INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT FLENOX® (FLENOX)

Composition:

Active substance: enoxaparin sodium;

1 ml of solution contains: 10000 anti-Xa IU, equivalent to 100 mg of enoxaparin sodium;

2000 anti-Xa IU/0.2 ml, equivalent to 20 mg of enoxaparin sodium;

4000 anti-Xa IU/0.4 ml, equivalent to 40 mg of enoxaparin sodium;

6000 anti-Xa IU/0.6 ml, equivalent to 60 mg of enoxaparin sodium;

8000 anti-Xa IU/0.8 ml, equivalent to 80 mg of enoxaparin sodium;

Excipient: water for injections.

Pharmaceutical form. Solution for injection.

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

Pharmacotherapeutic group.

Antithrombotic agents. Heparin group. Enoxaparins.

ATC code B01AB05.

Pharmacological properties.

Pharmacodynamics.

Enoxaparin is a low molecular weight heparin (LMWH) with a dalton weight 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, further antithrombotic and anti-inflammatory properties of enoxaparin have been identified in healthy volunteers, patients, and 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 no significant 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 peak drug activity.

Clinical efficacy and safety.

Prevention of venous thromboembolic complications associated with surgical procedures.

Long-term prevention of venous thromboembolism (VTE) after orthopedic surgery. In a double-blind study on long-term prophylaxis following hip replacement surgery, 179 patients without any venous thromboembolic complications who initially received enoxaparin sodium 4000 IU (40 mg) subcutaneously (s.c.) during hospitalization were randomized after hospital discharge to 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

* The p-value compared to placebo is 0.008.

The p-value compared to placebo is 0.537. In another double-blind study, 262 patients without any venous thromboembolism (VTE), who underwent elective hip replacement surgery and initially received enoxaparin sodium 4000 IU (40 mg) subcutaneously (s.c.) during hospitalization, were randomized to receive after hospital discharge either enoxaparin sodium 4000 IU (40 mg) (n = 131) once daily s.c. or placebo (n = 131) for 3 weeks. Consistent with the results of the first study, the incidence of VTE during extended prophylaxis was statistically significantly lower in the enoxaparin sodium group compared to placebo, both in terms of total VTE (enoxaparin sodium − 21 [16%] 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). There were no differences in the frequency of major bleeding between the enoxaparin sodium and placebo groups.

Extended prophylaxis of DVT after surgery for cancer. In a double-blind, multicenter study, the safety and efficacy of 4-week versus 1-week prophylactic regimens of enoxaparin sodium were compared in 332 patients undergoing planned abdominal or pelvic surgery for cancer. Patients received enoxaparin sodium (4000 IU [40 mg] s.c.) 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 day 25 and day 31, or earlier if symptoms of VTE occurred. Patients were followed for 3 months. Prophylactic administration of enoxaparin sodium for 4 weeks after abdominal or pelvic cancer surgery significantly reduced the incidence of venographically confirmed thrombosis compared to a 1-week prophylaxis regimen. The incidence of VTE at the end of the double-blind phase was 12.0% (n = 20) in the placebo group and 4.8% (n = 8) in the enoxaparin sodium group; p = 0.02. This difference persisted over 3 months [13.8% vs. 5.5% (n = 23 vs. 9), p = 0.01]. No differences were observed between groups in the frequency of bleeding or other adverse events during the double-blind period or the follow-up period.

Prevention of venous thromboembolic complications in medically ill patients with acute conditions expected to limit 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 s.c. was compared to placebo for VTE prophylaxis in medically ill patients with markedly reduced mobility (defined as walking less than 10 meters within ≤ 3 days) due to an acute illness. The study included patients with heart failure (NYHA class III or IV), acute respiratory insufficiency or complicated chronic respiratory insufficiency, 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). When administered at a dose of 4000 IU (40 mg) once daily s.c., enoxaparin sodium significantly reduced the incidence of VTE compared to placebo. Efficacy data are presented in Table 2.

Table 2

VTE − venous thromboembolic events, including cases of DVT, PE, and death considered to be due to a thromboembolic event.

* p-value compared to placebo is 0.0002

Approximately 3 months after patient enrollment in the study, the incidence of VTE in the group receiving sodium enoxaparin 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 sodium enoxaparin at a dose of 2000 IU (20 mg), and 12.6% and 1.7% in the group receiving sodium enoxaparin 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 lower-limb DVT, with or without PE, were randomized to receive in-hospital treatment either with sodium enoxaparin 150 IU/kg (1.5 mg/kg) once daily subcutaneously; or sodium enoxaparin 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 of 2.0 to 3.0), which was initiated within 72 hours after starting sodium enoxaparin or standard heparin therapy and continued for 90 days. Sodium enoxaparin or standard heparin therapy was administered for at least 5 days and until the target INR was achieved on sodium warfarin. Both sodium enoxaparin 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

VTE − venous thromboembolism (DVT and/or PE).

* 95% confidence intervals for the difference between treatment groups in the overall VTE rate were:

• for once-daily sodium enoxaparin compared with heparin: from -3.0 to 3.5.
• for sodium enoxaparin every 12 hours compared with hepar0in: from -4.2 to 1.7.

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 either sodium enoxaparin 100 IU/kg (1 mg/kg) every 12 hours or unfractionated heparin (UFH) intravenously with dose adjustment based on aPTT levels, 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 for up to 30 days. Compared with heparin, sodium enoxaparin significantly reduced the composite incidence of angina, myocardial infarction, and death from 19.8% to 16.6% by day 14 (relative risk reduction of 16.2%). 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 rate of major bleeding, although injection site bleeding occurred more frequently.

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

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

4716 patients underwent percutaneous coronary intervention (PCI) 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), according to a regimen studied in previous trials: no additional enoxaparin bolus was administered if the last subcutaneous dose had been given less than 8 hours before balloon inflation; an intravenous bolus of sodium enoxaparin at 30 IU/kg (0.3 mg/kg) was administered if the last subcutaneous dose had been given more than 8 hours before balloon inflation.

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

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

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

Statistically significant advantages of sodium enoxaparin 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 rate 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 with the UFH group (12.2%), corresponding to a 17% relative risk reduction in favor of sodium enoxaparin.

The incidence of major bleeding at 30 days was significantly higher (p < 0.0001) in the sodium enoxaparin group (2.1%) compared with the heparin group (1.4%). The rate of gastrointestinal bleeding was higher in the sodium enoxaparin group (0.5%) compared with the heparin group (0.1%), while the rate of intracranial hemorrhage was similar in both groups (0.8% with sodium enoxaparin vs. 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 published data, administration of sodium enoxaparin 4000 IU (40 mg) in patients with liver cirrhosis (Child-Pugh classes B−C) is safe and effective for prevention of portal vein thrombosis. However, it should be noted that published studies 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 pharmacokinetic studies have been conducted to determine appropriate dosing in patients with liver cirrhosis (Child-Pugh classes A, B, or C).

Pharmacokinetics.

General characteristics.

The pharmacokinetic parameters of sodium enoxaparin were primarily assessed based on plasma anti-Xa activity, as well as 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 anti-Xa and anti-IIa activities was performed using validated amidolytic methods.

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 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 mean exposure corresponded to 88% of steady-state levels. Steady state was achieved by day 2 of treatment.

After multiple subcutaneous administrations 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 dosing 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-individual variability is low. No accumulation occurs after multiple subcutaneous administrations.

Anti-IIa activity in plasma after subcutaneous administration is approximately 10 times 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 regimens 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 low-clearance drug, with a mean plasma anti-Xa clearance of 0.74 L/h after a 6-hour infusion 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 active and inactive fragments accounts for 40% of the dose.

Special patient populations.

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 normal.

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 dysfunction (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 impairment.

Renal impairment. A linear relationship was observed between anti-Xa plasma 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 markedly in patients with mild renal impairment (creatinine clearance 50−80 mL/min) and 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 dosing 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 with the control group.

Body weight. After multiple subcutaneous doses of 150 IU/kg (1.5 mg/kg) once daily, mean AUC of anti-Xa activity at steady state was marginally higher in healthy volunteers with obesity (BMI 30−48 kg/m²) compared with non-obese controls, 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 at fixed doses without weight adjustment, 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 with controls of normal body weight (see section "Special precautions for use").

Pharmacokinetic interactions. No pharmacokinetic interactions were 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 after administration at doses of 15 mg/kg/day in 13-week toxicity studies with subcutaneous administration in rats and dogs, and at 10 mg/kg/day in 26-week toxicity studies with 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 chromosomal aberration tests in human lymphocytes and in vivo chromosomal aberration tests in rat bone marrow.

Studies in pregnant rats and rabbits receiving subcutaneous enoxaparin at doses up to 30 mg/kg/day showed no evidence of teratogenic effects or fetal toxicity. Sodium enoxaparin was shown to have no effect on 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 at moderate and 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 conditions (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.
• Prevention of thrombus formation in the extracorporeal circulation during hemodialysis.
• In acute coronary syndrome:
  • for treatment of unstable angina and non-ST-segment elevation myocardial infarction (NSTEMI), in combination with oral acetylsalicylic acid;
  • for treatment of acute ST-segment elevation myocardial infarction (STEMI), including in patients planned for pharmacological treatment or subsequent percutaneous coronary intervention (PCI).

Contraindications.

Sodium enoxaparin is contraindicated in patients with the following conditions:

• Hypersensitivity to sodium enoxaparin, heparin or its derivatives, including other low molecular weight heparins, or to any of the excipients (see section "Composition").
• History of immune-mediated heparin-induced thrombocytopenia (HIT) within the 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 locoregional anesthesia if sodium enoxaparin has been used for treatment within the previous 24 hours (see section "Special precautions").

Interaction with other medicinal products and other types of interactions.

Concomitant use with the following medicinal products is not recommended.

Medicinal products affecting hemostasis (see section "Special precautions"). Some agents affecting hemostasis should be discontinued prior to initiating enoxaparin sodium treatment, except when such agents are absolutely indicated. If such combination is indicated, sodium enoxaparin must 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 that should be used concomitantly with caution.

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

• Other medicinal products affecting hemostasis, such as:
• platelet aggregation inhibitors, including acetylsalicylic acid used at antiplatelet 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 enoxaparin sodium with careful clinical and laboratory monitoring (see sections "Special precautions" and "Adverse reactions").

Special precautions for use.

General warnings.

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

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

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 the presence of 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 assessment of the benefit-risk ratio 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 sodium enoxaparin treatment.

The risk of HIT is higher in patients undergoing surgical procedures, particularly after cardiac surgery, and in patients with oncological diseases.

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

If clinical symptoms suggestive of HIT occur (any new episode of arterial and/or venous thromboembolism, any painful skin lesion at the injection site, any allergic or anaphylactoid reactions during treatment), platelet counts must be determined. Patients should be informed about the possibility of such symptoms and advised 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 should be switched to an alternative non-heparin anticoagulant agent.

Bleeding events.

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

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

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

Laboratory tests.

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

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

Use during spinal/epidural anaesthesia or lumbar puncture.

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

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

To minimize the potential risk of bleeding associated with concomitant use of sodium enoxaparin and spinal/epidural anaesthesia/analgesia or lumbar puncture, the pharmacokinetic profile of sodium enoxaparin should be considered (see section "Pharmacokinetics"). Placement or removal of an epidural catheter or performance of lumbar puncture should ideally be performed when the anticoagulant effect of sodium enoxaparin is low; however, the exact time to achieve sufficiently low anticoagulant effect in individual patients is unknown. It should also be noted that elimination of sodium enoxaparin is prolonged in patients with creatinine clearance of 15−30 ml/min (see section "Method of administration and dosage").

If the physician decides to use anticoagulant therapy during spinal/epidural anaesthesia/analgesia or lumbar puncture, frequent 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 immediately report any of these symptoms to their physician. 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 invasive vascular procedures in the treatment of unstable angina, non-ST-elevation myocardial infarction (NSTEMI), and acute ST-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 enoxaparin treatment is 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 prosthetic heart valves has not been adequately studied. Isolated cases of mechanical valve thrombosis have been reported in patients receiving sodium enoxaparin for thromboprophylaxis. The presence of additional risk factors, including underlying disease and insufficient clinical data, limits the evaluation of these cases. Some of these cases occurred in pregnant women, where thrombosis led to 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 described valve thrombosis in pregnant women with mechanical heart valves receiving sodium enoxaparin for thromboprophylaxis. Pregnant women with mechanical heart valves may have an increased risk of thromboembolic events.

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

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

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 the prevention of clotting in the extracorporeal circuit during hemodialysis.

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

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

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

Low body weight. Increased exposure to sodium enoxaparin 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), which may lead to an increased 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 "Side effects"), particularly in patients with diabetes mellitus, chronic renal failure, 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 of hyperkalemia.

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

Acute generalized exanthematous pustulosis

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

Use during pregnancy or breastfeeding

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

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

Sodium enoxaparin should be prescribed to pregnant women only if the physician clearly establishes a medical need.

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 anaesthesia is planned, discontinuation of enoxaparin treatment is recommended 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.

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 did not demonstrate any effect of the drug on fertility.

Ability to affect reaction speed when driving or operating machinery.

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

Method of Administration and Dosage.

Dosage.

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

• For patients with 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 (2 hours before surgery) of sodium enoxaparin at a dose of 2000 IU (20 mg) has been shown to be effective and safe in surgeries associated with moderate risk.

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

• For patients with high risk of thromboembolic events, the recommended dose of sodium enoxaparin is 4000 IU (40 mg) once daily, preferably administered by subcutaneous (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.
• For patients undergoing major orthopedic surgery, prolonged thromboprophylaxis is recommended — up to 5 weeks.
• For high-risk patients undergoing abdominal or pelvic surgery for oncological diseases, prolonged thromboprophylaxis is recommended — up to 4 weeks.

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

Treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE). Sodium enoxaparin should be administered s.c. as a single injection of 150 IU/kg (1.5 mg/kg) once daily or as 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 should be used in uncomplicated patients with low risk of recurrent VTE. The regimen of 100 IU/kg (1 mg/kg) twice daily should be prescribed to 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 "Transition 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). In patients at high risk of bleeding, the dose should be reduced to 50 IU/kg (0.5 mg/kg) with dual vascular access or to 75 IU/kg (0.75 mg/kg) with single vascular access.

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

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

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

• For treatment of unstable angina and NSTEMI, the recommended dose of sodium enoxaparin is 100 IU/kg (1 mg/kg), administered every 12 hours by 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 2–8 days.
• In all uncomplicated patients, oral acetylsalicylic acid is recommended 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 (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 start of fibrinolytic therapy.
• Dosage specifics for patients aged ≥75 years are provided below ("Elderly Patients").
• For patients undergoing PCI, if the last dose of sodium enoxaparin was administered s.c. less than 8 hours before balloon inflation, no additional dose is 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 given.

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

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

For treatment of STEMI, elderly patients (≥75 years) should not receive the initial i.v. bolus. Treatment should be initiated with a s.c. dose of 75 IU/kg (0.75 mg/kg) 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 below in the section "Ren/renal Impairment" and in the "Special Warnings and Precautions" section.

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

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

Severe renal impairment. Sodium enoxaparin is not recommended for 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.

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

Route of administration. Flénoks® must not be administered intramuscularly.

For the prevention of venous thromboembolic complications after surgery, treatment of DVT and PE, and treatment of unstable angina and NSTEMI, enoxaparin sodium should be administered by subcutaneous injection.

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

Technique for subcutaneous injection.

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

To avoid loss of medication when using pre-filled syringes, air bubbles should not be expelled before injection. If it is necessary to adjust the amount of medication to be administered according to the patient's body weight, graduated pre-filled syringes should be used, allowing the required volume to be obtained by removing the excess prior to injection. Please note that in some cases it may not be possible to obtain the exact dose due to the graduation markings on the syringe, and the volume should then be rounded to the nearest graduation mark.

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

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

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

If the patient is self-administering the drug, he/she should be advised to follow the instructions for self-administration of Flénoks® from a pre-filled syringe with a needle protection system.

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

For the treatment of acute STEMI, therapy should be initiated with a single intravenous bolus injection, followed immediately by subcutaneous administration.

Enoxaparin sodium should be administered via an intravenous 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 intravenous access should be flushed with an adequate amount of 0.9% sodium chloride solution or glucose solution before and after the intravenous bolus administration of enoxaparin sodium to clear the administration port of other drugs. Enoxaparin sodium can be safely administered with 0.9% sodium chloride solution or 5% glucose solution.

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

Additional bolus in the case of PCI when the last subcutaneous administration of the drug was performed more than 8 hours before balloon inflation. For patients undergoing PCI, an additional intravenous bolus of 30 IU/kg (0.3 mg/kg) must be administered if the last subcutaneous dose was given more than 8 hours before balloon inflation.

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

Withdraw the required volume of the diluted solution with a syringe for administration into the intravenous infusion system.

After dilution, the volume to be administered can be calculated using the following formula: [Volume of diluted solution (ml) = Patient's body weight (kg) x 0.1] or by using Table 5. Dilution should be performed immediately before drug administration.

Table 5.

Volume to be administered via the intravenous 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 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 (VKA). Clinical monitoring and laboratory tests [prothrombin time expressed as international normalized ratio (INR)] should be intensified to monitor the effect of VKA.

Since there is a certain period required for VKA to reach its maximum effect, administration of sodium enoxaparin should be continued at a constant dose for as long as necessary to maintain the INR within the target therapeutic range for the corresponding indication, as confirmed by two consecutive test results.

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

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

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

Use of the medicinal product 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 for use").

Use of 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.

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

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

Use of therapeutic doses. A 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.

In patients with creatinine clearance [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 medicinal product according to a regimen of twice-daily administration (i.e., 75 IU/kg [0.75 mg/kg] twice daily or 100 IU/kg [1 mg/kg] twice daily) should skip the second dose of sodium enoxaparin to ensure an adequate time interval before catheter insertion or removal.

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

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

Instructions for self-administration of Flenox® pre-filled syringe

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

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1. Change the injection site by alternating between the right and left sides of the abdomen, depending on which side was used for the previous injection. Clean the injection site with an alcohol swab.

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

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

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

1. Press the syringe plunger with your finger. It is essential to maintain the skin fold throughout the entire injection.
2. Remove the needle straight out in the reverse direction. You may now release the skin fold. Immediately dispose of the syringe in the nearest sharps container.

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

Children.

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

Overdose.

Symptoms. Accidental overdose of sodium enoxaparin due to intravenous, extracorporeal, or subcutaneous administration may lead to hemorrhagic complications. After 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 administered dose of sodium enoxaparin:

• 1 mg of protamine neutralizes the anticoagulant effect of 100 IU (1 mg) of sodium enoxaparin if sodium enoxaparin was administered within the previous 8 hours.
• 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 administration.

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

Adverse Reactions

General description of the drug safety profile. Sodium enoxaparin has been studied in more than 15,000 patients who received sodium enoxaparin in clinical trials. Among them were 1776 cases of drug use for prophylaxis of deep vein thrombosis after orthopedic surgery or abdominal surgery in patients at high risk of thromboembolic complications, 1169 cases of drug use for prophylaxis of deep vein thrombosis in patients with acute medical conditions and very limited mobility, 559 cases of drug use for treatment of deep vein thrombosis with or without pulmonary artery embolism, 1578 cases of drug use for treatment of unstable angina and non-Q-wave myocardial infarction, and 10,176 cases of drug use for treatment of acute ST-segment elevation myocardial infarction.

Dosing regimens of sodium enoxaparin in these clinical trials varied depending on the indication. The dose of sodium enoxaparin for prophylaxis 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 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 treatment of unstable angina and non-Q-wave myocardial infarction, doses were 100 IU/kg (1 mg/kg) subcutaneously every 12 hours, and in the clinical trial where the drug was used for treatment of acute ST-segment elevation myocardial infarction, the dosing regimen of sodium enoxaparin included an 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 events, thrombocytopenia, and thrombocytosis (see sections "Special Warnings and Precautions for Use" and "Description of Selected Adverse Reactions" below).

Acute generalized exanthematous pustulosis (AGEP) has been reported in association with enoxaparin therapy (see section "Special Warnings and Precautions for Use").

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 is 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*.

Rare: 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 Warnings and Precautions for Use").

Immune system disorders.

Common: allergic reaction.

Rare: anaphylactic/anaphylactoid reactions, including shock*.

Nervous system disorders.

Common: headache*.

Vascular disorders.

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

Hepatobiliary disorders.

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

Uncommon: hepatocellular liver injury*.

Rare: cholestatic liver injury*.

Skin and subcutaneous tissue disorders.

Common: urticaria, pruritus, erythema.

Uncommon: bullous dermatitis.

Rare: alopecia*, skin vasculitis*, skin necrosis*, which typically occurs at the injection site (these events are usually 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, bone disorders.

Rare: osteoporosis* after long-term 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 "Special Warnings and Precautions for Use" and "Interaction with Other Medicinal Products and Other Forms of Interaction").

Description of Selected Adverse Reactions.

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

As with other anticoagulants, hemorrhagic events may occur in the presence of concomitant risk factors such as: organic lesions with a potential for bleeding, invasive procedures, or concomitant use of medicinal products affecting hemostasis (see sections "Special Warnings and Precautions for Use" 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, epistaxis, and gastrointestinal hemorrhage.

Table 7.

Thrombocytopenia and thrombocytosis.

β Increase in platelet count > 400 G/L.

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

Reporting suspected adverse reactions

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

Shelf life.

2 years.

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

Storage conditions.

Store in the original packaging 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 treatment of acute ST-segment elevation myocardial infarction). Sodium enoxaparin may be safely administered with 0.9% sodium chloride solution or 5% glucose solution (see section "Dosage and administration").

Packaging.

0.2 mL, 0.4 mL, 0.6 mL or 0.8 mL in a pre-filled syringe.

One syringe per blister. One, two or ten blisters (containing medicinal product with 2000 anti-Xa IU, 4000 anti-Xa IU, 6000 anti-Xa IU activity) or one or two blisters (containing medicinal product with 8000 anti-Xa IU activity) per cardboard pack.

Two syringes per blister. One or five blisters (containing medicinal product with 2000 anti-Xa IU, 4000 anti-Xa IU, 6000 anti-Xa IU activity) or one blister (containing medicinal product with 8000 anti-Xa IU activity) per cardboard pack, or 25 blisters in a cardboard box.

Prescription status. Prescription only.

Manufacturer. JSC "Farmak".

Address of the manufacturer and location of its business operations.

74, Kyrylivska Street, Kyiv, 04080, Ukraine.