaparin sodium for thromboprophylaxis. The presence of risk factors, including underlying disease and insufficient clinical data, limits the 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 enoxaparin sodium 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 enoxaparin sodium (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 occlusion and maternal and fetal death. Post-marketing reports have described valve thrombosis in pregnant women with mechanical heart valves receiving enoxaparin sodium for thromboprophylaxis. Pregnant women with mechanical heart valves are at 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 and older) may have an increased risk of hemorrhagic complications when enoxaparin sodium is used at therapeutic doses. For patients aged over 75 years receiving enoxaparin sodium for ST-segment elevation myocardial infarction (STEMI), careful clinical monitoring is recommended, and dose reduction may be considered (see sections "Dosage and administration" and "Pharmacokinetics").

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

Enoxaparin sodium 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 clotting in the extracorporeal circuit during hemodialysis.

For patients with severe renal impairment (creatinine clearance 15–30 mL/min), dose adjustment is recommended for both therapeutic and prophylactic use due to significantly increased enoxaparin sodium 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. Enoxaparin sodium should be used with caution in patients with hepatic impairment due to increased bleeding risk. 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 enoxaparin sodium administered at prophylactic doses (without body weight adjustment) has been observed in women with low body weight (<45 kg) and men with low body weight (<57 kg), 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 enoxaparin sodium 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 signs 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 failure, pre-existing metabolic acidosis, or those receiving drugs that can 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 advised to record the trade name and batch number of the administered product in the patient's medical records.

Acute generalized exanthematous pustulosis (AGEP). Acute generalized exanthematous pustulosis (AGEP) has been reported with unknown frequency in association with enoxaparin treatment. Patients should be informed of the signs and symptoms, and skin reactions should be closely monitored. If signs or symptoms suggestive of AGEP occur, enoxaparin should be discontinued immediately and alternative treatment considered (if necessary).

This medicinal product contains benzyl alcohol and must not be used in preterm infants and newborns. It may cause toxic and allergic reactions in infants and children under 3 years of age.

Use during pregnancy or breastfeeding.

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

Animal studies have shown no evidence of fetotoxicity or teratogenicity (see section "Preclinical safety data"). Placental transfer of enoxaparin in animals was minimal.

Enoxaparin sodium should be administered to pregnant women only if clearly needed.

Pregnant women receiving enoxaparin sodium should be closely monitored for signs of bleeding or excessive anticoagulant effect, and should be warned about the risk of hemorrhagic complications. Overall, available data indicate no evidence of increased risk of bleeding, thrombocytopenia, or osteoporosis in these 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, enoxaparin sodium treatment should be discontinued prior to the procedure (see section "Special precautions for use").

Breastfeeding. It is unknown whether 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 enoxaparin sodium is unlikely, it may be used during breastfeeding.

Fertility. Clinical data on the effect of enoxaparin sodium on fertility are currently lacking. Animal studies have shown no effect of the drug on fertility.

Ability to influence the ability to drive and use machines.

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

Method of Administration and Dosage.

Dosing.

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

• For patients with moderate risk of thromboembolic complications, 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) two 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 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 complications, the recommended dose of sodium enoxaparin is 4000 IU (40 mg) once daily, preferably administered 12 hours before surgery via subcutaneous (SC) injection. If prophylactic use 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 injection should be given no later than 12 hours before surgery, and prophylactic dosing should be resumed 12 hours after surgery.
• For patients undergoing major orthopedic surgery, extended thromboprophylaxis is recommended — up to 5 weeks.
• For patients at high risk of venous thromboembolism (VTE) undergoing abdominal or pelvic surgery for oncological conditions, extended thromboprophylaxis is recommended — up to 4 weeks.

Prophylaxis of venous thromboembolism 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 been established.

Treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE). Sodium enoxaparin should be administered SC as a single injection of 150 IU/kg (1.5 mg/kg) once daily or as 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, such as 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 "Switching from sodium enoxaparin to oral anticoagulants and vice versa" at the end of this section).

Prophylaxis of thrombus formation during hemodialysis. The recommended dose of sodium enoxaparin is 100 IU/kg (1 mg/kg). For patients at high risk of bleeding complications, 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 develop, 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 prevention 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 are recommended to receive oral acetylsalicylic acid with an initial loading dose of 150–300 mg (for patients not previously 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 (IV) bolus of 3000 IU (30 mg) plus a SC dose of 100 IU/kg (1 mg/kg), 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). 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 up to 30 minutes after the initiation of fibrinolytic therapy.
• Dosing specifics for patients aged ≥75 years are provided below ("Elderly Patients").
• For patients undergoing 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 adjustment is not required in elderly patients, unless renal impairment is present (see below "Renal impairment" and section "Special precautions").

For treatment of STEMI, elderly patients (≥75 years) must not receive the initial IV bolus. 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. Dosing specifics for elderly patients with renal impairment are provided below in the subsection "Renal impairment" and section "Special precautions".

Hepatic impairment. 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 "Pharmacokinetics" and "Special precautions").Severe renal impairment. 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 prophylaxis of thrombus formation in the extracorporeal circuit during hemodialysis.

Table 4.

Dosing 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) and moderate (creatinine clearance 30–50 mL/min) renal impairment, careful clinical monitoring of such patients is required.

Administration method. The medicinal product FLENOX® must not be administered intramuscularly.

For prophylaxis of venous thromboembolic complications after surgical procedures, treatment of VTE and PE, treatment of unstable angina and NSTEMI, enoxaparin sodium should be administered by subcutaneous (s.c.) injection.

• For treatment of acute STEMI, administration of the medicinal product should begin with a single intravenous (i.v.) bolus injection followed immediately by s.c. administration.
• For prevention of clot formation in the extracorporeal circulation during hemodialysis, the drug is administered into the arterial line of the dialysis circuit.

Technique of s.c. injection.

It is advisable for the patient to be in a lying position during administration of the medicinal product. Enoxaparin sodium is administered by deep subcutaneous injection.

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

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

The needle should be inserted fully and vertically 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 of the medicinal product.

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

If the patient is self-administering the medicinal product, he or she should be advised to follow the instructions for self-administration of FLENOX® in a pre-filled syringe with a needle protection device.

Intravenous (bolus) injection [only when the medicinal product is used for the indication acute ST-segment elevation myocardial infarction (STEMI)].

For treatment of acute STEMI, administration of the medicinal product 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.

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

Initial bolus 3000 IU (30 mg). To administer the initial bolus of 3000 IU (30 mg) using a graduated pre-filled syringe, the excess volume should be removed from the syringe so that only 3000 IU (30 mg) remains in the syringe. The 3000 IU (30 mg) dose can then be administered directly i.v.

Additional bolus in case of PCI when the last s.c. administration of the medicinal product was performed more than 8 hours before balloon inflation. For patients undergoing PCI, an additional i.v. bolus of 30 IU/kg (0.3 mg/kg) is required if the last s.c. administration of the medicinal product was performed more than 8 hours before balloon inflation.

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

Draw the required volume of the diluted solution into 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 5. Dilution should be performed immediately before administration of the medicinal product.

Table 5.

Volume to be administered through the intravenous infusion system after dilution of the medicinal product to a concentration of 300 IU (3 mg)/ml.

Administration into the arterial segment of the dialysis circuit. The medicinal product is administered into the arterial line of the dialysis circuit to prevent thrombus formation in the extracorporeal circulation during hemodialysis.

Transition from sodium enoxaparin to oral anticoagulants.

Transition from sodium enoxaparin to vitamin K antagonists (VKAs). Clinical and laboratory monitoring [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, 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 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) and vice versa. For patients currently receiving sodium enoxaparin, it 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 was 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 developing neuraxial hematoma (see section "Special precautions").

Prophylactic doses. A minimum interval of at least 12 hours without performing punctures 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.

For 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 2000 IU (20 mg) two hours before surgery is not applicable in neuraxial anesthesia.

Therapeutic doses. A minimum interval of at least 24 hours without performing punctures 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.

For 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 neuraxial hematoma.

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

Children.

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

The medicinal product FLENOX® contains benzyl alcohol and should not be used in neonates and preterm infants (see section "Special precautions").

Overdose.

Symptoms. Accidental overdose of sodium enoxaparin due to intravenous, extracorporeal, or subcutaneous administration may lead to hemorrhagic complications. Following oral ingestion, even of relatively high doses, absorption of sodium enoxaparin is unlikely.

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

• 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 earlier 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 sulfate).

Side effects.

The effects of sodium enoxaparin have been studied in more than 15,000 patients who received sodium enoxaparin in clinical trials. Among them, there were 1776 cases of drug use for the prevention of deep vein thrombosis after orthopedic surgery or abdominal surgery in patients with an increased risk of thromboembolic complications; 1169 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; 1578 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 sodium enoxaparin in these clinical trials varied depending on the indication. The dose of sodium enoxaparin for the prevention of deep vein thrombosis after surgery or in patients with acute medical conditions and very limited mobility was 4000 IU (40 mg) subcutaneously once daily. For the treatment of deep vein thrombosis with or without pulmonary embolism, patients received sodium enoxaparin 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 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 dosing regimen of sodium enoxaparin included an initial intravenous bolus of 3000 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 complications, thrombocytopenia, and thrombocytosis (see section "Special precautions" and "Description of selected adverse reactions" below).

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

Other adverse reactions observed in clinical trials and reported during the post-marketing period are described in detail below (reactions marked with an asterisk * occurred during the post-marketing period).

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 organ system, adverse reactions are listed in order of decreasing severity.

Disorders of the blood and lymphatic system.

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

Rare: eosinophilia*.

Rare: 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").

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 neuroaxial hematoma). These reactions led to neurological disorders of varying severity, including permanent or irreversible paralysis (see section "Special precautions").

Hepatobiliary disorders.

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

Uncommon: hepatocellular liver injury*.

Rare: cholestatic liver injury*.

Disorders of the skin and subcutaneous tissue.

Common: urticaria, pruritus, erythema.

Uncommon: bullous dermatitis.

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

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

Disorders of the musculoskeletal and connective tissue system, and bones.

Rare: osteoporosis* after prolonged therapy (for 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, induration, pain, or other reactions).

Uncommon: local irritation, skin necrosis at injection site.

Investigations.

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

Description of selected adverse reactions.

Hemorrhagic complications. Serious hemorrhagic complications 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 bleeding event caused a significant clinical condition 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 complications 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" and "Interaction with other medicinal products and other forms of interaction").

Table 6.

α Such as hematoma, ecchymosis (except that observed at the injection site), wound hematoma, hematuria, nasal hemorrhage, and gastrointestinal hemorrhage. font size 10

Table 7.

Thrombocytopenia and thrombocytosis.

β Increase in platelet count > 400 G/L. font size 10

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 authorization of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals should report any suspected adverse reactions via the national pharmacovigilance system.

Shelf life.

2 years. Shelf life after opening the vial — no more than 28 days.

Do not use the medicinal product after the expiry date stated on the packaging.

Storage conditions.

Store at a temperature not exceeding 25 °C. Do not freeze.

Keep out of reach and sight of children.

Incompatibilities.

Subcutaneous injection. Do not mix with other medicinal products.

Intravenous (bolus) injection (exclusively for the treatment of acute ST-segment elevation myocardial infarction). Sodium enoxaparin can be safely administered with physiological saline (0.9% sodium chloride) or 5% glucose solution (see section "Dosage and administration").

Packaging.

3 ml in a multidose vial; 1 vial in a carton.

Prescription category. Prescription only.

Manufacturer. JSC "Farmak".

Address of the manufacturer and location of the place of business.

74 Kyrylivska Street, Kyiv, 04080, Ukraine