Novoparin

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT NOVOPARIN® (NOVOPARIN)

Composition:

Active substance: enoxaparin sodium;

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

1 vial contains enoxaparin sodium with anti-factor Xa activity of 50,000 IU, equivalent to 500 mg of enoxaparin sodium in 5.0 ml of water for injections;

or

1 vial contains enoxaparin sodium with anti-factor Xa activity of 30,000 IU, equivalent to 300 mg of enoxaparin sodium in 3.0 ml of water for injections;

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

Excipients: benzyl alcohol, water for injections.

Pharmaceutical form. Solution for injection.

Main physicochemical characteristics: colorless or slightly yellowish clear solution.

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 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 and patients, as well as in experimental models within preclinical studies. These include ATIII-dependent inhibition of other coagulation factors, such as factor VIIa, induction of endogenous release of tissue factor pathway inhibitor (TFPI), and reduction of von Willebrand factor (vWF) release from vascular endothelium into the circulation. These mechanisms contribute to the overall antithrombotic effect of enoxaparin sodium.

When used for prophylaxis, enoxaparin sodium 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.

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

Efficacy data are presented in Table 1.

Table 1

In another double-blind study, 262 patients without any venous thromboembolic events who underwent hip replacement surgery and initially received 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 during extended prophylaxis was statistically significantly lower in the enoxaparin sodium group compared to placebo, both in terms of total VTE events (enoxaparin sodium – 21 [16%] versus placebo – 45 [34.4%]; p = 0.001) and proximal DVT events (enoxaparin sodium – 8 [6.1%] versus placebo – 28 [21.4%]; p < 0.001). There were no differences in the frequency of major bleeding between the enoxaparin sodium and placebo groups.

Extended prophylaxis of DVT after oncological surgery.

In a double-blind, multicenter study, the 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 oncological surgery. 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 oncological 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 complications during the double-blind phase or the follow-up period.

Prophylaxis of venous thromboembolic complications in medically ill patients with acute conditions expected to cause limited mobility.

In a double-blind, multicenter, parallel-group study, enoxaparin sodium 2000 IU (20 mg) or 4000 IU (40 mg) once daily subcutaneously was compared with placebo for DVT prophylaxis in medically ill patients with severely limited mobility (defined as walking distance < 10 meters within ≤ 3 days) due to an acute illness. Patients included in this study had 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 risk factor for VTE (age ≥ 75 years, cancer, previous VTE, obesity, varicose veins, hormonal therapy, or chronic cardiac or respiratory insufficiency).

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

Table 2

After approximately 3 months from 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; or enoxaparin sodium at a dose of 100 IU/kg (1 mg/kg) every 12 hours subcutaneously; or heparin as an intravenous bolus (5000 IU) followed by continuous intravenous infusion (to achieve an aPTT of 55 to 85 seconds). Overall, 900 patients were randomized in the study, all of whom received the study treatment. All patients also received 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 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 on warfarin therapy. 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 either sodium enoxaparin 100 IU/kg (1 mg/kg) every 12 hours or unfractionated heparin (UFH) intravenously (IV), both in combination with acetylsalicylic acid (100–325 mg once daily). Heparin dosing was adjusted based on activated partial thromboplastin time (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. Follow-up continued until day 30. Compared with heparin, sodium enoxaparin significantly reduced the combined 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 combined 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 bleeding 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 IV bolus of 3000 IU (30 mg), followed by subcutaneous (SC) administration at 100 IU/kg (1 mg/kg) and subsequent dosing at 100 IU/kg (1 mg/kg) SC 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 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 antithrombotic support maintained using the study drugs in a blinded manner. Thus, patients receiving sodium enoxaparin underwent PCI while continuing enoxaparin (without switching to the comparator drug), following a regimen studied in prior trials: no additional enoxaparin was administered if the last SC dose had been given less than 8 hours before balloon inflation; otherwise, an IV bolus of sodium enoxaparin at 30 IU/kg (0.3 mg/kg) was administered.

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

The benefits of sodium enoxaparin treatment, evident across multiple efficacy measures, were apparent as early as 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 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 with medical therapy alone (15% relative risk reduction, p = 0.27 for interaction).

The incidence of the composite endpoint—death, recurrent myocardial infarction, or intracranial hemorrhage (a measure of overall 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 vs. 0.7% with heparin).

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

Hepatic impairment. According to literature data, 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, it should be noted that the studies described in the literature may have certain limitations. Caution is advised in patients with hepatic impairment, as they are more prone to bleeding (see section "Special precautions for use"), and no formal dose-finding studies have been conducted in patients with liver cirrhosis (Child-Pugh class A, B, or C).

Pharmacokinetics.

General characteristics.

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

Absorption. The absolute bioavailability of sodium enoxaparin after SC injection, assessed by anti-Xa activity, approaches 100%.

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

The mean peak plasma anti-Xa activity is observed within 3–5 hours after SC injection and reaches approximately 0.2, 0.4, 1.0, and 1.3 IU/mL of anti-Xa activity after single SC 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 IV bolus administration of 3000 IU (30 mg), followed by immediate SC 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 SC administrations using regimens of 4000 IU (40 mg) once daily and 150 IU/kg (1.5 mg/kg) once daily in healthy volunteers, steady state was reached by day 2, with mean exposure approximately 15% higher than after single-dose administration. After multiple SC 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 activity levels of approximately 1.2 and 0.52 IU/mL, respectively.

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

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

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

Anti-IIa activity in plasma after SC administration is approximately 10 times lower than anti-Xa activity. The mean peak anti-IIa activity occurs approximately 3–4 hours after SC injection, reaching 0.13 IU/mL and 0.19 IU/mL after multiple administrations 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 plasma clearance of 0.74 L/h after a 6-hour infusion at 150 IU/kg (1.5 mg/kg).

Elimination is monophasic, with a half-life ranging from approximately 5 hours after single SC 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, provided 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 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 activity 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 (creatinine clearance 50–80 mL/min) and moderate (creatinine clearance 30–50 mL/min) renal impairment after multiple SC administrations 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 SC administrations 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 IV administration 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 SC administrations 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 control group without obesity, while peak plasma anti-Xa activity did not increase. In obese individuals, lower clearance was observed after SC administration when corrected for body weight.

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

Pharmacokinetic interactions. No pharmacokinetic interactions were observed between 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 administered at 15 mg/kg/day in 13-week toxicity studies following SC administration in rats and dogs, and at 10 mg/kg/day in 26-week toxicity studies following SC and IV 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 or in vivo rat bone marrow chromosome aberration analysis.

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

Clinical characteristics.

Indications.

The drug is indicated for use in adults for:

• Prevention of venous thromboembolic complications in surgical patients with moderate and high risk, especially in patients undergoing orthopedic or general surgical procedures, including surgery for oncological diseases.
• Prevention of venous thromboembolic complications in medical patients with acute illnesses (such as acute heart failure, respiratory failure, severe infections, or rheumatic diseases) and reduced mobility who are at increased risk of venous thromboembolism.
• Treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE), except in cases of PE where thrombolytic therapy or surgical intervention may be required.
• Prevention of clot formation in the extracorporeal circulation during hemodialysis.
• In acute coronary syndrome:
  • for treatment of unstable angina and non-ST-segment elevation myocardial infarction (NSTEMI), in combination with oral acetylsalicylic acid;
  • for treatment of acute ST-segment elevation myocardial infarction (STEMI), including in patients planned for medical 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 excipients contained in the medicinal product.
• History of immune-mediated heparin-induced thrombocytopenia (HIT) within the last 100 days in the presence of circulating antibodies (see also section "Special precautions").
• Active clinically significant bleeding and conditions with a high risk of bleeding, including recent hemorrhagic stroke, gastrointestinal ulcer, presence of malignant tumors 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 abnormalities of intraspinal or intracerebral vessels.
• Spinal or epidural anesthesia or locoregional anesthesia if sodium enoxaparin has been administered for treatment within the previous 24 hours (see section "Special precautions").
• Due to the presence of benzyl alcohol, the multidose vial formulation should not be administered to newborns or premature infants.

Interaction with other medicinal products and other forms of interaction.

Concomitant use with the following drugs is not recommended.

Medicinal products affecting hemostasis (see section "Special precautions"). Some agents affecting hemostasis should be discontinued prior to initiating enoxaparin sodium therapy, except when such agents are absolutely indicated. If combination therapy is necessary, enoxaparin sodium 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 cautious concomitant use.

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

Special precautions for use.

General warnings.

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

Therefore, it is essential to pay close attention to the instructions for medical use specific to each branded 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 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., sodium danaparoid or lepirudin).

Platelet count monitoring.

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

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

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

If clinical symptoms suggestive of HIT occur (any new episode of arterial and/or venous thromboembolism, any painful skin lesion at the injection site, or any allergic or anaphylactoid reactions during treatment), platelet count should 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 significant decrease in platelet count (30−50% from baseline) is confirmed, 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 or hemorrhage may occur at any site. In case of bleeding, the source should be investigated and appropriate treatment initiated.

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

• coagulation disorders;
• history of peptic ulcer;
• recent ischemic stroke;
• severe arterial hypertension;
• recent development 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, at doses used for prevention of venous thromboembolism, has no significant effect on bleeding time, general coagulation parameters, platelet aggregation, or fibrinogen binding to platelets.

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

Use during spinal/epidural anesthesia or lumbar puncture.

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

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

To reduce the potential risk of bleeding associated with concomitant use of sodium enoxaparin and procedures involving epidural or spinal anesthesia/analgesia or lumbar puncture, the pharmacokinetic profile of sodium enoxaparin should be considered (see section "Pharmacokinetics"). Placement or removal of an epidural catheter or performance of lumbar puncture should ideally be performed when the anticoagulant effect of sodium enoxaparin is low, although the exact time to achieve a 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 epidural or spinal anesthesia/analgesia or lumbar puncture, frequent monitoring for neurological disorders is required, including symptoms such as back pain along the midline, sensory and motor disturbances (numbness or weakness in the lower limbs), or bowel and/or bladder dysfunction. Patients should be instructed to immediately report any of these symptoms to their physician. If a spinal hematoma is suspected, appropriate diagnostic and therapeutic measures should be initiated immediately, including consideration of spinal cord decompression, even though such treatment may not prevent adverse neurological outcomes.

Skin necrosis/skin vasculitis. Cases of skin necrosis and skin 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 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 injection of sodium enoxaparin. If treatment with sodium enoxaparin is to be continued, the next scheduled dose should be administered no earlier than 6−8 hours after removal of the introducer. The puncture site should be monitored for early detection of signs of bleeding or hematoma formation.

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

Mechanical heart valves. The use of sodium enoxaparin for thromboprophylaxis in patients with mechanical heart valves has not been adequately studied. Isolated cases of mechanical heart valve thrombosis have been reported in patients receiving sodium enoxaparin for thromboprophylaxis. The presence of risk factors, including underlying disease and insufficient clinical data, limits the evaluation of these cases. In some of these cases observed in pregnant women, 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 occlusion and maternal and fetal death. Post-marketing reports have included isolated cases of valve thrombosis in pregnant women with mechanical heart valves receiving sodium enoxaparin for thromboprophylaxis. Pregnant women with mechanical heart valves may have an increased risk of thromboembolic events.

Elderly patients. When used in the prophylactic dose range, no increased tendency to bleeding 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 aged 75 years and older receiving treatment with the drug 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 by measuring anti-Xa activity 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 the lack of adequate data in this population, except for prevention of clot formation in the extracorporeal circuit during hemodialysis.

For patients with severe renal impairment (creatinine clearance 15−30 mL/min), dose adjustment of the drug is recommended for both therapeutic and prophylactic use due to significantly increased exposure to sodium enoxaparin (see section "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 monitoring of anti-Xa activity levels 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 (body mass index) > 30 kg/m²) have not been sufficiently studied, and there is currently no consensus on the need for dose adjustment in this patient group. These patients should be closely monitored for possible symptoms of thromboembolism.

Hyperkalemia. Heparins may suppress aldosterone secretion in the adrenal glands, leading to hyperkalemia (see section "Adverse reactions"), particularly in patients with diabetes mellitus, chronic renal failure, pre-existing metabolic acidosis, and in patients 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.

Benzyl alcohol

Benzyl alcohol may cause allergic reactions.

Intravenous administration of benzyl alcohol has been associated with serious adverse reactions and fatal outcomes in neonates ("Gasping syndrome") (see section "Contraindications"). The minimal amount of benzyl alcohol that may cause toxicity is unknown. Benzyl alcohol may also cause toxic reactions in infants and children under 3 years of age due to an increased risk of accumulation.

Large volumes of medicinal products containing benzyl alcohol should be used with caution and only if necessary in patients with hepatic or renal impairment or in pregnant women due to the risk of accumulation of benzyl alcohol and its toxicity (metabolic acidosis).

Sodium

This medicinal product contains less than 1 mmol (23 mg)/dose of sodium, i.e., essentially "sodium-free".

Acute generalized exanthematous pustulosis (AGEP)

Acute generalized exanthematous pustulosis (AGEP) has been reported with unknown frequency during treatment with enoxaparin. When prescribing this medicinal product to patients, signs and symptoms should be explained, and skin reactions should be closely monitored. If signs or symptoms suggestive of such reactions occur, enoxaparin should be discontinued immediately, and alternative treatment should be considered (if necessary).

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

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.

No signs of fetotoxicity or teratogenicity were observed in animal studies. Data from animal experiments showed minimal placental transfer of enoxaparin.

Sodium enoxaparin should be administered to pregnant women only if the physician clearly establishes a need for such treatment.

Pregnant women receiving sodium enoxaparin should be closely monitored for signs of bleeding or excessive anticoagulant effect, and they should be informed 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 heart valves (see section "Special precautions for use").

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

Since benzyl alcohol may cross the placenta, it is recommended to use NOVOPARIN® in prefilled syringes, which does not contain this excipient.

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 vehicles or operating machinery

The effect of sodium enoxaparin on the ability to drive vehicles 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 (SC) 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 surgical procedures associated with moderate risk.

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

• For patients with high risk of thromboembolic events, the recommended dose of sodium enoxaparin is 4000 IU (40 mg) once daily, preferably administered by subcutaneous (SC) injection 12 hours before surgery. If prophylactic administration of sodium enoxaparin needs to be initiated more than 12 hours before surgery (e.g., 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 patients at high risk of venous thromboembolism (VTE) undergoing abdominal or pelvic surgery for oncological conditions, prolonged 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 regimen of 150 IU/kg (1.5 mg/kg) once daily is recommended for uncomplicated patients at low risk of recurrent VTE. The regimen of 100 IU/kg (1 mg/kg) twice daily should be prescribed for all other patients, including those with obesity, symptomatic PE, cancer, recurrent VTE, or proximal venous thrombosis (iliac vein).

Sodium enoxaparin should be 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, 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 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 prophylaxis or treatment during hemodialysis sessions.

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

• For treatment of unstable angina and NSTEMI, the recommended dose of sodium enoxaparin is 100 IU/kg (1 mg/kg), administered every 12 hours by SC injection, in combination with antiplatelet therapy. Treatment should be initiated for at least 2 days and continued until clinical stabilization of the patient. The usual duration of treatment is 2 to 8 days.

• All uncomplicated patients should receive oral acetylsalicylic acid: an initial loading dose of 150–300 mg (for patients not previously on acetylsalicylic acid), followed by 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 subcutaneous dose of 100 IU/kg (1 mg/kg), followed by 100 IU/kg (1 mg/kg) SC every 12 hours (maximum 10,000 IU [100 mg] for each of the first two SC doses). Appropriate antiplatelet therapy, such as oral acetylsalicylic acid (75–325 mg once daily), should be administered concomitantly, in the absence of contraindications. The recommended duration of treatment is 8 days or until hospital discharge, whichever occurs earlier. When used in combination with thrombolytic therapy (fibrin-specific or non-fibrin-specific), sodium enoxaparin should be administered between 15 minutes before and 30 minutes after the start of fibrinolytic therapy.

• Dosage specifics for patients aged ≥75 years are 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 reduction is not required in elderly patients, except in cases of renal impairment (see below "Renal impairment" and section "Special precautions").

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

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

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

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

Dosage for patients with severe renal impairment (creatinine clearance 15–30 mL/min)

Table 1

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 necessary.

Route of administration. Novoparin® must not be administered by intramuscular injection.

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

• For the treatment of acute STEMI, administration of the drug should begin 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 is administered into the arterial line of the dialysis circuit.

It is recommended to use a tuberculin syringe or equivalent of appropriate volume for administering the drug from multidose vials.

Technique for subcutaneous injection.

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

To avoid loss of drug when using prefilled syringes, air bubbles should not be expelled before injection. If it is necessary to adjust the amount of drug to be administered according to the patient's body weight, graduated prefilled syringes should be used, allowing the required volume to be obtained by removing the excess before injection. It should be noted that in some cases it may not be possible to obtain the exact dose due to the nature of the syringe graduations, and in such cases the volume should be rounded to the nearest graduation mark.

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

The needle should be inserted fully at a vertical angle into a skin fold gently held between the thumb and index finger. The skin fold should be held throughout the injection until completion. The injection site should not be massaged after administration.

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

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

For intravenous injection, either a multidose vial or a prefilled syringe may be used.

Sodium enoxaparin should be administered through an intravenous infusion system. It must not be mixed or co-administered with other medicinal products. To avoid potential mixing of sodium enoxaparin with other medicinal products, the selected intravenous access should be flushed with an adequate amount of 0.9% sodium chloride solution or 5% glucose solution before and after administration of the sodium enoxaparin bolus to clear the administration port of other drugs. Sodium enoxaparin 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 prefilled syringe, the excess volume should be removed from the syringe so that only 3000 IU (30 mg) remains. The dose of 3000 IU (30 mg) can then be administered directly intravenously.

Additional bolus for patients undergoing PCI: an additional intravenous bolus of 30 IU/kg (0.3 mg/kg) should be administered if the last subcutaneous dose of the drug 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.

To prepare a solution of 300 IU/mL (3 mg/mL) using a 6000 IU (60 mg) prefilled syringe of sodium enoxaparin, it is recommended to use a 50 mL infusion bag (i.e., 0.9% sodium chloride solution (9 mg/mL) for infusion or 5% glucose in water for injection):

30 mL of the solution should be withdrawn from the infusion bag using a syringe and discarded. The entire content of the prefilled syringe containing 6000 IU (60 mg) of sodium enoxaparin should be added to the bag, which now contains 20 mL. The contents of the bag should be gently mixed. Then, the required volume of the diluted solution should be drawn into a syringe for administration via 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) × 0.1] or by using Table 2. Dilution should be performed immediately before administration of the drug.

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

Table 2

Administration into the arterial segment of the dialysis circuit. The drug should be 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 specific indication, confirmed by two consecutive test results.

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, sodium enoxaparin should be discontinued and DOAC therapy should be initiated 0–2 hours (depending on the instructions for medical use of each DOAC) before the next scheduled dose of sodium enoxaparin is due.

For patients currently receiving DOACs, the first dose of sodium enoxaparin should be administered at the time the next DOAC dose would have been 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 neuraxial hematoma (see section "Special precautions").

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

For procedures involving 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 interval before catheter insertion or removal to at least 24 hours.

Initial administration of sodium enoxaparin 2000 IU (20 mg) two hours before surgery should not be used when neuraxial anesthesia is performed.

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

For procedures involving 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 interval before catheter insertion or removal to at least 48 hours.

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

At these time points, anti-Xa activity of the drug may still be present, 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 and after catheter removal. This time interval should be based on an individualized benefit-risk assessment, taking into account both the risk of thrombosis and the risk of bleeding for this procedure, considering the patient's specific risk factors.

Children.

The safety and efficacy of sodium enoxaparin in pediatric patients have not yet been established. The medicinal product contains benzyl alcohol and should not be used in neonates and preterm newborns (see section "Contraindications").

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

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

• protamine infusion at a dose of 0.5 mg per 100 IU (1 mg) of sodium enoxaparin may be used if sodium enoxaparin was administered more than 8 hours prior to protamine administration or if a second dose of protamine is required.

• Administration of protamine 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. More than 15,000 patients received enoxaparin sodium in clinical studies. Among them, there were 1776 cases of enoxaparin sodium use for prophylaxis of deep vein thrombosis following orthopedic or abdominal surgery in patients at high risk of thromboembolic complications, 1169 cases of enoxaparin sodium use for prophylaxis of deep vein thrombosis in patients with acute medical conditions and very limited mobility, 559 cases of enoxaparin sodium use for treatment of deep vein thrombosis with or without pulmonary embolism, 1578 cases of enoxaparin sodium use for treatment of unstable angina and non-Q-wave myocardial infarction, and 10,176 cases of enoxaparin sodium use for treatment of acute ST-segment elevation myocardial infarction.

Dosing regimens of enoxaparin sodium in these clinical studies varied depending on the indication. The dose of enoxaparin sodium for prophylaxis of deep vein thrombosis following 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 enoxaparin sodium either at a dose of 100 IU/kg (1 mg/kg) subcutaneously every 12 hours, or 150 IU/kg (1.5 mg/kg) subcutaneously once daily. In clinical studies evaluating enoxaparin sodium for treatment of unstable angina and non-Q-wave myocardial infarction, the dose was 100 IU/kg (1 mg/kg) subcutaneously every 12 hours. In the clinical study evaluating enoxaparin sodium for treatment of acute ST-segment elevation myocardial infarction, the regimen included an initial intravenous bolus of 3000 IU (30 mg), followed by subcutaneous administration of enoxaparin sodium at a dose of 100 IU/kg (1 mg/kg) every 12 hours.

In clinical studies, the most frequently reported adverse reactions were hemorrhagic events, thrombocytopenia, and thrombocytosis (see sections «Special precautions for use» and «Description of selected adverse reactions» below).

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

Frequency categories are 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.

Blood and lymphatic system disorders.

Common: hemorrhagic events, hemorrhagic anemia*, thrombocytopenia, thrombocytosis.
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 for use»).
Rare: eosinophilia*.

Immune system disorders.

Common: allergic reaction.
Rare: anaphylactic/anaphylactoid reactions, including shock*.

Nervous system disorders.

Common: headache*.

Vascular disorders.

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

Hepatobiliary disorders.

Very common: increased liver enzymes (predominantly transaminases more than 3 times above the upper limit of normal).
Uncommon: hepatocellular liver injury*.
Rare: cholestatic liver injury*.

Skin and subcutaneous tissue disorders.

Common: urticaria, pruritus, erythema.
Uncommon: bullous dermatitis.
Rare: alopecia*, skin vasculitis*, skin necrosis*, which usually occurs at the injection site (these events are typically preceded by purpura or erythematous, infiltrated, and painful plaques). Injection site nodules* (inflammatory nodules representing non-cystic «pockets» of enoxaparin). These resolve within several days and do not require discontinuation of the drug.
Frequency not known: acute generalized exanthematous pustulosis (AGEP).

Musculoskeletal and connective tissue disorders.

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

General disorders and administration site conditions.

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 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 reported 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 led to a significant clinical 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 risk of bleeding, invasive procedures, or concomitant use of medicinal products affecting hemostasis (see sections «Special precautions for use» and «Interaction with other medicinal products and other forms of interaction»).

Table 3

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

Thrombocytopenia and thrombocytosis

Table 4

β Increase in platelet count > 400 G/L.

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

Intravenous administration of benzyl alcohol is associated with serious adverse reactions and fatal outcomes in neonates ("Gasping syndrome") (see section "Contraindications").

Benzyl alcohol may also cause toxic reactions in infants and children under 3 years of age due to an increased risk of accumulation (see section "Special precautions").

Reporting of suspected adverse reactions after marketing authorization 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. 3 years.

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

Proposed shelf life after first opening of the vial. Chemical and physical in-use stability has been demonstrated for 28 days at 25 °C. From a microbiological standpoint, after opening the vial, the medicinal product may be stored for up to 28 days at a temperature not exceeding 25 °C. Any other storage period and conditions are the responsibility of the user.

Proposed shelf life after dilution. After dilution with 0.9 % sodium chloride solution or 5 % glucose solution. Chemical and physical in-use stability has been demonstrated for 8 hours at 25 °C. From a microbiological standpoint, if the dilution method does not exclude the risk of microbial contamination, the diluted solution should be used immediately after preparation. If the solution is not used immediately, any other storage period and conditions are the responsibility of the user.

Storage conditions.

Store out of the reach of children, at a temperature not exceeding 25 °C, in the original packaging. Do not freeze.

Incompatibilities.

Subcutaneous injection. Do not mix with other medicinal products.

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

Packaging.

1 or 5 multi-dose vials of 3 ml or 5 ml in a cardboard box.

Prescription status. Prescription only.

Manufacturer.

Shenzhen Techdow Pharmaceutical Co. Ltd.

Manufacturer's address and place of business.

No. 19 Gaoxinzhongyi Road, Nanshan District, Shenzhen, 518057, China.