Clexane 0.4 injections instructions for use. Clexane injections for thrombosis of various etiology and nature. Rules for use and dosage

- These are common diseases that almost everyone faces. If appropriate treatment is not provided in time, then serious consequences, including death, may result.

Modern pharmacological firms provide a huge selection of drugs for the treatment of these diseases. Each of them can not only relieve pain, but also the inflammatory process.

These drugs include the drug Clexane. It has not only anti-inflammatory properties, but also a tonic effect, so it is often prescribed during prophylaxis before and after operations.

general information

Clexane is a drug that belongs to the group. The drug is used for and, thrombosis, embolism. The active ingredient of the drug is enoxaparin sodium.

This component is also called heparin, which is in a low molecular weight state, obtained by hydrolysis of heparin with alkali (in the form of an ether in benzyl form).

The main raw material for enoxaparin sodium is heparin, which is obtained from the intestinal mucosa of thin-looking pigs.

The composition of Clexane includes the active substance - sodium enexoparin and a clear liquid with a yellow tint for injection.

Produced in the form of syringes, which are filled with a clear liquid for injection under the skin. Syringes are available with different volumes - 0.2 ml, 0.4 ml, 0.6 ml, 0.8 ml and 1 ml, which contain 20 mg, 40 mg, 60 mg, 80 mg and 1 gram of the main component - enexoparin and water for injection as a solvent. 1 blister contains 2 syringes.

Pharmacological properties and pharmacodynamics

Clexane has antithrombotic properties. It is used as injections under the skin during the treatment of acute coronary syndrome, deep vein thrombosis, and also as a preventive treatment for various pathologies of the veins.

The second international non-proprietary name for this drug is enoxaparin. The drug is heparin in low molecular weight form, the molecular weight of which is approximately 4500 daltons.

During the use of the agent for prophylactic treatment, it has a slight change in the activated partial thromboplastin time. It also has almost no effect on the state of platelets and binding to fibrogen. Also, during the treatment of various diseases with this drug, the APTT is increased by almost 1.5-2 times.

After prolonged subcutaneous injections of a systematic nature in the amount of 1.5 mg per 1 kilogram of body weight, the maximum level of enoxaparin sodium in the body is reached after two days. Bioavailability during subcutaneous administration is 100%.

Metabolization of enoxaparin in the liver is achieved by desulfation and depolymerization. The metabolites that are formed during this process are of low activity.

The half-life of the drug lasts from 4 hours to 5 hours during a single dose. If the medicine is taken repeatedly - 7 hours. About 40% of the drug is excreted through the kidneys. The excretion of the active substance enexoparin in the elderly is slower, this is due to the deterioration of kidney function.

Indications for use

The main purpose of Clexane is to use it during prophylactic treatment for venous thrombosis, embolism, thromboembolism.

Also, Clexane injections are prescribed for the following indications:

• recommended for patients who observe bed rest, who have undergone therapeutic diseases in an acute form - infectious diseases in severe form, the presence of respiratory and heart failure, heart failure in a chronic form, rheumatic diseases in an acute form with the presence of risk factors for thrombus formation;
• during surgical interventions;
• prescribed for hemodialysis, but provided that the procedure lasts no more than 4 hours;
• during deep vein varicose veins which may or may not be accompanied by pulmonary embolism;
• prescribed for unstable rhythm of angina pectoris and myocardial infarction. And also during acute myocardial infarction in patients who receive medical treatment procedures with coronary intervention.

Assignment restrictions

According to the instructions, the drug is not recommended for use in the following indications:

• in the presence of increased sensitivity of the body to the main component- enoxaparin sodium, as well as to heparin and its derivatives;
• should not be taken under the age of 18;
• all kinds of diseases and conditions that are accompanied by an increased risk of severe bleeding - these include a hemorrhagic stroke, aneurysm of the aorta or vessels of the brain of the head, as well as in the presence of enoxaparin- and heparin-induced thrombocytopenia in severe form, uncontrolled bleeding.

It is also worth paying attention to the fact that the drug should be used with extreme caution in the following conditions:

• in the presence of renal or hepatic insufficiency;
• if there is a peptic ulcer of the stomach or duodenum, as well as any other erosive and ulcerative lesions of the gastrointestinal tract;
• with severe diabetes mellitus;
• with retinopathy of hemorrhagic or diabetic type;
• severe vasculitis;
• problems with hemostasis;
• bacterial type endocarditis;
• with uncontrolled hypertension of the arterial type of severe type;
• when performing epidural or spinal anesthesia;
• if there are severe injuries associated with the central nervous system;
• if there is intrauterine contraception;
• in the presence of extensive wounds with severe bleeding;
• when taken simultaneously with drugs that affect the homeostasis system.

During pregnancy and lactation

The drug Clexane during pregnancy is prescribed in rare cases. It is usually prescribed when the expected therapeutic effect for the mother is higher than the potential rice for the child.

In addition, there is no information on whether enoxaparin sodium crosses the placental barrier during pregnancy.

If treatment with the drug is necessary during lactation, then feeding should be stopped for the period of treatment.

Rules for use and dosage

The solution is administered using the injection method, while the patient should be in the supine position. The drug is injected into the anterior or posterolateral abdominal region of the wall at the site of the belt.

The needle should be inserted vertically completely, into the skin layer, which is clamped in the form of a fold. After the introduction of the fold is not straightened. It should be borne in mind that after the injection, the place does not need to be rubbed.

With venous thrombosis, varicose veins and thromboembolism

If the disease has an average form of development with a slightly pronounced risk, Clexane is used at 20 mg (0.2 g) for subcutaneous administration 1 time per day.

The injection of the drug is made 2 hours before the operation, and continues as long as there is a possibility of complications of a thromboembolic nature. The duration of the injections lasts about a week.

If the disease is severe, then the drug is used at 40 mg (0.4 g) for subcutaneous administration 1 time per day. The first injection is carried out 12 hours before the operation, and continues in the subsequent period, while there is a possibility of complications of a thromboembolic nature. Injections are made for about 10 days.

How to inject Clexane yourself - a visual video:

Treatment of deep vein thrombosis

During deep vein thrombosis, a drug is prescribed at a dosage of 1 gram for injection under the skin. Injections are administered every up to 2 times a day after 12 hours.

Simultaneously with Clexane, treatment with oral anticoagulants is prescribed. The course of injection is 10 days.

Side effects

The instructions indicate the side effects that may occur when using the drug:

• bleeding;
• the occurrence of thrombocytopenia;
• skin rashes;
• the occurrence of allergies, which may be systemic.

In addition, after the administration of the drug, local reactions may occur - pain at the injection site, the appearance of hematomas, in rare cases, necrosis.

Also, many reviews of experts note that with long-term treatment with this drug, there may be a risk of developing osteoporosis.

Opinion of experts of different profiles

From the reviews of doctors about the drug Clexane.

In my opinion, Clexane is a good remedy for the treatment of thrombosis, embolism and thromboembolism.

In all my practice of using this drug, I can say with confidence that this remedy has a positive effect and leads to a quick recovery. But still, it should be used only according to indications and only after a doctor's prescription.

Vascular surgeon

The drug Clexane performs well both in the treatment of heart failure, myocardial infarction, and various vein diseases - varicose veins, thrombosis, embolism, thromboembolism. This remedy has passed clinical trials and has proven its effectiveness. However, do not forget about side effects and contraindications, it is not advisable to use this remedy for hemorrhagic diseases and other conditions indicated in the instructions.

Cardiologist

The voice of the people

Patients' thoughts.

The drug Clexane was prescribed to me by my doctor for the treatment of vein thrombosis. I did it in accordance with the instructions before the operation and further in the subsequent period. The whole course of treatment I had a week.

After the treatment, I noticed relief, pain disappeared, inflammation and heaviness disappeared. However, there are still many contraindications and side effects of this remedy, and it is so effective!

Lyudmila, 48 years old

I was prescribed Clexane for the treatment of deep vein varicose veins and thrombosis. I have a high risk disease.

I was given it at a dosage of 40 mg, first before the operation, then in the subsequent period. I received 10 injections in total. Of course, the situation has improved, but not by much. Perhaps I have a severe lesion and advanced disease. And there are too many contraindications.

Mikhail, 52 years old

Issue price

The cost of the drug Clexane depends on the form of release and the volume of the syringe:

• 0.2 grams 10 pieces - from 1750 rubles;
• 0.4 grams 10 pieces - from 2900 rubles;
• 0.6 grams 2 pieces - from 880 rubles;
• 0.8 grams 10 pieces - from 5000 rubles.

• Fragmin;
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Instruction

Compound

1 ml solution for injection contains 100 mg (10,000 anti-Xa ME) of enoxaparin.

Clear, colorless to pale yellow solution.

Pharmacotherapeutic group

Antithrombotic agents. derivatives of heparin. The codeATX: B01AB05.

Pharmacological properties

Pharmacodynamics

Enoxaparin is a low molecular weight heparin (LMWH) with an average molecular weight of about 4500 daltons, in which the antithrombotic and anticoagulant activity of standard heparin has been separated. The medicinal substance is the sodium salt.

In purified in vitro enoxaparin sodium system has 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 properties are due to interaction with antithrombin III (ATIII), which manifests itself in the form of antithrombotic activity in humans.

Following anti-Xa/IIa activity in studies conducted on healthy people and patients, as well as in preclinical models, other antithrombotic and anti-inflammatory properties have been found in enoxaparin. These include ATIII-dependent inhibition of other coagulation factors such as Vila factor, induction of endogenous tissue factor pathway inhibitor (TFPI), and reduced release of von Willebrand factor (vWF) from the vascular endothelium into the bloodstream. All of the above mechanisms of action of enoxaparin lead to the manifestation of its antithrombotic properties.

When using enoxaparin in prophylactic doses it slightly alters activated partial thromboplastin time (APTT). When used in therapeutic doses, APTT can be extended by 1.5-2.2 times relative to the control time at peak activity.

Clinical efficacy and safety

Prevention of venous thromboembolic complications associated with surgery

Extended prophylaxis of VTE after orthopedic intervention

In a double-blind extended prophylaxis study in patients undergoing total hip replacement, 179 patients without venous thromboembolic events who were initially treated during hospitalization with enoxaparin sodium 4000 IU (40 mg) s.c. were randomized to a post-discharge regimen at enoxaparin sodium 4000 IU (40 mg) (n = 90) once daily s.c. or placebo (n = 89) for 3 weeks. The incidence of DVT during extended prophylaxis was significantly lower with enoxaparin sodium compared with placebo. There were no cases of PE and major bleeding.

Efficiency data are presented in the table below.

In a second double-blind study, 262 patients without VTE undergoing hip arthroplasty who were initially treated during hospitalization with enoxaparin sodium 4000 IU (40 mg) s.c. were randomized to post-discharge enoxaparin sodium 4000 IU. (40 mg) (n = 131) once daily s.c. or placebo (n = 131) for 3 weeks. Similar to the first study, the incidence of VTE during extended prophylaxis was significantly lower for enoxaparin sodium compared with placebo for both total VTE (enoxaparin sodium: 21 versus placebo: 45; p = 0.001) and proximal DVT (enoxaparin sodium: 8 versus placebo: 28 p =

Long-term prophylaxis of DVT after cancer surgery

A double-blind, multicenter study compared a four-week versus a week-long regimen of enoxaparin sodium prophylaxis for safety and efficacy in 332 patients undergoing elective surgery for abdominal or pelvic cancer. Patients received enoxaparin sodium 4000 IU (40 mg) s.c. daily for 6-10 days and 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 venous thromboembolism appeared. The patients were followed up for three months. Prophylaxis with enoxaparin sodium for four weeks after surgery for abdominal or pelvic malignancy significantly reduced the incidence of venographically confirmed thrombosis compared with prophylaxis with enoxaparin sodium for one week. The incidence of venous thromboembolism 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 after three months. There were no differences in bleeding or other complications during the double-blind study or follow-up periods.

Prevention of venous thromboembolic complications in therapeutic patients with acute diseases and limited mobility

In a double-blind, multicenter, parallel group study, enoxaparin sodium 2000 IU (20 mg) or 4000 IU (40 mg) once daily s.c. was compared with placebo for the prevention of DVT in medical patients with severely limited mobility during acute illness (as determined by by walking distance

A total of 1102 patients were included in the study and 1073 patients received treatment. Treatment continued for 6-14 days (average duration 7 days). Enoxaparin sodium 4000 IU (40 mg) once daily s.c. significantly reduced the incidence of VTE compared with placebo. Efficiency data are presented in the table below.

Approximately 3 months after inclusion, the incidence of VTE remained significantly lower in the enoxaparin sodium 4000 IU (40 mg) group compared to the placebo group.

The incidence of all and major bleeding was 8.6% and 1.1% in the placebo group, 11.7% and 0.3% in the group on enoxaparin sodium at a dose of 2000 ME (20 mg) and 12.6% and 1.7 % in the group on enoxaparin sodium at a dose of 4000 IU (40 mg), respectively.

Treatment of deep vein thrombosis with or without PE

In a multicenter, parallel group study, 900 patients with acute lower limb DVT with or without PE were randomized to inpatient (hospital) treatment with either (i) enoxaparin sodium 150 IU/kg (1.5 mg/kg) once daily n /c, (ii) enoxaparin sodium 100 IU/kg (1 mg/kg) every 12 hours sc, or (iii) heparin IV bolus (5000 IU) followed by continuous infusion (used to achieve APTT 55 - 85 seconds). A total of 900 patients were randomized into the study, and all patients received treatment. All patients also received warfarin (dose adjusted according to prothrombin time to achieve an INR of 2.0 to 3.0) starting 72 hours from the start of enoxaparin sodium or standard heparin therapy and continuing for 90 days. Enoxaparin sodium or standard heparin therapy was used for at least 5 days and until the warfarin INR target was reached. Both enoxaparin sodium regimens were equivalent to standard heparin therapy in reducing the risk of recurrent venous thromboembolism (DVT and/or PE). Efficiency data are presented in the table below.

Major bleeding occurred 1.7% in the enoxaparin sodium 150 IU/kg (1.5 mg/kg) once daily group, 1.3% in the enoxaparin sodium 100 IU/kg (1 mg/kg) twice daily group per day and 2.1% in the heparin group, respectively.

Treatment of unstable angina and myocardial infarction without segment elevationST

In a large multicenter study, 3171 patients in the acute phase of unstable angina or non-Q wave myocardial infarction were randomized to receive acetylsalicylic acid (100 mg to 325 mg once daily) in combination with enoxaparin sodium 100 IU/kg (1 mg /kg) every 12 hours, or IV unfractionated heparin, the dose of which was adjusted based on the APTT. Patients must have been treated in the hospital for a minimum of 2 days and a maximum of 8 days before clinical stabilization, revascularization procedures, or discharge from the hospital. Patients were to be observed for up to 30 days. Compared with heparin, enoxaparin sodium significantly reduced the combined outcome of angina recurrence, myocardial infarction, and death, showing a reduction from 19.8% to 16.6% (16.2% relative risk reduction) at day 14. This decrease was maintained after 30 days (from 23.3% to 19.8%; relative risk reduction 15%).

There were no significant differences in the incidence of major bleeding, although bleeding at the SC injection site was more common.

Treatment of acute myocardial infarction with segment elevationST

In a large multicenter study, 20479 patients with acute ST-segment elevation myocardial infarction (OKCcST) who were eligible for fibrinolysis were randomized to receive enoxaparin sodium 3000 IU (30 mg) IV bolus injection plus doses of 100 IU/kg (1 mg/kg) s.c. followed by s.c. injection of 100 IU/kg (1 mg/kg) every 12 hours or IV unfractionated heparin over 48 hours at a dose adjusted for the aPTT. All patients also received acetylsalicylic acid treatment for at least 30 days. Enoxaparin sodium dosing strategy has been adjusted for patients with severe renal impairment, as well as for the elderly at least 75 years of age. SC injections of enoxaparin sodium were given until discharge from the hospital or for a maximum of eight days (whichever comes first).

In this study, 4,716 (23%) patients underwent coronary angioplasty during antithrombotic therapy using a blinded study drug approach. Therefore, for patients on enoxaparin sodium, PCI should have been performed on the background of enoxaparin sodium (not transfer) in the regimen established in previous studies, i.e. patients did not receive an additional dose of the drug if the last subcutaneous injection of enoxaparin was carried out less than 8 hours before the intervention, or received an intravenous bolus injection of the drug at a dose of 30 IU / kg (0.3 mg / kg) if the last subcutaneous injection of enoxaparin was carried out more than than 8 hours before angioplasty. Enoxaparin significantly reduced the rate of events measured (primary endpoint - combined efficacy assessment, including recurrent myocardial infarction and death without clarification of the cause within 30 days of enrollment in the study: 9.9% in the enoxaparin group compared from 12.0% in the unfractionated heparin group - a 17% relative risk reduction (p

The benefit of treatment with enoxaparin sodium, evident for a range of efficacy outcomes, was seen at 48 hours, at which time there was a 35% relative risk reduction in recurrent myocardial infarction compared with treatment with unfractionated heparin (p

The benefit of enoxaparin on the primary endpoint was consistent across subgroups of patients, regardless of age, gender, location of myocardial infarction, history of diabetes mellitus or myocardial infarction, type of thrombolytic agent used, and time interval between onset of clinical signs and initiation of treatment.

Enoxaparin showed a significant benefit compared with unfractionated heparin in patients who underwent coronary angioplasty within 30 days of entry into the study (relative risk reduction 23%) and in patients who did not undergo coronary angioplasty (relative risk reduction 15%, p = 0.27 for interaction).

The incidence of the 30-day composite endpoint of death, recurrent myocardial infarction, or intracranial bleeding (an indicator of net clinical benefit) was significantly lower (p

The frequency of major bleeding after 30 days was significantly higher (p

The positive effect of enoxaparin on the primary end point of the study, found by day 30, was maintained through 12 months of follow-up.

Impaired liver function

Based on literature data, the use of enoxaparin sodium 4000 IU (40 mg) in patients with cirrhosis (Child-Pugh class B-C) ​​was safe and effective in preventing portal vein thrombosis. It should be noted that literature studies may have limitations. Caution should be exercised in patients with hepatic impairment, as these patients are at an increased risk of bleeding (see section Precautionary measures), and formal dose selection studies have not been conducted in patients with cirrhosis (Child-Pugh class A, B, not C).

Pharmacokinetics

General characteristics

The pharmacokinetic parameters of enoxaparin have been studied mainly in relation to the duration of anti-Xa activity in plasma, as well as in relation to anti-Pa activity in the recommended dose range after single or multiple subcutaneous administration and after a single intravenous administration.

Quantitative determination of anti-Xa and anti-Pa pharmacokinetic activity was carried out using approved amidolytic methods.

Suction

The bioavailability of enoxaparin when administered subcutaneously, estimated on the basis of anti-Xa activity, is close to 100%.

Various doses, forms and dosing regimens may be used.

The average maximum anti-Xa plasma activity is observed 3-5 hours after subcutaneous administration of the drug and is approximately 0.2; 0.4; 1.0 and 1.3 anti-Xa IU/ml after subcutaneous injection of 20, 40 mg and 1 mg/kg and 1.5 mg/kg (2,000 anti-Xa ME, 4,000 anti-Xa ME and 100 anti- Xa IU/kg and 150 anti-Xa IU/kg), respectively.

An intravenous bolus injection of 30 mg (3,000 anti-Xa IU) followed by immediate subcutaneous injection of enoxaparin at a dose of 1 mg/kg (100 anti-Xa IU/kg) and then every 12 hours resulted in an initial anti-Xa peak. Xa activity at the level of 1.16 IU / ml (n = 16) and an average exposure corresponding to 88% of the level of stationary concentration. Stationary concentration was reached on the second day of treatment.

Following repeated s.c. regimens of 4000 IU (40 mg) once daily and 150 IU/kg (1.5 mg/kg) once daily in healthy volunteers, steady-state concentrations are reached on day 2 with a moderate exposure that about 15% higher than after a single dose. Following repeated sc application of the 100 IU/kg (1 mg/kg) twice daily regimen, steady-state concentrations are reached on days 3-4 with an average exposure that is about 65% higher than after a single dose and average maximum and minimum anti-Xa activity levels were approximately 1.2 IU/ml and 0.52 IU/ml, respectively.

The administered volume and dose concentration in the range of 100-200 mg/mL had no effect on pharmacokinetic parameters in healthy volunteers.

The pharmacokinetics of enoxaparin in these dosing regimens is linear. Variability within and between patient groups is low. After repeated s / c introduction of accumulation does not occur.

Plasma anti-IIa activity is about 10 times lower than anti-Xa activity. The average maximum anti-IIa activity is observed approximately 3-4 hours after subcutaneous administration and reaches 0.13 IU / ml and 0.19 IU / ml after repeated administration of 1 mg / kg (100 anti-Xa IU / kg) of body weight at two doses and 1.5 mg/kg (150 anti-Xa IU/kg) body weight for a single dose, respectively.

Distribution

The volume of distribution of anti-Xa activity of enoxaparin sodium is about 4.3 liters and is close to the blood volume.

Biotransformation

Enoxaparin is mainly metabolized in the liver by desulfation and/or depolymerization to low molecular weight substances with very low biological activity.

breeding

Enoxaparin is a low clearance drug. After intravenous administration for 6 hours at a dose of 1.5 mg / kg (150 anti-Xa IU / kg) of body weight, the average clearance of anti-Xa in plasma is 0.74 l / hour.

Elimination of the drug is monophasic with half-lives of 5 hours (after a single subcutaneous injection) and 7 hours (after repeated administration of the drug). The excretion through the kidneys of the active fragments of the drug is approximately 10% of the administered dose, and the total renal excretion of active and inactive fragments is approximately 40% of the administered dose.

Special populations

Elderly

Based on the results of a population pharmacokinetic analysis, it was found that the kinetic profile of enoxaparin does not differ in elderly patients compared with young patients with normal renal function. However, since renal function is known to decrease with age, reduced elimination of enoxaparin may occur in elderly patients (see section 4.4). Method of application and dosage, Contraindications and Precautionary measures).

Impaired liver function

In a study in patients with advanced cirrhosis treated with enoxaparin sodium 4000 IU (40 mg) once daily, a decrease in peak anti-Xa activity was associated with the severity of Child-Pugh hepatic dysfunction. This decrease is mainly due to a decrease in ATIII levels as a result of reduced ATIII synthesis in patients with impaired liver function.

kidney failure

There is a linear relationship between clearance of anti-Xa activity and creatinine clearance upon reaching stationary concentration, indicating a reduced clearance of enoxaparin in patients with reduced renal function. The effect of anti-Xa factor, expressed by AUC (area under the pharmacokinetic curve) at stationary concentration, increases slightly with mild (creatinine clearance 50-80 ml / min) and moderate (creatinine clearance 30-50 ml / min) impaired function kidneys after repeated subcutaneous administration of enoxaparin sodium at a dose of 4,000 IU (40 mg) once a day. In patients with severe renal impairment (creatinine clearance Dosage and administration and Precautionary measures).

Hemodialysis

The pharmacokinetics of enoxaparin sodium is similar to the pharmacokinetics in the control population after single intravenous injections of enoxaparin at doses of 25 IU/kg, 50 IU/kg or 100 IU/kg (0.25 mg/kg, 0.50 mg/kg or 1.0 mg/kg), but the AUC was two times higher than in the control population.

Patient weight

After repeated subcutaneous administration of enoxaparin at a dose of 1.5 mg/kg (150 anti-Xa IU/kg) once a day, the mean area under the pharmacokinetic curve (AUC) of anti-Xa activity is significantly higher at steady state concentration in healthy overweight volunteers (body mass index 30-48 kg/m2) compared with healthy volunteers with normal weight, while the magnitude of the maximum anti-Xa activity does not increase. With subcutaneous administration of the drug to overweight patients, a lower weight-adjusted clearance is noted.

It was found that when the drug was administered as a single subcutaneous dose of 40 mg (4,000 anti-Xa ME) without dose adjustment depending on the patient's weight, anti-Xa exposure was 52% higher in women with low weight (

Pharmacokinetic interactions

No pharmacokinetic interactions have been observed between enoxaparin and thrombolytic drugs when these medicinal products were co-administered.

Preclinical safety data

Other than the anticoagulant effects of enoxaparin sodium, there was no evidence of adverse effects at 15 mg/kg/day in 13-week SC dose toxicity studies in rats and dogs and at 10 mg/kg/day in 26-week studies. toxicity studies of s / c and / in doses in rats and monkeys.

Enoxaparin was not mutagenic when tested in the in vitro system, including the Ames test, in the test for the induction of mutations in mouse lymphoma cells and the test for the induction of chromosomal aberrations in human lymphocytes, and also in the in vivo system in the test for the induction of chromosomal aberrations in rat bone marrow cells.

Studies conducted in pregnant rats and rabbits with sc doses of enoxaparin sodium up to 30 mg/kg/day did not reveal any evidence of teratogenic effects or fetotoxicity. Enoxaparin sodium has been found to have no effect on fertility and reproductive function in male and female rats at SC doses up to 20 mg/kg/day.

Clexaneshownin adults for:

Prevention of venous thromboembolism in moderate-to-high-risk surgical patients, in particular those undergoing orthopedic or general surgery, including surgery for malignancy. Prevention of venous thromboembolism in medical patients with acute illness (such as acute heart failure, respiratory failure, severe infections or rheumatic diseases), and limited mobility with an increased risk of venous thromboembolism. Treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE), with the exception of PE, which may require treatment with thrombolytic drugs or surgery. Prevention of thrombosis in the extracorporeal circuit during hemodialysis.

Acute coronary syndrome:

Treatment of unstable angina and non-ST elevation myocardial infarction (OKCST) in combination with acetylsalicylic acid. Treatment of patients with ST-segment elevation myocardial infarction (OKCsST), including patients who are subject to medical treatment or subsequent percutaneous coronary intervention (PCI).

Features of dosing of the drug when used for various indications.

Prevention of venous thromboembolic complications in moderate and high-risk surgical patients

The individual risk of thromboembolism in patients can be assessed using a validated risk stratification model.

In patients at moderate risk of thromboembolism, the recommended dose of enoxaparin sodium is 2000 IU (20 mg) once daily by subcutaneous (SC) injection. Preoperative initiation (2 hours before surgery) of enoxaparin sodium 2000 IU (20 mg) has been shown to be effective and safe in moderate-risk surgery.

In patients at moderate risk, treatment with enoxaparin sodium should be continued for a minimum period of 7-10 days, regardless of the status of recovery (eg, patient mobility). Prophylaxis should be continued for as long as the patient has significant limitation of mobility.

In patients at high risk of thromboembolism, the recommended dose of enoxaparin sodium is 4000 IU (40 mg) once daily given by subcutaneous injection, preferably 12 hours prior to surgery. If there is a need for preoperative prophylactic administration of enoxaparin sodium earlier than 12 hours (for example, a high-risk patient awaiting delayed orthopedic surgery), the last injection should be given no later than 12 hours before surgery and resumed after 12 hours after surgery. For patients undergoing major orthopedic surgery, extended thromboprophylaxis up to 5 weeks is recommended. For patients at high risk of venous thromboembolism (VTE) undergoing surgery for malignancy in the abdominal cavity or pelvis, extended thromboprophylaxis up to 4 weeks is recommended.

Prevention of venous thromboembolism in medical patients

Treatment with enoxaparin sodium is prescribed for at least 6 to 14 days, regardless of the status of recovery (eg, the patient's mobility). For treatment lasting more than 14 days, benefit has not been established.

Treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE)

Enoxaparin sodium can be administered sc as a once daily injection at 150 IU/kg (1.5 mg/kg) or as an injection twice daily at 100 IU/kg (1 mg/kg).

The regimen should be chosen by the physician based on an individual assessment, including an assessment of the risk of thromboembolism and the risk of bleeding. A once-daily dose regimen of 150 IU/kg (1.5 mg/kg) should be used in uncomplicated patients with a low risk of recurrent VTE. A dose regimen of 100 IU/kg (1 mg/kg) administered twice daily should be used in all other patients such as obese patients with symptomatic PE, malignancy, recurrent VTE, or proximal (iliac vein) thrombosis.

Treatment with enoxaparin sodium is prescribed for an average of 10 days. Oral anticoagulant therapy should be initiated as needed (see "Switching from enoxaparin sodium to oral anticoagulants and vice versa" at the end of the section

Prevention of thrombus formation during hemodialysis

If there is a high risk of bleeding, the dose should be reduced to 50 IU/kg (0.5 mg/kg) in dual vascular access or 75 IU/kg (0.75 mg/kg) in single vascular access.

In hemodialysis, the drug should be injected into the arterial site of the shunt at the beginning of the hemodialysis session. One dose is usually enough for a four-hour session, however, if fibrin rings are detected during longer hemodialysis, you can additionally administer the drug at a rate of 50 IU/kg to 100 IU/kg (from 0.5 mg/kg to 1 mg/kg ) body weight.

There are no data available on patients who use enoxaparin sodium for prophylaxis or treatment and during hemodialysis sessions.

Acute coronary syndrome: treatment of unstable angina andOKCbpST, as well as treatmentOKCcPST

For the treatment of unstable angina and NSTE OKC, the recommended dose of enoxaparin sodium is 100 IU/kg (1 mg/kg) every 12 hours by subcutaneous injection when used in combination with antiplatelet therapy. Treatment should be carried out for at least 2 days and continued until clinical stabilization. The usual duration of treatment is 2-8 days. Acetylsalicylic acid is recommended for all patients without contraindications at an initial oral loading dose of 150 mg - 300 mg (in patients who have not previously received acetylsalicylic acid) and a maintenance dose of 75 mg / day - 325 mg / day for a long time, regardless of treatment strategy. For the treatment of acute OKCCnST, the recommended dose of enoxaparin sodium is a single intravenous (IV) bolus of 3000 IU (30 mg) plus 100 IU/kg (1 mg/kg) sc followed by 100 IU/kg (1 mg /kg) s / c every 12 hours (maximum 10,000 ME (100 mg) for each of their first two s / c doses). Appropriate antiplatelet therapy, such as oral acetylsalicylic acid (75 mg to 325 mg once daily), should be used concomitantly unless contraindicated. The recommended duration of treatment is 8 days, or until the patient is discharged from the hospital if the hospital stay is less than 8 days. In the case of co-administration of enoxaparin with thrombolytics (fibrin-specific or non-fibrin-specific), enoxaparin should be administered at any time between 15 minutes before and 30 minutes after the start of fibrinolytic therapy. For dosage in patients >75 years of age, see chapter "Elderly Patients". For patients treated with PCI, if the last dose of enoxaparin sodium SC was administered less than 8 hours before angioplasty, no additional doses are required. If the last subcutaneous injection was made more than 8 hours before angioplasty, an intravenous bolus of 30 IU/kg (0.3 mg/kg) of enoxaparin sodium should be given.

Pediatric population

The safety and efficacy of enoxaparin sodium in the treatment of children have not been established.

Elderly patients

For all indications other than OKCcnST, there is no need for dose reduction in elderly patients unless renal function is impaired (see below). "Renal failure" and section Precautionary measures).

For the treatment of acute OKCcnST, the initiating IV bolus injection should not be used in elderly patients 75 years of age or older. The initial dose should be 75 IU/kg (0.75 mg/kg) s.c. every 12 hours (maximum 7500 IU (75 mg) for each of the first two s.c. injections only, followed by 75 IU s.c.) /kg (0.75 mg/kg) for the remaining doses). For dosing in elderly patients with impaired renal function, see "Renal failure" below and section Precautionary measures.

Impaired liver function

Data on the use of the drug in patients with impaired liver function are limited (see sections Pharmacodynamics and Pharmacokinetics), and when used in such patients (see section Precautionary measures) caution should be exercised.

Renal failure (see Precautions and Pharmacokinetics sections)

severe kidney failure

Dosages for patients with severe renal insufficiency (creatinine clearance ml / min) are presented below:

Indication: Dosing regimen

Prevention of venous thromboembolic complications: 2000 IU (20 mg) s / c once a day;

Treatment of DVT and PE: 100 IU/kg (1 mg/kg) body weight s.c. once a day;

Treatment of unstable angina and NSTE-ACS: 100 IU/kg (1 mg/kg) body weight s.c. once a day;

Treatment of acute OKCcnST (patients younger than 75 years): 1 x 3000 IU (30 mg) IV bolus plus 100 IU/kg (1 mg/kg) body weight sc, then 100 IU/kg (1 mg/kg) ) body weight s / c every 24 hours;

Treatment of acute OKCcnST (patients over 75 years): No IV initiation bolus, 100 IU/kg (1 mg/kg) body weight s.c. followed by 100 IU/kg (1 mg/kg) body weight s.c. every 24 hours. Correction of recommended dosages does not apply to the indication "hemodialysis".

Moderate and mild renal failure

Despite the fact that dose adjustment in patients with moderate (creatinine clearance 30-50 ml / min) and mild (creatinine clearance 50-80 ml / min) degree of renal insufficiency is not required, careful clinical monitoring of the patient's condition is recommended.

Mode of application

Clexane should not be administered intramuscularly!

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

In acute ST-segment elevation myocardial infarction, treatment should begin with a single IV bolus injection followed immediately by a subcutaneous injection. To prevent thrombus formation during extracorporeal circulation during hemodialysis, it is injected into the arterial line of the dialysis circuit.

The pre-filled disposable syringe is ready for immediate use.

Methodology P /to the injection

The injection is preferably carried out with the patient in the supine position. Enoxaparin sodium is administered by deep subcutaneous injection.

Air bubbles should not be removed from the syringe prior to injection to avoid drug loss when using pre-filled syringes. If the amount of the drug to be administered must be adjusted based on the patient's body weight; graduated pre-filled syringes should be used to achieve the required volume by removing excess before injection. It should be borne in mind that in some cases it is impossible to achieve an accurate dose using the graduations on the syringe, in which case the volume should be rounded up to the nearest division.

Injections should be carried out alternately in the left or right upper lateral or lower lateral parts of the patient's anterior abdominal wall.

During the injection, the syringe needle is inserted vertically to its full length into the skin fold, carefully held between the thumb and forefinger. The skin fold should not be released until the injection is complete. Do not massage the injection site after drug administration.

It should be noted that for pre-filled syringes equipped with an automatic safety system: the safety system is activated at the end of the injection (see instructions in section Instructions for self-administration of CLEXANE (in pre-filled syringes with the PREVENTIS protective system)).

In the case of self-administration, the patient should be advised to follow the instructions provided in the patient information leaflet enclosed in the medicinal product package.

IV (bolus) injection (for "OKCcnST" indication only):

In the case of acute OKCcpST, treatment should begin with a single IV bolus injection followed immediately by an SC injection.

For IV injection, either a multi-dose vial or a pre-filled syringe can be used. Enoxaparin must be injected into the injection site of the intravenous infusion system. This drug should not be mixed or administered simultaneously with other drugs. In order to avoid the presence of any trace amounts of other drugs and thus prevent any mixing with enoxaparin, the intravenous infusion system must be flushed with sufficient saline or glucose solution before and after the intravenous bolus injection of enoxaparin. Enoxaparin can be administered safely using 0.9% saline or 5% glucose.

For an initial bolus of 3000 IU (30 mg) using a prefilled graduated syringe with enoxaparin sodium, excess volume is removed to leave only 3000 IU (30 mg) in the syringe. The dose of 3000 IU (30 mg) can then be directly injected into the IV catheter.

For patients treated with PCI, an additional intravenous bolus of the drug at a dose of 30 IU/kg (0.3 mg/kg) is carried out if the last s / c administration was carried out more than 8 hours before angioplasty.

In order to ensure the accuracy of the small volume of enoxaparin to be administered to a patient, it is recommended that this medicinal product be diluted to a concentration of 300 IU/mL (3 mg/mL).

To obtain a solution concentration of 300 IU/ml (3 mg/ml) using a pre-filled syringe with 6,000 IU (60 mg) of enoxaparin, it is recommended to use a 50 ml infusion bag (i.e., with 0.9% sodium chloride solution or 5% glucose solution) as follows: withdraw 30 ml of the solution from the infusion bag using a syringe and pour out the extracted liquid. Inject the entire contents of the pre-filled syringe, equivalent to 6,000 IU (60 mg) of enoxaparin, to 20 ml of the remaining fluid in the infusion bag. Mix the contents of the package carefully. Withdraw the required volume of the diluted solution with a syringe and inject into the injection site of the intravenous infusion system.

After the dilution process is completed, the volume of the solution to be injected is calculated using the following formula: [volume of the diluted solution (ml) = patient weight (kg) × 0.1] or using the table below. It is recommended to prepare the dilution immediately before use.

The volume to be injected through the IV catheter after dilution is performed at a concentration of 300 IU (3 mg) / ml.

The drug is administered through the intra-arterial catheter of the dialysis circuit to prevent thrombus formation in the extracorporeal circulation during hemodialysis.

Transfer from enoxaparin sodium to oral anticoagulants and vice versa

Clinical observation and laboratory tests [prothrombin time expressed as international normalized ratio (INR)] should be performed more frequently in order to monitor the effect of VKA.

Since there is a time lag before VKA reaches its maximum effect, enoxaparin sodium therapy should be continued at a constant dose for as long as necessary to achieve an INR level within the desired therapeutic range in two consecutive assays.

For patients receiving VKAs, VKAs should be discontinued and the first dose of enoxaparin sodium administered when the INR falls below the therapeutic range.

For patients currently receiving enoxaparin sodium, in accordance with the instructions for the use of direct-acting oral anticoagulants, you should stop using enoxaparin sodium and start using direct-acting oral anticoagulants 0-2 hours before the time at which the next dose of enoxaparin sodium was scheduled.

For patients currently receiving direct-acting oral anticoagulants, the first dose of enoxaparin sodium should be administered at the time when the next dose of direct-acting oral anticoagulants should have been taken.

Application forspinal/epidural anesthesia or lumbar puncture

If the clinician decides to proceed with anticoagulation therapy in the presence of epidural or spinal anesthesia/analgesia or lumbar puncture, careful neurological monitoring is recommended due to the risk of neuraxial hematomas (see section Precautionary measures).

There must be at least a 12-hour interval between the last injection of enoxaparin sodium at a prophylactic dose (2000 IU (20 mg) once a day, 3000 IU (30 mg) once or twice a day, 4000 IU (40 mg) once a day ) and placement of a needle or catheter.

For continuous insertion techniques, a similar delay of at least 12 hours should also be observed before withdrawing the catheter.

For patients with creatinine clearance ml/min, doubling this time interval to at least 24 hours should be observed before puncture/catheter insertion or removal.

Preoperative (2 hours before the operation) use of enoxaparin sodium 2000 ME (20 mg) is not compatible with neuraxial anesthesia.

There must be at least a 24-hour interval between the last injection of enoxaparin sodium at a therapeutic dose (75 IU (0.75 mg) / kg twice a day, 100 IU (1 mg) / kg twice a day, 150 IU (1.5 mg)/kg once daily) and placement of a needle or catheter (see also section contraindications).

For continuous insertion techniques, a similar delay of 24 hours should be observed before the catheter is withdrawn.

For patients with creatinine clearance ml/min, doubling this interval should be observed before puncture/catheter insertion or removal for at least 48 hours.

Patients receiving twice daily injections (i.e. 75 IU/kg (0.75 mg/kg) twice daily or 100 IU/kg (1 mg/kg) twice daily) should skip the second dose enoxaparin sodium to allow sufficient interval before insertion or removal of the catheter.

Anti-Xa levels are still detectable at these time points, and these intervals are not a guarantee that a neuraxial hematoma will be avoided.

However, although it is not possible to give clear recommendations on the timing of the next dose of enoxaparin sodium after catheter removal, the use of enoxaparin sodium should be avoided until at least 4 hours after spinal/epidural puncture or after the catheter has been removed. The interval should be based on a benefit-risk assessment, taking into account both the risk of thrombosis and the risk of bleeding during spinal procedures, as well as taking into account the risk factors of the patient.

Side effect

Security Profile Summary

Enoxaparin sodium has been evaluated in over 15,000 patients who received enoxaparin sodium in clinical studies. They included 1776 cases of prophylaxis of deep vein thrombosis after orthopedic or abdominal surgery in patients at risk of thromboembolic complications, 1169 cases of prophylaxis of deep vein thrombosis in medical patients with acute disease with severely limited mobility, 559 cases for the treatment of DVT with PE or without PE, 1578 cases for the treatment of unstable angina and non-Q wave myocardial infarction, and 10176 cases for the treatment of acute OKCCnST.

The mode of application of enoxaparin sodium during these clinical studies varies depending on the indication. The dose of enoxaparin sodium was 4000 IU (40 mg) s.c. once daily for the prevention of deep vein thrombosis after surgery or in medical patients with acute illness and severely limited mobility. In the treatment of DVT with or without PE, patients received enoxoparin sodium at a dose of 100 IU/kg (1 mg/kg) s.c. every 12 hours, or at a dose of 150 IU/kg (1.5 mg/kg) s.c. once a day. In clinical studies for the treatment of unstable angina and non-Q wave myocardial infarction, doses were 100 IU/kg (1 mg/kg) s.c. every 12 hours, and in a clinical study for the treatment of acute OKCcnST, the dose of enoxaparin sodium was 3000 IU (30 mg) IV bolus followed by 100 IU/kg (1 mg/kg) s.c. every 12 hours.

In clinical studies, bleeding, thrombocytopenia, and thrombocytosis were the most commonly reported reactions (see section Precautionary measures and "Description of selected adverse reactions" below).

Summary table with a list of adverse reactions

Other adverse reactions observed in clinical studies and reported in the course of post-marketing experience of use (* indicates reactions from post-marketing experience of use) are described in detail below.

The frequency is defined as follows: very frequent (≥ 1/10); frequent (from ≥ 1/100 to

Blood disorders andlymphaticsystems

Common: Bleeding, hemorrhagic anemia*, thrombocytopenia, thrombocytosis Rare: Eosinophilia* Rare: Cases of immune-allergic thrombocytopenia with thrombosis; in some cases, thrombosis was complicated by the development of organ infarction or limb ischemia (see section Precautionary measures).

Immune System Disorders

Common: Allergic reaction Rare: Anaphylactic/anaphylactoid reactions, including shock*

Nervous System Disorders

Frequent: Headache*

Vascular disorders

Rare: Spinal hematoma* (or neuraxial hematoma) with enoxaparin sodium and concomitant spinal/epidural anesthesia or lumbar puncture. These reactions led to the development of neurological disorders of varying severity, including persistent or irreversible paralysis (see section Precautionary measures).

Liver and biliary tract disorders

Very common: Elevated liver enzymes (mainly transaminase > 3 times upper limit of normal) Uncommon: Hepatocellular (hepatocellular) liver damage* Rare: Cholestatic liver damage*

Skin and subcutaneous tissue disorders

Common: Urticaria, pruritus, erythema Uncommon: Bullous dermatitis Rare: Alopecia (baldness)* Rare: Cutaneous vasculitis*, skin necrosis*, usually developing at the injection site (these phenomena were usually preceded by purpura or erythematous papules, infiltrated and painful). In these cases, Clexane therapy should be discontinued. Injection site nodules* (inflammatory nodules that were not cystic cavities containing enoxaparin). They disappear after a few days and are not a reason to stop treatment.

Musculoskeletal and connective tissue disorders

Rare: Osteoporosis* after long-term therapy (more than 3 months)

Systemic disorders and complications at the injection site

Common: Hematoma at the injection site, pain at the injection site, other reactions at the injection site (such as swelling, bleeding, hypersensitivity, inflammation, mass, pain or reaction) Uncommon: Local irritation, necrosis of the skin at the injection site

Abnormalities in laboratory tests

Rare: Hyperkalemia* (see sections Precautionary measures and

Description of individual adverse reactions

Bleeding

These reactions include heavy bleeding occurring with a maximum frequency of 4.2% in patients (surgical patients). Some of these cases have been fatal. In surgical patients, bleeding is considered major if: (1) if the bleeding caused a significant clinical event or (2) if it was accompanied by a decrease in hemoglobin ≥ 2 g/dL or if 2 or more units of blood products were transfused. Retroperitoneal and intracranial bleeding has always been considered large.

As with other anticoagulants, bleeding may occur with enoxaparin in the presence of concomitant risk factors, such as: organic lesions prone to bleeding, invasive procedures, or concomitant use of drugs that affect hemostasis (see sections Precautionary measures and Interaction with other drugs).

Class of Organ Systems - Blood and Lymphatic System Disorders:

Very common: Bleedingα

Rare: retroperitoneal bleeding

Prevention in patients:

Frequent: Bleedingα

Treatment in patients with DVTWith/without TELA:

Very common: Bleedingα

Infrequent:

Treatment in patients with unstable angina and non-serrated MI- Q:

Frequent: Bleedingα

Rare: retroperitoneal bleeding

Treatment in patients withsharpOKccPST:

Frequent: Bleedingα

Infrequent: Intracranial hemorrhage, Retroperitoneal bleeding

α: such as hematoma, bruising other than that at the injection site, wound hematoma, hematuria, epistaxis and gastrointestinal bleeding.

Thrombocytopenia and thrombocytosis

Organ system class - Blood and lymphatic system disorders

Prevention in surgical patients:

Very common: Thrombocytosisβ

Frequent: Thrombocytopenia

Prevention in patients:

Infrequent: Thrombocytopenia

Treatment in patients with DVTWith/without TELA:

Very common: Thrombocytosisβ

Frequent: Thrombocytopenia

Treatment in patients with unstable angina and MItoothless- Q:

Infrequent: Thrombocytopenia

Treatment in patients withsharpOKCcPST:

Frequent: Thrombocytosisβ, Thrombocytopenia

Very rare: immuno-allergic thrombocytopenia

β: Increased platelet count > 400 g/l

Pediatric population

The safety and efficacy of enoxaparin sodium in children has not been established (see section Method of application and dosage).

Reporting suspected adverse reactions

Reporting suspected adverse reactions after drug registration is important. This allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions through the national reporting system.

Contraindications

Enoxaparin sodium is contraindicated in patients with:

Hypersensitivity to enoxaparin sodium, heparin or its derivatives, including other low molecular weight heparins (LMWH), or any of the excipients listed in the composition section; History of immune-mediated heparin-induced thrombocytopenia (HIT) within the past 100 days or in the presence of circulating antibodies (see also section Precautionary measures); Active clinically significant bleeding and other conditions with a high risk of bleeding, including recent hemorrhagic stroke, gastrointestinal ulcer, malignancy with a high risk of bleeding, recent brain surgery, spinal or ophthalmic surgery, known or suspected esophageal varices, arteriovenous malformations, vascular aneurysms, or serious intraspinal or intracranial vascular disorders;

Spinal or epidural anesthesia, or regional anesthesia when enoxaparin sodium is used for treatment in the previous 24 hours (see section Precautionary measures).

Overdose

Signs and symptoms

Accidental overdose of intravenous, extracorporeal or subcutaneous enoxaparin can lead to hemorrhagic complications. After oral administration of even large doses, absorption of enoxaparin is unlikely.

Overdose treatment

Anticoagulant effects can be largely neutralized by slow intravenous administration of protamine sulfate, the dose of which depends on the dose of enoxaparin administered. One 1 mg protamine sulfate neutralizes the anticoagulant effect of one 1 mg (100 anti-Xa IU) of enoxaparin (see information on the use of protamine salts), if enoxaparin was administered no more than 8 hours before the administration of protamine. 0.5 mg of protamine neutralizes the anticoagulant effect of 1 mg (100 anti-Xa ME) of enoxaparin if more than 8 hours have passed since the administration of the latter or if a second dose of protamine is necessary. If 12 or more hours have passed since the administration of enoxaparin, the administration of protamine may not be required.

However, even with the introduction of large doses of protamine sulfate, the anti-Xa activity of enoxaparin is not completely neutralized (by a maximum of 60%).

Pregnancy, fertility and breastfeeding

Pregnancy

There is no evidence that enoxaparin crosses the placental barrier in the second and third trimesters of pregnancy. There is no information available regarding the first trimester.

No evidence of fetotoxicity or teratogenicity has been found in animal studies (see section According to animal studies, it was found that the penetration of enoxaparin through the placenta is minimal.

Because there are no adequate and well-controlled studies in pregnant women, and because animal studies cannot always predict human response, enoxaparin sodium should only be used during pregnancy if clearly needed by a physician.

Pregnant women receiving enoxaparin sodium should be closely monitored for signs of bleeding or excessive anticoagulation, and warned of the risk of bleeding. Overall, the data indicate that there is no evidence of an increased risk of bleeding, thrombocytopenia, or osteoporosis compared with the risk seen in non-pregnant women, other than in pregnant women with a prosthetic heart valve (see section Precautionary measures).

If epidural anesthesia is planned, it is recommended to cancel enoxaparin treatment in advance (see section Precautionary measures).

Breast-feeding

In rats during lactation, the concentration of 35S-enoxaparin or its known metabolites in milk was extremely low.

Until now, it remains unknown whether unchanged enoxaparin is excreted in breast milk. Absorption of enoxaparin when taken orally is unlikely. Clexane can be used during breastfeeding.

Fertility

There are no clinical data on the effect of enoxaparin on fertility. Animal studies have shown no effect on fertility (see section Preclinical safety data).

Influence on the ability to drive vehicles or other mechanisms

Enoxaparin sodium has no or negligible effect on the ability to drive or use machines.

Precautionary measures

General

Enoxaparin must not be mixed with other drugs!

The use of enoxaparin and other low molecular weight heparins should not be alternated, as they differ from each other in the way of production, molecular weight, specific anti-Xa and anti-Pa activity, units of measurement and dosage, as well as clinical efficacy and safety. And, as a consequence, the drugs have different pharmacokinetics, biological activity (anti-Xa activity and platelet interaction). Therefore, it is necessary to pay special attention to and follow the instructions for use specific to each brand-name drug.

History of heparin-induced thrombocytopenia (>100 days)

The use of enoxaparin sodium in patients with a history of immune-mediated heparin-induced thrombocytopenia in the past 100 days or in the presence of circulating antibodies is contraindicated (see section contraindications). Circulating antibodies may persist for several years.

Enoxaparin sodium should be used with extreme caution in patients with a history (>100 days) of heparin-induced thrombocytopenia without circulating antibodies. The decision to use enoxaparin sodium in such a case should only be taken after a careful assessment of the benefits and risks, and after considering the use of non-heparin alternative treatments (for example, danaparoid sodium or lepirudin).

Platelet count control

The risk of antibody-mediated HIT also exists with LMWH. If thrombocytopenia develops, it usually occurs between the 5th and 21st days after the start of treatment with enoxaparin sodium.

The risk of HIT is higher in postoperative patients and mainly after cardiac surgery and in patients with malignancy.

If there are clinical symptoms suggestive of HIT (any new episode of arterial and/or venous thromboembolism, any painful skin lesion at the injection site, any allergic or anaphylactoid reaction to treatment), the platelet count should be determined. Patients should be aware that these symptoms may occur and if they do, they should inform their physician.

In practice, if there is a confirmed significant decrease in the platelet count (from 30% to 50% of the initial value), treatment with enoxaparin sodium should be stopped immediately, and the patient should be transferred to another non-heparin anticoagulant alternative treatment.

Bleeding

As with other anticoagulants, bleeding may occur. With the development of bleeding, its cause should be determined and appropriate treatment should be prescribed.

Enoxaparin sodium, as with any other anticoagulant therapy, should be used with caution in conditions with an increased likelihood of bleeding, such as:

Impaired hemostasis, history of peptic ulcer, recent ischemic stroke, severe hypertension, recent diabetic retinopathy, neurosurgical or ophthalmic surgery, concomitant use of drugs that affect hemostasis (see section Interaction with other drugs).

Laboratory tests

At doses used for the prevention of thromboembolic complications, enoxaparin sodium does not significantly affect bleeding time and blood coagulation, as well as platelet aggregation or their binding to fibrinogen.

At higher doses, activated partial thromboplastin time (APTT) and activated clotting time (ABC) may increase. An increase in APTT and ABC values ​​is not in a direct linear relationship with an increase in the antithrombotic activity of enoxaparin sodium and, therefore, cannot be used as reliable indicators in monitoring the activity of enoxaparin sodium.

Spinal/epidural anesthesia orlumbarpuncture

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

Cases of the occurrence of neuraxial hematomas with the use of enoxaparin sodium and simultaneous spinal / epidural anesthesia or spinal puncture with the development of prolonged or irreversible paralysis are described. These events are rare with enoxaparin sodium 4000 IU (40 mg) once daily or lower dosing regimens. The risk of these events is higher with the use of high doses of enoxaparin sodium, with the use of postoperative indwelling epidural catheters, with concomitant use of additional drugs that affect hemostasis, such as non-steroidal anti-inflammatory drugs (NSAIDs), with traumatic or repeated epidural or spinal puncture, or with patients with a history of spinal surgery or spinal deformity.

In order to reduce the potential risk of bleeding associated with the simultaneous use of enoxaparin sodium and epidural or spinal anesthesia / analgesia or spinal puncture, the pharmacokinetic profile of enoxaparin sodium should be taken into account (see section Pharmacokinetics). To reduce the potential risk of bleeding, insertion and removal of the catheter is best done when the anticoagulant effect after enoxaparin is low, but the exact time to achieve a sufficiently low anticoagulant effect in different patients is not known. In patients with creatinine clearance, additional caution should be exercised due to the fact that the elimination of enoxaparin sodium is longer (see section Method of application and dosage).

If the clinician decides to administer anticoagulation therapy during epidural or spinal anesthesia/analgesia or lumbar puncture, frequent monitoring should be performed to detect any signs and symptoms of neurological disorders such as pain in the midline of the back, sensory or motor disturbances (numbness or weakness in the lower extremities), bowel and/or bladder dysfunction. The patient should be warned about the need to immediately inform the doctor if there are signs of the development of any of the above neurological symptoms. If signs or symptoms of a spinal hematoma are suspected, prompt diagnosis and treatment should be initiated, including consideration of spinal cord decompression, even if such treatment fails to prevent or reverse neurological complications.

Skin necrosis/cutaneous vasculitis

Skin necrosis and cutaneous vasculitis have been reported with LMWH, in which case enoxaparin should be discontinued immediately.

Percutaneousproceduresrevascularizationcoronary vessels

In order to minimize the risk of bleeding after instrumental interventions on the vessels during the treatment of unstable angina, OKCcnST and acute OKCcnST, the recommended intervals between doses of enoxaparin sodium injections should be strictly observed. It is very important to achieve a state of adequate hemostasis at the site of arterial access after PCI. If a closure device is used, the introducer can be removed immediately. When using the local bleeding control method with a pressure bandage, the sheath should be removed 6 hours after the last intravenous or subcutaneous injection of enoxaparin. If treatment with enoxaparin is continued, the next dose of the drug should be administered no earlier than 6-8 hours after the removal of the sheath. The site of arterial access should be monitored in order to detect signs of bleeding and hematoma formation in a timely manner.

Acute infective endocarditis

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

Mechanical heart valves

Studies to reliably assess the efficacy and safety of enoxaparin in preventing thromboembolic complications in patients with mechanical heart valves have not been conducted. However, isolated cases of mechanical heart valve thrombosis have been reported in patients taking enoxaparin to prevent thromboembolism. Confounding factors, including underlying disease and lack of clinical data, limit the evaluation of these cases. Some of these cases have been described in pregnant women in whom thrombosis resulted in maternal and fetal death. Therefore, pregnant women with mechanical heart valves are at increased risk of developing thromboembolism.

Pregnant women with mechanical heart valves

The use of enoxaparin for the prevention of blood clots in pregnant women with mechanical heart valves has not been adequately studied. In a clinical study in pregnant women with mechanical heart valves who received enoxaparin 100 IU/kg (1 mg/kg) twice daily to reduce the risk of thromboembolic complications, 2 of 8 women developed thrombosis, which caused valvular obstruction resulting in to maternal and fetal death. During post-marketing surveillance of the use of the drug, isolated cases of thrombosis have been reported in pregnant women with mechanical heart valves who received enoxaparin for the prevention of thromboembolic complications. Therefore, pregnant women with mechanical heart valves are at increased risk of developing thromboembolism.

Elderly patients

When using the drug in prophylactic doses in elderly patients, there is no increased risk of bleeding. Elderly patients (especially patients aged eighty years and older) may have an increased risk of bleeding when using the drug at a therapeutic dose. Careful clinical monitoring is recommended, and dose reduction may be considered in patients over 75 years of age who are being treated for OKCcnST (see sections Method of application and dosage and Pharmacokinetics).

kidney failure

In patients with renal insufficiency, as a result of increased exposure to enoxaparin sodium, the risk of bleeding increases. Careful clinical monitoring is recommended for these patients, and biological monitoring by anti-Xa activity should be considered (see sections Method of application and dosage and Pharmacokinetics).

In patients with severe renal insufficiency (creatinine clearance 15-30 ml / min), since exposure to enoxaparin sodium is significantly increased, dosage adjustments are recommended for therapeutic and prophylactic dosage ranges (see section Method of application and dosage).

Dose adjustment is not required in patients with moderate (creatinine clearance 30-50 ml/min) and mild (creatinine clearance 50-80 ml/min) renal insufficiency.

Impaired liver function

Enoxaparin sodium 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 levels is not reliable in patients with cirrhosis and is not recommended (see section Pharmacokinetics).

Low body weight

There is an increase in the exposure of enoxaparin in its prophylactic administration (without dose adjustment depending on the patient's weight) in women weighing less than 45 kg and in men weighing less than 57 kg, which may lead to an increased risk of bleeding. Therefore, careful clinical monitoring is recommended in these patients (see section 4.4). Pharmacokinetics).

Obese patients

Obese patients have a higher risk of developing thromboembolism. The safety and efficacy of prophylactic doses in obese patients (BMI >30 kg/m2) has not been fully established and there is no agreement on dose adjustments. Closer monitoring is needed for the occurrence of signs and symptoms of thromboembolism in these patients.

Hypercalemia

Heparins can suppress adrenal secretion of aldosterone, leading to hyperkalemia (see section Side effect), in particular in patients such as those with diabetes mellitus, chronic renal failure, pre-existing metabolic acidosis, and those taking drugs that increase potassium levels (see section Interaction with other drugs). Plasma potassium levels should be monitored regularly, especially in patients at risk.

Traceability

LMWHs are biological medicinal products. In order to improve LMWH traceability, it is recommended that healthcare professionals record the trade name and batch number of the drug used in the patient file.

Interaction with other drugs

Drugs affecting hemostasis (see section Precautionary measures)

It is recommended that certain drugs that affect haemostasis be discontinued prior to enoxaparin sodium therapy, unless strictly indicated. If a combination is indicated, enoxaparin sodium should be used, if necessary, under close clinical and laboratory monitoring.

Drugs that affect hemostasis include drugs such as:

Systemic salicylates, acetylsalicylic acid at anti-inflammatory doses, and NSAIDs, including ketorolac, Other thrombolytics (eg, alteplase, reteplase, streptokinase, tenecteplase, urokinase), and anticoagulants (see section Method of application and dosage).

Simultaneous use with caution

The following medicines may be used with caution at the same time as enoxaparin sodium:

Other drugs that affect hemostasis, such as: Platelet aggregation inhibitors, including acetylsalicylic acid, used in an antiplatelet dose (cardioprotection), clopidogrel, ticlopidine and Ilb / IIIa glycoprotein antagonists, indicated in acute coronary syndrome due to the risk of bleeding, Dextran 40, Systemic glucocorticoids. Medications that increase potassium levels:

Medicinal products that increase serum potassium levels may be co-administered with enoxaparin sodium with close clinical and laboratory monitoring (see sections Precautionary measures and Side effect).

Release form

For dosages of 2000 anti-Xa IU / 0.2 ml; 6000 anti-Xa IU/0.6 ml: 0.2 ml and 0.6 ml of the drug, respectively, into a glass syringe with a Preventis protective system. 2 syringes in a blister. 1 or 5 blisters, together with instructions for use, are packed in a cardboard box.

For dosages of 4000 anti-Xa IU/0.4 ml; 8000 anti-Xa IU/0.8 ml: 0.4 ml and 0.8 ml of the preparation, respectively, into a glass syringe with a Preventis protective system. 2 syringes in a blister. 5 blisters, together with instructions for use, are packed in a cardboard box.

Storage conditions

Do not store above 25°C.

Keep out of the reach of children!

Best before date

3 years. Do not use the drug after the expiration date.

Holiday conditions

On prescription.

Manufacturer:

SANOFI-AVENTIS FRANCE, manufactured by Sanofi Winthrop Industria, France.

Addressmanufacturer:

180 Rue Jean Jaures

94702, MAISONS-ALFORT,

FRANCE (FRANCE).

Instructions for self-administration of CLEXANE (in pre-filled syringes with the PREVENTIS protective system):

Clexane is an injectable solution in pre-filled syringes with an automatic safety system to prevent accidental needle sticks after injection. Instructions for use are listed below.

Proper use of syringes is essential to reduce the risk of pain and bruising at the injection site. The instructions for use must be followed. In order to avoid accidental needle stick after injection, the pre-filled syringes are equipped with an automatic safety system.

Preparation of the injection site

The injection should be carried out in the adipose tissue under the skin, in the left or right upper-lateral or lower-lateral parts of the anterior abdominal wall of the patient, preferably in the supine position.

Injections should be carried out alternately. The injection site should be located at least 5 centimeters to either side of the navel.

Wash your hands before injecting. Wipe (without effort) the selected injection site with cotton soaked in alcohol. The injection site should be changed with each new injection.

Preparing the syringe for injection

Check the expiration date on the label or package. It is forbidden to use an expired drug.

Make sure that the syringe is not damaged and that the drug in it is a clear solution without particles. If the syringe is damaged or the drug solution is not clear, take another syringe.

For dosages of 20 mg and 40 mg:

The pre-filled syringe is ready to use. Do not attempt to remove the air bubble from the syringe prior to injection.

For pre-filled 60 mg, 80 mg syringes

Remove the protective cap of the needle.

Set the required dose (if necessary):

The amount of drug administered should be adjusted to the patient's body weight; accordingly, before injection, excess drug must be removed from the syringe. Holding the syringe with the needle down (the air bubble must remain in the syringe), remove the excess drug from the syringe into a suitable container.

NOTE:At the end of the injection

the safety device will not be able to activate if the excess drug has not been removed before its administration.

If the injected dose does not need to be adjusted, the pre-filled syringe is ready for use. Do not attempt to remove the air bubble from the syringe prior to injection.

A drop may appear at the tip of the needle. In this case, turn the syringe with the needle down and remove the drop by tapping the syringe gently.

Injection for all dosages of pre-filled syringes: 20, 40, 60, 80

Take a comfortable sitting or lying position and grasp the skin fold with your thumb and forefinger.

Holding the syringe perpendicular to the skin surface, insert the needle into the skin fold. Do not insert the needle into the skin fold from the side! Hold the skin fold throughout the injection. Complete the injection by injecting all the drug contained in the syringe.

Remove the syringe from the insertion site by keeping your finger on the plunger of the syringe.

Point the needle away from yourself or other people and activate the safety system by pressing hard on the syringe plunger. The syringe needle will automatically close with a protective cap, and an audible click will be heard, confirming the activation of the system.

Note: The safety system can only be activated after the syringe has been emptied!

Throw the syringe into a sharps container immediately.

Any unused drug or waste should be disposed of in accordance with local regulations.

The period of pregnancy is characterized by changes in all organs and systems of the expectant mother. While carrying a baby, some women experience an increase in the viscosity of the intravascular fluid and an increase in platelet activity. The described transformations of the coagulation system lead to the formation of blood clots.

Clexane during pregnancy is used to treat pathologies associated with an increase in blood viscosity and the formation of blood clots. The drug is highly effective, its use improves tissue nutrition. However, the drug has a large list of contraindications and side effects, so it can only be used under the supervision of specialists.

The composition of the drug

The drug has an antithrombotic effect. The drug affects the reactions that carry out the synthesis of blood clots. Taking the medication prevents the activation of platelets. Due to these actions, Enoxaparin contributes to a shift in homeostasis towards the anticoagulant blood system.

According to the instructions for use, the drug quickly enters the bloodstream after the injection. The maximum concentration of the drug in plasma is observed 4 hours after the injection of Clexane. Most of the drug is excreted by the kidneys in the urine. Complete cleansing of the blood is observed after 3 days from the last dose of the drug.

Release form and expiration date

The drug is dispensed from pharmacies only with a prescription form. The drug should not be stored at temperatures above 24 degrees. The shelf life of Clexane is 36 months, after its expiration, the use of the drug is strictly prohibited.

Indications for use

Sometimes there are failures in the processes of platelet activation, leading to excessive stimulation of the blood coagulation system. This phenomenon is facilitated by the hereditary predisposition of a woman, the bearing of twins, high blood pressure, as well as other conditions and concomitant diseases.

Increased platelet activity is a risk factor for the formation of blood clots in the vessels. Blood clots clog arteries and veins, reducing tissue metabolism.

If a blood clot enters the arteries of the placenta, there is a risk of its premature detachment and spontaneous abortion. Also, the formation of blood clots is the cause of premature aging of the body, a strong increase in blood pressure.

If a thrombus forms in a vein, the outflow of fluid from the organ is disrupted. This process leads to the development of edema and a decrease in the nutrition of the affected tissue. The danger of venous clots lies in the risk of their separation and the occurrence of pulmonary thromboembolism.

Attention! The effect of the active substance of Enoxaparin sodium on the fetus has not been fully studied. Clexane should only be used during pregnancy if clearly needed by your doctor.

• reduction of blood clotting time;
• increase in prothrombin index;
• decrease in the amount of antithrombin III;
• increasing the amount of d-dimer;
• an increase in the number of platelets.

Also, the drug can be used for the treatment of thrombosis in the deep veins of the lower extremities and the treatment of pulmonary embolism. The drug is used for coronary heart disease and the presence of myocardial infarction.

The effect of the drug on the fetus

It was also found that the drug does not have a toxic effect on the embryos of laboratory animals - Enoxaparin did not contribute to intrauterine growth retardation and development. However, taking the drug must be justified by the presence of strict indications.

Clexane in the first trimester of pregnancy must be used with extreme caution. In the early stages of bearing a baby, the formation of all organs of the embryo is observed. Taking medications can have a negative effect on the health of the unborn child.

Cancellation of Clexane during pregnancy should occur gradually. A sharp refusal to take the drug can contribute to the development of complications from the blood coagulation system and lead to spontaneous abortion.

Taking the drug in the second and third trimester should be monitored by a doctor. The use of the drug is possible only if there are vital indications from the future mother or fetus.

Instructions for use

For preventive purposes, the drug can only be injected subcutaneously. In no case should the drug be administered intravenously. This use of the drug can lead to severe side effects. Intravenous administration of Clexane is carried out only in the presence of serious diseases in a hospital setting.

The syringe with the medication is ready for use. When using a dosage form with a volume of 0.2 or 0.4 milliliters, gas bubbles should not be released.

Usually at home, the drug is injected into the skin of the abdomen to the side of the navel by at least 5 centimeters. Alternate right and left sides of the body. Do not inject the drug into the skin where there is a bruise. Also, the syringe is allowed to be used on the shoulder and thigh.

Before using the syringe with the drug of the expectant mother, you should thoroughly wash your hands and the injection site with soap and water, then dry them. After that, she should treat the skin of the abdomen with an antiseptic wipe or a cotton swab soaked in ethyl alcohol.

To maintain the sterility of the needle, you need to remove the cap and immediately inject the drug into the skin, avoiding touching the syringe on any objects. A woman needs to make a fold on her stomach with the thumb and forefinger. Then she should insert the needle into it to its full length at a right angle and press the plunger of the syringe. Do not let go of the skin fold before removing the drug.

After the introduction of the full dose of the drug, the needle should be pulled out of the skin fold. Then it is allowed to release it from the fingers. The expectant mother does not need to rub or touch the injection site. It is recommended to throw away the used syringe, preventing it from reaching children.

Contraindications

Clexane should not be used in patients with hereditary or acquired diseases, accompanied by a violation of the rheological properties of the blood in the direction of reducing platelet activity. These include systemic vasculitis, stomach or duodenal ulcers, and a severe drop in blood pressure.

The drug should not be used in the presence of diabetes in the stage of decompensation. Also, the drug is forbidden to be taken after a hemorrhagic stroke suffered over the past three months. Clexane is not used in persons with severe organic lesions in the central nervous system.

Among other contraindications for admission, the following diseases and conditions are distinguished:

• severe pathology of the filtration function of the kidneys;
• chronic liver diseases in the stage of decompensation;
• bacterial damage to the heart valves;
• pericarditis;
• open wounds;
• use of an intrauterine device.

Side effects

The drug quite often causes allergic reactions. Usually they are manifested by skin changes - itching, rashes, swelling of the fiber. Less commonly, the drug contributes to systemic lesions of the body - anaphylactic shock and vasospasm.

Also, after the injection of Clexane, many patients note the appearance of a bruise at the site of use of the syringe. From the side of the central nervous system, headaches and nausea may occur. Prolonged use of the drug causes damage to the liver tissue and a violation of the structure of the bones. Rarely, taking the drug contributes to the development of subcutaneous infiltrates and nodules.

Kleksan's analogs

A drug derived from calf erythrocytes. This remedy is a stimulator of tissue regeneration and improvement of metabolism. The medicine is sold in the form of ampoules with a solution for intravenous and intramuscular injections. The drug is indicated in the presence of stroke, heart attack and pathologies of tissue nutrition.

It is an antiplatelet agent with the active ingredient Dipyridamole. The drug is prescribed to improve tissue nutrition in atherosclerosis and other lesions. The drug is available in the form of pills and tablets. Curantyl is allowed to be taken by expectant mothers if there are serious indications.

A drug belonging to the group of steroid hormones. The drug is indicated for maintaining pregnancy in violation of androgen synthesis. Also, the drug can be used for hormonal therapy before the planned conception or IVF. Metipred in small doses is allowed to be taken during the period of bearing a baby.

Flenox is a complete analogue of Clexane in terms of the active substance. The drug is indicated for the treatment and prevention of increased activity of the coagulation system. If it is impossible to use Clexane as prescribed by a doctor, the expectant mother can replace it with Flenox.

Fragmin is a direct acting anticoagulant drug. The drug is indicated for use in patients with disorders in the coagulogram towards the activation of the blood coagulation system. The drug is available in the form of ready-made syringes with a solution for injection, it can be used during pregnancy.

Composition and form of release

Injection:

• 2000 anti-Xa IU/0.2 ml; 4000 anti-Xa IU/0.4 ml; 6000 anti-Xa IU/0.6 ml; 8000 anti-Xa IU/0.8 ml; 10,000 anti-Xa IU/1 ml.

* weight calculated based on the content of enoxaparin sodium used (theoretical activity 100 anti-Xa IU/mg).

For dosages of 2000 anti-Xa IU/0.2 ml; 4000 anti-Xa IU/0.4 ml; 8000 anti-Xa IU / 0.8 ml: 0.2 ml, or 0.4 ml, or 0.8 ml of the drug solution in a glass syringe, respectively.

2 syringes in a blister. 1 or 5 blisters per carton/

For dosages of 6000 anti-Xa IU/0.6 ml; 10,000 anti-Xa IU / 1 ml: 0.6 ml or 1 ml of the drug solution in a glass syringe, respectively.

2 syringes in a blister. 1 blister in a cardboard box.

Description of the dosage form

Clear, colorless to pale yellow solution.

Pharmacokinetics

The pharmacokinetics of enoxaparin in these dosing regimens is linear. Variability within and between patient groups is low. After repeated s / c administration of 40 mg enoxaparin sodium once a day and s / c administration of enoxaparin sodium at a dose of 1.5 mg / kg once a day in healthy volunteers, the equilibrium concentration is reached by day 2, and the area under the pharmacokinetic curve is on average 15% higher than after a single injection.

After repeated s / c injections of enoxaparin sodium at a daily dose of 1 mg / kg twice a day, the equilibrium concentration is reached after 3-4 days, and the area under the pharmacokinetic curve is on average 65% higher than after a single injection and the average values ​​of Cmax are respectively 1.2 and 0.52 IU/ml. The bioavailability of enoxaparin sodium with s / c administration, estimated on the basis of anti-Xa activity, is close to 100%. The volume of distribution of anti-Xa activity of enoxaparin sodium is approximately 5 liters and approaches the blood volume. Enoxaparin sodium is a low clearance drug. After intravenous administration for 6 hours at a dose of 1.5 mg/kg, the average clearance of anti-Xa in plasma is 0.74 l/h. The excretion of the drug is monophasic with a T1 / 2 of 4 hours (after a single subcutaneous injection) and 7 hours (after repeated administration of the drug). Enoxaparin sodium is mainly metabolized in the liver by desulfation and / or depolymerization with the formation of low molecular weight substances with very low biological activity.

The excretion through the kidneys of the active fragments of the drug is approximately 10% of the administered dose, and the total excretion of active and inactive fragments is approximately 40% of the administered dose. There may be a delay in the excretion of enoxaparin sodium in elderly patients as a result of a decrease in renal function with age. There was a decrease in the clearance of enoxaparin sodium in patients with reduced renal function.

After repeated s / c administration of 40 mg of enoxaparin sodium once a day, there is an increase in anti-Xa activity, represented by the area under the pharmacokinetic curve in patients with minor (Cl creatinine 50-80 ml / min) and moderate (Cl creatinine 30-50 ml / min). min) impaired renal function.

In patients with severe renal impairment (Cl creatinine<30 мл/мин) площадь под фармакокинетической кривой в состоянии равновесия в среднем на 65% выше при повторном п/к введении 40 мг препарата один раз в сутки.

In overweight people with s / c administration of the drug, the clearance is somewhat less. If the dose is not adjusted for the patient's body weight, then after a single s / c administration of 40 mg of enoxaparin sodium, anti-Xa activity will be 50% higher in women weighing less than 45 kg and 27% higher in men weighing less than 57 kg compared with patients with normal average body weight.

Pharmacodynamics

Enoxaparin sodium - low molecular weight heparin with an average molecular weight of about 4500 daltons: less than 2000 daltons -<20%, от 2000 до 8000 дальтон - >68%, more than 8000 daltons -<18%. Эноксапарин натрия получают щелочным гидролизом бензилового эфира гепарина, выделенного из слизистой оболочки тонкого кишечника свиньи. Его структура характеризуется невосстанавливающимся фрагментом 2-О-сульфо-4-енпиразиносуроновой кислоты и восстанавливающимся фрагментом 2-N,6-О-дисульфо-D-глюкопиранозида.

The enoxaparin structure contains about 20% (ranging from 15 to 25%) of the 1,6-anhydro derivative in the reducing fragment of the polysaccharide chain. In a purified in vitro system, enoxaparin sodium has anti-Xa activity (about 100 IU/ml) and low anti-IIa or antithrombin activity (about 28 IU/ml). When used in prophylactic doses, it slightly changes the APTT, has virtually no effect on platelet aggregation and the level of fibrinogen binding to platelet receptors. Plasma anti-IIa activity is approximately 10 times lower than anti-Xa activity.

The average maximum anti-IIa activity is observed approximately 3-4 hours after s / c injection and reaches 0.13 IU / ml and 0.19 IU / ml after repeated administration of 1 mg / kg - with a double injection and 1.5 mg / kg - with a single injection, respectively. The average maximum anti-Xa plasma activity is observed 3-5 hours after s / c administration of the drug and is approximately 0.2; 0.4; 1.0 and 1.3 anti-Xa IU/ml after s.c. administration of 20, 40 mg and 1 mg/kg and 1.5 mg/kg, respectively.

Indications for use

Clexane is a low molecular weight heparin, a direct acting anticoagulant.

It is used to prevent deep vein thrombosis in surgery, traumatology, orthopedics, in hospitalized patients of a therapeutic profile, to prevent the formation of blood clots in the extracorporeal circulation during hemodialysis. Clexane is used to treat deep vein thrombosis, for the treatment of acute coronary syndrome without ST elevation on the ECG.

Contraindications for use

Clexane should not be used in the presence of hypersensitivity reactions to heparin and its derivatives, as well as in any conditions or diseases with a high risk of bleeding. It is not recommended for use in pregnant women with artificial heart valves and in patients under the age of 18 years.

Use in pregnancy and children

Side effects

When using Clexane, adverse reactions may occur: pinpoint hemorrhages (petechiae), ecchymosis, rarely - hemorrhagic syndrome (including retroperitoneal and intracranial bleeding, up to death), hyperemia and soreness at the injection site, rarely - hematoma, the occurrence of dense inflammatory nodes (resolve after a few days, discontinuation of treatment is not required); rarely - necrosis at the injection site, preceded by purpura or erythematous plaques (infiltrated and painful); asymptomatic thrombocytopenia (in the first days of treatment), rarely - immunoallergic thrombocytopenia (on days 5-21 of treatment) with the development of rebound thrombosis (heparin thrombotic thrombocytopenia), which can be complicated by organ infarction or limb ischemia; increased activity of "liver" transaminases. Rarely - systemic and skin allergic reactions.

With traumatic spinal / epidural anesthesia (the likelihood increases with the use of a permanent postoperative epidural catheter) - intraspinal hematoma (rare), which can lead to temporary or permanent paralysis.

drug interaction

Clexane® must not be mixed with other drugs.

You should not alternate the use of enoxaparin sodium and other low molecular weight heparins, because. they differ from each other in the way of production, molecular weight, specific anti-Xa activity, units of measurement and dosage. And, as a result, the drugs are characterized by different pharmacokinetics and biological activity (anti-IIa activity, interaction with platelets

With systemic salicylates, acetylsalicylic acid, NSAIDs (including ketorolac), dextran with a molecular weight of 40 kDa, ticlopidine and clopidogrel, systemic corticosteroids, thrombolytics or anticoagulants, other antiplatelet drugs (including glycoprotein IIb / IIIa antagonists) - an increase in the risk of bleeding.

Dosage

Clexane is administered to the patient in the supine position, only subcutaneously in the anterolateral or posterolateral region (lateral regions) of the abdominal wall at the level of the belt.

For surgical interventions, the drug is administered 2 hours before general surgery and 12 hours before orthopedic surgery.

For treatment, the dose and duration of treatment are selected individually from 0.5 mg / kg of body weight to 1.5 mg / kg of body weight, depending on the disease.

Overdose

Accidental overdose of Clexane® (with intravenous, s / c or extracorporeal use) can lead to hemorrhagic complications. When ingesting even large doses, absorption of the drug is unlikely. Anticoagulant effects can be largely neutralized by slow intravenous administration of protamine sulfate, the dose of which depends on the dose of Clexane administered. 1 mg of protamine sulfate neutralizes the anticoagulant activity of 1 mg of Clexane® if enoxaparin sodium was administered no more than 8 hours before the administration of protamine. 0.5 mg of protamine neutralizes the anticoagulant effect of 1 mg of Clexane® if it was administered more than 8 hours ago or if a second dose of protamine is required. If 12 hours or more have passed after the administration of enoxaparin sodium, the administration of protamine is not required. However, even with the introduction of large doses of protamine sulfate, the anti-Xa activity of Clexane® is not completely neutralized (maximum - by 60%).

Low molecular weight heparin preparation (molecular weight about 4500 daltons: less than 2000 daltons - 68%, more than 8000 daltons -

Pharmacokinetics

The pharmacokinetics of enoxaparin in these dosing regimens is linear. The variability within and between groups of patients is low. by day 2, and the AUC is on average 15% higher than after a single injection. After repeated s / c injections of enoxaparin sodium at a daily dose of 1 mg / kg of body weight 2 times / day, Css is achieved after 3-4 days, and AUC is on average 65% higher than after a single injection and the average values ​​​​of Cmax are 1.2 IU, respectively / ml and 0.52 IU / ml. The bioavailability of enoxaparin sodium with s / c administration, estimated on the basis of anti-Xa activity, is close to 100%. Vd enoxaparin sodium (according to anti-Xa activity) is approximately 5 liters and approaches the blood volume. Metabolism Enoxaparin sodium is mainly biotransformed in the liver by desulfation and / or depolymerization with the formation of low molecular weight substances with very low biological activity. . After intravenous administration for 6 hours at a dose of 1.5 mg/kg of body weight, the average clearance of anti-Xa in plasma is 0.74 l/h. The excretion of the drug is monophasic. T1 / 2 is 4 hours (after a single s / c injection) and 7 hours (after repeated administration of the drug). 40% of the administered dose is excreted by the kidneys, with 10% unchanged. Pharmacokinetics in special clinical situations It is possible to delay the excretion of enoxaparin sodium in elderly patients as a result of a decrease in kidney function. In patients with impaired renal function, there is a decrease in the clearance of enoxaparin sodium. In patients with mild (CC 50-80 ml / min) and moderate (CC 30-50 ml / min) impaired renal function, after repeated s / c administration of 40 mg enoxaparin sodium 1 time / day, there is an increase in anti-Xa activity, represented by AUC . In patients with severe renal impairment (CC less than 30 ml / min), with repeated s / c administration of the drug at a dose of 40 mg 1 time / day, AUC in the equilibrium state is on average 65% higher. In patients with overweight with s / to the introduction of the drug, the clearance is somewhat less. If the dose is not adjusted for the patient's body weight, then after a single s / c injection of enoxaparin sodium at a dose of 40 mg, anti-Xa activity will be 50% higher in women weighing less than 45 kg and 27% higher in men weighing less than 45 kg. body weight less than 57 kg, compared with patients with normal average body weight.

Indications

Prevention of venous thrombosis and embolism during surgical interventions, especially orthopedic and general surgical operations; - prevention of venous thrombosis and thromboembolism in patients on bed rest due to acute therapeutic diseases (acute heart failure, chronic heart failure in the stage of decompensation III or IV functional class according to NYHA classification, acute respiratory failure, severe acute infection, acute rheumatic diseases in combination with one of the risk factors for venous thrombosis); - treatment of deep vein thrombosis with or without pulmonary embolism; - prevention of thrombosis in the extracorporeal circulation during hemodialysis (usually with a session duration of not more than 4 hours); - treatment of unstable angina and myocardial infarction without a Q wave in combination with acetylsalicylic acid; - treatment of acute myocardial infarction with ST segment elevation in patients patients subject to medical treatment or subsequent percutaneous coronary intervention.

Contraindications

Hypersensitivity to enoxaparin, heparin and its derivatives, including other low molecular weight heparins; - active major bleeding, as well as conditions and diseases in which there is a high risk of bleeding: threatened abortion, cerebral aneurysm or dissecting aortic aneurysm (except in cases of surgical intervention on this matter), recent hemorrhagic stroke, uncontrolled bleeding, thrombocytopenia in combination with a positive in vitro test for antiplatelet antibodies in the presence of enoxaparin sodium; - age under 18 years (efficacy and safety have not been established). The use of Clexane is not recommended in order to prevent thrombus formation in pregnant women with mechanical artificial heart valves (lack of clinical experience with use). With caution Conditions in which there is a potential risk of bleeding: - thrombocytopenia, hypocoagulation, von Willebrand's disease), severe vasculitis; - peptic ulcer of the stomach and duodenum or other erosive and ulcerative lesions of the gastrointestinal tract in history; - recent ischemic stroke; - uncontrolled severe arterial hypertension; - diabetic or hemorrhagic retinopathy; - severe sugar Diabetes Recent or proposed neurological or ophthalmic surgery Spinal or epidural anesthesia (potential risk of hematoma), lumbar puncture (recent) Recent childbirth Bacterial endocarditis (acute or subacute) Pericarditis or pericardial effusion ; - renal and / or liver failure; - intrauterine contraception (IUD); - severe trauma (especially the central nervous system), open wounds with a large wound surface; - simultaneous administration of drugs that affect the hemostasis system; - heparin-induced thrombocytopenia (history) with or without thrombosis .The company does not have data on the clinical use of the drug Clexane in the following conditions: active tuberculosis, radiation therapy (recently transferred).

Precautionary measures

Use during pregnancy and lactation

There is no information that enoxaparin sodium crosses the placental barrier in the II trimester, there is no relevant information regarding the I and III trimesters of pregnancy. there are no adequate and well-controlled studies in pregnant women, and animal studies do not always predict the response to the administration of enoxaparin sodium in human pregnancy, Clexane should be used in pregnancy only when there is an urgent need for its use, established by the doctor. whether unchanged enoxaparin sodium is excreted in breast milk. Breast-feeding should be discontinued during maternal treatment with Clexane. Pregnant women with mechanical prosthetic heart valves The use of Clexane for the prevention of blood clots in pregnant women with mechanical prosthetic heart valves has not been adequately studied. In a clinical study of pregnant women with mechanical prosthetic heart valves, when using enoxaparin sodium at a dose of 1 mg/kg body weight 2 times a day to reduce the risk of thrombosis and embolism, 2 out of 8 women developed a blood clot, which led to blockage of the heart valves and death of the mother and the fetus. There are separate post-marketing reports of valvular thrombosis in pregnant women with mechanical prosthetic heart valves treated with enoxaparin to prevent thrombosis. Pregnant women with mechanical prosthetic heart valves have a high risk of thrombosis and embolism.

Dosage and administration

With the exception of special cases (treatment of ST-segment elevation myocardial infarction, medical or percutaneous coronary intervention and prevention of thrombus formation in the extracorporeal circulation system during hemodialysis), enoxaparin sodium is injected deeply SC. Injections are preferably carried out with the patient lying down. When using pre-filled 20 mg and 40 mg syringes, do not remove air bubbles from the syringe before injection to avoid loss of drug. Injections should be carried out alternately in the left or right anterolateral or posterolateral surface of the abdomen. The needle must be inserted to its full length vertically (not laterally) into the skin fold, collected and held until the injection is completed between the thumb and forefinger. The skin fold is released only after the injection is completed. Do not massage the injection site after administration of the drug. The pre-filled disposable syringe is ready for use. 20 mg or 40 mg 1 time / day s / c. The first injection is made 2 hours before surgery. For patients with a high risk of developing thrombosis and embolism (for example, during orthopedic operations), the drug is recommended at a dose of 40 mg 1 time / day s / c, the first dose is administered 12 hours before surgery, or 30 mg 2 times / day s / c with the onset of administration 12-24 hours after the operation. The duration of treatment with Clexane is on average 7-10 days. If necessary, therapy can be continued as long as the risk of thrombosis and embolism persists, and until the patient switches to an outpatient regimen. In orthopedic operations, it may be advisable to continue treatment after initial therapy by administering Clexane at a dose of 40 mg 1 times / day for 3 weeks. Features of the use of Clexane in spinal / epidural anesthesia, as well as in coronary revascularization procedures are described in the Special Instructions section. Prevention of venous thrombosis and embolism in patients on bed rest due to acute therapeutic diseases Recommended dose of Clexane is 40 mg 1 time / day s / c, at least for 6 days. Therapy should be continued until the patient is completely transferred to the outpatient regimen (maximum within 14 days). Treatment of deep vein thrombosis with pulmonary embolism or without pulmonary embolism The drug is administered s / c at the rate of 1.5 mg / kg of body weight 1 time / day or at a dose of 1 mg / kg of body weight 2 times / day. In patients with complicated thromboembolic disorders, the drug is recommended to be used at a dose of 1 mg / kg 2 times / day. The average duration of treatment is 10 days. Treatment with indirect anticoagulants should be started immediately, while therapy with Clexane should be continued until a therapeutic anticoagulant effect is achieved, i.e. MHO should be 2-3. Prevention of thrombus formation in the extracorporeal circulation system during hemodialysis The recommended dose of Clexane is an average of 1 mg/kg of body weight. With a high risk of bleeding, the dose should be reduced to 0.5 mg / kg body weight with a double vascular access or 0.75 mg with a single vascular access. In hemodialysis, the drug should be injected into the arterial site of the shunt at the beginning of the hemodialysis session. One dose is usually sufficient for a 4-hour session, however, if fibrin rings are detected during longer hemodialysis, you can additionally administer the drug at the rate of 0.5-1 mg / kg of body weight. Treatment of unstable angina and myocardial infarction without a Q wave 1 mg / kg body weight every 12 hours s / c, while using acetylsalicylic acid at a dose of 100-325 mg 1 time / day. The average duration of therapy is at least 2 days (until the patient's clinical condition stabilizes). Usually, the administration of the drug lasts from 2 to 8 days. Treatment of acute myocardial infarction with ST segment elevation, medically or with the help of percutaneous coronary intervention Treatment begins with a single intravenous bolus injection of enoxaparin sodium at a dose of 30 mg. Immediately after it, enoxaparin sodium is administered s.c. at a dose of 1 mg/kg. Further, the drug is prescribed s / c at 1 mg / kg body weight every 12 hours (maximum 100 mg enoxaparin sodium for each of the first two s / c injections, then 1 mg / kg body weight for the remaining subcutaneous doses, i.e. with a body weight of more than 100 kg, a single dose may exceed 100 mg). In patients aged 75 years and older, the initial IV bolus is not used. Enoxaparin sodium is injected s/c at a dose of 0.75 mg/kg every 12 hours (moreover, during the first two s/c injections, a maximum of 75 mg of enoxaparin sodium can be administered per injection, then all subsequent s/c doses of 0. 75 mg/kg body weight, i.e. with a body weight of more than 100 kg, the dose may exceed 75 mg). When combined with thrombolytics (fibrin-specific and fibrin-nonspecific), enoxaparin sodium should be administered in the range from 15 minutes before the start of thrombolytic therapy to 30 minutes after it. As soon as possible after the detection of acute myocardial infarction with ST segment elevation, acetylsalicylic acid should be started simultaneously (in doses from 75 to 325 mg) and, if there are no contraindications, it should continue for at least 30 days. The recommended duration of treatment with the drug is 8 days or until the patient is discharged from the hospital if the period of hospitalization is less than 8 days. IV bolus administration of enoxaparin sodium should be carried out through a venous catheter and enoxaparin sodium should not be mixed or administered together with other drugs. In order to avoid the presence of traces of other drugs in the infusion system and their interaction with enoxaparin sodium, the venous catheter should be flushed with a sufficient amount of 0.9% sodium chloride solution or dextrose before and after the intravenous bolus administration of enoxaparin sodium. Enoxaparin sodium can be safely administered with 0.9% sodium chloride solution and 5% dextrose solution. For bolus administration of enoxaparin sodium at a dose of 30 mg in the treatment of acute ST-segment elevation myocardial infarction, excess amount is removed from glass syringes 60 mg, 80 mg and 100 mg of the drug so that only 30 mg (0.3 ml) remain in them. A dose of 30 mg can be administered directly iv. For intravenous bolus administration of enoxaparin sodium through a venous catheter, pre-filled syringes for s / c administration of the drug 60 mg, 80 mg and 100 mg can be used. It is recommended to use 60 mg syringes, as this reduces the amount of drug removed from the syringe. Syringes 20 mg are not used, because. they do not have enough drug for a 30 mg bolus of enoxaparin sodium. 40 mg syringes are not used because there are no divisions on them and therefore it is impossible to accurately measure the amount of 30 mg. In patients undergoing percutaneous coronary intervention, if the last s / c injection of enoxaparin sodium was carried out less than 8 hours before inflating the balloon inserted into the site of the narrowing of the coronary artery catheter, additional administration of enoxaparin sodium is not required. If the last s.c. injection of enoxaparin sodium was given more than 8 hours before the balloon catheter was inflated, an additional bolus of enoxaparin sodium at a dose of 0 should be given intravenously. 3 mg/kg. To improve the accuracy of additional bolus administration of small volumes into the venous catheter during percutaneous coronary interventions, it is recommended to dilute the drug to a concentration of 3 mg/ml. It is recommended to dilute the solution immediately before administration.

Side effects

The study of side effects of enoxaparin sodium was carried out in more than 15,000 patients participating in clinical trials, of which 1776 patients - in the prevention of venous thrombosis and embolism in general surgical and orthopedic operations, in 1169 patients - in the prevention of venous thrombosis and embolism in patients who are on bed rest, due to acute therapeutic diseases, in 559 patients - in the treatment of deep vein thrombosis with pulmonary embolism or without pulmonary embolism, in 1578 patients - in the treatment of unstable angina and myocardial infarction without a Q wave, in 10,176 patients - in the treatment of myocardial infarction with ST segment elevation. The mode of administration of enoxaparin sodium differed depending on the indications. In the prevention of venous thrombosis and embolism during general surgical and orthopedic operations or in patients on bed rest, 40 mg s / c was administered 1 time / day. In the treatment of deep vein thrombosis with or without pulmonary embolism, patients received enoxaparin sodium at the rate of 1 mg/kg body weight s/c every 12 hours or 1.5 mg/kg body weight s/c 1 time/day. In the treatment of unstable angina and non-Q wave myocardial infarction, the dose of enoxaparin sodium was 1 mg/kg body weight s.c. every 12 hours, and in the case of myocardial infarction with ST segment elevation, a bolus dose of 30 mg was administered followed by a dose of 1 mg / kg body weight s / c every 12 hours. Adverse reactions were classified according to the frequency of occurrence as follows: very often (≥1 / 10), often (≥1 / 100-

Overdose

Symptoms: accidental overdose with intravenous, extracorporeal or s / c administration can lead to hemorrhagic complications. When taken orally, even in large doses, absorption of the drug is unlikely. Treatment: as a neutralizing agent, slow intravenous administration of protamine sulfate is indicated, the dose of which depends on the dose of Clexane administered. It should be taken into account that 1 mg of protamine neutralizes the anticoagulant effect of 1 mg of enoxaparin if Clexane was administered no more than 8 hours before the administration of protamine. 0.5 mg of protamine neutralizes the anticoagulant effect of 1 mg of Clexane if it was administered more than 8 hours ago or if a second dose of protamine is required. If more than 12 hours have passed after the administration of Clexane, then the administration of protamine is not required. However, even with the introduction of protamine sulfate in high doses, the anti-Xa activity of Clexane is not completely neutralized (by a maximum of 60%).

Interaction with other drugs

Clexane should not be mixed with other drugs! When used simultaneously with drugs that affect hemostasis (systemic salicylates, acetylsalicylic acid, NSAIDs (including ketorolac), dextran with a molecular weight of 40 kDa, ticlopidine and clopidogrel, systemic corticosteroids, thrombolytics or anticoagulants, other antiplatelet drugs (including glycoprotein IIb/IIIa antagonists) increase the risk of bleeding.

special instructions

General Low molecular weight heparins are not interchangeable, because they differ in their manufacturing process, molecular weight, specific anti-Xa activity, dosing units and dosing regimen, resulting in differences in their pharmacokinetics and biological activity (antithrombin activity and interaction with platelets). Therefore, it is required to strictly follow the recommendations for use for each drug belonging to the class of low molecular weight heparins. With the development of bleeding, it is necessary to find its source and carry out appropriate treatment. Bleeding in elderly patients When using the drug Clexane in prophylactic doses in elderly patients, there was no risk of bleeding. When using the drug in therapeutic doses in elderly patients (especially those aged ≥80 years ) there is an increased risk of bleeding. Careful monitoring of the condition of such patients is recommended. Simultaneous use of other drugs that affect hemostasis clopidogrel; corticosteroids, thrombolytics, anticoagulants, antiplatelet agents, including glycoprotein IIb/IIIa receptor antagonists), were discontinued prior to treatment with enoxaparin sodium, unless their use is necessary. If combinations of enoxaparin sodium with these drugs are indicated, then careful clinical observation and monitoring of relevant laboratory parameters should be carried out. Renal failure In patients with impaired renal function, there is a risk of bleeding as a result of an increase in the systemic exposure of enoxaparin sodium. kg/m2) are not fully defined, and there is no consensus on dose adjustment. Such patients should be carefully monitored for the development of symptoms and signs of thrombosis and embolism. Monitoring the number of platelets in peripheral blood The risk of developing antibody-mediated heparin-induced thrombocytopenia also exists with the use of low molecular weight heparins. Thrombocytopenia usually develops between days 5 and 21 after initiation of enoxaparin sodium therapy. In this regard, it is recommended to regularly monitor the number of platelets in peripheral blood before starting treatment with Clexane and during its use. In the presence of a confirmed significant decrease in the number of platelets (by 30-50% compared with the baseline), it is necessary to immediately cancel enoxaparin sodium and transfer the patient to another therapy. with simultaneous spinal / epidural anesthesia with the development of persistent or irreversible paralysis. The risk of these phenomena is reduced when using the drug at a dose of 40 mg or lower. The risk increases with the use of Clexane at higher doses, as well as with the use of indwelling catheters after surgery, or with the simultaneous use of additional drugs that affect hemostasis, such as NSAIDs. The risk is also increased with a traumatic or repeated spinal puncture or in patients with a history of indications of previous spinal surgery or spinal deformity. To reduce the possible risk of bleeding associated with the use of enoxaparin sodium and epidural or spinal anesthesia / analgesia, pharmacokinetic drug profile. Placement or removal of a catheter is best done with a low anticoagulant effect of enoxaparin sodium, however, the exact time to achieve a sufficient decrease in the anticoagulant effect in different patients is unknown. times / day, 30 mg 1-2 times / day, 40 mg 1 time / day) and at least 24 hours after the administration of Clexane at higher doses (0.75 mg / kg body weight 2 times / day, 1 mg /kg body weight 2 times / day, 1.5 mg / kg body weight 1 time / day). At these time points, anti-Xa activity of the drug still continues to be detected, and delays in time are not a guarantee that the development of neuraxial hematoma can be avoided. Patients receiving enoxaparin sodium at doses of 0.75 mg / kg of body weight 2 times / day or 1 mg /kg of body weight 2 times / day, with this (twice during the day) dosing regimen, a second dose should not be administered in order to increase the interval before installing or replacing the catheter. Similarly, the possibility of delaying the next dose of the drug by at least 4 hours should be considered, based on an assessment of the benefit / risk ratio (the risk of thrombosis and bleeding during the procedure, taking into account the presence of risk factors in patients). However, it is not possible to give clear recommendations on the timing of the next dose of enoxaparin sodium after removal of the catheter. It should be borne in mind that in patients with CC less than 30 ml / min, the excretion of enoxaparin sodium slows down. Therefore, in this category of patients, consideration should be given to doubling the time from catheter removal: at least 24 hours for lower doses of enoxaparin sodium (30 mg 1 time / day) and at least 48 hours for higher doses (1 mg / kg body weight per day). If, as prescribed by a doctor, anticoagulant therapy is used during epidural / spinal anesthesia, especially careful constant monitoring of the patient is necessary to detect any neurological symptoms, such as: back pain, sensory and motor dysfunctions (numbness or weakness in the lower limbs), bowel and/or bladder dysfunction. The patient should be instructed to immediately inform the doctor if the above symptoms occur. If symptoms characteristic of a spinal cord hematoma are suspected, urgent diagnosis and treatment are necessary, including, if necessary, decompression of the spinal cord. Heparin-induced thrombocytopenia with or without thrombosis. The risk of heparin-induced thrombocytopenia may persist for several years. If the history suggests the presence of heparin-induced thrombocytopenia, then in vitro platelet aggregation tests are of limited value in predicting the risk of its development. The decision to prescribe Clexane in this case should only be taken after consultation with the appropriate specialist. these procedures should be carried out in the intervals between the introduction of the drug Clexane. This is necessary in order to achieve hemostasis after percutaneous coronary intervention. When using a closure device, the femoral artery sheath can be removed immediately. When using manual compression, the femoral artery sheath should be removed 6 hours after the last IV or SC injection of enoxaparin sodium. If treatment with enoxaparin sodium is continued, then the next dose should be administered no earlier than 6-8 hours after removal of the femoral artery sheath. It is necessary to monitor the insertion site of the sheath in order to timely detect signs of bleeding and hematoma formation. Patients with mechanical prosthetic heart valves The use of Clexane for the prevention of thrombosis in patients with mechanical prosthetic heart valves has not been studied enough. There are isolated reports of valvular thrombosis in patients with mechanical prosthetic heart valves treated with enoxaparin sodium to prevent thrombus formation. The evaluation of these reports is limited due to the presence of competing factors that contribute to the development of prosthetic heart valve thrombosis, including the underlying disease, and due to insufficient clinical data. Laboratory tests At doses used to prevent thromboembolic complications, Clexane does not significantly affect bleeding time and parameters blood clotting, as well as platelet aggregation or their binding to fibrinogen. When the dose is increased, APTT and activated clotting time may be prolonged. An increase in APTT and activated clotting time is not in a direct linear relationship with an increase in the anticoagulant activity of the drug, so there is no need to monitor them. Prevention of venous thrombosis and embolism in patients with acute therapeutic diseases who are on bed rest the appointment of enoxaparin sodium is justified only if the above conditions are combined with one of the following risk factors for venous thrombosis: age over 75 years, malignant neoplasms, history of thrombosis and embolism, obesity, hormonal therapy, heart failure, chronic respiratory failure. Influence on ability to drive vehicles and mechanisms Clexane does not affect the ability to drive vehicles and mechanisms.