ENOPAR-40

ENOPAR-40  40 mg/0.4 ml solution for injection
ENOPAR-40

International non-patented name: Enoxaparin Sodium 

Composition
Active substance: 0.4 ml solution contains 40 mg enoxaparin sodium.
Excipients: water for injection.

Description
Clear colorless solution.

Pharmacotherapeutic group
Directly acting anticoagulant

ATC :B01AB05. 

Pharmacological properties
Enoxaparin is a low molecular weight heparin with an average molecular weight of approximately 4,500 daltons. The preparation is sodium salt. Enoxaparin sodium is made by alkaline depolymerization of the benzyl ester of heparin from porcine intestinal mucosa.

PharmacodynamicsThe ratio of antithrombotic activity to anticoagulant activity of enoxaparin sodium is higher than that of unfractionated heparin. At recommended doses, it has no significant effect on platelet aggregation, binding of fibrinogen to platelets, or general blood coagulation tests such as AQTV and prothrombin time. Enoxaparin binds to anti-thrombin time III, thereby inhibiting coagulation factors IIa and Xa. PharmacokineticsAbsorption Enoxaparin is rapidly and completely absorbed after subcutaneous injection. Maximal plasma anti-Xa activity occurs 1-4 hours after injection. Distribution The resulting anti-Xa activity is localized in the sections of the vessel and is characterized by a half-life of 4-5 hours. Anti-Xa activity can last for 24 hours. An intravenous bolus injection every 12 hours provides initial maximal levels of anti-Xa factor and a mean exposure corresponding to 88% of steady-state levels. There is a linear relationship between plasma anti-Xa clearance and steady-state creatinine clearance, indicating that enoxaparin sodium clearance is reduced in patients with impaired renal function. Enoxaparin, detected by anti-Xa activity, does not cross the placental barrier in the second trimester of pregnancy. Metabolism It is metabolized in the liver by desulfation and depolymerization, which increases its excretion. Exclusion Although dose adjustment is not required in the elderly, the elimination half-life may be prolonged.

Instructions for use
Prevention of venous thromboembolism during surgical interventions with medium and high thrombogenic risk; Prevention of deep vein thrombosis in bedridden patients due to acute therapeutic illnesses: class III or IV heart failure according to the NYHA classification, acute respiratory failure, acute infectious or rheumatic disease, in the presence of at least one other risk factor for venous thromboembolism; Prevention of thrombus formation in the extracorporeal circulation during hemodialysis (the procedure lasts about 4 hours on average); Treatment of diagnosed deep vein thrombosis without severe clinical symptoms with or without pulmonary embolism, except pulmonary embolism requiring thrombolytic agent or surgical intervention; Treatment of unstable angina pectoris and acute myocardial infarction without ST segment elevation together with acetylsalicylic acid; Treatment of acute ST-segment elevation/elevation myocardial infarction with a thrombolytic agent in patients who can proceed with coronary angioplasty, as well as in patients who cannot undergo this procedure.

Contraindications
2000 anti-Xa BV/0.2 ml, for doses equivalent to 20 mg of enoxaparin sodium; ˗ 4000 anti-Xa BV/0.4 ml, equivalent to enoxaparin sodium 40 mg; ˗ 6000 anti-Xa BV/0.6 ml, equivalent to enoxaparin sodium 60 mg;˗ 8000 anti-Xa BV/0.8 ml, equivalent to enoxaparin sodium 80 mg. This drug is generally not recommended in the following cases: Hypersensitivity to enoxaparin, heparin or its derivatives, including other low molecular weight heparins. History of severe heparin-induced thrombocytopenia (HIT) type II caused by unfractionated heparin or low molecular weight heparin (see section “Special warnings and special precautions”). Bleeding or bleeding tendency associated with a violation of hemostasis (a possible exception to this contraindication may be disseminated intravascular coagulation if it is not associated with heparin therapy (see the section “Special warnings and special instructions for use”). Organic injuries that can cause bleeding. Active clinically significant bleeding. Spinal and epidural anesthesia or local-regional anesthesia (used within the previous 24 hours). In addition, it is not recommended to use this drug in prophylactic doses in patients over 65 years of age with the following drugs (see the section “Interaction with other drugs and other forms of interaction”): 1. Acetylsalicylic acid in analgesic, antipyretic and anti-inflammatory doses. 2. Non-steroidal anti-inflammatory drugs (NSAIDs) (systemic use). 3. Dextran 40 (parenteral use). 2000 anti-Xa BV/0.2 ml, for doses equivalent to 20 mg of enoxaparin sodium; 4000 anti-Xa BV/0.4 ml, equivalent to enoxaparin sodium 40 mg. This medicine is not usually recommended for use: – Patients with severe renal failure (creatinine clearance calculated according to the Cockroft formula, 30 ml/min, see the section “Special warnings and special precautions for use”); – within the first 24 hours after intracerebral hemorrhage. 6000 anti-Xa BV/0.6 ml, for doses equivalent to 60 mg of enoxaparin sodium; 8000 anti-Xa BV/0.8 ml, equivalent to enoxaparin sodium 80 mg; This drug is generally not recommended in the following cases: Intracerebral hemorrhage. Active gastric or duodenal ulcer. Due to the lack of relevant data, the drug is not used in patients with severe renal failure (creatinine clearance calculated according to the Cockroft formula, 30 ml / min), except for patients on dialysis. Patients with severe renal failure should be treated with unfractionated heparin. To calculate using the Cockroft formula, you must have the last measurement of the patient’s body weight (see the section “Special warnings and special precautions for use”). Spinal or epidural anesthesia should never be used in patients treated with low molecular weight heparins (LMWHs). Patients receiving heparin for treatment rather than prophylaxis are contraindicated in local anesthesia for elective surgical interventions. In such cases, it is not recommended to use this drug. In acute extensive ischemic stroke of the brain with or without loss of consciousness. If the stroke is caused by an embolism, enoxaparin should not be used within the first 72 hours after the stroke. To date, the effectiveness of therapeutic doses of ACE inhibitors has not been established regardless of the cause, degree of injury, or severity of clinical manifestations of cerebral infarction. In acute infective endocarditis (except for some heart diseases caused by embolism). With mild or moderate renal failure (creatinine clearance 30-60 ml / min).

Special instructions and precautions
Intramuscular use of the drug is not allowed. Although the concentrations of different AMCPs are measured in international units (IU) of anti-Xa activity, their effectiveness is more dependent on their anti-Xa activity. It is dangerous to switch from one AMCP dosage regimen to another or to other synthetic polysaccharides, as each regimen has been supported by specific clinical studies. Therefore, special care should be taken when using each drug and special instructions for use should be followed. Precautions for use. Risk of bleeding. It is necessary to follow the recommended dosage regimen (doses and duration of treatment). Failure to follow these recommendations can lead to the development of bleeding, especially in patients at high risk (elderly patients, patients with renal failure). Cases of severe bleeding have been reported in elderly patients, including due to age-related decline in renal function; in patients with kidney failure; in patients whose weight is less than 40 kg; during treatment, the duration of which is more than the recommended 10 days; if the therapeutic recommendations are not followed (especially regarding the duration of treatment and the adjustment of the dose according to body weight during treatment); when used simultaneously with drugs that increase the risk of bleeding (see the section “Interaction with other drugs and other types of interactions”).In any case, elderly patients and/or patients with renal failure, as well as patients whose treatment lasts more than 10 days, should be under special supervision. In some cases, quantification of anti-Xa activity may be useful to detect drug accumulation (see section “Special warnings and special precautions for use”). Risk of HIT. If the following thrombolytic complications develop in a patient receiving ACE inhibitors (in therapeutic or prophylactic doses), the possibility of HIT should always be considered and the platelet count should be checked urgently (see section “Special warnings and special precautions for use”): – exacerbation of treated thrombosis; – phlebitis; – pulmonary embolism; – acute ischemia of the lower limbs; – myocardial infarction or ischemic stroke. Mechanical prosthetic heart valves. The use of enoxaparin for the prevention of thromboembolic complications in patients with mechanical prosthetic heart valves has not been studied separately. However, a few isolated cases of thrombosis have been reported in patients with mechanical prosthetic heart valves receiving enoxaparin to prevent thromboembolic events. Pregnancy In a clinical study in pregnant women with mechanical prosthetic heart valves receiving enoxaparin 100 anti-Xa BV/kg twice daily to reduce the risk of thromboembolic complications, two of eight pregnant women developed thrombosis, resulting in valve obstruction, resulting in maternal and fetal death. During the post-registration monitoring of the drug, isolated cases of mechanical thrombosis of the heart valves were also reported in pregnant women taking enoxaparin for the prevention of thromboembolic complications. Thus, the risk of thromboembolic complications increases in these patients. Medical prevention Prophylactic treatment during acute infection or rheumatic disease is justified only if at least one of the following risk factors for venous thromboembolism is present: – over 75 years old; – cancer diseases; – history of venous thromboembolism; – obesity; – treatment with hormones; – heart problem; – chronic respiratory failure. The experience of prophylactic use in patients over 80 years old and weighing less than 40 kg is very limited. Precautions for use. Don’t bleed As with other anticoagulants, bleeding may occur (see section “Side effects”). With the development of bleeding, its cause should be investigated and appropriate treatment prescribed.Kidney functionBefore starting treatment with AMCH, renal function should be assessed, especially in patients older than 75 years, by determining creatinine clearance (CC) according to the Cockroft formula, using data from the last body weight measurement: – for male patients: KK = (140 – age) × body weight / (0.814 × serum creatinine), where age is expressed in years, body weight in kilograms, and serum creatinine in µmol/l; – for women, this formula is adjusted by multiplying the result by 0.85. If creatinine in blood serum is expressed in mg / ml, the value of the indicator should be multiplied by a factor of 8.8. The use of AMCH in therapeutic doses is contraindicated in patients with diagnosed severe renal failure (CC – about 30 ml / min) (see the section “Contraindications”). Patients with obesity Obesity increases the risk of thromboembolism in patients. The safety and efficacy of prophylactic doses in obese patients (body mass index > 30 kg/m2) have not been fully established, and there are no recommendations for dose adjustment in these patients. These patients should be closely monitored for thromboembolic signs and symptoms. Laboratory indicators Monitoring of platelet levels in patients using ACE inhibitors and at risk of HIT (eg HIT type II). AMCC can lead to the development of type II HIT – severe immune-mediated thrombocytopenia, which can lead to arterial or venous thromboembolic events that can be life-threatening or worsen the functional prognosis of patients (see section “Adverse reactions”). In order to timely detect HIT in patients, it is necessary to carry out appropriate control. Patients who have undergone surgery or recent trauma (within 3 months) Regardless of whether it is prescribed for treatment or prevention, systematic laboratory studies should be performed in all patients, since the frequency of HIT in surgery and traumatology is > 0.1% or even > 1%. These studies should include determining the number of platelets: – before prescribing AMCH or no later than 24 hours after the start of drug treatment; – then twice a week for a month (maximum risk period); – during long-term treatment in the future – once a week until the end of treatment. Patients with conditions other than surgery or recent trauma (within 3 months). Regardless of whether the drug is prescribed for treatment or prevention, patients need systematic laboratory studies according to the same principles applied in surgery and traumatology (see above): – previously treated with unfractionated heparin (UFH) or AMCH in the last 6 months, considering the frequency of HIT > 0.1% or even > 1%; – those with significant comorbidities, given the potential severity of HIT in these patients. In other cases, given the lower incidence of HIT (<0.1%), platelet count monitoring may be limited to the following measures:one-time control of the number of platelets at the beginning of treatment or no later than 24 hours after the start of treatment; – Monitor platelet count in case of clinical symptoms suggestive of HIT (any new episode of arterial and/or venous thromboembolism, any painful skin trauma at the injection site, any allergic or anaphylactic symptoms during treatment). Patients should be informed about the possibility of such symptoms and the need to inform the doctor about it. HIT should be suspected if the platelet count is below 150,000/mm3 (or 150 g/L) and/or if there is a 30-50% relative decrease in the platelet count compared to the pretreatment platelet count. HIT mainly develops 5-21 days after the start of heparin treatment (the maximum frequency of development after about 10 days). However, this complication may occur earlier in patients with a history of HIT. Isolated cases were also observed after the 21st day of treatment. In this regard, a systematic effort should be made to identify patients with such an anamnesis through a detailed interview before starting treatment. HIT in all these cases creates an urgent situation and requires consultation with a doctor. Any significant decrease in the number of platelets (30-50% compared to the initial values) is a warning signal, even if the values have not reached a critical level. If there is a decrease in the number of platelets, the following measures should be taken in all cases: 1. Immediately determine the platelet count to confirm the results. 2. Discontinue enoxaparin therapy if this test confirms a decrease in the platelet count or even an increase in it, and no other obvious cause has been identified. For in vitro platelet aggregation testing and immunological testing, the sample should be placed in a citrate tube. However, in these conditions, urgent measures should not be taken based on the results of in vitro platelet aggregation or immunological studies, because they are possible in specialized laboratories and the results are obtained after a few hours at the earliest. However, such studies are necessary because they may help to diagnose this complication, since the risk of thrombosis is very high with continued treatment with enoxaparin in such cases. 3. Prevention or treatment of thrombotic complications associated with HIT. If the continuation of anticoagulant therapy is essential, enoxaparin should be replaced with an antithrombotic agent belonging to another group of drugs, such as danaparoid sodium or lepirudin, prescribed individually for each patient in therapeutic or prophylactic doses. Replacement with oral anticoagulants can be performed only after the platelet count has returned to normal, because there is a risk of exacerbation of thrombosis when using oral anticoagulants.Replacement of enoxaparin with oral anticoagulants. Clinical supervision should be strengthened and the frequency of laboratory tests (expressed as international normalized ratio (INR)) to monitor the effectiveness of oral anticoagulants should be increased. Because there is a time interval for achieving the maximum effect of an oral anticoagulant, treatment with a fixed dose of enoxaparin should be continued for as long as necessary to maintain the BNN within the desired therapeutic interval, as determined in two consecutive analyses. Antifactor-Xa activity monitoring. Since most of the clinical studies demonstrating the effectiveness of AMCH were conducted using a dose calculated according to the patient’s body weight and without specific monitoring of laboratory parameters, the value of laboratory control to assess the effectiveness of AMCH has not been established. However, monitoring of anti-Xa activity may be useful to monitor the risk of bleeding in certain clinical situations that are often associated with the risk of overdose. These cases are mainly related to the therapeutic indications of AMCH use and the doses applied to the following patients: – mild and moderate renal insufficiency (CC – approximately 30-60 ml/min, calculated by the Cockroft formula). Unlike standard unfractionated enoxaparin, as AMCH is mainly excreted in the urine, any renal impairment may lead to relative overdose. Severe renal insufficiency is a contraindication to the use of AMCH in therapeutic doses (see the section “Contraindications”); – excessive or excessively low body weight (weight loss or even cachexia, obesity); – bleeding of unknown etiology. On the contrary, if AMCH is used according to therapeutic recommendations (especially regarding the duration of treatment) or during hemodialysis, laboratory monitoring is not recommended when using prophylactic doses. In order to detect the possible accumulation of enoxaparin after repeated administration of the drug, if necessary, it is recommended to take a blood sample for analysis at the peak of activity (based on available data), that is, approximately 4 hours after the third injection. The drug is given as a subcutaneous injection 2 times a day. To determine the level of enoxaparin in the blood, for the purpose of repeated studies of anti-Xa activity, for example, every 2-3 days, it should be solved individually, depending on the results of the previous study. Dose adjustment of AMCH should also be considered. It has been found that anti-Xa activity varies depending on each type of AMCC and each dosage regimen. Based on available data, the mean value (± standard deviation) observed 4 hours after the seventh injection of enoxaparin at a dose of 100 anti-Xa BV/kg/injection twice daily was 1.20 ± 0.17 anti-Xa BV/ml. This average value was observed in clinical studies where the study of anti-Xa activity was carried out by the chromogenic (amidolytic) method. AQTV control. Some ACE inhibitors cause a moderate increase in AQTV. Because the clinical significance of this test has not been established, it is not recommended to use this test for the purpose of monitoring treatment. Spinal/epidural anesthesia in patients receiving prophylactic treatment with AMCH. Epidural or spinal anesthesia should never be administered to patients receiving therapeutic doses of AMCH therapy. As with other anticoagulants, rare cases of spinal hematoma causing long-term or permanent paralysis have been reported with the use of AMCH during spinal/epidural anesthesia. The risk of spinal hematoma is higher with catheter epidural anesthesia than with spinal anesthesia. The risk of these rare events may be increased in patients with spinal surgery or spinal deformity (eg, ankylosing spondylitis) with prolonged use of epidural catheters in the postoperative period. Catheter insertion or removal is best done when the anticoagulant effect of enoxaparin is low. However, the exact time to achieve sufficiently low anticoagulant effect in each individual patient is not known. If preoperative use of AMCH is necessary (long-term bedridden patients, trauma) and the benefit of local regional spinal anesthesia or lumbar puncture has been carefully measured, it can be given to patients who have received an injection of AMCH before surgery. At least 12 hours must elapse between enoxaparin injection and spinal anesthesia. However, since anti-Xa activity may persist beyond this 12-hour time interval, neuraxial hematoma may still occur. In patients with CK <30 mL/min, it may be appropriate to wait at least 24 hours between enoxaparin administration and spinal anesthesia.

Considering the risk of spinal hematoma, careful monitoring of the patient’s neurological condition is recommended. In almost all patients, prophylactic therapy with AMCH can be started 6-8 hours after anesthesia or after catheter removal with neurological monitoring. Special care should be taken when using the drug simultaneously with other drugs affecting hemostasis (especially non-steroidal anti-inflammatory drugs, aspirin). Conditions associated with special risk. Treatment monitoring should be increased in the following cases: – liver failure; – gastrointestinal ulcer or other organic damage that can cause bleeding; – vascular chorioretinal disease; – the period after surgery in the brain or spinal cord; – lumbar puncture: the risk of intraspinal bleeding should be taken into account and, if possible, delayed as much as possible; – simultaneous use with drugs affecting hemostasis (see the section “Interaction with other drugs and other types of interactions”). Percutaneous coronary artery revascularization procedures. In patients undergoing PCI for the treatment of unstable angina, non-Q-wave myocardial infarction, or acute ST-segment elevation myocardial infarction, the recommended intervals between doses of enoxaparin should be strictly followed to minimize the risk of bleeding. It is important to achieve hemostasis at the puncture site after PKR. When special means are used to close the vein (hemostatic devices), the conductor must be removed immediately. In the case of manual clamping, the guidewire should be removed 6 hours after the last subcutaneous, intravenous administration of enoxaparin. When continuing treatment with enoxaparin, the next injection should be made no later than 6-8 hours after the catheter is removed. Observe the PKR skin puncture site for any signs of bleeding or hematoma.

Interaction with other medicinesCertain drugs or classes of therapeutic drugs may contribute to the development of hyperkalemia: potassium salts, potassium-sparing diuretics, angiotensin-converting enzyme inhibitors, angiotensin II receptor inhibitors, NSAIDs, heparins (low molecular weight or unfractionated), tacrolysin, and trimethoprim. The development of hyperkalemia may depend on the presence or absence of associated risk factors in the patient. The risk of hyperkalemia increases when the above drugs are used simultaneously. Elderly patients (over 65 years old). Undesirable compounds In analgesic, antipyretic and anti-inflammatory doses with acetylsalicylic acid (and similarly, with other salicylates). The risk of bleeding increases (inhibition of platelet function and damage to the mucous membrane of the gastrointestinal tract under the influence of salicylates). Antipyretic pain relievers (such as paracetamol) should be used in addition to salicylates. NSAIDs, including ketorolac (systemic use). The risk of bleeding increases (inhibition of platelet function and damage to the mucous membrane of the gastrointestinal tract under the influence of NSAIDs). If co-administration cannot be avoided, careful clinical monitoring should be carried out. With dextran 40 (parenteral use). Increased risk of bleeding (inhibition of platelet function with dextran 40). 3 other thrombolytics (eg alteplase, reteplase, streptokinase, tenecteplase, urokinase) and anticoagulants. Compounds requiring precautions. With oral anticoagulants. Enhancement of anticoagulant effect. When replacing enoxaparin with an oral anticoagulant, clinical supervision should be strengthened. Combinations to consider. With inhibitors of platelet aggregation (except acetylsalicylic acid in analgesic, antipyretic and anti-inflammatory doses), for example, abciximab, acetylsalicylic acid in antiplatelet doses for cardiac and neurological indications, beraprost, clopidogrel, eptifibatide, tirban, ilopropistin: the risk of bleeding increases. Enoxaparin sodium should be used with caution with systemic corticosteroids. Patients under 65 years of age. Undesirable compounds. Hemostaza təsir edən dərmanların birgə istifadəsi qanaxma riskini artıra bilər. Buna görə də, xəstələrin yaşından asılı olmayaraq, bu cür dərmanlarla profilaktik dozalarda AMÇH-nin eyni vaxtda istifadəsi ilə baş verən təsirləri nəzərə almaq (və buna görə də uzunmüddətli klinik müşahidə və bəlkə də laboratoriya müayinəsi aparmaq) lazımdır: peroral antikoaqulyantlar, trombositlərin aqreqasiyasının inhibitorları (absiximab, QSİƏP-lar, istənilən dozada asetilsalisil turşusu, klopidoqrel, eptifibatid, iloprost, tiklopidin, tirofiban) və trombolitik dərmanlar.

Use during pregnancy and lactation2000 anti-Xa BV/0.2 ml, for doses equivalent to 20 mg of enoxaparin sodium; 4000 anti-Xa BV/0.4 ml, equivalent to enoxaparin sodium 40 mg Pregnancy. No evidence of teratogenic effects of enoxaparin was found in animal studies. In the absence of any teratogenic effects in animals, this effect is not expected in humans. Substances that cause defects in humans have been shown to be teratogenic in animals in well-conducted studies in two species Preventive treatment in the first trimester of pregnancy. There are insufficient clinical data to assess the possible teratogenic or fetotoxic effects of enoxaparin when used prophylactically in the first trimester of pregnancy or as therapeutic therapy throughout pregnancy. Therefore, as a precautionary measure, it is undesirable to prescribe enoxaparin for prophylactic purposes in the first trimester of pregnancy. If epidural anesthesia is planned, prophylactic enoxaparin should be stopped at least 12 hours before anesthesia, if possible. Preventive treatment in the II and III trimesters of pregnancy. Based on the limited available data on the clinical use of enoxaparin during the II and III trimesters of pregnancy, no teratogenic or fetotoxic effects of enoxaparin at prophylactic doses are known. However, further studies are needed to evaluate its effect under these conditions. Thus, the use of prophylactic doses of enoxaparin in the II and III trimesters should be considered only if necessary. If epidural anesthesia is planned, prophylactic enoxaparin should be stopped at least 12 hours before anesthesia, if possible. Lactation. Since absorption from the gastrointestinal tract is unlikely in newborns, treatment with enoxaparin in breastfeeding women is not contraindicated.

Effects on the ability to drive a vehicle and other potentially dangerous mechanisms
Taking the drug does not affect the ability to drive a vehicle and work with other mechanisms. However, you should be careful considering the possible side effects (see the “Side effects” section).

İstifadə qaydası və dozası
1 mg (0.01 ml) of enoxaparin sodium corresponds to approximately 100 units of anti-Xa BV activity. Enopar 40 should be administered subcutaneously for prophylactic and therapeutic use, except in the following cases: – use of anticoagulation drug in hemodialysis practice; – treatment of patients with ST-segment myocardial infarction requiring intravenous bolus administration. Intramuscular use of Enopar 40 is prohibited. The drug is recommended for use only in adult patients. The technique of subcutaneous use. The syringes filled by the manufacturer are ready for immediate use. If necessary, the dose of Enopar 40 can be adjusted depending on the patient’s body weight. To do this, if necessary, it is necessary to remove the excess amount of the drug from the syringe before injection. If it is not necessary to remove the excess amount of the drug, then it is not necessary to remove the air bubbles from the syringe before the injection in order not to lose the drug. Subcutaneous injection of Enopar 40 is best done when the patient is lying down. Inject the drug into the subcutaneous fat tissue of the front side or back side surface of the abdominal wall alternately on the right and left side, using different sites for each injection. The needle should be inserted vertically into the thickness of the skin layer, and not at the angle formed between the thumb and forefinger, but its full length. The skin layer should be held throughout the injection. Do not rub the injection site after injection. Technique of intravenous (bolus) administration/use of Enopar 40 for the treatment of ST-segment acute myocardial infarction Treatment begins with an intravenous bolus injection, followed by an immediate subcutaneous injection. Administration of an intravenous bolus from a manufacturer-filled Enopar 40 grade syringe containing 40 mg (0.4 ml; 4000 anti-Xa BV), 60 mg (0.6 ml; 6000 anti-Xa BV), or 80 mg (0.8 ml; 8000 anti-Xa BV) for. BV), 30 mg (0.3 ml; 3000 anti-Xa BV) of one dose should be removed from the syringe. This dose of Enopar 40 should be injected into the tube of the system for intravenous administration of solutions. It is forbidden to mix the drug with other drugs or take them at the same time. Before and after an intravenous bolus injection of Enopar 40, the system should be flushed with a sufficient amount of 0.9% sodium chloride solution or 5% glucose solution to eliminate residues of other drugs and therefore prevent their mixing with Enopar 40. Enopar 40 can be safely administered in 0.9% sodium chloride solution or 5% glucose solution. In hospital settings, Enopar 40 can be used for: – administration of a dose of 1 mg/kg (100 anti-Xa BV/kg) for the first subcutaneous injection, followed by an intravenous bolus injection, as well as additional doses of 1 mg/kg (100 anti-Xa) BV/kg), every 12 hours to be injected under the skin;– administration of a dose of 0.3 mg/kg (30 anti-Xa BV/kg) as an intravenous bolus in patients undergoing subsequent coronary angioplasty. Platelet count should be regularly monitored throughout treatment because of the risk of enoxaparin-induced thrombocytopenia (HIT). Prevention of venous thromboembolism in surgical interventions with moderate and high thrombogenic risk As a rule, these recommendations apply to surgical operations performed under general anesthesia. In the case of spinal and epidural anesthesia, the benefit of preoperative administration of enoxaparin should be compared with the theoretical risk of the development of a spinal hematoma (see the section “Special warnings and special precautions for use”). • Presentation scheme. Enopar is injected subcutaneously once every 40 days. • Dose. The dose should be determined based on the risk assessment for the individual patient and the type of surgery. Surgical operations with a moderate risk of thrombosis. During operations with a moderate risk of thrombosis and in patients with a low risk of thromboembolism, effective prevention is provided by taking Enopar 40 in a daily dose of 20 mg (0.2 ml; 2000 anti-Xa BV). The applied dosage regimen involves the administration of the first injection 2 hours before surgery. Surgical operations with a high risk of thrombosis. Hip, knee joint operations. The dose of Enopar 40 is 40 mg (0.4 ml; 4000 anti-Xa) once a day. The dosing regimen used is a first injection of 4000 IU anti-Xa (full dose) 12 hours before surgery or a first injection of 2000 anti-Xa BV (half dose) 2 hours before surgery. Other situations. If there is an increased risk of venous thromboembolism due to the type of operation (especially for oncological operations) and/or the patient’s history (there have been cases of venous thromboembolism), the same prophylactic dose should be applied as in high-risk patients, orthopedic operations such as hip and knee joints. Duration of treatment. Treatment with AMCH should be continued along with the application of traditional compression elastic bandages to the legs until the patient is able to move fully and actively: – with general surgical interventions, treatment with AMCH should last less Within 10 days, the patient is at risk of developing venous thromboembolism (see the section “Special warnings and special precautions for use”); – therapeutic benefit of preventive treatment with enoxaparin at a dose of 4000 anti-Xa BV per day for 4-5 weeks after knee surgery; – if the patient is still at risk of venous thromboembolism after the recommended treatment period, the possibility of continuing prophylactic therapy, especially the use of oral anticoagulants, should be considered.It should be noted that the clinical benefit of long-term treatment with low molecular weight heparins or oral anticoagulants has not been investigated. Prevention of deep vein thrombosis in bedridden patients due to acute diseases The recommended dose of Enopar 40 is 40 mg (0.4 ml; 4000 anti-Xa BV) subcutaneously once daily. Enopar 40 is prescribed for at least 6 days, the duration of treatment does not exceed 14 days. If the risk of venous thromboembolism still persists, long-term prophylactic treatment with oral anticoagulants should be administered. Prevention of thrombus formation in extracorporeal circuit blood circulation during hemodialysis The drug is injected intravenously (with an intra-arterial catheter or into the dialysis circuit). For patients receiving repeated hemodialysis sessions, prevention of blood clotting in the extrarenal blood purification system is ensured by the introduction of an initial dose of 100 anti-Xa BV/kg into the intra-arterial catheter or dialysis circuit. This dose is given intravenously as a single bolus injection. The anticoagulant effect of this dose is usually sufficient for a hemodialysis session lasting 4 hours or less. The response can then be adjusted to account for significant individual fluctuations. The maximum recommended dose is 100 anti-Xa BV/kg. 50 anti-Xa BV/kg (dual vein access) or 75 anti-Xa BV/kg (single vein access) for hemodialysis patients at high risk of bleeding (especially during preoperative and postoperative dialysis) or with active bleeding during dialysis sessions dosage can be prescribed. Treatment of diagnosed deep vein thrombosis with or without pulmonary embolism and without severe clinical symptoms Any suspicion of deep vein thrombosis should be confirmed immediately using appropriate testing methods. Dosing. Enopar 40 is injected subcutaneously twice a day at a dose of 100 anti-Xa BV/kg every 12 hours. Dose adjustment of ACE inhibitors in patients weighing more than 100 kg and less than 40 kg has not been studied. AMCH may be less effective in patients weighing more than 100 kg. May cause an increased risk of bleeding in patients weighing less than 40 kg. Therefore, it is necessary to carefully monitor the clinical condition of these patients. Duration of treatment for deep vein thrombosis. When treated with low molecular weight heparin, you should switch to oral anticoagulants as soon as possible, unless contraindicated. The duration of treatment with AMCH should not exceed 10 days, including the time required to achieve equilibrium with oral coagulants, unless equilibrium is difficult to achieve. Therefore, oral anticoagulant therapy should be started as soon as possible. Treatment of unstable angina and non-ST segment elevation myocardial infarction The recommended single dose of Enopar 40 is 1 mg/kg (100 anti-Xa BV/kg) subcutaneously every 12 hours; simultaneous oral administration of acetylsalicylic acid (recommended doses: 75-325 mg orally after an initial loading dose of 160 mg).The duration of treatment is at least 2-8 days, until the patient’s condition is clinically stabilized. Treatment of acute ST-segment myocardial infarction with a thrombolytic agent in patients who subsequently underwent coronary angioplasty and in patients who did not undergo this procedure The initial intravenous bolus injection of Enopar 40 is given at a dose of 30 mg (0.3 ml; 3000 anti-Xa IU). Then 1 mg/kg (100 anti-Xa BV/kg) is given subcutaneously over 15 minutes and every 12 hours thereafter (maximum total dose is 10,000 anti-Xa BV for the first two subcutaneous injections). The first dose of Enopar 40 should be administered at any time 15 minutes before or 30 minutes after the start of thrombolytic therapy. The recommended duration of treatment is 8 days, or until the patient is discharged if the hospitalization lasts less than 8 days. Adjunctive therapy: Acetylsalicylic acid should be started as soon as possible after the onset of symptoms and continued at a dose of 75-325 mg daily for at least 30 days unless otherwise indicated. Patients undergoing coronary angioplasty: – If less than 8 hours have passed before the balloon is inflated after the last subcutaneous injection of Enopar 40, no additional administration of the drug is required; – If more than 8 hours have elapsed since the last subcutaneous injection of Enopar 40 before balloon inflation, an intravenous bolus of Enopar 40 at 0.3 mg/kg (30 anti-Xa BV/kg) should be administered. To ensure accuracy of injection volumes, it is recommended to dilute the drug to 300 anti-Xa BV/ml (0.3 ml (3000 anti-Xa BV)) by dissolving the drug in 10 ml of solvent (0.9% sodium chloride solution or 5% glucose) (see table). Volumes required for injection during dilution for patients undergoing coronary angioplasty. 

 Patients older than 75 years treated for ST segment acute myocardial infarction do not receive an initial intravenous bolus injection. They should be given six subcutaneous doses of 0.75 mg/kg (75 anti-Xa BV/kg) every 12 hours (maximum total dose is 75 mg (7500 anti-Xa BV) for the first two injections only).1. Wash your hands with soap and dry them. 2. Select an area on the right or left side of the mine. This area should be at least 5 centimeters from the navel (towards the sides)..  3. Depending on which side the needle was injected last time, change the injection site alternately on the right and left sides of the abdominal cavity. Clean the injection site with alcohol.  4. Carefully remove the cap from the needle attached to the Enopar 40 syringe. Discard this cap. The syringe is pre-filled and ready to use. DO NOT depress the plunger to inject to get rid of air bubbles. This may cause the drug to be lost. Do not let the needle touch anything after the cap is removed. This is to ensure that the needle remains clean (sterile).   5. Hold the syringe in your hand while writing with a pencil, slightly stretch the skin of the cleaned abdomen with the index finger and thumb of your other hand to create a crease. Make sure to hold the skin fold during the entire injection.  6. Hold the syringe so that the needle is pointing down (at a 90° angle to the vertical). Insert the needle all the way into the skin layer.  7. Press the plunger of the syringe with your finger. Make sure to hold the skin fold during the entire injection. 8. Insert the needle by pulling it in the opposite direction. Then you can release the skin layer. Immediately dispose of the syringe in the nearest sharps container. Do not rub the injection site after the injection to prevent bruising. Side effectsAdverse reactions observed in clinical studies and reported in the post-marketing period are detailed below. According to the frequency of occurrence, adverse reactions are divided into the following categories: very often (≥1/10); often (≥1/100 to <1/10); rarely (≥1/1000 to <1/100); rarely (≥1/10,000 to <1/1,000); very rarely (<1/10000); frequency unknown (cannot be estimated from available data). Experience in clinical trials. Enoxaparin has been studied in more than 15,000 patients in clinical trials. The number of patients, indications and dosage regimens are detailed in Table 1.Don’t bleed. Bleeding was the most commonly reported adverse reaction in clinical studies. This included serious bleeding reported in 4.2% of patients (surgical profile). Some of these incidents have been fatal. Hemorrhagic complications are considered serious in the following cases: – if bleeding causes a significant clinical event; – when bleeding is observed with a decrease in the level of hemoglobin ≥ 2 g/dl or the transfusion of 2 or more units of blood products; – retroperitoneal and intracranial hemorrhages have always been considered serious. As with other anticoagulants, bleeding may occur if the following risk factors are present: – organic injuries with bleeding tendency; – invasive procedures or simultaneous use of drugs affecting hemostasis (see the sections “Special warnings and special precautions for use” and “Interaction with other drugs and other types of interactions”). Experience in post-marketing Adverse reactions listed below have been identified in the post-registration period. Because these reactions are reported voluntarily, their frequency is rated as “unknown” (cannot be estimated from available data). The immune system Cutaneous or systemic allergic reactions (anaphylactic or anaphylactoid reactions, including shock) may in some cases lead to drug withdrawal. To the nervous system Headache. To the veins Significant hemorrhagic complications have been reported, some of which have been fatal. Rare adverse reactions were intracranial and retroperitoneal hemorrhages. Hemorrhagic complications (bleeding) such as hematoma, ecchymosis at sites other than the injection site, wound hematoma, hematuria, epistaxis, and gastrointestinal bleeding have also been reported. Hemorrhagic episodes mainly associated with: – observed risk factors: organic injuries with the possibility of bleeding and some drug combinations (see sections “Contraindications” and “Interactions with other drugs and other types of interactions”), age, kidney failure, low body weight; – non-compliance with therapeutic recommendations, namely: treatment duration and dose adjustment according to body weight (see the section “Special warnings and special precautions for use”). Rare cases of spinal hematoma have been reported after using AMCH for spinal anesthesia, analgesia, or epidural anesthesia. These side effects have led to neurological disorders of varying severity, including long-term or permanent paralysis (see section “Special warnings and special precautions for use”). To the blood and lymphatic system Thrombocytopenia has been reported. It has two types. Type I, which is the most common, is usually of moderate severity (more than 100,000/mm3) and appears early (up to 5 days) and does not require discontinuation of treatment. Type II, i.e. rarely severe immunoallergic thrombocytopenia (HIT). The frequency of occurrence has not been adequately studied (see the section “Special warnings and special precautions for use”). An asymptomatic reversible increase in platelet levels is possible. Hemorrhagic anemia.There is evidence that hypereosinophilia occurs both in isolation and against the background of skin reactions that disappear after discontinuation of treatment. To the skin and subcutaneous tissue Cases of vasculitis due to skin sensitization have been reported. Skin necrosis has been reported mainly at the injection site. They may be preceded by purpura or infiltrated and painful erythematous patches. In such cases, therapy should be stopped immediately. Alopecia. To the liver and bile ducts Cases of hepatocellular or cholestatic liver disease have been reported To the musculoskeletal system Perhaps the development of osteoporosis in long-term treatment. Common disorders and reactions at the injection site A hematoma may form at the injection site after subcutaneous injection. Other reactions have been reported, including injection site pain, irritation, injection site swelling, hypersensitivity, inflammation, and nodule formation. This risk is increased if the recommended injection technique is not followed and if inappropriate injection material is used. As a result of the inflammatory reaction, nodules may appear at the injection site, which disappear within a few days. Their appearance does not require stopping treatment. Unfractionated heparins can cause hypoaldosteronism, which leads to increased plasma potassium levels. In rare cases, clinically significant hyperkalemia may occur, especially in patients with chronic renal failure and diabetes mellitus. Transient elevations in transaminase levels have been reported. A few cases of hyperkalemia have been reported.

Overdose
An accidental overdose may cause hemorrhagic complications during subcutaneous administration of significant doses of AMCH. In case of bleeding, some patients can be treated with protamine sulfate, taking into account: – the effectiveness of protamine sulfate is significantly lower than the effectiveness observed with an overdose of unfractionated enoxaparin; – before using protamine sulfate, due to the possibility of adverse events (especially anaphylactic shock), the benefit/risk ratio should be carefully weighed. Enoxaparin is neutralized by slow intravenous administration of protamine (sulfate or hydrochloride). The required dose of protamine depends on: – if no more than 8 hours have passed after taking enoxaparin sodium, the applied dose of enoxaparin (100 antiheparin units of protamine 100 anti-Xa BV neutralizes AMCH activity); – time elapsed after enoxaparin injection: – if enoxaparin sodium was taken more than 8 hours ago or if a second dose of protamine is needed, infusion of 50 antiheparin units of protamine per 100 anti-Xa BV enoxaparin can be performed; – if enoxaparin was taken more than 12 hours ago, then there is no need to give protamine. These recommendations are intended for patients with normal renal function receiving repeated doses of the drug. However, the anti-Xa activity of enoxaparin cannot be completely neutralized. In addition, neutralization may be temporary due to the pharmacokinetics of AMCH absorption, resulting in the need to divide the total calculated dose of protamine into several injections (2-4) within 24 hours. If low molecular weight heparin enters the stomach, even in large amounts, serious complications are unlikely due to the slight absorption of the drug in the stomach and intestines (such cases have not been reported)

Packing form
0.4 ml solution in a glass syringe. A self-adhesive label is attached to each syringe. 1 syringe is packed in a blister made of polymer material. 10 blisters (with a drug with 4000 anti-Xa BV activity) are packed in a cardboard box with an insert, or 2 syringes are packed in a blister made of polymer material..

Store condition
It should be stored at a temperature not exceeding 25°C, in the original packaging and out of the reach of children. Do not freeze.

Shelf life
2 years

By prescription 

Manufacturer
Farmak JSC, Ukraine.
74 Kirillovskaya Str., Kiev city, 04080, Ukraine.