Enoxaparin sodium - instructions for use, dose, side effects, contraindications

Active substanceSodium EnoxaparinSodium Enoxaparin

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Sodium Enoxaparin

solution for injections

BIOCAD, CJSC Russia

Dosage form: & nbspinjection

Composition:

Composition per syringe

Dosage 2000 anti-Ha IU / 0.2 mL (equivalent to 20 mg / 0.2 mL):

Active substance: Enoxaparin sodium - 20 mg * (2000 anti-Xa ME); Excipients: water for injection up to 0.2 ml.

Dosage 4000 anti-Ha IU / 0.4 mL (equivalent to 40 mg / 0.4 mL):

Active substance: enoxaparin sodium-40 mg * (4000 anti-Xa ME); Excipients: water for injection up to 0.4 ml.

Dosage 6,000 anti-Xa IU / 0.6 mL (equivalent to 60 mg / 0.6 mL):

Active substance: enoxaparin sodium - 60 mg * (6000 anti-Xa ME); Excipients: water for injection up to 0.6 ml.

The dosage of 8000 anti-Ha IU / 0.8 ml (equivalent to 80 mg / 0.8 ml):

Active substance: Enoxaparin sodium - 80 mg * (8000 anti-Xa ME); Excipients: water for injection up to 0.8 ml.

Dosage 10,000 anti-Ha IU / 1 mL (equivalent to 100 mg / 1 mL):

Active substance: Enoxaparin sodium - 100 mg * (10,000 anti-Xa ME); Excipients: water for injection up to 1 ml.

* The mass is calculated on the basis of the content of sodium enoxaparin used (theoretical activity 100 anti-Xa IU / mg).

Description:Transparent, from a colorless to pale yellow solution.

Pharmacotherapeutic group:Anticoagulant means of direct action

ATX: & nbsp

B.01.A.B.05 Enoxaparin

Pharmacodynamics:

Pharmacological properties

Enoxaparin sodium is a preparation of low molecular weight heparin (molecular weight about 4500 daltons: less than 2000 daltons - <20%, from 2000 to 8000 daltons -> 68%, more than 8000 daltons - <18%). Sodium Enoxaparin are obtained by alkaline hydrolysis of benzyl ester of heparin isolated from the mucosa of the small intestine of the pig. Its structure is characterized by a nonreducing fragment of 2-O-sulfo-4-enapyrazinosuronic acid and a reducing fragment of 2-N, 6-O-disulfo-D-glucopyranoside. The structure of sodium enoxaparin contains about 20.0% (ranging from 15% to 25%) of the 1,6-anhydro derivative in the reducing fragment of the polysaccharide chain.

Pharmacodynamics

In a purified in vitro system sodium enoxaparin has a high anti-Xa activity (about 100 IU / ml) and low anti-IIa or antithrombin activity (about 28 IU / ml).This anticoagulant activity acts through antithrombin III (AT-III), providing anticoagulant activity in humans. In addition to anti-Xa / IIa activity, additional anticoagulant and anti-inflammatory properties of sodium enoxaparin have been identified both in healthy individuals and patients and in animal models. This includes AT-III-dependent inhibition of other clotting factors, such as Vila factor, activation of the release of the tissue factor pathway inhibitor (PTF), as well as a reduction in vWF release from the vascular endothelium into the bloodstream. These factors provide an anticoagulant effect of sodium enoxaparin as a whole.

When using the drug in prophylactic doses, it slightly changes the activated partial thromboplastin time, practically does not affect the aggregation of platelets and the level of binding of fibrinogen to platelet receptors.

Anti-IIa activity in plasma is about 10 times lower than anti-Xa activity. The mean 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 body weight with a double administration and 1.5 mg / kg body weight and single administration, respectively.

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 administration of 20, 40 mg, and 1 mg / kg and 1.5 mg / kg, respectively.

Pharmacokinetics:

The pharmacokinetics of enoxaparin sodium in these dosing regimes is linear.

Suction and distribution

After repeated subcutaneous administration of enoxaparin sodium 40 mg and 1.5 mg / kg body weight one time per day in healthy volunteers equilibrium concentration is achieved on the second day, the curve area "concentration - time" on average 15% higher than after a single administration. After repeated subcutaneous administration of enoxaparin sodium in a daily dose of 1 mg / kg of body weight, 2 times a day equilibrium concentration is reached after 3-4 days, and the area under the curve "concentration-time" on average 65% higher than after a single injection and the average the maximum concentrations are 1.2 IU / ml and 0.52 IU / ml, respectively. The bioavailability of enoxaparin sodium subcutaneous administration, which is estimated on the basis of the anti-Xa activity was close to 100%.The volume of distribution of enoxaparin sodium (according to anti-Xa activity) is approximately 5 liters and approaches the blood volume.

Metabolism

Enoxaparin sodium is biotransformed mainly in the liver by desulfating and / or depolymerizing to form low molecular weight substances with very low biological activity.

Excretion

Enoxaparin sodium is a preparation with low clearance. After intravenous administration for 6 hours at a dose of 1.5 mg / kg body weight, the average value of anti-Xa clearance in plasma is 0.74 l / h.

Excretion of the drug is monophasic, with a half-life of 4 hours (after a single subcutaneous injection) and 7 hours (after repeated administration of the drug). Kidney excretion of active fragments of the drug about 10% of the administered dose, and total excretion of active and inactive fragments is approximately 40% of the administered dose.

Pharmacokinetics in special groups of patients.

It is possible to delay the rate of excretion of sodium enoxaparin in elderly patients as a result of a decrease in renal function.

In patients with decreased renal function, there is a decrease in the clearance of enoxaparin sodium.In patients with a mild (creatinine clearance 50-80 ml / min) and moderate (creatinine clearance 30-50 ml / min), renal dysfunction after repeated subcutaneous administration of 40 mg enoxaparin sodium once a day increases the activity of anti-Xa represented by the area under the pharmaceutical curve. In patients with severe renal dysfunction (creatinine clearance less than 30 ml / min) with repeated subcutaneous administration of the drug at a dose of 40 mg once a day, the area under the pharmaceutical curve in the equilibrium state is on average 65% higher.

In patients with excessive body weight with subcutaneous injection of the drug, the clearance is slightly less. If you do not adjust the dose taking into account the patient's body weight, then after a single subcutaneous administration of enoxaparin sodium in a dose of 40 mg of anti-Xa activity will be 50% higher in women with a body weight of less than 45 kg and 27% higher in men with 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,(acute cardiac insufficiency, chronic heart failure in the stage of decompensation of III or IV functional class according to the classification NYHA, 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 thromboembolism or without pulmonary embolism;

- treatment of unstable angina and myocardial infarction without a tooth Q in combination with acetylsalicylic acid;

- Treatment of acute myocardial infarction with segment elevation ST patients who are subject to drug treatment or subsequent percutaneous coronary intervention;

- prevention of thrombus formation in the extracorporeal circulation system during hemodialysis (usually with a session duration of no more than 4 hours).

Contraindications:

- Hypersensitivity to enoxaparin sodium, heparin or its derivative, including other low molecular weight heparins;

- active large bleeding, as well as conditions and diseases,at which there is a high risk of bleeding: threatening abortion, cerebral aneurysm or exfoliating aortic aneurysm (with the exception of cases of surgical intervention in this regard), recent hemorrhagic stroke, uncontrolled bleeding, thrombocytopenia in combination with a positive test in conditions in vitro on antiplatelet antibodies in the presence of enoxaparin sodium;

- age to 18 years (efficacy and safety not established).

Carefully:

Conditions in which there is a potential risk of bleeding:

- hemostasis disorders (including hemophilia, thrombocytopenia, hypocoagulation, von Willebrand disease, etc.), severe vasculitis;

- peptic ulcer of the stomach or duodenum, or other erosive-ulcerative lesions of the gastrointestinal tract in the anamnesis;

- recent ischemic stroke;

- uncontrolled severe arterial hypertension;

- diabetic or hemorrhagic retinopathy;

- severe diabetes mellitus;

- recent or alleged neurologic or ophthalmic surgery;

- spinal or epidural anesthesia (potential risk of hematoma), spinal puncture (recently transferred);

- recent childbirth;

- endocarditis bacterial (acute or subacute);

- pericarditis or pericardial effusion;

- renal and / or liver failure;

- intrauterine contraception (IUD);

- severe trauma (especially the central nervous system), open wounds on large surfaces;

- simultaneous reception of drugs that affect the hemostasis system;

- heparin-induced thrombocytopenia (in the anamnesis) in combination with or without thrombosis.

There are no data on the clinical use of enoxaparin sodium in the following diseases: active tuberculosis, radiation therapy (recently transferred).

Pregnancy and lactation:

Information about the fact that sodium enoxaparin penetrates the placental barrier during the second trimester of pregnancy in humans, no. There is no relevant information regarding the first and third trimester of pregnancy.

Since there are no adequate and well-controlled studies in pregnant women,and animal studies do not always predict a response to sodium enoxaparin during pregnancy in humans, should be used during pregnancy only when there is an urgent need for its use, as established by the doctor.

It is not known whether the unchanged sodium enoxaparin in human milk. Absorption of enoxaparin sodium in the digestive tract in a newborn is unlikely. However, as precautionary measures, breastfeeding women receiving treatment with the drug Sodium Enoxaparin, it should be recommended to interrupt breastfeeding.

Dosing and Administration:

Except for special cases (see below subsections "Treatment of myocardial infarction with segment elevation ST, medication or by percutaneous coronary intervention " and "Prevention of thrombosis in the system of extracorporeal circulation during hemodialysis"), sodium enoxaparin is injected deeply subcutaneously. Injections should preferably be performed in the patient's prone position. When using pre-filled syringes for 20 mg and 40 mg to avoid loss of the drug before the injection, do not remove air bubbles from the syringe.Injections should be performed alternately in the left or right anterolateral or posterolateral surface of the abdomen. The needle must be inserted the entire length vertically (not laterally) into the skin fold, collected and held until the injection is completed between the thumb and forefinger. Skin fold is released only after the injection is completed. Do not massage the injection site after injection. The pre-filled disposable syringe is ready for use.

The drug can not be administered intramuscularly!

Prevention of venous thrombosis and embolism in surgical interventions, especially in orthopedic and general surgical operations

Patients with a moderate risk of developing thrombosis and embolism (eg, abdominal surgery) the recommended dose of the drug Sodium Enoxaparin is 20 mg once a day subcutaneously. The first injection should be done 2 hours before surgery.

Patients with a high risk of developing thrombosis and embolism (for example, in orthopedic operations, surgical operations in oncology, patients with additional risk factors not associated with the operation, such as congenital or acquired thrombophilia,malignant neoplasm, bed rest more than three days, obesity, venous thrombosis in the anamnesis, varicose veins of the lower extremities, pregnancy) the drug is recommended at a dose of 40 mg once a day subcutaneously, with the administration of the first dose 12 hours before surgery, or in a dose 30 mg twice a day with the onset of the injection 12-24 h after the operation.

The duration of treatment with enoxaparin sodium is on average 7-10 days. If necessary, therapy can be continued as long as there is a risk of developing thrombosis and embolism, and until the patient goes into an outpatient setting.

In orthopedic operations, it may be advisable after the initial therapy to continue treatment by administering enoxaparin sodium at a dose of 40 mg once daily for 3 weeks.

The specificity of the administration of sodium enoxaparin for spinal / epidural anesthesia, as well as for coronary revascularization procedures, is described in the section "Special instructions".

Prevention of venous thrombosis and embolism in patients on bed rest, due to acute therapeutic diseases

The recommended dose of enoxaparin sodium is 40 mg once a day, subcutaneously, for at least 6 days. Therapy should be continued until the patient fully switches to an outpatient schedule (maximum for 14 days).

Treatment of deep vein thrombosis with pulmonary embolism or without pulmonary arterial thromboembolism

The drug is administered subcutaneously at a rate of 1.5 mg / kg body weight once a day or 1 mg / kg body weight twice a day. In patients with complicated thromboembolic disorders, the drug is recommended to be applied at a dose of 1 mg / kg twice a day. The average duration of treatment is 10 days. Immediately begin therapy with indirect anticoagulants, while treatment with enoxaparin sodium is necessary continue until the therapeutic anticoagulant effect is achieved (the values of INR [International Normalized Relations] should be 2.0-3.0).

Prevention of thrombus formation in the extracorporeal circulation system during hemodialysis

The recommended dose of enoxaparin sodium is on average 1 mg / kg body weight. At a high risk of bleeding, the dose should be reduced to 0.5 mg / kg of body weight with dual vascular access or up to 0.75 mg with single vascular access.

With hemodialysis sodium enoxaparin should be injected into the arterial region of the shunt at the beginning of the hemodialysis session. A single dose, as a rule, is sufficient for a four-hour session, however, when fibrin rings are detected with a longer hemodialysis, the drug can be additionally administered at a rate of 0.5-1 mg / kg body weight.

Treatment of unstable angina and myocardial infarction without a tooth Q

Enoxaparin sodium is administered at a rate of 1 mg / kg body weight every 12 hours, subcutaneously, while concomitant administration of acetylsalicylic acid at a dose of 100-325 mg once a day. The average duration of therapy is at least two days, and continues until the patient's clinical condition is stabilized. Usually, the drug is administered from 2 to 8 days.

Treatment of acute myocardial infarction with segment elevation ST, medication or by percutaneous coronary intervention

Treatment begins with a single intravenous bolus administration of enoxaparin sodium at a dose of 30 mg. Immediately after it, subcutaneously injected sodium enoxaparin in a dose of 1 mg / kg body weight. Next, the drug is administered subcutaneously at 1 mg / kg body weight every 12 hours (maximum 100 mg of sodium enoxaparin for each of the first two subcutaneous injections, then 1 mg / kg of body weight for the remaining subcutaneous doses, that is,with a body weight of more than 100 kg, a single dose may exceed 100 mg).

Patients 75 years of age or older do not have an initial intravenous bolus injection. The drug is administered subcutaneously at a dose of 0.75 mg / kg every 12 hours (maximum 75 mg of sodium enoxaparin for each of the first two subcutaneous injections, then 0.75 mg / kg of body weight for the remaining subcutaneous doses, ie, 100 kg, single dose may exceed 75 mg).

When combined with thrombolytics (fibrin-specific and fibrin-nonspecific) sodium enoxaparin should be administered in the range from 15 minutes before the start of thrombolytic therapy and up to 30 minutes after it. As soon as possible after the detection of acute myocardial infarction with segment elevation ST, patients should be assigned simultaneously acetylsalicylic acid and, if there are no contraindications, the intake of acetylsalicylic acid (in doses of 75-325 mg) should be continued daily for at least 30 days.

The recommended duration of treatment with enoxaparin sodium is 8 days or until discharge from the hospital (if the hospitalization period is less than 8 days). Intravenous bolus administration of sodium enoxaparin should be performed through a venous catheter. Sodium Enoxaparin should not be mixed or administered together with other medicinal products. In order to avoid the presence of traces of other drugs in the infusion system and their interaction with sodium enoxaparin, the venous catheter should be washed with a sufficient amount of 0.9% sodium chloride solution or 5 % solution of dextrose before and after intravenous bolus administration of enoxaparin sodium. Sodium Enoxaparin can be safely administered with 0.9% sodium chloride solution and 5 % solution of dextrose.

For the bolus administration of 30 mg of sodium enoxaparin in the treatment of acute myocardial infarction with segment elevation ST from glass syringes 60 mg, 80 mg and 100 mg remove the excess amount of the drug so that they remain only 30 mg (0.3 ml). A dose of 30 mg can be directly administered intravenously.

Pre-filled syringes for subcutaneous administration of 60 mg, 80 mg and 100 mg can be used to perform an intravenous bolus injection of enoxaparin sodium through a venous catheter. It is recommended to use 60 mg syringes, as this reduces the amount of drug removed from the syringe.Syringes of 20 mg are not used, since they are not sufficient for bolus administration of 30 mg of enoxaparin sodium. 40 mg syringes are not used, as there are no fissions on them and it is therefore impossible to accurately measure the amount of 30 mg.

In patients undergoing percutaneous coronary intervention, in the event that the last subcutaneous injection of enoxaparin sodium was performed less than 8 hours before the balloon catheter inserted into the narrowing of the coronary artery is inflated, no additional sodium enoxaparin is required. If the last subcutaneous injection of sodium enoxaparin was carried out more than 8 hours before the balloon catheter was inflated, an additional intravenous bolus injection of sodium enoxaparin at a dose of 0.3 mg / kg should be performed.

To increase the accuracy of the additional intravenous bolus injection 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. Dilution of the solution is recommended immediately before administration.

To obtain a solution of enoxaparin sodium with a concentration of 3 mg / ml with the help of preliminaryfilled syringe 60 mg is recommended to use a container with an infusion solution of 50 ml (that is, with 0.9% sodium chloride solution or 5 % solution of dextrose). 30 ml of the solution is removed from the container with the infusion solution using a conventional syringe. Sodium Enoxaparin (the contents of the syringe for subcutaneous administration of 60 mg) is introduced into the remaining 20 ml of the infusion solution in the containers. The contents of the container with diluted sodium enoxaparin solution are gently mixed. For administration by means of a syringe, the required volume of the diluted solution of sodium enoxaparin is extracted, which is calculated by the formula:

Volume of reconstituted solution = Body weight of the patient (kg) x 0.1 or using the table below.

Table 1. Volumes to be administered intravenously after dilution

Body weight of the patient [kg]	The required dose (0.3 mg / kg) [mg]	The volume of the solution diluted to a concentration of 3 mg / ml
45	13,5	4,5
50	15	5
55	16,5	5,5
60	18	6
65	19,5	6,5
70	21	7
75	22,5	7,5
80	24	8
85	25,5	8,5
90	27	9
95	28,5	9,5
100	30	10

Dosage regimen for specific patient groups

Elderly patients

Except for the treatment of myocardial infarction with segment elevation ST (see above) for all other indications of a reduction in the dose of enoxaparin sodium in elderly patients, if they are not impaired renal function, is not required.

Patients with impaired renal function

Severe renal impairment (creatinine clearance less than 30 mL / min)

The dose of sodium enoxaparin is reduced in accordance with the tables presented below, as these patients have an increase in the exposure system (duration of action) of the drug.

When using the drug with a therapeutic purpose, the following correction of the dosing regimen is recommended:

The usual dosing regimen	Dosing regimen for severe renal failure
1 mg / kg body weight subcutaneously twice a day	1 mg / kg body weight subcutaneously once a day
1.5 mg / kg body weight subcutaneously once a day	1 mg / kg body weight subcutaneously once a day
Treatment of acute myocardial infarction with segment elevation ST in patients younger than 75 years
A single intravenous bolus injection of 30 mg + 1 mg / kg body weight subcutaneously; followed by subcutaneous administration at a dose of 1 mg / kg body weight twice a day (maximum 100 mg for each of the first two subcutaneous injections)	A single intravenous bolus injection of 30 mg + 1 mg / kg body weight subcutaneously; followed by subcutaneous administration at a dose of 1 mg / kg body weight once a day (maximum 100 mg only for the first subcutaneous injection)
Treatment of acute myocardial infarction with segment elevation ST in patients 75 years and older
0.75 mg / kg body weight subcutaneously twice daily without initial intravenous bolus administration (maximum 75 mg for each of the first two subcutaneous injections)	1 mg / kg body weight subcutaneously once daily without initial intravenous bolus administration (maximum 100 mg only for the first subcutaneous injection)

When using the drug for prophylactic purposes in patients with a moderate risk of thromboembolic complications, correction of the dosing regimen is recommended, as shown in the table below.

The usual dosing regimen	Dosing regimen for severe renal failure
40 mg subcutaneously once daily	20 mg subcutaneously once daily
20 mg subcutaneously once daily	20 mg subcutaneously once daily

The recommended dosage adjustment is not used for hemodialysis.

With a mild (creatinine clearance 50-80 ml / min) and moderate (creatinine clearance 30-50 ml / min), renal dysfunction dosage adjustment is not required, but patients should be under close medical supervision.

Patients from impaired hepatic function

Due to the lack of clinical studies, sodium enoxaparin Use with caution in patients with impaired hepatic function.

Instructions for self-administered injection of enoxaparin sodium (pre-filled syringe with a protective needle system).

1. Wash your hands and skin area (injection site) into which you will administer the drug, with soap and water. Dry them.

2. Take a comfortable "sitting" or "lying" position and relax. Make sure you see the place where you are going to inject the drug. It is best to use a reclining chair, a chaise longue or a bed covered with cushions for support.

3. Choose a place for an injection in the right or left side of the abdomen. This place should be at least 5 centimeters from the navel in the direction to the sides. Do not perform an independent injection at a distance of 5 centimeters from the navel or around existing scars or bruises. Alternate injection sites in the right and left parts of the abdomen, depending on where you injected the drug the previous time.

4. Wipe the place for injection with a swab dampened with alcohol.

5. Carefully remove the cap from the syringe needle of the sodium enoxaparin preparation. Set the cap aside.The syringe is pre-filled and ready for use. Do not press the plunger to expel air bubbles before inserting the needle into the injection site. This can lead to loss of the drug. After removing the cap, do not allow the needle to touch any objects. This is necessary to maintain the sterility of the needle.

6. Hold the syringe in the hand that you are writing, the way you hold the pencil, and the other hand gently squeeze the alcohol rubbed place to inject the drug between the thumb and forefinger so as to form a skin fold. Hold the skin fold the entire time you enter the drug.

7. Hold the syringe in such a way that the needle is pointing down (vertically at an angle of 90 °). Insert the needle on its entire dinas into the skin fold.

8. Press your finger on the piston. This will ensure the introduction of the drug into the subcutaneous adipose tissue of the abdomen. Hold the skin fold the entire time you enter the drug.

9. Remove the needle by pulling it back without deviating from the axis. The protective mechanism automatically closes the needle. Now you can stop holding the skin fold. The safety system that starts the protective mechanism is activated only after the entire contents of the syringe are inserted by pressing the piston for the entire length of its stroke.

10.In order to prevent bruising, do not rub the injection site after injection.

11. Place the used syringe with the protective mechanism in the sharps container. Close the container tightly and keep it out of the reach of children.

When using the drug, adhere strictly to the recommendations given in this manual, as well as the directions of a doctor or pharmacist. If you have any questions, contact your doctor or pharmacist.

Side effects:

A study of the side effects of sodium enoxaparin was conducted in more than 15,000 patients who participated in clinical trials, including 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 on bed rest, due to acute therapeutic diseases; in 559 patients - in the treatment of deep vein thrombosis with pulmonary embolism or pulmonary embolism; in 1578 patients - in the treatment of unstable angina and myocardial infarction without a tooth Q; in 10,176 patients - in the treatment of myocardial infarction with segment elevation ST. The mode of administration of sodium enoxaparin differed depending on the indications. In the prevention of venous thrombosis and embolism in general surgery and orthopedic surgery or in patients on bed rest, 40 mg subcutaneously once a day was administered. In the treatment of deep vein thrombosis with or without pulmonary embolism, patients received sodium enoxaparin at the rate of 1 mg / kg body weight subcutaneously every 12 hours or 1.5 mg / kg body weight subcutaneously once a day. In the treatment of unstable angina and myocardial infarction without a tooth Q the dose of enoxaparin sodium was 1 mg / kg body weight subcutaneously every 12 hours, and in the case of myocardial infarction with segment elevation ST an intravenous bolus injection of 30 mg was administered followed by 1 mg / kg body weight subcutaneously every 12 hours.

Undesirable reactions were classified according to the frequency of occurrence as follows: very frequent (≥ 1/10), frequent (≥ 1/100 - <1/10), infrequent (≥ 1/1000 - <1/100), rare (≥ 1 / 10 000 - <1/1000), very rare (<1/10 000), or the frequency is unknown (according to available data, the frequency of occurrence of an undesirable reaction can not be estimated).The undesirable reactions observed after the release of the drug on the market were assigned to the frequency "frequency is unknown."

Vascular disorders

Bleeding

In clinical studies, bleeding was the most common adverse reaction. These included long bleeding observed in 4.2% of patients (bleeding was considered large, if it is accompanied by a decrease in hemoglobin of 2 g / l or more, required transfusion of 2 or more doses of blood components, and also if there was retroperitoneal or intracranial). Some of these cases were lethal.

As with other anticoagulants, the application enoxaparin sodium may experience bleeding, especially in the presence of risk factors for the development of bleeding during invasive procedures, or the use of drugs that violate hemostasis (see. The sections "Specific guidance" and "interaction with other drugs ").

In describing bleeding below the sign "*" means a reference to the following types of haemorrhage: hematoma, ecchymosis (except perhaps at the injection site), wound hematoma, hematuria, epistaxis, gastrointestinal bleeding.

Very frequent - bleeding * in the prevention of venous thrombosis in surgical patients and the treatment of deep vein thrombosis with or without pulmonary embolism.

Frequent - bleeding * in the prevention of venous thrombosis in patients on bed rest, and in the treatment of unstable angina, myocardial infarction without a tooth Q and myocardial infarction with segment elevation ST.

Infrequent - retroperitoneal bleeding and intracranial hemorrhage in patients with or without deep vein thrombosis with or without pulmonary embolism, and with myocardial infarction with segment elevation ST.

Rare - retroperitoneal bleeding in the prevention of venous thrombosis in surgical patients and in the treatment of unstable angina, myocardial infarction without a tooth Q.

Thrombocytopenia and thrombocytosis

Very Frequent - Thrombocytosis (the number of platelets in the peripheral blood is more than 400x10⁹/ l) in the prevention of venous thrombosis in surgical patients and in the treatment of deep vein thrombosis with or without pulmonary embolism.

Frequent - Thrombocytosis in the treatment of patients with acute myocardial infarction with segment elevation ST.

Thrombocytopenia in the prevention of venous thrombosis in surgical patients and the treatment of deep vein thrombosis with or without pulmonary embolism, as well as with acute myocardial infarction with segment elevation ST.

Infrequent - thrombocytopenia in the prevention of venous thrombosis in patients on bed rest, and in the treatment of unstable angina, myocardial infarction without a tooth Q.

Very rare - Immune-allergic thrombocytopenia in the treatment of patients with acute myocardial infarction with segment elevation ST.

Other clinically relevant adverse reactions, regardless of the indications

- These undesirable reactions, presented below, are grouped according to the system-organ classes, given with the indication of the frequency of their occurrence determined above and in order of decreasing their severity.

Immune system disorders

Frequent: allergic reactions.

Rare: anaphylactic and anaphylactoid reactions.

Disturbances from the liver and bile ducts

Very Frequent: an increase in the activity of "hepatic" enzymes, mainly, an increase in the activity of transaminases, more than three times the upper limit of the norm.

Disturbances from the skin and subcutaneous tissues

Frequent: hives, skin itching, erythema.

Infrequent: bullous dermatitis.

General disorders and disorders at the injection site

Frequent: hematoma at the injection site, pain at injection site, swelling at injection site, bleeding, hypersensitivity reactions, inflammation, formation of seals at the injection site.

Infrequent: irritation at the injection site, necrosis of the skin at the injection site.

Laboratory and instrumental data

Rare: hyperkalemia.

Data, received in the post-registration period

The following adverse reactions were noted during the post-marketing application of sodium enoxaparin. There were spontaneous reports of these adverse reactions, and their frequency was defined as "the frequency is unknown" (it can not be established from the available data).

Immune system disorders

Anaphylactic / anaphylactoid reactions, including shock.

Disturbances from the nervous system

Headache.

Vascular disorders

In applying enoxaparin sodium amid spinal / epidural anesthesia or spinal punctures have been cases of spinal hematoma (or neuraxial hematoma). These reactions lead to the development of neurological disorders of varying severity, including permanent or irreversible paralysis (see. The "Special instructions").

Violations of the blood and lymphatic system

Hemorrhagic anemia. Cases of development of immune-allergic thrombocytopenia with thrombosis; in some cases, thrombosis was complicated by the development of an organ infarction or limb ischemia (see section "Special instructions", sub-section "Quality control of platelets in peripheral blood").

Eosinophilia.

Disturbances from the skin and subcutaneous tissues

At the injection site, skin vasculitis, skin necrosis, which is usually preceded by the appearance of purpura or erythematous papules (infiltrated and painful) can develop. In these cases, sodium enoxaparin therapy should be discontinued. Possible formation of solid inflammatory nodules-infiltrates at the injection site of the drug, which disappear after a few days and are not grounds for drug withdrawal.

Alopecia.

Disturbances from the liver and bile ducts

Hepatocellular liver damage.

Cholestatic liver damage.

Disturbances from musculoskeletal and connective tissue

Osteoporosis with long-term therapy (more than three months).

Overdose:

Symptoms: a random overdose with intravenous, extracorporeal or subcutaneous administration can lead to hemorrhagic complications. When ingestion, even in large doses, absorption of the drug is unlikely.

Treatment: as a neutralizing agent shows a slow intravenous administration of protamine sulfate, the dose of which depends on the dose of sodium enoxaparin administered. It should be taken into account that 1 mg protamine neutralizes the anticoagulant effect of 1 mg enoxaparin sodium, if sodium enoxaparin was administered no more than 8 hours before the introduction of protamine. 0.5 mg of protamine neutralizes the anticoagulant effect of 1 mg of sodium enoxaparin if it was administered more than 8 hours ago or if a second dose of protamine is needed. If after the administration of the drug enoxaparin sodium passed more than 12 hours, the introduction of protamine is not required. However, even with the administration of protamine sulfate in high doses of anti-Xa, the activity of sodium enoxaparin is not completely neutralized (up to a maximum of 60%).

Interaction:

Enoxaparin sodium should not be mixed with other drugs!

While the use of drugs affecting hemostasis (salicylates systemic action of acetylsalicylic acid, nonsteroidal antiinflammatory drugs [including ketorolac], dextran with a molecular weight of 40 kDa, ticlopidine and clopidogrel, systemic glucocorticosteroids, thrombolytic or anticoagulant and other antiplatelet drugs [including glycoprotein antagonists IIb/IIIa]), the risk of bleeding increases (see "Special instructions").

Special instructions:

Are common

Low molecular weight heparins are not interchangeable, since they differ in the process of production, molecular weight, specific anti-Xa activity units dosing and dosing regimen, with associated 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.

Bleeding

As with the use of other anticoagulants, with the administration of enoxaparin sodium, bleeding of any localization is possible (see Fig.section "Side effect"). With the development of bleeding it is necessary to find its source and prescribe the appropriate treatment.

Bleeding in elderly patients

When sodium enoxaparin was used in prophylactic doses in elderly patients, there was no increased risk of bleeding.

When using the drug in therapeutic doses in elderly patients (especially at the age of 80 years and older) there is an increased risk of bleeding. It is recommended that careful monitoring of the condition of such patients is performed (see the sections "Pharmacokinetics" and "Method of administration and dose", subsection "Patients of advanced age").

Simultaneous use of other drugs, influencing hemostasis

It is recommended that the use of drugs that affect hemostasis (salicylates, including acetylsalicylic acid, non-steroidal anti-inflammatory drugs, including ketorolac; dextran with a molecular mass of 40 kD, ticlopidine, clopidogrel; glucocorticosteroids, thrombolytics, anticoagulants, antiaggregants, including glycoprotein IIb / IIIa receptor antagonists) was discontinued before treatment with enoxaparin sodium, unless they are necessary.If combinations of sodium enoxaparin with these drugs are shown, careful clinical observation and monitoring of relevant laboratory parameters should be carried out.

Renal insufficiency

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.

In patients with severe impairment of renal function (creatinine clearance <30 ml / min), there is a significant increase in exposure to sodium enoxaparin, therefore it is recommended to dose adjustments for both prophylactic and therapeutic use of the drug. Although dose adjustment is not required in patients with mild or moderate impairment of renal function (creatinine clearance 30-50 ml / min or 50-80 ml / min), careful monitoring of the condition of such patients is recommended (see sections "Pharmacokinetics" and "Method application and dose regimen ", subsection" Patients with renal insufficiency ").

Low body weight

An increase in the exposure of sodium enoxaparin was noted for its preventive use in women with a body weight of less than 45 kg and in men weighing less than 57 kg,which can lead to an increased risk of bleeding. It is recommended that careful monitoring of the condition of such patients is made.

Patients with obesity

Patients with obesity have an increased risk of developing thrombosis and embolism. Safety and efficacy of sodium enoxaparin in prophylactic doses in obese patients (BMI> 30 kg / m²) is not fully defined and there is no general consensus on dose adjustment. These patients should be closely monitored for the development of symptoms and signs of thrombosis and embolism.

Control of the number of platelets in the peripheral blood

The risk of developing antibody-mediated heparin-induced thrombocytopenia exists even when low molecular weight heparins are used. If thrombocytopenia develops, it is usually detected between the 5th and 21st days after initiation of sodium enoxaparin therapy. In this regard, it is recommended that the number of platelets in the peripheral blood be monitored regularly before treatment with enoxaparin sodium and during its use. In the presence of a confirmed significant decrease in the number of platelets (by 30-50% compared with the initial index), it is necessary immediatelyabolish sodium enoxaparin and transfer the patient to another therapy.

Spinal / epidural anesthesia

The cases of the appearance of neuroaxial hematomas with the use of sodium enoxaparin are described with simultaneous spinal / epidural anesthesia with the development of a long-term or irreversible paralysis. The risk of occurrence of these phenomena decreases with the use of the drug in a dose of 40 mg or lower. The risk increases with higher doses of sodium enoxaparin, as well as with the use of permanent catheters after surgery, or with the simultaneous use of additional drugs that affect hemostasis, such as non-steroidal anti-inflammatory drugs (see "Interactions with Other Drugs"). The risk also increases with a traumatically performed or repeated spinal puncture or in patients who have a history of referring to the transferred operations in the spine or deformity of the spine.

To reduce the possible risk of bleeding associated with the use of sodium enoxaparin and epidural or spinal anesthesia / analgesia, it is necessary to take into account the pharmacokinetic profile of the drug (see the section "Pharmacokinetics").

It is better to install or remove a catheter with a low anticoagulant effect of enoxaparin sodium, but the exact time to achieve a sufficient reduction in the anticoagulant effect in different patients is unknown.

The placement or removal of the catheter should be performed at least 12 hours after the administration of lower doses of enoxaparin sodium (20 mg once daily, 30 mg once or twice daily, 40 mg once daily) and, at a minimum, 24 hours after the administration of higher doses of enoxaparin sodium (0.75 mg / kg body weight twice a day, 1 mg / kg body weight twice a day, 1.5 mg / kg body weight once a day). At these time points, the anti-Xa activity of the drug still continues to be detected, and the time delays are not a guarantee that the development of the neuroaxyl hematoma can be avoided. Patients receiving sodium enoxaparin in doses of 0.75 mg / kg of body weight twice a day or 1 mg / kg of body weight twice a day, with this (two-time during the day) dosing regimen, do not enter a second dose, in order to increase the interval before installation or replacement of a catheter. Similarly, consideration should be given to the possibility of delaying the introduction of the next dose of the drug for at least 4 hours,based on an assessment of the benefit / risk ratio (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 noted that in patients with creatinine clearance less than 30 ml / min sodium enoxaparin is slowed down. Therefore, this category of patients should consider doubling the time from catheter removal: at least 24 hours for lower doses of enoxaparin sodium (30 mg once daily) and at least 48 hours for higher doses (1 mg / kg of body weight per day). If anticoagulant therapy is used as prescribed by the doctor during epidural / spinal anesthesia or lumbar puncture, constant monitoring of the patient is necessary to detect any neurological symptoms such as back pain, impaired sensory and motor functions (numbness or weakness in the lower extremities), violation function of the intestine and / or bladder. The patient should be instructed about the need to inform the doctor immediately if any of the above symptoms occur.When suspected of the symptoms characteristic of the hematoma of the spinal cord, urgent diagnosis and treatment is needed, including, if necessary, decompression of the spinal cord.

Heparin-induced thrombocytopenia

With extreme caution sodium enoxaparin should be used in patients who have a history of information about heparin-induced thrombocytopenia in combination with or without thrombosis. The risk of developing heparin-induced thrombocytopenia can persist for several years. If anamnesis is presumed to have heparin-induced thrombocytopenia, then platelet aggregation assays in vitro are of limited importance in forecasting the risk of its development. The decision on the use of enoxaparin sodium in this case can be taken only after consultation with the appropriate specialist.

Percutaneous coronary angioplasty

In order to minimize the risk of bleeding associated with invasive vascular instrumental manipulation in the treatment of unstable angina and myocardial infarction without a tooth Q and acute myocardium with segment elevation ST, these procedures should be performed at intervals between the administration of enoxaparin sodium. This is necessary in order to achieve hemostasis after percutaneous coronary intervention. When using a closure device, the introducer of the femoral artery can be removed immediately. When manual (manual) compression is used, the femoral artery introducer should be removed 6 hours after the last intravenous or subcutaneous injection of sodium enoxaparin. If sodium enoxaparin treatment is continued, the next dose should be administered no earlier than 6-8 hours after removal of the femoral artery introducer. It is necessary to monitor the place of introduction of the introdiocerera in time to reveal signs of bleeding and the formation of a hematoma.

Patients with mechanical heart valves

The use of sodium enoxaparin for the prevention of thrombosis in patients with mechanical heart valves has been studied insufficiently. There are separate reports on the development of thrombosis of heart valves in patients with mechanical heart valves on the background of therapy with enoxaparin sodium for the prevention of thrombosis.Assessment of these reports is limited due to the presence of competing factors contributing to the development of thrombosis of artificial heart valves, including the underlying disease, and because of the lack of clinical data.

Pregnant women with mechanical artificial heart valves

The use of sodium enoxaparin for the prevention of thrombosis in pregnant women with mechanical artificial heart valves has not been adequately studied. In a clinical study of pregnant women with mechanical heart valves using sodium enoxaparin at a dose of 1 mg / kg body weight twice a day to reduce the risk of thrombosis and embolism, 2 of 8 women developed thrombi that led to blockage of heart valves and to the death of the mother and the fetus.

There are separate post-marketing reports on thrombosis of heart valves in pregnant women with mechanical heart valves treated with sodium enoxaparin for the prevention of thrombosis.

Pregnant women with mechanical artificial heart valves have a high risk of developing thrombosis and embolism.

Laboratory Tests

In the doses used to prevent thromboembolic complications, sodium enoxaparin does not significantly affect bleeding time and blood coagulation, as well as platelet aggregation or binding to fibrinogen.

When the dose is raised, the APTT and the activated clotting time can be prolonged. The increase in APTT and the activated clotting time are not in a direct linear relationship with the increase in 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 in bed

In the case of acute infection, acute rheumatic conditions, the prophylactic use of sodium enoxaparin is justified only if the above conditions are combined with one of the following risk factors for venous thrombus formation:

- age over 75 years;

- malignant neoplasms;

- thrombosis and embolism in the anamnesis;

- obesity;

- hormone therapy;

- heart failure;

chronic respiratory failure.

Children

Safety and efficacy of sodium enoxaparin in children under the age of 18 years have not been established.

Effect on the ability to drive transp. cf. and fur:

Enoxaparin sodium does not affect the ability to drive vehicles and mechanisms.

Form release / dosage:

Solution for Injection 2000 anti-Ha IU / 0.2 ml; 4000 anti-Ha IU / 0.4 mL; 6000 anti-Ha IU / 0.6 mL; 8000 anti-Ha IU / 0.8 ml; 10,000 anti-Ha IU / 1 ml.

Packaging:

By 0.2 ml or 0.4 ml or 0.6 ml or 0.8 ml or 1.0 ml into three-component sterile syringes from colorless neutral glass I of the hydrolytic class. For each syringe stick a label.

1 syringe per contour mesh box made of PVC film. For 2 or 10 contour mesh packages together with instructions for use in a pack of cardboard.

Storage conditions:

Store at a temperature not exceeding 25 ° C.

Keep out of the reach of children.

Shelf life:

3 years.

Do not use after the expiry date shown on the package.

Terms of leave from pharmacies:On prescription

Registration number:LP-004284

Date of registration:04.05.2017

Expiration Date:04.05.2022

The owner of the registration certificate:BIOCAD, CJSC BIOCAD, CJSC Russia