Flenox injection solution 8000 anti-Xa IU syringe 0.8 ml blister No. 2

Instructions for use Flenox injection solution 8000 anti-Xa IU syringe 0.8 ml blister No. 2

Composition

active ingredient: enoxaparin sodium;

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

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

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

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

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

excipient: water for injections.

Dosage form

Solution for injection.

Main physicochemical properties: transparent colorless or light yellow liquid.

Pharmacotherapeutic group

Antithrombotic agents. Heparin group. Enoxaparin.

ATX code B01A B05.

Pharmacological properties

Pharmacodynamics.

Enoxaparin is a low molecular weight heparin (LMWH), dalton, in which the antithrombotic and anticoagulant activities of standard heparin are not related to each other. The active substance is presented in the form of a 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), with a ratio of 3.6. These anticoagulant activities are mediated by antithrombin III (ATIII), which accounts for the antithrombotic effects in humans.

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

When used for prophylaxis, enoxaparin sodium does not significantly affect the activated partial thromboplastin time (APTT). When used for treatment, APTT may be prolonged 1.5–2.2 times compared to the control time against the background of maximum drug activity.

Clinical efficacy and safety.

Prevention of venous thromboembolic complications associated with surgical interventions.

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

Efficacy data are presented in Table 1.

Table 1

* p-value compared to placebo is 0.008.

Long-term prophylaxis of DVT after cancer surgery. A double-blind, multicenter study compared the safety and efficacy of 4-week and 1-week prophylactic regimens of enoxaparin sodium in 332 patients undergoing elective surgery for abdominal or pelvic cancer. Patients received enoxaparin sodium (4000 IU (40 mg) subcutaneously) daily for 6 to 10 days and were then 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 surgery for abdominal or pelvic cancer significantly reduced the incidence of venographically confirmed thrombosis compared with prophylactic use of enoxaparin sodium for 1 week. 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 was maintained for 3 months [13.8% vs. 5.5% (n = 23 vs. 9), p = 0.01]. No differences were found between the groups in the incidence of bleeding or other complications during the double-blind period and the follow-up period.

Prevention of venous thromboembolic complications in therapeutic patients with acute illnesses that are expected to cause mobility limitations.

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 the prevention of DVT in therapeutic patients with severely limited mobility (defined as walking < 10 meters for ≤ 3 days) due to acute illness. This study enrolled patients with heart failure (NYHA functional class III or IV), acute respiratory failure or complicated chronic respiratory failure, or acute infection, or acute rheumatic disease, provided that at least one risk factor for VTE was present (age ≥ 75 years, cancer, previous VTE, obesity, varicose veins, hormone therapy, chronic heart or respiratory failure).

A total of 1102 patients were enrolled in the study, and 1073 patients received the study treatment. Treatment lasted for 6-14 days (median duration was 7 days). Enoxaparin sodium, when administered at a dose of 4000 IU (40 mg) once daily subcutaneously, statistically significantly reduced the incidence of VTE compared with placebo. Efficacy data are presented in Table 2.

Table 2

VTE - venous thromboembolic events, which included cases of DVT, PE and death that was considered to be due to a thromboembolic event.

* p-value compared to placebo is 0.0002

Approximately 3 months after inclusion of patients in the study, the incidence of VTE in the enoxaparin sodium 4000 IU (40 mg) group 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% in the placebo group, 11.7% and 0.3% in the enoxaparin sodium 2000 IU (20 mg) group, and 12.6% and 1.7% in the enoxaparin sodium 4000 IU (40 mg) group, respectively.

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

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

Table 3

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

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

for enoxaparin sodium once daily compared to heparin - from -3.0 to 3.5.

for enoxaparin sodium every 12 hours compared to heparin - from -4.2 to 1.7. The frequency of major bleeding was 1.7% in the group using enoxaparin sodium 150 IU/kg (1.5 mg/kg) once a day, 1.3% in the group using enoxaparin sodium 100 IU/kg (1 mg/kg) twice a day and 2.1% in the group using heparin, respectively.

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 enoxaparin sodium 100 IU/kg (1 mg/kg) every 12 hours in combination with acetylsalicylic acid (100-325 mg once daily) or unfractionated heparin (UFH) IV with dose adjustment based on aPTT. Patients were treated as inpatients for a minimum of 2 days and a maximum of 8 days until clinical stabilization, revascularization procedures, or discharge from the hospital. Patients were followed for up to 30 days. Compared with heparin, enoxaparin sodium statistically significantly reduced the combined incidence of angina, myocardial infarction, and death from 19.8 to 16.6% (relative risk reduction of 16.2%) at day 14. This reduction in the combined incidence 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 hemorrhages at the subcutaneous injection site 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 enoxaparin sodium as a single intravenous bolus of 3000 IU (30 mg) followed by 100 IU/kg (1 mg/kg) subcutaneously followed by 100 IU/kg (1 mg/kg) subcutaneously every 12 hours, or UFH for 48 hours with dose adjustments based on the aPTT level. All patients also received acetylsalicylic acid for at least 30 days. The enoxaparin sodium dosing regimen was adjusted for patients with severe renal impairment and for elderly patients (≥ 75 years). Enoxaparin sodium subcutaneous injections were administered until the patient was discharged from the hospital or for a maximum of 8 days (whichever came first).

4716 patients underwent percutaneous coronary intervention (PCI) with blinded antithrombotic support with study drugs. Thus, patients receiving enoxaparin sodium underwent PCI on the background of enoxaparin sodium (without switching to the comparator) using the regimen studied in previously conducted studies, i.e. without additional enoxaparin sodium if the last subcutaneous injection of the drug was performed less than 8 hours before balloon inflation, and with the use of an intravenous bolus of enoxaparin sodium at a dose of 30 IU/kg (0.3 mg/kg) if the last subcutaneous injection of the drug was performed more than 8 hours before balloon inflation.

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

The benefits of enoxaparin sodium treatment, evident across a range of efficacy endpoints, were evident at 48 hours, when a relative reduction in the risk of recurrent myocardial infarction of 35% was observed compared with UFH treatment (p < 0.001).

The positive effect of enoxaparin sodium treatment on the primary endpoint was similar in all key subgroups, including subgroups by age, gender, infarct location, history of diabetes mellitus, history of prior myocardial infarction, type of fibrinolytic drug prescribed, and time to initiation of study drug treatment.

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

The incidence of major bleeding at 30 days was statistically significantly higher (p < 0.0001) in the enoxaparin sodium group (2.1%) compared with the heparin group (1.4%). The incidence of gastrointestinal bleeding was higher in the enoxaparin sodium group (0.5%) compared with the heparin group (0.1%), while the incidence of intracranial hemorrhage was similar in both groups (0.8% with enoxaparin sodium compared with 0.7% with heparin).

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

Hepatic impairment. Published data suggest that enoxaparin sodium 4000 IU (40 mg) is safe and effective in preventing portal vein thrombosis in patients with cirrhosis (Child-Pugh class BC). It should be noted that the published studies may have some limitations. Caution should be exercised in patients with hepatic impairment, as they are more prone to bleeding (see section 4.4) and no formal dosing studies have been performed in patients with cirrhosis (Child-Pugh class A, B or C).

Pharmacokinetics.

General characteristics.

The pharmacokinetic parameters of enoxaparin sodium were studied mainly with regard to the dynamics of anti-Xa activity in blood plasma, as well as the effect on anti-IIa activity in the recommended dose range after single and multiple subcutaneous administration and after single intravenous administration. Quantitative determination of pharmacokinetic anti-Xa and anti-IIa activity was performed using validated amidolytic methods.

Absorption. The absolute bioavailability of enoxaparin sodium after subcutaneous injection, as assessed by anti-Xa activity, is close to 100%.

Different doses, dosage forms, and administration schedules may be used.

The average maximum level of anti-Xa activity in blood plasma is observed within 3-5 hours after subcutaneous injection and reaches approximately 0.2, 0.4, 1.0 and 1.3 IU anti-Xa activity per 1 ml after a single subcutaneous injection of the drug at 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 administration of 3000 IU (30 mg) IV bolus followed immediately by 100 IU/kg (1 mg/kg) SC every 12 hours, the initial maximum plasma anti-Xa activity level was 1.16 IU/mL (n = 16) and the mean exposure was 88% of steady-state levels. Steady-state was achieved by the second day of dosing.

After multiple subcutaneous administration of 4000 IU (40 mg) once daily and 150 IU/kg (1.5 mg/kg) once daily in healthy volunteers, steady state was reached on the second day of administration, with an average exposure ratio of approximately 15% higher than after a single dose. After multiple subcutaneous administration of 100 IU/kg (1 mg/kg) twice daily, steady state was reached between days 3 and 4, with an average exposure of approximately 65% higher than after a single dose, and mean maximum and minimum 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.

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

Intra- and interindividual variability is low. No accumulation is observed after repeated subcutaneous administration of the drug.

Anti-IIa activity in plasma after subcutaneous administration is approximately 10 times lower than anti-Xa activity. The average maximum level of anti-IIa activity is observed approximately 3-4 hours after subcutaneous injection, reaching 0.13 IU/ml and 0.19 IU/ml after multiple administration of the drug according to the regimens of 100 IU/kg (1 mg/kg) twice a day and 150 IU/kg (1.5 mg/kg) once a day, respectively.

Distribution: The volume of distribution of the anti-Xa activity of enoxaparin sodium is approximately 4.3 liters and approximates the volume of circulating blood.

Biotransformation: Enoxaparin sodium is metabolized mainly in the liver by desulfation and/or depolymerization to form compounds with lower molecular weight and significantly lower biological activity.

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

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

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.

Elderly patients. According to the results of a population pharmacokinetic analysis, the kinetic profile of enoxaparin sodium in elderly patients does not differ from that in younger patients, if renal function is not impaired.

However, since renal function may decline with age, lower levels of enoxaparin sodium elimination may be observed in elderly patients (see section "Method of administration and dosage").

Hepatic impairment: In a study of patients with severe cirrhosis receiving enoxaparin sodium 4000 IU (40 mg) once daily, a decrease in peak anti-Xa activity was associated with an increase in the severity of hepatic impairment (as assessed by the Child-Pugh classification). This decrease was mainly due to a decrease in ATIII levels secondary to a decrease in ATIII synthesis in patients with hepatic impairment.

Renal impairment. A linear relationship was observed between the clearance of anti-Xa activity from blood plasma and creatinine clearance at steady state, indicating a decrease in the clearance of enoxaparin sodium in patients with impaired renal function. The exposure to anti-Xa activity, expressed as AUC (area under the concentration/time curve), at steady state increased to a maximum in mild renal impairment (creatinine clearance 50-80 ml/min) and in moderate renal impairment (creatinine clearance 30-50 ml/min) after multiple subcutaneous administration of the drug at doses of 4000 IU (40 mg) once daily. In patients with severe renal impairment (creatinine clearance < 30 ml/min), steady-state AUC significantly increased by an average of 65% after multiple subcutaneous administration of 4000 IU (40 mg) once daily (see sections 4.2 and 4.4).

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

Body weight: After multiple subcutaneous administration of 150 IU/kg (1.5 mg/kg) once daily, the mean AUC of anti-Xa activity was marginally higher at steady state in obese healthy volunteers (BMI 30-48 kg/m2) compared to non-obese controls, while the maximum plasma anti-Xa activity was not increased. In obese subjects, lower clearance was observed after correction for body weight after subcutaneous administration.

When using the drug in doses without correction for body weight, it was found that after a single subcutaneous administration of the drug at a dose of 4000 IU (40 mg), the exposure to anti-Xa activity was 52% higher in women with low body weight (< 45 kg) and 27% higher in men with low body weight (< 57 kg) compared to control subjects with normal body weight (see section "Special instructions for use").

Pharmacokinetic interactions: No pharmacokinetic interaction was observed between enoxaparin sodium and thrombolytics when administered concomitantly.

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

Enoxaparin sodium did not demonstrate any mutagenic activity in in vitro studies, including the Ames test, a direct mutation assay in mouse lymphoma cells, and no clastogenic activity in an in vitro human lymphocyte chromosome aberration assay and an in vivo rat bone marrow chromosome aberration assay.

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

Indication

The drug is indicated for use in adults for:

Prevention of venous thromboembolic complications in surgical patients at moderate and high risk, especially in patients undergoing orthopedic or general surgical interventions, including surgical interventions for oncological diseases.

Prevention of venous thromboembolic complications in therapeutic 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, which may require thrombolytic therapy or surgery.

Prevention of blood clot formation in extracorporeal circulation during hemodialysis.

In acute coronary syndrome:

for the treatment of acute ST-segment elevation myocardial infarction (STEMI), including in patients who are scheduled for medical treatment or subsequent percutaneous coronary intervention (PCI).

Contraindication

Enoxaparin sodium is contraindicated for use in patients with the following conditions:

Hypersensitivity to enoxaparin sodium, heparin or its derivatives, including other low molecular weight heparins, or to any of the excipients (see section "Composition").

History of immune-mediated heparin-induced thrombocytopenia (HIT) within the last 100 days or in the presence of circulating antibodies (see also section "Special warnings and precautions for use").

Active clinically significant bleeding and conditions with a high risk of bleeding, including recent hemorrhagic stroke, gastrointestinal ulcer, presence of a malignant neoplasm with a high risk of bleeding, recent brain, spinal cord or eye surgery, known or suspected esophageal varices, arteriovenous malformations, vascular aneurysms or serious malformations of intraspinal or intracerebral vessels.

Spinal or epidural anesthesia or locoregional anesthesia if enoxaparin sodium has been used for treatment within the previous 24 hours (see section "Special instructions").

Interaction with other medicinal products and other types of interactions

Concomitant use with the following drugs is not recommended.

Medicinal products affecting haemostasis (see section 4.4). It is recommended that certain medicinal products affecting haemostasis be discontinued prior to initiation of treatment with enoxaparin sodium, unless absolutely necessary. If this combination is indicated, enoxaparin sodium should be used with close clinical and laboratory monitoring.

Such drugs include:

salicylates for systemic use, acetylsalicylic acid in anti-inflammatory doses and non-steroidal anti-inflammatory drugs (NSAIDs), including ketorolac;

other thrombolytics (e.g. alteplase, reteplase, streptokinase, tenecteplase, urokinase) and anticoagulants (see section "Method of administration and dosage").

Drugs with which simultaneous use should be carried out with caution.

The following medicines may be used concomitantly with enoxaparin sodium with caution.

Other drugs that affect hemostasis, such as:

platelet aggregation inhibitors, including acetylsalicylic acid used in an antiplatelet dose (cardioprotection), clopidogrel, ticlopidine and glycoprotein IIb/IIIa antagonists, which are indicated in acute coronary syndrome, due to the risk of bleeding;

dextran 40;

glucocorticoids for systemic use.

Medicinal products that increase potassium levels: Medicinal products that increase serum potassium levels may be administered concomitantly with enoxaparin sodium with careful clinical and laboratory monitoring (see sections 4.4 and 4.8).

Application features

General warnings.

Enoxaparin sodium should not be used interchangeably (unit for unit) with other low molecular weight heparins (LMWHs). These drugs differ in their manufacturing processes, molecular weights, specific anti-Xa and anti-IIa activities, units of activity, dosage, and clinical efficacy and safety. This results in differences in pharmacokinetics and biological activity (e.g. antithrombin activity, platelet interaction).

In this regard, it is necessary to pay special attention to and adhere to the instructions for medical use specific to each patented medicinal product.

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

Enoxaparin sodium is contraindicated in patients with a history of immune-mediated HIT within the past 100 days or in whom circulating antibodies are present (see Contraindications). Circulating antibodies may persist for several years.

Enoxaparin sodium should be used with extreme caution in patients with a history (> 100 days) of immune-mediated HIT without circulating antibodies. The decision to use enoxaparin sodium in such cases should be made only after a careful benefit/risk assessment and after consideration of alternative non-heparin treatments (e.g. danaparoid sodium or lepirudin).

Monitoring platelet count.

Also, when using LMWH, there is a risk of antibody-mediated HIT, which usually develops between the 5th and 21st days after the start of treatment with enoxaparin sodium.

The risk of HIT is higher in patients who have undergone surgery and is observed mainly after cardiac surgery and in patients with cancer.

If clinical symptoms suggestive of HIT are present (any new episode of arterial and/or venous thromboembolism, any painful skin lesion at the injection site, any allergic or anaphylactoid reaction during treatment), platelet counts should be determined. Patients should be aware that they may experience such symptoms and should inform their physician if they experience them.

In clinical practice, in the event of a confirmed significant decrease in platelet levels (30-50% of the initial value), enoxaparin sodium should be immediately discontinued and the patient transferred to another alternative non-heparin treatment.

Hemorrhagic phenomena.

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

Enoxaparin sodium, as with any other anticoagulant, should be used with caution in conditions that increase the risk of bleeding, such as:

hemostasis disorders;

history of peptic ulcer;

recent ischemic stroke;

severe arterial hypertension;

recent development of diabetic retinopathy;

surgery on the nervous system or eyes;

simultaneous use of drugs that affect hemostasis (see section "Interaction with other drugs and other types of interactions").

Laboratory tests.

Enoxaparin sodium in doses used for the prevention of venous thromboembolism has no significant effect on bleeding time, general coagulation parameters, and does not affect platelet aggregation and fibrinogen binding to platelets.

When using the drug in higher doses, the activated partial thromboplastin time (APTT) and activated clotting time (ACT) may increase. Since there is no linear relationship between the increase in APTT and ACTT and the increase in the antithrombotic activity of enoxaparin sodium, these indicators are unreliable and cannot be used to monitor the activity of enoxaparin sodium.

Use of the drug during spinal/epidural anesthesia or lumbar puncture.

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

Cases of neuraxial hematomas have been reported with the concomitant use of enoxaparin sodium and spinal/epidural anesthesia or spinal puncture procedures, resulting in long-term or irreversible paralysis. These cases are rare with enoxaparin sodium 4000 IU (40 mg) once daily or lower doses. The risk of such events is higher with the use of postoperative indwelling epidural catheters, with the concomitant use of other drugs that affect hemostasis, such as nonsteroidal anti-inflammatory drugs, with traumatic or repeated epidural or spinal procedures, or in patients with a history of spinal surgery or spinal deformity.

To reduce the potential risk of bleeding associated with the concomitant use of enoxaparin sodium and epidural or spinal anesthesia/analgesia or spinal puncture, the pharmacokinetic profile of enoxaparin sodium should be considered (see section 5.2). Insertion or removal of an epidural catheter or lumbar puncture is best performed when the anticoagulant effect of enoxaparin sodium is low, but the exact time to achieve a sufficiently low anticoagulant effect in each individual patient is unknown. It should also be considered that the elimination of enoxaparin sodium is longer.