Клексан®

General characteristics. Structure:

Active вещество:Эноксапарин sodium (Evr. T., ND of firm) 20 mg *
Rastvoritel:voda for injections (Evr. T.) to 0,2 ml

Dosage 4000 Anti-ha ml ME/0,4 (40 mg / 0,4 are equivalent to ml).
Active вещество:Эноксапарин sodium (Evr. T., ND of firm) 40 mg *
Rastvoritel:voda for injections (Evr. T.) to 0,4 ml

Dosage 6000 Anti-ha ml ME/0,6 (60 mg / 0,6 are equivalent to ml).
Active вещество:Эноксапарин sodium (Evr. T., ND of firm) 60 mg *
Rastvoritel:voda for injections (Evr. T.) to 0,6 ml

Dosage of 8000 anti-HAME/0,8 of ml (80 mg / 0,8 are equivalent to ml).
Active вещество:Эноксапарин sodium (Evr. T., ND of firm) 80 mg *
Rastvoritel:voda for injections (Evr. T.) to 0,8 ml

Dosage of 10000 anti-Ha/1 of ml (100 mg / 1 are equivalent to ml).
Active вещество:Эноксапарин sodium (Evr. T., ND of firm) 100 mg *
Rastvoritel:voda for injections (Evr. T.) to 1,0 ml

* - weight is calculated on the basis of the maintenance of the used enoksaparin of sodium (theoretical activity 100 Anti-ha of ME/mg).

Description: transparent, from colourless till pale yellow color solution.

Pharmacological properties:

Characteristic.

Enoksaparin of sodium - low-molecular heparin with an average molecular weight about 4,500 дальтон: less than 2000 дальтон - <20%, from 2000 to 8000 дальтон-> 68%, more than 8000 дальтон - <18%. Enoksaparin of sodium receive alkaline hydrolysis of benzylic ether of the heparin emitted from a mucous membrane of a small bowel of a pig. Fro structure is characterized by not recovered fragment 2-O-sulfo-4-enpirazinosuronovoy of acid and the recovered fragment 2-N,6-0 of disulfo-E-glyukopiranozida. The structure of an enoksaparin of sodium contains about 20% (ranging from 15% to 25%) 1,6-angidroproizvodny in the recovered fragment of a polisakharidny chain

Pharmacodynamics. In the cleared in vitro system эноксапарин sodium has activity high Anti-ha (about 100 MF/ml) and low anti-11а or antithrombic activity (about 28 MF/ml). This anticoagulating activity works through antithrombin III (AT-III), providing anticoagulating activity at people. Except Anti-ha/Pa activity, additional anticoagulating and antiinflammatory properties of an enoksaparin of sodium both at healthy people and patients, and on models of animals are also revealed. It includes AT-III dependent inhibition of other factors of coagulation as VIta factor, activation of release of inhibitor of the way of a fabric factor (WFF), and also decrease in release of a factor of Villebrand from an endothelium of vessels in a blood stream. These factors provide anticoagulating effect enoksaparina sodium in general. When using it in preventive doses it slightly changes the activated partial tromboplastinovy time (APTT), practically does not make impact on aggregation of thrombocytes and on extent of linkng of fibrinogen with receptors of thrombocytes. Activity in plasma is about 10 times lower than anti-IIa, than an antique activity. Average maximum anti-Xа activity is observed approximately in 3-4 hours after hypodermic introduction and reaches 0,13 MF/ml and 0,19 MF/ml after repeated introduction of 1 mg/kg of body weight at double introduction and 1,5 mg/kg of body weight at single introduction, respectively. Average activity of plasma maximum Anti-ha is observed in 3-5 hours after hypodermic administration of drug and makes about 0,2; 0,4; 1,0 and 1,3 Anti-ha MF/ml after hypodermic introduction 20, 40 mg and 1 mg/kg and 1,5 mg/kg respectively.

Pharmacokinetics. The pharmacokinetics of an enoksaparin in the specified modes of dosing has linear character. Variability inside and between groups of patients low. After repeated hypodermic introduction of 40 mg of an enoksaparin of sodium once a day and hypodermic introduction of an enoksaparin of sodium in a dose of 1,5 mg/kg of body weight once a day at healthy volunteers equilibrium concentration is reached by 2nd day, and the area under a pharmacokinetic curve is on average 15% higher, than after single introduction. After repeated hypodermic introductions of an enoksaparin of sodium in a daily dose of 1 mg/kg of body weight two times a day equilibrium concentration is reached in 3-4 days, and the area under a pharmacokinetic curve is on average 65% higher, than after single introduction, and average values of the maximum concentration make respectively 1,2 ME/ml and 0,52 ME/ml. The bioavailability of an enoksaparin of sodium at hypodermic introduction estimated on the basis of Anti-ha activity is close to 100%.

Distribution volume Anti-ha makes activities of an enoksaparin of sodium about 5 l and approaches blood volume.

Enoksaparin of sodium is drug with low clearance. After intravenous administration within 6 hours in a dose of 1,5 mg/kg of body weight average value of clearance Anti-ha in plasma makes 0,74 l/hour. Removal of drug has monophase character with elimination half-lives 4 hours (after single hypodermic introduction) and 7 hours (after repeated administration of drug). Enoksaparin of sodium, is generally metabolized in a liver by a desulfatirovaniye and/or a depolymerization with formation of low-molecular substances with very low biological activity.

Removal through kidneys of active fragments of drug makes about 10% of the entered dose, and the general excretion of active and inactive fragments makes about 40% of the entered dose. The delay of removal of an enoksaparin of sodium at elderly patients as a result of depression of function of kidneys is possible with age.

Reduction of clearance of an enoksaparin of sodium at patients with reduced function of kidneys is noted. After repeated hypodermic introduction of 40 mg of an enoksaparin of sodium once a day there is an increase in the activity Anti-ha presented by the area under a pharmacokinetic curve at patients with insignificant (clearance of creatinine of 50-80 ml/min.) and moderated (clearance of creatinine of 30-50 ml/min.) a renal failure. At patients with a heavy renal failure (clearance of creatinine less than 30 ml/min.) the area under a pharmacokinetic curve in equilibrium state is on average 65% higher at repeated hypodermic introduction than 40 mg of drug once a day.

People with excess body weight at hypodermic administration of drug have a clearance slightly less. Not to do to Faw the amendment of a dose taking into account the body weight of the patient, after single hypodermic introduction of 40 mg of an enoksaparin of sodium Anti-ha activity will be 50% higher at women with body weight less than 45 kg and less than 57 kg in comparison with patients with usual average body weight are 27% higher at men with body weight.

Indications to use:

• Prevention of venous thromboses and embolisms at surgical interventions, especially at orthopedic and all-surgeries.
• Prevention of venous thromboses and embolisms at the patients who are on a bed rest owing to acute therapeutic diseases, including an acute heart failure and a decompensation of chronic heart failure (III or the IV class NYHA), acute respiratory insufficiency, and also at heavy acute infections and acute rheumatic diseases in combination with one of risk factors of a venous thrombogenesis (see. "Special instructions").
• Treatment of a deep vein thrombosis with a thromboembolism of a pulmonary artery or without thromboembolism of a pulmonary artery.
• Prevention of a thrombogenesis in system of extracorporal blood circulation during a hemodialysis (usually lasting session no more than 4 watch).
• Treatment of unstable stenocardia and myocardial infarction without Q tooth in combination with acetylsalicylic acid.
• Treatment of an acute myocardial infarction with raising of a segment of ST at the patients who are subject to drug treatment or the subsequent chrezkozhny coronary intervention.

Route of administration and doses:

Except for special cases (see below "Treatment of a myocardial infarction with raising of a segment of ST, medicamentous or by means of chrezkozhny coronary intervention" and "Prevention of a thrombogenesis in system of extracorporal blood circulation when carrying out a hemodialysis"), эноксапарин sodium it is entered deeply subcutaneously. It is desirable for injection to carry out in position of the patient "lying". When using of previously filled syringes on 20 mg and 40 mg in order to avoid loss of drug before an injection it is not necessary to delete vials of air from the syringe. Injections should be carried out serially to the left or right anterolateral or posterolateral surface of a stomach.
The needle needs to be entered vertically (not sideways) into a skin fold at all length collected and withheld before end of an injection between big and index fingers. The fold of skin is released only after end of an injection. It is not necessary to mass the place of an injection after administration of drug. Previously filled one-time syringe is ready to use. The drug cannot be administered intramusculary!

Prevention of venous thromboses and an embolism at surgical interventions, especially at orthopedic and all-surgeries
The patient with moderate risk of development of thromboses and embolisms (all-surgeries) the recommended Kleksan's dose makes 20 mg once a day subcutaneously. The first injection is made in 2 hours prior to surgical intervention. Drug is recommended to patients with high risk of development of thromboses and embolisms (all-surgical and orthopedic operations) in a dose of 40 mg once a day subcutaneously, the first dose is entered in 12 hours prior to surgical intervention, or 30 mg two times a day from the beginning of introduction in 12-24 hours after operation. Duration of treatment by Kleksan averages 7-10 days. If necessary therapy can be continued until the risk of development of thrombosis and embolism remains (for example, in orthopedics Kleksan is appointed in a dose of 40 mg within 5 weeks once a day).
Features of appointment of Kleksan at spinal/epidural anesthesia, and also at procedures of coronary revascularization are described in the section "Special Instructions".

Prevention of venous thromboses and embolisms at the patients who are on a bed  rest  owing to  acute therapeutic diseases.
The recommended Kleksan's dose makes 40 mg once a day subcutaneously during 6k14 days.

Treatment of a deep vein thrombosis with a thromboembolism of a pulmonary artery or without thromboembolism of a pulmonary artery.
The drug is administered subcutaneously at the rate of 1,5 mg/kg of body weight once a day or in a dose of 1 mg/kg of body weight two times a day. At patients with the complicated thromboembolic disturbances it is recommended to use drug in a dose 1 mg/kg twice a day.
Duration of treatment averages 10 days. It is desirable to begin at once therapy with indirect anticoagulants, at the same time therapy by Kleksan needs to be continued before achievement of sufficient anticoagulating effect, i.e. the international normalized relation (INR) has to make 2,0-3,0.
Prevention of a thrombogenesis in system of extracorporal blood circulation during a hemodialysis
Kleksan's dose averages 1 mg/kg of body weight. At high risk of development of bleeding the dose should be lowered to 0,5 mg/kg of body weight at double vascular access or 0,75 mg at unary vascular access.
At a hemodialysis the drug should be administered to the arterial site of the shunt at the beginning of the hemodialysis session. One dose, as a rule, is enough for a four-hour session, however at detection of fibrinous rings at more long hemodialysis it is possible to administer in addition the drug at the rate of 0,5-1 mg/kg of body weight.

Treatment of unstable stenocardia and myocardial infarction without Q tooth
Kleksan is entered at the rate of 1 mg/kg of body weight each 12 hours subcutaneously, at simultaneous use of acetylsalicylic acid in a dose of 100-325 mg once a day.
The average duration of therapy makes 2-8 days (before stabilization of a clinical condition of the patient).

Treatment of a myocardial infarction with raising of a segment of ST, medicamentous or by means of chrezkozhny coronary intervention
Treatment is begun with intravenous bolyusny administration эноксапарин sodium in a dose of 30 mg and at once after it (within 15 minutes) carry out hypodermic introduction эноксапарин sodium in a dose of 1 mg/kg (and when carrying out the first two subcutaneous injections as much as possible it can be entered 100 mg of an enoksaparin of sodium). Then all subsequent hypodermic doses are entered each 12 hours at the rate of 1 mg/kg of body weight (that is, at body weight more than 100 kg the dose can exceed 100 mg). Persons have 75 years and are more senior initial intravenous bolyusny administration is not applied. Enoksaparin of sodium is entered subcutaneously in a dose of 0,75 mg/kg each 12 hours (and, when carrying out the first two subcutaneous injections as much as possible it can be entered 75 mg of an enoksaparin of sodium). Then all subsequent hypodermic doses are entered each 12 hours at the rate of 0,75 mg/kg of body weight (that is, weighing more than 100 kg the dose can exceed 75 mg).
At a combination from trombolitika (fibrin - specific and fibrin - nonspecific) эноксапарин sodium it has to be entered in the range from 15 min. prior to thrombolytic therapy up to 30 min. after it. As soon as possible after detection of an acute myocardial infarction with raising of a segment of ST reception of acetylsalicylic acid has to begin at the same time and if there are no contraindications, it has to proceed within not less than 30 days in doses from 75 to 325 mg daily. The recommended treatment duration drug makes 8 days or to the patient's extract of a hospital if the period of hospitalization makes less than 8 days. Bolyusny introduction of an enoksaparin of sodium has to be carried out through a venous catheter and эноксапарин sodium should not mix up or be entered together with other medicines. To avoid presence at system of traces of other medicines and their interaction with enoksapariny sodium the venous catheter has to be washed out by enough 0,9% of solution of sodium of chloride or a dextrose before and after intravenous bolyusny administration of an enoksaparin of sodium. Enoksaparin of sodium can safely be entered from 0,9% by solution of sodium of chloride and 5% dextrose solution.
For carrying out bolyusny introduction of 30 mg of an enoksaparin of sodium at treatment of an acute myocardial infarction with raising of a segment of ST delete excessive amount of drug from glass syringes of 60 mg, 80 mg and 100 mg in them there were only 30 mg (0,3 ml). The dose of 30 mg can intravenously be entered directly.
For carrying out intravenous bolyusny administration of an enoksaparin of sodium through a venous catheter previously filled syringes for hypodermic administration of drug of 60 mg, 80 mg and 100 mg can be used. It is recommended to use syringes of 60 mg as it reduces amount of the drug deleted from the syringe. Syringes of 20 mg are not used as in them drug for bolyusny introduction of 30 mg of an enoksaparin of sodium does not suffice. Syringes of 40 mg are not used as on them there are no divisions and therefore it is impossible to measure precisely quantity in 30 mg. If the last subcutaneous injection of an enoksaparin of sodium was carried out less than in 8 hours prior to inflating of the narrowing of a coronary artery of a balloon catheter entered into the place, additional introduction of an enoksaparin of sodium is not required from patients to whom chrezkozhny coronary intervention is carried out. If the last subcutaneous injection of an enoksaparin of sodium was carried out more than in 8 hours prior to inflating of a balloon catheter it is necessary to make intravenous additional bolyusny administration of an enoksaparin of sodium in a dose of 0,3 mg/kg.
For increase in accuracy of additional bolyusny introduction of small volumes to a venous catheter when carrying out chrezkozhny coronary interventions it is recommended to dissolve drug to concentration of 3 mg/ml. Cultivation of solution is recommended to be made just before use. For receiving solution of an enoksaparin of sodium with concentration of 3 mg/ml by means of previously filled syringe of 60 mg it is recommended to use capacity with infusion solution of 50 ml (that is from 0,9% solution of sodium of chloride or 5% of solution of a dextrose). From capacity with infusion solution by means of the ordinary syringe 30 ml of solution are taken and removed. Enoksaparin of sodium (syringe contents for hypodermic introduction of 60 mg) is entered in remained in the volume of 20 ml of infusion solution. Capacity contents with divorced solution of an enoksaparin of sodium carefully mix up. For introduction by means of the syringe the necessary volume of divorced solution of an enoksaparin of sodium which is calculated by a formula is taken:
             85 25,5 8,5
       90 27 9
            95 28,5 9,5
     100 30         10

Patients of advanced age
Except for treatment of a myocardial infarction with raising of a segment of ST (see above) for all other indications of decrease in doses of an enoksaparin of sodium at patients of advanced age if they have no renal failure, it is not required.

Patients with a renal failure
- The heavy renal failure (clearance of endogenous creatinine less than 30 ml/min.) the Dose of an enoksaparin of sodium decreases according to the tables given below as these patients have a drug accumulation. At use of drug with the medical purpose the following correction is recommended

The usual mode of dosing the dosing Mode at a heavy renal failure
1 mg/kg subcutaneously 2 times in days              of 1 mg/kg subcutaneously 1 time a day
1,5 mg subcutaneously once a day           1 mg/kg subcutaneously once a day
Treatment of an acute myocardial infarction with raising of a segment of ST at patients <75 years
Once: bolyusny intravenous administration of 30 mg plus 1 mg/kg subcutaneously; with the subsequent hypodermic introduction in a dose of 1 mg/kg two times a day (at most 100 mg for each of the two first subcutaneous injections) Once: bolyusny intravenous administration of 30 mg plus 1 mg/kg subcutaneously; with the subsequent hypodermic introduction in a dose of 1 mg/kg once a day (at most 100 mg for the first subcutaneous injection)
Treatment of an acute myocardial infarction with raising of a segment of ST at patients> 75 years
0,75 mg/kg subcutaneously two times a day without initial bolyusny introduction (at most 75 mg for each of the two first subcutaneous injections) 1 mg/kg subcutaneously once a day without initial bolyusny introduction (at most 100 mg for the first subcutaneous injection)
20 mg subcutaneously once a day 20 mg subcutaneously once a day.

Features of use:

At purpose of drug in the preventive purposes the tendency to increase in bleeding was not revealed. At purpose of drug in the medical purposes there is a risk of development of bleedings in patients of advanced age (80 years are especially more senior). Carrying out careful observation of a condition of the patient is recommended. It is recommended that use of the drugs capable to break a hemostasis (salicylates, including, acetylsalicylic acid, non-steroidal anti-inflammatory drugs, including кеторолак; a dextran with a molecular weight of 40 kd, a tiklopidina, a klopidogrela; glucocorticosteroid drugs, trombolitik, anticoagulants, antiagregant, including antagonists of glycoprotein receptors of IIb/IIIa) it was stopped prior to treatment enoksapariny sodium, except for cases when their use is strictly shown. Fww are shown to a combination of an enoksaparin of sodium with these drugs, it is necessary to make careful clinical observation and monitoring of the corresponding laboratory indicators. Patients with a renal failure have a risk of development of bleeding as a result of increase Anti-ha in activity of an enoksaparin of sodium. At patients with heavy renal failures (clearance of creatinine less than 30 ml/min.) it is recommended to carry out dose adjustment, as at preventive, and therapeutic purpose of drug. Though it is not required to carry out dose adjustment at patients with an easy and moderate renal failure (clearance of creatinine of 30-50 ml/min. or 50-80 ml/min.), carrying out careful control of a condition of such patients is recommended (see. "Route of administration and doses"). Increase Anti-ha activities of an enoksaparin of sodium at its preventive appointment at women with body weight less than 45 kg and at men with body weight can result less than 57 kg in the increased risk of development of bleedings. The risk of the autoimmune thrombocytopenia caused by heparin exists also when using low-molecular heparins. Fww develops thrombocytopenia, it is usually revealed between the 5th and 21st days after the beginning of therapy enoksapariny sodium. In this regard it is regularly recommended to control quantity of thrombocytes prior to treatment by drug and during its use.

In the presence of the confirmed considerable decrease in quantity of thrombocytes (for 30-50% in comparison with an initial indicator) it is necessary to cancel immediately эноксапарин sodium and to transfer the patient to other therapy.

Spinal/epidural anesthesia As well as at use of other anticoagulants, cases of developing of neuroaxial hematomas when using Kleksana® against the background of spinal / epidural anesthesia with development of persistent or irreversible paralysis are described. The risk of emergence of these phenomena decreases at use of drug in a dose of 40 mg or below. The risk increases at increase in a dose of drug, and also when using catheters after operation, or at the accompanying use of the additional drugs exerting the same impact on a hemostasis as non-steroidal anti-inflammatory drugs (see. "Interaction with other medicines"). The risk also increases at traumatic the carried-out or repeated spinal puncture or at the patients having in the anamnesis of the instruction on the undergone operations in a backbone or deformation of a backbone. For decrease in risk of bleeding from the spinal channel at epidural or spinal anesthesia it is necessary to consider a pharmacokinetic profile of drug (see. "Pharmacological properties"). It is better to carry out installation or removal of a catheter at low anticoagulating effect of an enoksaparin of sodium. Installation or removal of a catheter have to be carried out 10-12 hours later after use of preventive doses of Kleksana® for prevention of a deep vein thrombosis. When patients receive higher doses of an enoksaparin of sodium (1 mg/kg 2 times a day or 1,5 mg/kg once a day), these procedures should be postponed for longer period (24 hours). The subsequent administration of drug has to be carried out not earlier than in 2 hours after removal of a catheter. The doctor appoints by Fww anticoagulating therapy during epidural/spinal anesthesia, especially careful constant observation of the patient is necessary for identification of any neurologic symptoms, such as: dorsodynias, disturbance of touch and motor functions (numbness or weakness in the lower extremities), dysfunction of intestines and/or bladder. The patient needs to be instructed about need of immediate informing the doctor at emergence of the above described symptoms. At detection of the symptoms characteristic of a hematoma of a spinal cord, urgent diagnosis and the treatment including, if necessary, a decompression of a spinal cord is necessary.

The heparin-induced thrombocytopenia With extra care of Kleksan® it is necessary to appoint the patient in whose anamnesis there are data on the thrombocytopenia caused by heparin in combination with thrombosis or without it.

The risk of the thrombocytopenia caused by heparin can remain within several years. Faw anamnesticly is supposed existence of the thrombocytopenia caused by heparin, tests for aggregation of thrombocytes of in vitro have limited value when forecasting risk of its development. The decision on purpose of Kleksana® in that case can be made only after consultation with the corresponding specialist. Transdermal coronary angioplasty for the purpose of reduction of risk of the bleeding connected with invasive vascular manipulation at treatment of unstable stenocardia and myocardial infarction without Q tooth, an introdyyuser of a femoral artery it is not necessary to delete within 6-8 hours after hypodermic introduction of Kleksana®. The following calculated dose should be entered not earlier than in 6-8 hours after removal of an introdyyuser of a femoral artery. It is necessary to watch the place of an invasion timely to reveal symptoms of bleeding and formation of a hematoma.

The artificial valves of heart of the Research allowing to estimate authentically efficiency and safety of Kleksana® in prevention of tromboembolic episodes at patients with artificial valves of heart were not carried out. Drug use is for this purpose not recommended (see the section "Contraindications").

Laboratory tests

In the doses used for prevention of tromboembolic episodes, Kleksan® significantly does not influence a bleeding time and indicators of a blood coagulation, and also aggregation of thrombocytes or their linkng with fibrinogen. At increase in a dose AChTV and a blood clotting time can be extended. Increase in AChTV and time of coagulation are not in direct linear dependence on increase in anticoagulating activity of drug therefore there is no need for their monitoring.

Prevention of venous thromboses and embolisms at the patients with acute therapeutic diseases who are on a bed rest

In case of development of an acute infection, acute rheumatic states preventive purpose of an enoksaparin of sodium is justified, only if above-mentioned states are combined with one of following risk factors of a venous thrombogenesis:

- age more than 75 years
- malignant new growths
- fibrinferments and embolisms in the anamnesis
- obesity
- hormonal therapy
- heart failure
- chronic respiratory insufficiency

Клексан® does not exert impact on ability to manage vehicles and mechanisms.

Side effects:

Studying of side effects of an enoksaparin of sodium was carried out on more than 15000 patients participating in clinical trials. Prevention of venous thromboses and embolisms at all-surgical and orthopedic operations - 1776 patients. Prevention of venous thromboses and embolisms at the patients who are on a bed rest owing to acute therapeutic diseases - 1169 patients. Treatment of a deep vein thrombosis with a thromboembolism of a pulmonary artery or without thromboembolism of a pulmonary artery - 559 patients. Treatment of unstable stenocardia and myocardial infarction without tooth of Q - 1578 patients. Treatment of a myocardial infarction with raising of a segment of ST - 10176 patients. The mode of introduction of an enoksaparin of sodium differed depending on indications. At prevention of venous thromboses and embolisms at all-surgical and orthopedic operations or at the patients who are on a bed rest made 40 mg subcutaneously once. At treatment of a deep vein thrombosis with a thromboembolism of a pulmonary artery or without it patients received эноксапарин sodium at the rate of 1 mg/kg of body weight subcutaneously each 12 hours or 1,5 mg/kg of body weight subcutaneously once in days. At treatment of unstable stenocardia and myocardial infarction without tooth Q dose of an enoksaparin of sodium made 1 mg/kg of body weight subcutaneously each 12 hours, and in case of a myocardial infarction with raising of a segment of ST - 30 mg of bolyusny introduction with the subsequent introduction of 1 mg/kg of body weight subcutaneously each 12 hours. Side effects classified by frequency as follows: very frequent (> 1/10), frequent (> 1/100 - <1/10), infrequent (> 1/1000 - <1/100), rare (> 1/10000 - <1/1000), very rare (<1/10000).

Bleeding

Bleeding was the most widespread side effect. It met in 4,2% of cases and was considered significant if also more was followed by decrease in a hemoglobin content by 2 g/l, demanded transfusion of 2 or more doses of components of blood, and also if it was retroperitoneal or intracranial. Some of these cases were lethal. As well as at use of other anticoagulants, developing of bleeding, especially with the risk factors promoting development of bleeding is possible when holding invasive procedures or using the drugs breaking a hemostasis (see. "special
instructions" and "Interaction with other medicines").

Very frequent - bleedings at prevention of venous thromboses at surgical patients and treatment of a deep vein thrombosis with a thromboembolism or without it. Frequent - bleedings at prevention of venous thromboses at the patients who are on a bed rest and at treatment of stenocardia, myocardial infarction without tooth of Q and a myocardial infarction with raising of a segment of ST. Infrequent - retroperitoneal bleedings and intracranial bleedings at patients at treatment of a deep vein thrombosis with a thromboembolism or without it, and also at a myocardial infarction with raising of a segment of ST. Rare - retroperitoneal bleedings at prevention of venous thromboses at surgical patients and at treatment of stenocardia, myocardial infarction without Q tooth. At use of Kleksana® against the background of spinal / epidural anesthesia and postoperative use of the getting catheters exceptional cases of formation of the neuroaxial hematomas leading to neurologic disturbances of various degree of manifestation are described, including is long the remaining or irreversible paralysis (see. "Special instructions").

Thrombocytopenia and thrombocytosis

Very frequent - a thrombocytosis at prevention of venous thromboses at surgical patients and treatment of a deep vein thrombosis with a thromboembolism or without it.

Frequent - thrombocytopenia at prevention of venous thromboses at surgical patients and treatment of a deep vein thrombosis with a thromboembolism or without it, and also at a myocardial infarction with raising of a segment of ST.

Infrequent - thrombocytopenia at prevention of venous thromboses at the patients who are on a bed rest and at treatment of stenocardia, myocardial infarction without Q tooth.

Very rare - autoimmune thrombocytopenia at a myocardial infarction with raising of a segment of ST. It was in rare instances reported about development of autoimmune thrombocytopenia in combination with thrombosis. In some of them thrombosis was complicated by a heart attack of body or ischemia of an extremity (see the section "Special Instructions").

Others

Very often - increase in activity of "hepatic" transaminases.

Often - allergic reactions, urticaria, an itch, reddening of integuments, a hematoma and pain in the place of an injection.

Infrequently - skin (violent rashes), inflammatory reaction in an injection site, a skin necrosis in an injection site. Seldom - anaphylactic and anaphylactoid reactions, a hyperpotassemia. In the place of an injection the skin necrosis to which emergence of a purpura or erythematic painful papules precedes can develop. In these cases therapy of Kleksanom® should be stopped. Formation of firm inflammatory small knots infiltrates in the place of injections of drug which disappear in several days is possible and are not the basis for drug withdrawal.

Interaction with other medicines:

Клексан® it is impossible to mix with other drugs! It is not necessary to alternate use of an enoksaparin of sodium and other low-molecular heparins as they differ from each other in way of production, the molecular weight, activity specific Anti-ha, units and a dosage. And, as a result of it, at drugs various pharmacokinetics and biological activity (anti-Xа activity, interaction with thrombocytes).

With salicylates of systemic action, acetylsalicylic acid, non-steroidal anti-inflammatory drugs (including кеторолак), a dextran with a smolekulyarny weight of 40 kd, tiklopidiny and klopidogrely, system glucocorticosteroids, trombolitika or anticoagulants, other antithrombocytic drugs (including antagonists of a glycoprotein of IIb/IIIa) - increase of risk of development of bleeding (see. "Special instructions").

Contraindications:

• Hypersensitivity to a sodium enoksaparin, heparin or its derivatives, including other low-molecular heparins.
• States and diseases at which there is a high risk of development of bleeding: the menacing abortion, aneurism of vessels of a brain or the stratifying aortic aneurysm (except for surgical intervention), a hemorrhagic stroke, uncontrollable bleeding, heavy enoksaparin-or geparinindutsirovanny thrombocytopenia.
• Kleksan's use for pregnant women with artificial valves of heart is not recommended.
• Age up to 18 years (efficiency and safety are not established).

With care to use at the following states:
- disturbances of a hemostasis (including hemophilia, thrombocytopenia, hypocoagulation, angiohemophilia, etc.), heavy vasculitis;
- peptic ulcer of a stomach or 12-perstny gut or other erosive cankers of digestive tract;
- recently had ischemic stroke;
- uncontrollable heavy arterial hypertension;
- diabetic or hemorrhagic retinopathy;
- heavy diabetes mellitus;
-    recently postponed or    assumed    neurologic    or
ophthalmologic operations;
- carrying out spinal or epidural anesthesia (potential danger of development of a hematoma), the spinal puncture which is (recently postponed);
- recent childbirth;
- endocarditis bacterial (acute or subacute);
- pericardis or pericardiac exudate;
- renal and/or liver failure;
- intrauterine contraception (VMK);
- a severe injury (especially the central nervous system), open wounds on big surfaces;
- a concomitant use of the drugs influencing system of a hemostasis.

The company has no data on a clinical use of drug Kleksan at the following diseases: active tuberculosis, the radiation therapy which is (recently postponed).

Pregnancy and period of a lactation
Data on what эноксапарин sodium gets through a placenta of the person during the second trimester of pregnancy no. There is no information concerning the first and third trimesters of pregnancy. Therefore Kleksan it is not necessary to apply during pregnancy except for cases when the potential advantage for mother exceeds possible risk for a fruit.
It is necessary to stop breastfeeding during treatment of mother by Kleksan.

Overdose:

The accidental overdose of Kleksan at intravenous, extracorporal or hypodermic use can lead to hemorrhagic complications. At intake even of high doses absorption of drug is improbable.

It is possible, generally to neutralize anticoagulating effects by slow intravenous administration of protamin of sulfate which dose depends on a dose of the entered Kleksan. One mg (1 mg) of protamin of sulfate neutralizes anticoagulating effect of one mg (1 mg) of Kleksan (see information on use of salts of protamin) if эноксапарин sodium it was entered no more, than in 8 hours prior to administration of protamin. 0,5 mg of protamin are neutralized by anticoagulating effect of 1 mg of Kleksan if from the moment of introduction of the last there passed more than 8 hours or in need of introduction of the second dose of protamin. If after introduction эноксапарин sodium there passed 12 and more hours, administration of protamin is not required. However, even at introduction of high doses of protamin of sulfate, Anti-ha Kleksan's activity completely is not neutralized (as much as possible for 60%).

Storage conditions:

At a temperature not above 25 °C. To store in the place, unavailable to children! Period of validity 3 years. After a period of validity it is impossible to use drug.

Issue conditions:

According to the recipe

Packaging:

Solution for injections 2000 Anti-ha ml ME/0,2; 4000 Anti-ha ml ME/0,4; 6000 Anti-ha ml ME/0,6; 8000 Anti-ha ml ME/0,8; 10000 Anti-ha ml ME/1.

For dosages of 2000 Anti-ha ml ME/0,2; 4000 Anti-ha ml ME/0,4; 8000 Anti-ha ml ME/0,8: 0,2 ml or 0,4 ml or 0,8 ml of solution of drug in the glass syringe respectively. On 2 syringes in the blister. On 1 or 5 blisters together with the application instruction in a cardboard pack.

For dosages 6000 Anti-ha ml ME/0,6; 10000 Anti-ha ml ME/1: 0,6 ml or 1,0 ml
drug solution in the glass syringe respectively. On 2 syringes in the blister. On 1 blister together with the application instruction in a cardboard pack.