Enoxaparin-Pharmex Solution 10,000 anti-Ha IU / mL 0.4 mL syringe No. 1

Enoxaparin (ENOXAPARIN) instructions for use

Composition

active ingredient: sodium enoxaparin

1 ml of 10,000 anti-Xa IU, equivalent to 100 mg of sodium enoxaparin
2000 anti-Ha IU / 0.2 ml equivalent to 20 mg of sodium enoxaparin
4000 anti-Ha IU / 0.4 mL equivalent to 40 mg of sodium enoxaparin
6000 anti-Xa IU / 0.6 ml equivalent to 60 mg of sodium enoxaparin
8000 anti-Xa IU / 0.8 ml equivalent to 80 mg of sodium enoxaparin

excipients: water for injection.

Dosage form

Injection.

Basic physical and chemical properties:

transparent colorless or yellowish solution.

Pharmacological group

Antithrombotic agents. Group of heparin. Code ATX B01A B05.

Pharmacological properties

Pharmacodynamics.

Enoxaparin is a low-molecular-weight heparin, in which the antithrombotic and anticoagulant activity of standard heparin is not related. It is characterized by a higher anti-Xa activity than anti-Pa or anti-thrombin activity. For enoxaparin, the ratio of these two activities is 3.6.

In preventive doses, it has no significant effect on the level of activated partial thromboplastin time (APTT).

At the peak of the activity of therapeutic doses, the aHTTV can be 1.5-2.2 times the control time. This elongation indicates a residual antithrombin effect.

Pharmacokinetics.

The pharmacokinetic parameters of enoxaparin were evaluated based on the duration of anti-Xa and anti-Pa activity in blood plasma at the recommended doses (validated amidolytic methods) after a single and repeated subcutaneous administration and after a single injection.

Bioavailability

Enoxaparin administered subcutaneously is rapidly and almost completely absorbed (about 100%). Maximum activity in the blood plasma is achieved 3-4 hours after the administration. This maximum activity (expressed in anti-XA IU) is 0.18 ± 0.04 (after 2000 anti-Xa IU), 0.43 ± 0.11 (after 4,000 anti-Xa IU) for prophylactic treatment and 1, 01 ± 0.14 (after 10,000 anti-HA IU) with curative therapy.

A bolus intravenous injection of 3000 anti-Ha IU with further subcutaneous injections of 100 anti-Ha IU / kg every 12:00 results in the first maximum antifactor concentration level Xa equal to 1.16 IU / ml (n = 16) and the mean area under the pharmacokinetic curve corresponding to 88% of the equilibrium level. The equilibrium state is reached on the second day of treatment.

Within the recommended doses, the pharmacokinetics of enoxaparin is linear.

Intraindividual and interindividual variability is low. After repeated subcutaneous injections to healthy volunteers, 4000 anti-Ha IU once a day is reached on the 2nd day, with an average enoxaparin activity of about 15% higher than after a single dose. The level of activity of enoxaparin in the equilibrium state can be predicted from the pharmacokinetics of a single dose. After repeated subcutaneous administration of 100 anti-Ha IU / kg twice a day, the equilibrium state is reached on the 3rd-4th day, the average area under the pharmacokinetic curve is approximately 65% higher than after a single dose, and the maximum and minimum levels of anti -ha activity are 1.2 and 0.52 anti-Ha IU / ml, respectively.Based on the pharmacokinetics of sodium enoxaparin, this difference is observed for the equilibrium state, is predictable and is within the therapeutic interval. Anti-Pa activity in blood plasma after subcutaneous administration is about 10 times lower than anti-Xa activity. The average maximum anti-Pa activity is observed approximately 3-4 hours after the administration of the drug and reaches 0.13 anti-Pa IU / ml with repeated administration of 100 anti-Ha IU / kg dose twice a day.

The pharmacokinetic interaction between enoxaparin and thrombolytic agents with simultaneous administration was not observed.

Distribution

The volume of distribution of anti-Xa activity of enoxaparin is about 5 liters and is close to the volume of blood.

Metabolism

Enoxaparin is metabolized in the liver (desulfatization, depolymerization).

Conclusion

After subcutaneous administration, the half-life of anti-Xa activity in low molecular weight heparins is higher than in unfractionated heparin.

Enoxaparin is characteristic of monophasic inference with a half-life of about 4:00 after subcutaneous administration of a single dose and about 7:00 after the administration of repeated doses.

In low-molecular-weight heparin, anti-Pa activity in blood plasma decreases faster than anti-Xa activity.

Enoxaparin and its metabolites are excreted by the kidneys (unsaturated mechanism) and through the biliary tract.

Renal clearance of fragments with anti-Xa activity is about 10% of the administered dose, and total renal excretion of active and inactive substances is 40% of the dose.

High-risk groups

Patients of advanced age.

Infertility is slowed down through physiologically reduced kidney function in this group. This change does not affect the dosage and administration regimen for prophylactic therapy if the kidney function in such patients remains within acceptable limits, that is, when it is only slightly reduced.

Before beginning treatment with low molecular weight heparin (LMWH) in patients older than 75 years, it is necessary to systematically assess the kidney function using the Cockcroft-Gault formula (see Section "Application Specificity").

Patients with mild or moderate renal insufficiency (creatinine clearance> 30 ml / min):

it may sometimes be useful to monitor the activity of the circulating anti-Xa factor to prevent an overdose if enoxaparin is used for therapeutic purposes (see section "Application features").

Hemodialysis.

Low molecular weight heparin is injected into the arterial route of the hemodialysis circuit in appropriate doses in order to prevent thrombus formation in the system.

Pharmacokinetic parameters, in principle, remain unchanged, except for cases of overdose or cases when the drug enters the common bloodstream, which leads to an increase in anti-Xa activity associated with terminal renal failure.

Indications

• Prevention of venous thromboembolism in surgical interventions accompanied by moderate and high thrombogenic risk;
• prevention of thrombus formation in the extracorporeal circuit of blood circulation during hemodialysis (the procedure on average lasts until about 4:00)
• treatment of diagnosed deep vein thrombosis that is accompanied or not accompanied by pulmonary embolism and does not have severe clinical symptoms, except for thromboembolism of pulmonary arthritis that requires thrombolytic treatment or surgery
• treatment of unstable angina and acute myocardial infarction without Q wave in combination with acetylsalicylic acid
• treatment of acute myocardial infarction with ST elevation / elevation in combination with thrombolytic agents in patients who may continue to use coronary angioplasty, as well as in patients who do not receive this procedure.

Contraindications

For doses of 2000 anti-Ha IU / 0.2 mL, equivalent to sodium enoxaparin 20 mg

4000 anti-Ha IU / 0.4 mL, equivalent to sodium enoxaparin 40 mg

6000 anti-factor Ha IU / 0.6 ml, equivalent to sodium enoxaparin 60 mg

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

This medicine can not be used in the following cases:

• increased sensitivity to enoxaparin, heparin or its derivatives, including other low molecular weight heparins;
• the presence in the history of severe heparin type II thrombocytopenia (HIT) caused by the use of unfractionated or low-molecular-weight heparin (see the section "Features of application");
• hemorrhagic manifestations or propensity to bleed due to hemostasis disorder (except for this contraindication may be the syndrome of disseminated intravascular coagulation, if it is not associated with heparin treatment (see section "Features of application");
• organic organ damage with a probability of bleeding
• clinically significant active bleeding;
• active ulcer of the stomach or duodenum;
• childhood.

Patients receiving heparin for treatment, and not for prophylaxis, do not apply local regional anesthesia in planned surgical interventions.

For doses of 2000 anti-Xa IU / 0.2 mL, equivalent to sodium enoxaparin 20 mg 4000 anti-Xa IU / 0.4 mL, equivalent to sodium enoxaparin 40 mg

This medication is generally not recommended in the following cases:

• severe renal insufficiency (creatinine clearance about 30 ml / min according to the Cockcroft-Gault formula, see "Features of application");
• in the first 24 hours after an intracerebral hemorrhage.

In addition, it is desirable not to prescribe this drug in prophylactic doses to patients over 65 years of age combined with such drugs (see the section "Interaction with other drugs and other interactions"):

• Acetylsalicylic acid in analgesic, antipyretic and anti-inflammatory doses
• non-steroidal anti-inflammatory drugs (NSAIDs) (systemic application);
• dextran 40 (parenteral administration).

For doses of 6000 anti-factor Ha IU / 0.6 mL, equivalent to enoxaparin sodium 60 mg 8000 anti-factor Ha IU / 0.8 mL, equivalent to sodium enoxaparin 80 mg

This medication is generally not recommended in the following cases:

• intracerebral haemorrhage
• due to the lack of relevant data, the drug should not be used in patients with severe renal insufficiency (creatinine clearance calculated by the Cockcroft-Gault formula, 30 ml / min), except for patients on dialysis. Patients with severe renal failure should be assigned unfractionated heparin.

To perform the calculation using the Cockcroft-Gault formula, you need to have data from the last measurement of the patient's body weight (see "Features of application").

Spinal or epidural anesthesia should not in any case be used for patients undergoing treatment with LMWH.
It is not recommended to apply the drug in the following cases:

• acute extensive ischemic stroke of the brain with loss of consciousness or without. If the stroke is caused by embolism, enoxaparin can not be applied in the first 72 hours after a stroke; the effectiveness of therapeutic doses of LMWH is still not determined, regardless of the cause, the extent of the lesion, or the severity of the clinical manifestations of cerebral infarction
• acute infectious endocarditis (except for some heart diseases caused by embolism)
• renal failure of mild to moderate degree (creatinine clearance 30-60 ml / min).

In addition, this drug is generally not recommended in combination with such drugs (see the section "Interaction with other drugs and other interactions"):

• Acetylsalicylic acid in analgesic, antipyretic and anti-inflammatory doses
• non-steroidal anti-inflammatory drugs (systemic application);
• dextran 40 (parenteral administration).

Interaction with other drugs and other interactions

Certain drugs or therapeutic classes can promote the development of hyperkalemia: potassium salts, potassium-sparing diuretics, ACE inhibitors, angiotensin II inhibitors, non-steroidal anti-inflammatory drugs, heparin (low molecular weight or unfractionated heparin), cyclosporin and tacrolimus, trimethoprim.

The development of hyperkalemia may depend on the associated risk factors.

The risk of its occurrence increases if the above medicines are used simultaneously.

Patients of advanced age (over 65 years).

Unwanted combinations

Acetylsalicylic acid in analgesic, antipyretic and anti-inflammatory doses (and by analogy with other salicylates)

The risk of bleeding increases (oppression of platelet function under the action of salicylates and lesions of the mucous membrane of the gastrointestinal tract).

It should be used antipyretic analgesics, not related to salicylates (for example, paracetamol).

NSAIDs, including ketorolac (systemic application)

Increased risk of bleeding (suppression of platelet function under the influence of NSAIDs and lesions of the mucous membrane of the digestive tract).

If simultaneous use can not be avoided, careful clinical observation should be carried out.

Dextran 40 (parenteral administration)

Increased risk of bleeding (oppression of dextran 40 function of platelets).

Combinations that require the application of measures

Oral anticoagulants

Increased anticoagulant effect.

When replacing heparin with an oral anticoagulant, clinical monitoring should be strengthened.

Combinations that should be considered

Inhibitors of platelet aggregation (in addition to acetylsalicylic acid in analgesics, antipyretic and anti-inflammatory doses of NSAIDs): abciximab, acetylsalicylic acid in antiaggregant doses for cardiac and neurological indications, beraprost, clopidogrel, eptifibatid, iloprost, ticlopidine, tirofiban.

Increased risk of bleeding

Patients under the age of 65 years.

Combinations that should be considered.

The combined use of drugs that affect different phases of hemostasis increases the risk of bleeding. Therefore, regardless of the age of the patient, continuous monitoring of the clinical picture should be carried out and, if necessary, laboratory tests should be performed when prophylactic doses of LMWH are prescribed simultaneously with oral anticoagulants, platelet aggregation inhibitors (abciximab, NSAIDs, acetylsalicylic acid at any dose, clopidrogel, systemic glucocorticosteroids, eptifibatide , iloprost, ticlopidine, tirofiban) and thrombolytic agents.

Application features

The drug is not allowed to enter intramuscularly.

Low molecular weight heparins are not interchangeable preparations, since they differ in molecular weight, specific activity values against factor Xa, dosing. It is necessary to pay attention and observe the specific methods of application recommended for each of the preparations of low molecular weight heparins.

Precautions for use

Bleeding

As with all anticoagulants, bleeding may occur (see Section "Adverse Reactions"). With the development of bleeding, you should determine its cause and prescribe appropriate treatment.

Kidney function

Before starting treatment with low molecular weight heparin, renal function should be evaluated, especially in patients aged 75 years, by determining the creatinine clearance according to the Cockcroft-Gault formula using the latest measurement of body weight:

For male patients: creatinine clearance (140 years) x body weight / (0.814 × creatinine in serum), where age is expressed in years, weight is in kilograms, and creatinine in serum is in μmol / l.

For women, this formula is adjusted by multiplying the result by 0.85.

If serum creatinine is expressed in mg / ml, the indicator should be multiplied by a factor of 8.8.

The use of therapeutic doses of LMWH in patients with diagnosed severe renal insufficiency (creatinine clearance 30 ml / min) is contraindicated (see Section "Contraindications").

Suppressing the secretion of aldosterone.

Heparin can inhibit the secretion of aldosterone by the adrenal glands, especially in patients with diabetes mellitus, chronic renal failure, pre-existing metabolic acidosis, elevated potassium levels in blood plasma, and also in patients taking potassium preparations. The risk of hyperkalemia increases with the duration of therapy, but is usually reversible.In patients with an increased risk of this complication, the level of potassium in the blood plasma should be measured before starting treatment with heparin and monitored regularly thereafter, especially if the treatment is extended to more than 7 days.

Monitoring the number of platelets

Heparin thrombocytopenia (HIT)

There is a danger of developing severe, sometimes thrombogenic HIT (which was registered in connection with the use of unfractionated heparin and less frequently in connection with LMWH) of immunological origin, called HIT type II (see Section "Adverse Reactions").

In connection with this danger of determining the number of platelets is mandatory, regardless of the therapeutic indications and the administered dose.

The number of platelets must be determined before the start of the drug administration, or no later than 24 hours from the start of treatment, and then 2 times a week during treatment with a standard duration.

If in separate special cases (the operations in the hip joint in II and III trimester of high risk (see. Section "use during pregnancy and lactation")) prolonged treatment with enoxaparin it is necessary, then determining the number of platelets should be 2 once a week for the first month (high-risk period), and then 1 time per week until the termination of treatment.

It is suspected occurrence HIT if the platelet count below 100,000 / mm 3, and / or if between two successive determinations observed platelet count decrease by 30-50%. In general, HIT develops within 5-21 days after the start of treatment with heparin (most cases occur after 10 days).

However, in patients with HIT in the history of this complication can occur much earlier, about the individual cases have been reported in 21 days. So, should systematically identify patients with such a history, conducting detailed interviews with the patients before treatment.

Moreover, the risk of relapse in the reduction treatment with heparin may persist for several years or even for an unlimited period of time (see Section:. "Contra ').

In all cases, HIT is a critical condition and requires specialist advice.

Any significant reduction in the number of platelets (30-50% from baseline) is a warning sign even before it will reach the critical level. In all cases, a decrease in the platelet count should take the following measures:

• urgently carry out control of the quantity of platelets;
• in confirming or even the progression of thrombocytopenia in the absence of other obvious causes of this phenomenon it is necessary to cancel the heparin treatment.

(A blood sample is taken into a test tube with citrate for conducting tests on aggregation in vitro Platelet and immunological tests. However, under such conditions urgent measures taken not on the basis of test results on aggregation in vitro platelet or immunoassay, since such assays are performed in the usual manner only in some specialized laboratories and the results are, at best, ready in just a few hours. These tests are needed to diagnose complications, since the continuation of treatment of heparin om the risk of thrombosis is very high) to carry out the prevention or treatment of thrombotic complications associated with HIT.

If there is a need to continue to anticoagulant therapy, heparin should be replaced by another group antithrombotic agent, for example sodium or danaparoid hirudin, which is administered in therapeutic or prophylactic doses in each case.

Substitution oral anticoagulant available after normalization of platelet counts, as there is a threat of thrombosis recurrence influenced by oral anticoagulants.

Replacing heparin with oral anticoagulants

In order to monitor effects of oral anticoagulants should enhance the clinical observation and increase the frequency of laboratory tests (prothrombin time, expressed as International Normalized Ratio (MES)).

Since the maximum effect of oral anticoagulant take some time, it is necessary to continue in a constant dose of heparin for a time sufficient to maintain the indicator at a desired MOE for this therapeutic indication interval between two successively executed analyzes.

Monitoring anti-Xa activity

Since the majority of studies that demonstrated the efficacy of LMWH were conducted using doses calculated by the body weight of the patient, without special laboratory control, the need for laboratory analysis to determine the effectiveness of treatment with LMWH is not installed. However, in certain clinical situations, which are often accompanied by the risk of overdose, laboratory tests, namely the monitoring of anti-Xa activity may be useful for the prevention of the risk of bleeding.

These situations relate primarily to the use of medical indications associated with IGM and doses that are assigned to the patient:

• with mild and moderate renal impairment (creatinine clearance of 30-60 ml / min by Cockcroft-Gault). Since, in contrast to standard unfractionated heparin, LMWH excreted mainly by the kidneys, any renal failure can cause relative overdose. Severe renal failure is a contraindication to the use of therapeutic doses of LMWH (see Section: "Contra.");
• with extremely high or low birth weight (weight loss or cachexia, obesity);
• bleeding of unknown etiology.

Conversely, carrying out laboratory monitoring is not recommended in the case of prophylactic doses of LMWH performed if treatment in accordance with treatment recommendations (particularly with respect to the duration of treatment) and during hemodialysis.

To identify a possible accumulation of heparin after repeated administration is recommended, if necessary to take a blood sample at the peak of activity (according to the available data), i.e. through 4:00 third injection after subcutaneous injection of the drug twice a day.

Need for repeated tests of anti-Xa activity to determine the level of heparin in the blood, for example, every 2-3 days, decided on an individual basis depending on the results of the preliminary analysis. It may also be necessary to adjust the dose of LMWH.

Certain anti-Xa activity varies depending on the individual and separate LMWH dosing regimen.

Information: given the existing data, the average (± standard deviation), which was observed through 4:00 seven Enoxaparin injections, administered at a dose of 100 anti-Xa IU / kg / injection 2 times a day, was 1,2 ± 17 0 anti-Xa IU / ml.

This average was observed during studies in which the quantitative determination of anti-Xa chromogenic activity was performed (amidolitichnim) method.

Activated partial thromboplastin time (APTT)

Some LMWHs cause a modest increase in the aPTT. Since the clinical relevance of this effect is not clear, it is not necessary to use this test to monitor treatment.

Spinal / epidural anesthesia in patients receiving prophylactic treatment with LMWH

Reported cases neuraxial hematomas while the use of enoxaparin sodium and spinal / epidural anesthesia, leading to long-term or permanent paralysis. When enoxaparin sodium dosage regimen of 40 mg 1 time per day or less, these cases are rare. The risk increases with higher doses of enoxaparin sodium, postoperative use of indwelling catheters, or the simultaneous use of additional drugs affecting hemostasis, such as NSAIDs (see. Section "interaction with other drugs and other types of interactions"). There is a possibility of increased risk in traumatic or repeated neuraxial puncture or in patients with a surgical procedure on the spine or spinal deformities in history.

should take into account the pharmacokinetic profile of the drug to reduce the potential risk of bleeding associated with the simultaneous use of enoxaparin sodium and spinal / epidural anesthesia (see. Section "Pharmacokinetics"). Installation and removal of the catheter is best performed when the anticoagulant effect of low enoxaparin; However, the exact timing to reach a sufficiently low anticoagulant effect in individual patients is unknown.

Installation and removal of the catheter should be delayed for at least 10-12 hours after administration of prophylactic doses of enoxaparin sodium deep vein thrombosis, whereas patients who received higher doses of enoxaparin sodium (1 mg / kg, 2 times a day, or 1.5 mg / kg 1 times a day), require a longer delay (24 hours). The next dose of enoxaparin sodium to be taken no earlier than 2:00 after catheter removal. Lower doses (1 to 20 mg once daily, 30 mg of 1 or 2 times per day, or 1 to 40 mg once a day) and enoxaparin during the 24 hours after administration of high doses (0.75 mg / kg, 2 times a day, 1 mg / kg, 2 times a day, or 1.5 mg / kg 1 time a day) of enoxaparin. anti-Xa levels are still at these time points, and such delay is not a guarantee that neuraxial hematoma can be avoided. patientsreceiving a daily dose of 0.75 mg / kg, 2 times a day, should not take a second dose of enoxaparin during twice daily basis to provide a longer delay before installing or removing the catheter. Similarly, although we can not provide specific recommendations for the timing to receive the next dose of enoxaparin after removal of the catheter should take into account the possibility of delay next dose for at least 4 hours based on the evaluation benefits and risks taking into account both the risk of thrombosis or risk of bleeding in the context of the procedure and risk factors for patients. For patients with a creatinine clearance <30 mL / min, additional calculations as enoxaparin longer excretion; should consider doubling the timing of catheter removal,at least 24 hours to lower the recommended dose of enoxaparin (1 30 mg once a day) and no less than 48 hours for the higher dose (1 mg / kg / day).

If the doctor decides on the use of anticoagulants in the context of epidural / spinal anesthesia or spinal puncture, it is necessary to exercise careful supervision and regular monitoring to detect any symptoms of neurological disorders such as pain in the middle back, sensory or motor failure (numbness or weakness of the lower limbs), bowel dysfunction and / or urinary bladder. Should tell patients, you must immediately inform your doctor if you experience any of the above symptoms. If you have symptoms of spinal hematoma is necessary to begin an urgent diagnosis and treatment including spinal cord decompression.

State, accompanied by a special risk

Treatment supervision should be strengthened in the following cases:

• liver failure
• a history of gastroduodenal ulcers or other organic lesions which cause bleeding
• chorioretinal vascular diseases;
• postoperative period after surgery on the brain or spinal cord;
• Lumbar puncture: should take into account the risk of intraspinal bleeding and postpone a lumbar puncture as possible on longer time;
• simultaneous application of drugs affecting hemostasis (cm. 'interaction with other drugs and other types of interactions "section).

Although the concentrations of different molecular weight heparins are determined in international units (IU) anti-Xa activity, their effectiveness depends not only on their anti-Xa activity. It is dangerous to replace one LMWH dosing regimen to another, as each mode has been justified by special clinical studies. Therefore, it should be particularly careful and execute special instructions for its use in the application of each drug.

Warning

The risk of bleeding

Observe recommended dosage regimen (dose and duration of treatment). Failure to comply with these recommendations may lead to bleeding, particularly in patients at high risk (elderly patients with renal failure, etc.).

Cases of severe bleeding were observed in the following situations:

• in elderly patients, including due to the decline of renal function occurs with age;
• in patients with renal insufficiency,
• body weight less than 40 kg
• If the treatment duration exceeds the recommended duration of 10 days, average
• at default therapeutic recommendations (particularly regarding the duration of the treatment and correction of the dose according to the body weight of the treatment);
• while the use of drugs that increase the risk of bleeding (cm. 'interaction with other drugs and other types of interactions ").

In any case, older patients and / or patients with renal failure and patients whose treatment lasts more than 10 days must be under special medical supervision.

In some cases, the quantification of the anti-Xa activity may be useful for detection of drug accumulation.

The risk of heparin thrombocytopenia (HIT)

With the development of the following thrombotic events in patients treated with LMWH in therapeutic or prophylactic doses:

• exacerbation of thrombosis, which treatment is carried out;
• phlebitis;
• pulmonary embolism;
• acute ischemia of the lower limbs;
• or even myocardial infarction or ischemic stroke
• you should always include the possibility of HIT and immediately determine the number of platelets (see. "Features of the application" section).

Coronary revascularization procedures.

To limit the risk of bleeding in patients undergoing angioplasty of the coronary arteries for the treatment of unstable angina, myocardial infarction or Q-wave without acute myocardial infarction segment elevation ST, be adhered to the recommended time intervals between doses of enoxaparin. Important to achieve hemostasis at the site of injection after the angioplasty of the coronary arteries. In the case of application of special means for closing the container (hemostatic devices) must be removed immediately conductor. In the case of manual compression of the conductor must be removed through the last subcutaneous 6:00 / to administration of enoxaparin. With continued treatment with enoxaparin next injection should be carried out not earlier than 6-8 hours after removal of the conductor.You must monitor your skin puncture on the presence of any signs of bleeding or hematoma.

Artificial mechanical heart valves.

The use of enoxaparin for the prevention of thromboembolic complications in patients with mechanical mechanical valves of the heart has not been studied in special studies.

However, several single cases of thrombosis were reported in patients with mechanical mechanical heart valves who received enoxaparin to prevent thromboembolic complications.

Pregnant.

During the study, among pregnant women with artificial mechanical heart valves who received 100 anti-Ha IU / kg of enoxaparin 2 times a day in order to reduce the risk of thromboembolic complications, 2 out of 8 women developed thrombosis that resulted in valve tamponades and death of the mother and fetus . In addition, isolated cases of thrombosis in pregnant women with artificial mechanical heart valves, which received enoxaparin to reduce the risk of thromboembolic complications, were also recorded during post-marketing surveillance of the drug. Therefore, the risk of thromboembolic complications in these patients may be higher.

Bleeding in elderly patients.

In elderly patients, there is no increased tendency to bleeding within the preventive range of doses. Elderly patients (especially patients aged 80 years) may belong to the group at increased risk of complications associated with bleeding in the therapeutic range of doses. In the treatment of acute myocardial infarction with ST-segment elevation, the increase in bleeding events was noted in patients aged 65 to 75 years, indicating that these patients can be placed in a group of special risk of bleeding. Clinical monitoring is recommended.

Renal failure.

Patients with renal insufficiency come under the increased influence of enoxaparin, which increases the risk of bleeding.Since the effect of enoxaparin increases significantly in patients with severe renal insufficiency (creatinine clearance <30 mL / min), dose adjustment is recommended in the therapeutic and prophylactic range of doses. Although there is no recommendation for dose adjustment in patients with moderate renal insufficiency (CK 30-50 ml / min) and mild (creatinine clearance 50-80 ml / min), careful clinical monitoring is recommended. In the treatment of acute myocardial infarction with ST segment elevation, data for patients with a creatinine level above 220 and 175 μmol / l, respectively, for men and women are limited.

Low body weight.

In women with low body weight (<45 kg) and men with low body weight (<57 kg), the increased effect of enoxaparin in the preventive dose range was noted (not adjusted according to body weight), which can lead to a high risk of bleeding.Therefore, it is recommended that these patients be closely monitored.

Monitoring.

Risk assessment and clinical monitoring are the best predictors of the risk of potential bleeding. Usually there is no need for routine monitoring of anti-Xa activity. However, monitoring of anti-Xa activity can be considered in those patients who receive LMWH, and also have an increased risk of bleeding (eg in patients with renal insufficiency, elderly patients and patients with borderline body weight) or active bleeding.

Lab tests.

In doses used for the prevention of venous thromboembolism, sodium enoxaparin did not significantly affect either bleeding time and general blood coagulation assays, nor on platelet aggregation or fibrinogen binding to platelets. In the case of high doses, an increase in activated partial thromboplastin time (APTT) and activated clotting time (ABC) is possible. The increase in APTT and ABC does not correlate linearly with the increased antithrombotic activity of sodium enoxaparin and, therefore, can not be used to monitor the activity of sodium enoxaparin.

Use during pregnancy or lactation

Pregnancy.

For doses of 2000 anti-Xa IU / 0.2 mL, equivalent to sodium enoxaparin 20 mg 4000 anti-Xa IU / 0.4 mL, equivalent to sodium enoxaparin 40 mg

Pregnancy.

Preventive treatment in the first trimester.

Now there are not enough clinical data on the basis of which it would be possible to assess the possible teratogenic or fetotoxic effects of enoxaparin in its preventive use during the first trimester of pregnancy.

Therefore, as a precaution, enoxaparin should not be prescribed for preventive purposes to pregnant women during the first trimester.

If epidural anesthesia is planned, prophylactic treatment with heparin should be stopped, if possible, at 12:00 before anesthesia.

Preventative treatment in the II and III trimesters.

Since the limited data that currently exist clinical application of enoxaparin in the II and III trimesters of pregnancy, it is not known about any teratogenic or fetotoxic effects of enoxaparin in prophylactic doses. However, in order to assess its influence under these conditions, it is necessary to conduct additional studies.

Therefore, the possibility of prophylactic treatment with enoxaparin in the II and III trimesters of pregnancy should be considered only if necessary.

If epidural anesthesia is planned, prophylactic treatment with heparin should be stopped, if possible, at 12:00 before anesthesia.

For doses of 6000 anti-factor Ha IU / 0.6 mL, equivalent to sodium enoxaparin 60 mg 8000 anti-Xa IU / 0.8 mL, equivalent to sodium enoxaparin 80 mg

The available clinical data are insufficient to reveal the possible ability of enoxaparin to cause malformations or fetotoxic effects when administered at therapeutic doses during pregnancy, since it is not recommended to apply therapeutic doses of enoxaparin during pregnancy.

In no case can spinal or epidural anesthesia be carried out for patients receiving treatment with LMWH.

Breastfeeding.

Since absorption in the gastrointestinal tract of newborns is not possible in principle, treatment with enoxaparin is not contraindicated in women who breastfeed.

The ability to influence the reaction rate when driving vehicles or other mechanisms.

Admission of the drug does not affect the ability to drive a vehicle and work with mechanisms. However, one should be cautious considering possible side reactions (see Section "Adverse Reactions").

Dosing and Administration

The route of administration is subcutaneous (except for patients with ST-segment elevation myocardial infarction, which requires intravenous bolus administration).

Recommended for adults

The drug should not be administered intramuscularly.

1 ml of the injection solution is equivalent to approximately 10,000 anti-Xa I enoxaparin.

- The technique of subcutaneous injection

The dose of enoxaparin, which will be administered, should be adjusted depending on the patient's body weight. Before the injection, you must remove the excess volume of the drug. If there is no excess volume, then before the injection, you do not need to remove air bubbles from the syringe.

Enoxaparin should be injected into subcutaneous tissues. It is advisable that during the injection the patient is in a supine position on the back. Place the injection of the drug should be alternated, injecting it into the left, then into the right anterolateral or posterolateral area of the abdominal wall.

The needle should be inserted the entire length into the fold of the skin, collected between the thumb and forefinger, perpendicular to the skin surface, and not at an angle to it. This skin fold should be held by fingers throughout the entire injection.

The technique of intravenous (bolus) injection / use of Enoxaparin-Pharmex for the treatment of acute myocardial infarction with ST-segment elevation
Treatment is started with a bolus injection, followed by immediate subcutaneous injection. To perform an intravenous bolus from a manufacturer-filled graduated syringe with an Enoxaparin-Pharmex preparation containing 40 mg (0.4 ml 4000 anti-Xa MO) or 60 mg (0.6 ml 6000 anti-factor Ha MO), or 80 mg ( 0.8 ml of 8000 anti-Xa MO), it is necessary to remove the excess amount of the drug so that a dose of 30 mg (0.3 ml of 3000 anti-Xa MO) remains in the syringe.

This dose of enoxaparin is injected into the tube system for intravenous administration of solutions. Do not mix or inject the drug with other medicines at the same time. To remove the remnants of other drugs and, consequently, to prevent their mixing with enoxaparin before the bolus injection and after that the system must be washed with a sufficient amount of 0.9% sodium chloride solution or 5% glucose solution. Enoxaparin can be safely administered in a 0.9% solution of sodium chloride or in a 5% solution of glucose.

In a hospital, the drug can be used for:

• a dose of 1 mg / kg (100 anti-Ha IU / kg) for the first subcutaneous injection to be performed following the intravenous bolus injection, as well as further doses of 1 mg / kg (100 anti-Ha IU / kg) subcutaneously every 12:00;
• receiving a dose of 0.3 mg / kg (30 anti-Ha IU / kg) for bolus administration to patients undergoing further coronary angioplasty.

During the entire treatment period, the number of platelets should be monitored regularly, since there is a risk of HIT.

Prevention of venous thromboembolism in surgical interventions accompanied by moderate and high thrombogenic risk.

As a general rule, these recommendations relate to surgical procedures that are performed under general anesthesia.

In the case of spinal and epidural anesthesia, the benefits of administering enoxaparin before surgery and the theoretically increased risk of a spinal hematoma should be weighed (see Section "Application Features").

Scheme of introduction. The drug should be administered 1 time per day subcutaneously.
Dose. The dose should be determined on the basis of a risk assessment for the individual patient and the type of surgical intervention.
Surgical operations, which are accompanied by a moderate risk of thrombosis.

During operations with a moderate risk of thrombosis, and in patients who do not have a high risk of thromboembolism, effective prevention is provided by daily administration of the drug at a dose of 20 mg (0.2 ml 2000 anti-Ha IU). Dosage regimen, was investigated, provides for the introduction of the first injection 2:00 before the operation.

Surgical operations, which are accompanied by a high risk of thrombosis.

Operations on the hip, knee joints.

The dose is 40 mg (0.4 ml 4000 anti-Xa) once a day.

The dosage regimen, which was investigated, involves the administration of the first injection of 4,000 anti-Xa IU (full dose) 12.00 before surgery or the first injection of 2000 anti-Xa IU (half dose) at 2:00 before surgery.

Other situations.

If there is an increased risk of venous thromboembolism associated with the type of surgery (especially oncology operations) and / or with a patient's history (if he had cases of venous thromboembolism), the same prophylactic dose should be administered as in high-risk orthopedic operations, such as operations on the hip, knee joints.

Duration of treatment.
Treatment of LMWH should continue along with the imposition of conventional compression elastic bandages on the legs, until the patient can fully and actively move:

• with general surgery, LMWH treatment should last less than 10 days, while the patient has a risk of developing venous thromboembolism (see section "Features of application");
• the therapeutic benefit of prophylactic treatment with enoxaparin in a dose of 4000 anti-Xa IU / day was established for 4-5 weeks after surgery on the knee joint
• if the patient still has a risk of venous thromboembolism after the recommended duration of treatment, consideration should be given to continuing preventive therapy, in particular the administration of oral anticoagulants.

It should be noted that the clinical benefit of prolonged treatment of low molecular weight heparins or oral anticoagulants has not been investigated.

Prevention of thrombus formation in the extracorporeal circuit of blood circulation during hemodialysis.

The drug should be administered intravascularly (to the intra-arterial catheter or dialysis circuit).

For patients who receive repeated hemodialysis sessions, the prevention of blood clotting in the extrarenal blood purification system is ensured by administering an initial dose of 100 anti-Xa IU / kg to the intra-arterial catheter or dialysis circuit at the beginning of the session.

This dose is administered intravascularly in the form of a one-time bolus injection. The anticoagulant effect of this dose, as a rule, is sufficient for conducting a hemodialysis session, which lasts 4:00 or less. It can then be adjusted to account for significant individual variations in response.

The maximum recommended dose is 100 anti-Xa IU / kg.

For hemodialysis patients from the high-risk bleeding group (especially with dialysis in the pre- and post-operative period) or with active bleeding, a dose of 50 anti-Xa IU / kg (dual vascular access) or 75 anti-Xa IU / kg (one vascular access).

Treatment of diagnosed deep vein thrombosis, which is accompanied or not accompanied by pulmonary embolism, in the absence of severe clinical symptoms.

For any suspicion of deep vein thrombosis, this diagnosis should be quickly confirmed by appropriate examinations.

The scheme of introduction

Enter 2 injections a day at intervals of 12:00.

Dose

The dose for one injection is 100 anti-Ha IU / kg.

Dosage of LMWH for patients with a body weight of more than 100 kg or less than 40 kg has not been studied. In patients with a body weight of more than 100 kg, the effectiveness of LMWH therapy may be somewhat lower, and in patients with a body weight of less than 40 kg there may be an increased risk of bleeding. Such patients should be under special clinical supervision.

Duration of treatment for DVT

When treating low-molecular-weight heparin, it is necessary to switch to oral anticoagulant therapy as soon as possible, if there is no contraindication for this. The duration of treatment of LMWH should not exceed 10 days, taking into account the time required to achieve the desired therapeutic effect of taking anticoagulant, except when this effect is difficult to achieve. So, treatment with oral anticoagulants should be started as soon as possible.

Treatment of unstable angina and acute myocardial infarction without a Q wave

Enoxaparin is prescribed in a dose of 100 anti-Ha IU / kg, which is administered subcutaneously 2 times a day every 12:00, in combination with acetylsalicylic acid (the recommended dose is 75-325 mg inside after a minimum loading dose of 160 mg).

The recommended duration of treatment is 2-8 days (until the patient's clinical condition is stabilized).

Treatment of acute myocardial infarction with ST segment elevation in combination with thrombolytic agent, in patients undergoing further coronary angioplasty, as well as in patients who do not undergo this procedure.

The initial bolus injection is administered at a dose of 3000 anti-IC IU. Subcutaneously, 100 anti-Ha IU / kg administered subcutaneously for 15 minutes, then every 12:00 (for the first two subcutaneous injections, the maximum total dose is 10,000 anti-Ha IU).

The first dose of enoxaparin should be administered at any time 15 minutes before or 30 minutes after the onset of thrombolytic therapy (fibrin-specific or not).

The recommended duration of treatment is 8 days or until the patient is discharged from the hospital if hospitalization lasts less than 8 days.

Concomitant therapy: after the onset of symptoms, you should start taking acetylsalicylic acid as soon as possible and continue at a dose of 75-325 mg per day for at least 30 days, unless otherwise indicated.

Patients who undergo coronary angioplasty:

• if less than 8:00 has elapsed since the last subcutaneous injection of enoxaparin before inflation, no additional administration of enoxaparin is required;
• if more than 8:00 has passed since the last subcutaneous injection of enoxaparin before inflation of the balloon, a bolus injection of 30 anti-Ha IU / kg of enoxaparin should be performed. To ensure the accuracy of injectable amounts, it is recommended to dilute the drug to 300 IU / ml (ie 0.3 ml of enoxaparin diluted in 10 ml) (see Table).

Volumes required for injection, when dilution is performed for patients who undergo coronary angioplasty:

Body weight, kg	The required dose, MO	The volume required for injectable administration at a dilution of up to 300 IU / ml (i.e., 0.3 ml of enoxaparin diluted in 10 ml), ml
45	1350	4,5
50	1500	5
55	1650	5.5
60	1800	6th
65	1950	6.5
70	2100	7th
75	2250	7.5
80	2400	8
85	2550	8.5
90	2700	9
95	2850	9.5
100	3000	10

Patients aged 75 years who are on treatment for acute myocardial infarction with ST-segment elevation do not undergo an initial bolus injection. Every 12:00, they should inject a dose of 75 anti-Ha IU / kg subcutaneously (only for the first two injections, the maximum total dose is 7500 anti-Ha IU).

Children

Due to the lack of data should not be used in pediatric patients with LMWH.

Overdose

Accidental overdose by subcutaneous injection of massive doses of low molecular weight heparin can cause bleeding complications.

In case of bleeding in the treatment of some patients may be used protamine sulphate, taking into account the following factors:

• protamine efficiency much lower than the efficiency registered in overdose unfractionated heparin;
• -this side effects (especially anaphylactic shock) should first be carefully weigh the risk / benefit application protamine sulfate.

Neutralization is performed by slow injection of protamine (hydrochloride or sulfate).

The necessary dose depends protamine:

• of the administered dose of heparin (100 units protigeparinovih protamine neutralize the activity of 100 anti-Xa IU LMWH) if from the time of administration of enoxaparin sodium was not more than 8:00;
• the time elapsed since the introduction of heparin:
• 50 can be performed protigeparinovih infusion of protamine to 100 units anti-Xa IU enoxaparin sodium, if from the time of administration of enoxaparin sodium has been more than 8:00 or if need another dose of protamine;
• if from the time of enoxaparin sodium injection has been more than 12:00, no need to introduce protamine.

These recommendations deal with patients with normal renal function who receive repeated doses.

However, to completely neutralize the anti-Xa activity is not possible.

Furthermore, the neutralization may be temporary due to the pharmacokinetics of absorption characteristics of low molecular weight heparin, whereby it may be necessary to distribute the total calculated dose of protamine into several injections (2-4), which are introduced for 24 hours.

After hitting a low molecular weight heparin in the stomach, even in large quantities, serious complications are unlikely (such cases were not reported) due to a slight absorption of the drug in the stomach and intestines.

Adverse Reactions

cases of significant bleeding complications have been reported , some of which were fatal. There were intracranial and retroperitoneal hemorrhage. cases of hemorrhagic complications (bleeding), such as hematoma, ecchymosis in places other than the injection site hematoma injuries were also recorded, haematuria, epistaxis and gastrointestinal bleeding.

Hemorrhagic manifestations are mainly related to:

• with associated risk factors: the presence of organic lesions, have a tendency to bleeding, certain drug combinations (see sections "Contra" and "interaction with other drugs and other types of interactions."), age, presence of renal failure, low body weight
• non-compliance with therapeutic recommendations, particularly those that relate to the duration of the treatment and correction doses according to body weight (see. "Application Features" section).

Registered rare cases of spinal hematoma after administration of low molecular weight heparin during spinal anesthesia, epidural anesthesia or analgesia.

These side effects induced neurological damage of varying severity, including prolonged paralysis and constant (cm. "Applying Properties").

After injection, the formation of a hematoma at the injection site. This increases the risk of non-compliance with recommended technique of injection and when using injection unsuitable material. As a result of an inflammatory reaction may occur solidification which disappear within a few days. Their appearance does not require discontinuation of treatment.

Observed the occurrence of thrombocytopenia. There are two types of it:

• Type I, which is the most common cases, typically moderate (more than 100,000 / mm 3) appear in the early stages (before day 5), and do not require the cessation of treatment;
• AI type, there are rare cases of severe immunoallergic thrombocytopenia (HIT). The frequency of occurrence of insufficiently studied (see. Section "Properties application").

Perhaps asymptomatic and reversible increases in platelet count.

It reported cases of hemorrhagic anemia.

In applying heparin have been reported few cases of skin necrosis at the injection predominantly. They may precede the appearance of purpura or infiltrated and painful erythematous patches. In such cases, you should discontinue therapy immediately.

There were rare cases of cutaneous (urticaria, itching, erythema, bullous eruptions) or systemic allergic reactions (anaphylactic / anaphylactoid reactions including shock), which sometimes can lead to discontinuation of treatment.

As with unfractionated heparin, there is a possibility of developing osteoporosis elongational treatment duration.

Unfractionated heparin can cause gipoaldosteronizm, which leads to an increase in plasma potassium levels. Occasionally it may be clinically significant hyperkalemia, especially in patients with chronic renal failure and diabetes.

Reported cases of transient increase in transaminases, hepatocellular or cholestatic liver disease.

Several cases of hyperkalemia family.

It reported the occurrence of headache, alopecia.

Registered very rare cases vasculitis due to increased skin sensitivity.

Infrequently occurred hypereosinophilia, both alone and on the background of skin reactions, which disappeared after discontinuation of treatment.

Shelf life

2 years

Storage conditions

Stored in original package at a temperature not higher than 25 ° C.Ne zamorazhivat.Hranit the reach of children.

Incompatibility

Do not mix in the same syringe with any other drugs.

Packaging

0.2 ml or 0.4 ml or 0.6 ml in pre-filled syringes:

№ 1 to 1 pre-filled syringe in blisters, and 1 in the contour blister cardboard pack;

№ 2 (2 × 1): 2 pre-filled syringe in blisters, and 1 in the contour blister cardboard pack;

№ 10 (2 × 5): 2 for pre-filled syringe in blisters, 5 contour of cellular packages in cardboard pack.

0.8 ml in pre-filled syringes:

№ 1 to 1 pre-filled syringe in blisters, and 1 in the contour blister cardboard pack;

№ 2 (2 × 1): 2 pre-filled syringe in blisters, and 1 in the contour blister cardboard pack.

Category of leave

On prescription.