Enixum, 3000 anti-ha me/0.3 ml 0.3 ml 10 pcs

Pharmacotherapeutic group: direct acting anticoagulant.

ATX code: B01AВ05

Pharmacological properties

Pharmacodynamics

Enoxaparin sodium is a low molecular weight heparin. Its average molecular weight is about 4500 daltons. In a purified in vitro system, sodium enoxaparin has high activity against factor Xa clotting (anti-Xa activity of approximately 100 IU/ml) and low activity against factor IIa clotting (anti-IIa or antithrombin activity of approximately 28 IU/ml). The anticoagulant activity of enoxaparin is mediated by antithrombin III.

When used in prophylactic doses, enoxaparin sodium slightly changes the activated partial thromboplastin time (APT) and has almost no effect on platelet aggregation and on the level of fibrinogen binding to platelet receptors.

The anti-IIa activity of enoxaparin in plasma is about 10 times lower than the anti-Xa activity. Mean maximum anti-IIa activity is observed approximately 3-4 hours after subcutaneous administration and reaches 0.13 IU/ml and 0.19 IU/ml after repeated administration of 1 mg/kg body weight – when administered twice and 1.5 mg/kg body weight – when administered once, respectively.

The mean maximum plasma anti-Xa activity is observed 3-5 h after subcutaneous administration of the drug and is approximately 0.2; 0.4; 1.0 and 1.3 anti-Xa IU/ml after subcutaneous administration of 20, 40 mg and 1 mg/kg and 1.5 mg/kg, respectively.

Pharmacokinetics

The pharmacokinetics of enoxaparin sodium in the indicated dosing regimens are linear. Variability within and between patient groups is low. After repeated subcutaneous administration of 40 mg of enoxaparin sodium once daily and subcutaneous administration of 1.5 mg/kg once daily of enoxaparin sodium in healthy volunteers the equilibrium concentration is reached by day 2, with the area under the pharmacokinetic curve being on average 15% higher than after a single injection. After repeated subcutaneous administration of enoxaparin sodium at a daily dose of 1 mg/kg twice daily the equilibrium concentration is reached after 3-4 days, the area under the pharmacokinetic curve being on average 65 % higher than after a single injection and the mean values of maximum concentrations (Cmax) being respectively 1.2 IU/ml and 0.52 IU/ml.

The bioavailability of enoxaparin sodium by subcutaneous administration, estimated on the basis of anti-Xa activity, is close to 100%.

The volume of distribution of the anti-Xa activity of sodium enoxaparin is approximately 5 liters and approximates the blood volume.

Enoxaparin sodium is a low clearance drug. After IV administration for 6 h at a dose of 1.5 mg/kg body weight, the average anti-Xa plasma clearance is 0.74 L/h.

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

The excretion of the drug is monophasic with a half-life (T1/2) of 4 hours (after single hypodermic administration) and 7 hours (after multiple administration of the drug).

The excretion through the kidneys of the active fragments of the drug is approximately 10% of the administered dose and the total excretion of the active and inactive fragments is approximately 40% of the administered dose.

Patients in the elderly

Extraction is delayed due to physiological reduction in renal function. This change does not affect the dosing and administration regimen for prophylactic therapy as long as the renal function of such patients remains within acceptable limits, i.e., is mildly impaired.

Before initiating treatment with low molecular weight heparin in patients over 75 years of age, renal function should be systematically monitored.

Patients with impaired renal function

The clearance of enoxaparin sodium is decreased in patients with reduced renal function. In patients with severe renal impairment (creatinine clearance less than 30 ml/min), repeated subcutaneous administration increases the area under the pharmacokinetic curve at equilibrium by 65%.

Patients on hemodialysis

Enoxaparin sodium is injected into the arterial branch of the dialysis system in doses sufficient to prevent coagulation in the system.

In general, pharmacokinetic parameters remain unchanged except in cases of overdose, in which the drug enters the general bloodstream and may induce high anti-Kha activity associated with end-stage renal failure.

Patients with excess body weight

In overweight people, the clearance is slightly lower when the drug is administered subcutaneously.

If no dose adjustment is made for patient weight, after a single subcutaneous injection of 40 mg of Enoxaparin sodium anti-Xa activity will be 50% higher in women with a body weight less than 45 kg and 27% higher in men with a body weight less than 57 kg compared to patients of normal average body weight.

Indications

Active ingredient

Composition

How to take, the dosage

Prevention of venous thromboses and embolisms in surgical interventions, especially in orthopedic and general surgical operations
In patients with moderate risk of thromboses and embolisms (general surgical operations) the recommended dose of the drug is 20-40 mg once daily subcutaneously.
The first injection is made 2 hours before surgical intervention.

In patients with high risk of thrombosis and embolism (orthopedic surgery), the recommended dose of the drug is 40 mg once daily subcutaneously; the first dose is given 12 hours before surgical intervention or 30 mg twice daily with the beginning of the injection 12-24 hours after surgery.

The duration of treatment is 7-10 days on average. If necessary the therapy can be continued until the risk of thrombosis and embolism persists (e.g., in orthopedics Enixum® is used 40 mg once daily for 5 weeks). Peculiarities of drug administration in spinal/epidural anesthesia and in percutaneous coronary angioplasty are described in section “Special indications”.

Prevention of venous thrombosis and embolism in bedridden patients due to acute medical conditions
The recommended dose of enoxaparin sodium is 40 mg once daily by injection for 6-14 days.

The treatment of deep vein thrombosis with or without pulmonary embolism
Enixum® is administered subcutaneously at a rate of 1.5 mg/kg once daily or at a dose of 1 mg/kg twice daily. In patients with complicated thromboembolic disorders it is recommended to use the drug in a dose of 1 mg/kg twice a day. The duration of treatment is on average 10 days. It is desirable to immediately begin therapy with anticoagulants for oral administration, while therapy with Enoxaparin sodium should be continued until sufficient anticoagulant effect is achieved. If necessary, control of anticoagulant effect should be evaluated by anti-Xa activity.

Prevention of thrombosis in extracorporeal circulation during hemodialysis
The dose of enoxaparin sodium is 1 mg/kg body weight. For patients at high risk of bleeding, the dose should be reduced to 0.5 mg/kg for dual vascular access or 0.75 mg for single vascular access. In hemodialysis, Enixum® should be administered at the arterial site of the shunt at the beginning of the hemodialysis session. One dose is usually sufficient for a four-hour session, however, if fibrin rings are detected (e.g., during longer hemodialysis), Enixum® may be additionally administered at a dose of 0.5-1 mg/kg.

The treatment of unstable angina and myocardial infarction without Q-wave in combination with acetylsalicylic acid
Enixum® is administered at the rate of 1 mg/kg of body weight every 12 hours subcutaneously, with simultaneous administration of oral acetylsalicylic acid at the dose 100-325 mg once daily. The average duration of treatment is 2-8 days (until the stabilization of the clinical condition of the patient).

The treatment of acute myocardial infarction with ST-segment elevation in patients undergoing drug treatment or subsequent percutaneous coronary intervention
. Treatment begins with an intravenous bolus injection of 30 mg of enoxaparin sodium and is immediately followed (within 15 minutes) by a subcutaneous injection of 1 mg/kg of enoxaparin sodium (and the first two subcutaneous injections may be 100 mg of enoxaparin sodium maximum). Thereafter, all subsequent subcutaneous doses are administered every 12 hours at a rate of 1 mg/kg body weight (i.e., for body weights over 100 kg, the dose may exceed 100 mg).

In persons 75 years of age and older, an initial intravenous bolus infusion is not used. Enoxaparin sodium is administered subcutaneously at a dose of 0.75 mg/kg every 12 hours (with a maximum of 75 mg of enoxaparin sodium administered for the first two subcutaneous injections). Thereafter, all subsequent subcutaneous doses are administered every 12 hours at a rate of 0.75 mg/kg body weight (i.e., if the weight is greater than 100 kg, the dose may exceed 75 mg).

When combined with thrombolytics (fibrin-specific and fibrin-unspecific), enoxaparin sodium should be administered between 15 min before thrombolytic therapy and 30 min after it. As soon as possible after detection of acute ST-segment elevation myocardial infarction, acetylsalicylic acid should be started simultaneously and, if there are no contraindications, should be continued for at least 30 days in doses of 75 mg to 325 mg daily. The recommended duration of treatment with the drug is 8 days or until the patient is discharged from the hospital, if the period of hospitalization is less than 8 days. The bolus injection of enoxaparin sodium should be done through a venous catheter and enoxaparin sodium should not be mixed or administered together with other medications. In order to avoid the presence of traces of other drugs in the system and their interaction with sodium enoxaparin, the venous catheter should be flushed with an adequate amount of 0.9% sodium chloride solution or dextrose before and after intravenous bolus injection of sodium enoxaparin. Enoxaparin sodium can be administered safely with 0.9% sodium chloride solution and 5% dextrose solution.

To perform a 30 mg bolus infusion of enoxaparin sodium in the treatment of acute ST-segment elevation myocardial infarction, the 40 mg, 60 mg, 80 mg and 100 mg glass syringes are discarded so that only 30 mg (0.3 ml) remains. The 30 mg dose can be administered directly intravenously. For intravenous bolus injection of enoxaparin sodium through a venous catheter, pre-filled 40 mg, 60 mg, 80 mg and 100 mg hypodermic syringes without a needle protector can be used. 20 mg syringes are not used because they do not contain enough product for a 30 mg bolus injection of enoxaparin sodium.

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

In order to improve accuracy of additional bolus injection of small volumes into the venous catheter during percutaneous coronary interventions it is recommended to dilute the drug with infusion solution (0.9% sodium chloride solution or 5% dextrose solution) to a concentration of 3 mg/ml. Dilution of the solution is recommended immediately before use.

To obtain a 3 mg/ml solution of Enoxaparin sodium using a pre-filled syringe, it is recommended to use a container with an infusion solution from which a part of the solution is extracted to the desired volume using a normal syringe. Enoxaparin sodium (the contents of the hypodermic syringe) is injected into the remaining infusion solution in the container.

The contents of the container with diluted enoxaparin sodium solution is mixed gently. The required volume of the diluted enoxaparin sodium solution is extracted for injection using a syringe, which is calculated according to the formula:

Volume of diluted solution = Patient body weight (kg) x 0.1 or using the table below.

Volumes to be administered intravenously after dilution

Elderly patients

Except for treatment of ST-segment elevation myocardial infarction (see above), no dose reduction of enoxaparin sodium is required for all other indications in elderly patients if they do not have impaired renal function.

Patients with renal impairment

In severe renal impairment (endogenous creatinine clearance less than 30 ml/min), the dose of Enixum® should be adjusted because drug accumulation occurs in these patients.

The following dosing adjustment is recommended when using the drug for therapeutic purposes:

The following dosing regimen adjustment is recommended when using the drug for prophylactic purposes

This dosing regimen is not applicable in the case of hemodialysis.

In mild (creatinine clearance 50-80 ml/min) and moderate (creatinine clearance 30-50 ml/min) renal failure, no dose adjustment is required; however, more careful laboratory monitoring of therapy should be performed.

Patients with hepatic impairment

In the absence of clinical studies, caution should be exercised when administering enoxaparin sodium to patients with hepatic impairment.

Percutaneous administration technique

The pre-filled disposable syringe is ready for use. The injection is preferably performed in the supine position of the patient. Enixum® is injected deeply subcutaneously. When using 20 mg, 30 mg and 40 mg pre-filled syringes, air bubbles should not be removed from the syringe prior to injection to avoid loss of product. Injections should be administered alternately to the left or right upper or lower side of the anterior abdominal wall. The needle should be inserted vertically (not sideways) all the way into the skin, holding the skin fold with the thumb and forefinger until the injection is complete. The injection site should not be massaged after the injection.

Interaction

The use of enoxaparin sodium should not be alternated with other low molecular weight heparins, since they differ from each other in production method, molecular weight, specific anti-Xa activity, units and dosage. As a consequence, preparations of low molecular weight heparins are characterized by different pharmacokinetics and biological activity (anti-IIa activity, interaction with platelets).

Enixum® is not recommended for use in combination with:

Hyperkalemia may occur with potassium salts, potassium-saving diuretics, angiotensin-converting enzyme inhibitors, angiotensin-II antagonists, cyclosporines, tacrolimus and trimethoprim.

The anticoagulant effect of enoxaparin sodium is enhanced with concomitant use with oral anticoagulants.

Concomitant use with platelet aggregation inhibitors (acetylsalicylic acid in antiplatelet doses in cardiac and neurological diseases, clopidogrel, abciximab, ticlopidine, eptifibatide, tirofiban, beraprost, iloprost) increases the risk of bleeding.

Special Instructions

Before starting therapy it is recommended to cancel other medicinal products affecting the hemostasis system due to the risk of bleeding (salicylates, acetylsalicylic acid, NSAIDs including ketorolac, dextran 40, ticlopidine, clopidogrel, glucocorticosteroid drugs, thrombolytics, anticoagulants, antiaggregants, including glycoprotein IIb/IIIa receptor antagonists), unless their use is strictly indicated. In case of necessity of combined use of enoxaparin sodium with the above mentioned drugs it is necessary to carry out close monitoring of patient’s condition and monitoring of corresponding laboratory indexes.

In patients with impaired renal function there is a risk of bleeding due to increased anti-Xa activity of sodium enoxaparin. Due to the fact that anti-Xa activity increases significantly in patients with severe renal dysfunction (creatinine clearance less than 30 ml/min) it is recommended to perform dose adjustment both during prophylactic and therapeutic administration of enoxaparin sodium in these patients. In patients with mild and moderate renal dysfunction (creatinine clearance 50-80 ml/min or 30-50 ml/min, respectively) dosage adjustment is not required, but the condition of these patients should be carefully monitored.

On single subcutaneous administration of enoxaparin sodium at a dose of 40 mg, anti-Xa activity is increased by 52% in women with body weight less than 45 kg and by 27% in men with body weight less than 57 kg compared to persons of normal body weight.

The risk of heparin-induced immune thrombocytopenia also exists with low molecular weight heparins. If thrombocytopenia develops, signs are usually detected between days 5 and 21 after initiation of therapy with enoxaparin sodium. Therefore, platelet counts should be monitored regularly before and during administration of the drug. In case of confirmed significant decrease of platelet count (by 30-50 % compared to the initial value), Enixum® should be immediately discontinued and the patient should be transferred to another therapy.

Spinal/epidural anesthesia

As with other anticoagulants, there have been cases of neuroaxial hematomas when using Enoxaparin sodium with spinal/epidural anesthesia with development of permanent or irreversible paralysis. The risk of these phenomena is reduced when using enoxaparin sodium at a dose of 40 mg or lower. The risk increases if the drug dose is increased, if penetrating epidural catheters are used after surgery, or if additional drugs with the same effect on hemostasis as NSAIDs are used concomitantly (see “Interaction with other drugs”). The risk also increases with traumatic or repeated spinal tap and in patients with a history of spinal surgery or spinal deformity.

In order to reduce the risk of bleeding from the spinal canal during epidural or spinal anesthesia, the pharmacokinetic profile of the drug should be considered (see “Pharmacological properties”). Catheter insertion or removal is best performed when the anticoagulant effect of enoxaparin sodium is low. Catheter placement or removal should be performed 10-12 h after prophylactic doses of enoxaparin sodium have been administered for deep vein thrombosis. In cases where patients receive higher doses of sodium enoxaparin (1 mg/kg twice daily or 1.5 mg/kg once daily), these procedures should be delayed for a longer period (24 h). Subsequent administration of the drug should be carried out no earlier than 2 hours after catheter removal.

If the patient is prescribed anticoagulant therapy during spinal/epidural anesthesia, special close ongoing monitoring of the patient should be undertaken to detect any neurological symptoms such as: back pain, sensory and motor dysfunction (numbness or weakness in the lower extremities), abnormal bowel and/or bladder function. The patient should be instructed to inform the physician immediately if the symptoms described above occur. If symptoms characteristic of a brainstem hematoma are detected, immediate diagnosis and treatment, including spinal cord decompression if necessary, are necessary.

Heparin-induced thrombocytopenia

Enixum® should be administered with extreme caution to patients with a history of possible heparin-induced thrombocytopenia, with or without thrombosis. The risk of heparin-induced thrombocytopenia may persist for several years. If heparin-induced thrombocytopenia is suspected anamnesthetically, in vitro platelet aggregation tests are of limited value in predicting its risk. The decision to prescribe enoxaparin sodium in this case can only be made after consultation with an appropriate specialist.

Percutaneous coronary angioplasty

In order to reduce the risk of bleeding associated with percutaneous coronary angioplasty (PCI) in the treatment of unstable angina and myocardial infarction without Q-wave, the recommended intervals between Enixum® administration and catheter removal should be adhered to. In order to reduce the risk of bleeding associated with percutaneous coronary angioplasty (PCI) in the treatment of unstable angina and myocardial infarction without Q-wave, the recommended intervals between Enixum® administration and catheter removal should be strictly followed. Hemostasis must be achieved at the peripheral artery puncture site after PCI. If a closure device is used, the catheter can be removed immediately after completion of the procedure. If manual compression is used, the catheter should not be removed for 6 h after the last subcutaneous injection of enoxaparin sodium. If continued therapy is necessary, the next estimated dose of sodium enoxaparin should not be administered before 6-8 h after catheter removal. The place of injection should be monitored to detect timely signs of bleeding and hematoma formation.

In artificial heart valves

There have been no studies on the efficacy and safety of enoxaparin sodium in the prevention of thromboembolic complications in patients with artificial heart valves. Prophylactic doses of enoxaparin sodium are insufficient to prevent thrombosis of artificial valves. There were observed cases of prosthetic heart valve thrombosis in pregnant women when enoxaparin sodium was used in therapeutic doses. The use of Enixum® in this category of patients cannot be recommended (see section “Contraindications”).

Laboratory tests

In doses used for prevention of thromboembolic complications Enixum® has no significant effect on bleeding time and general coagulation indices, as well as on platelet aggregation or their binding to fibrinogen. The activated partial thromboplastin time (APTT) and clotting time may be prolonged when increasing the dose of enoxaparin sodium. The increase in these parameters is not in direct linear relationship with the increase in antithrombotic activity of enoxaparin sodium, so there is no need to monitor them.

Prevention of venous thrombosis and embolism in bedridden patients with acute therapeutic conditions

In case of acute infection, acute rheumatic conditions, prophylactic administration of enoxaparin sodium is warranted only if the above conditions are combined with one of the following risk factors for venous thrombosis:

Synopsis

Contraindications

Side effects

Bleeding

Bleeding is possible, especially in the presence of associated risk factors: organic changes with a tendency to bleeding, age, renal insufficiency, low body weight and certain drug combinations (see “Interactions with other drugs”). In clinical trials, major bleeding (leading to clinically significant complications and/or accompanied by hemoglobin decrease of 2 g/l or more and/or requiring transfusion of 2 or more doses of blood components) when administered enoxaparin developed in 4.2% of patients, and in some of these cases were fatal. Pitting hemorrhages (petechiae) and ecchymoses are possible.

Bleeding during prophylaxis of venous thrombosis during surgical interventions and treatment of deep vein thrombosis with or without pulmonary embolism is very frequent.

Frequent – bleeding in the prevention of venous thrombosis in bed-ridden patients due to acute therapeutic conditions and in the treatment of unstable angina and myocardial infarction without the Q-wave.

Infrequent – retroperitoneal bleeding or intracranial hemorrhage in the treatment of deep vein thrombosis with or without pulmonary embolism.

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

In case of bleeding, the drug administration should be stopped, the cause of the bleeding identified and appropriate therapy started.

When using enoxaparin sodium against the background of spinal/epidural anesthesia and postoperative use of penetrating catheters there have been described cases of neuroaxial hematomas (0.01-0.1% of cases), which resulted in neurological disorders of varying severity, including long-term or irreversible paralysis (see “Special Precautions”).

Thrombocytopenia and thrombocytosis:

In the first days after initiation of therapy, mild, transient asymptomatic thrombocytopenia may develop.

Very frequent – thrombocytosis in the prevention of venous thrombosis in surgical procedures and in the treatment of deep vein thrombosis with or without pulmonary embolism.

Frequent – thrombocytopenia in the prevention of venous thrombosis in surgical procedures and in the treatment of deep vein thrombosis with or without pulmonary embolism

. Infrequent – thrombocytopenia in the prevention of venous thrombosis in bed-ridden patients due to acute medical conditions and in the treatment of unstable angina and myocardial infarction without the Q-wave.

In very rare cases (less than 0.01%), autoimmune thrombocytopenia may develop in conjunction with thrombosis, which has sometimes been complicated by organ infarction or limb ischemia.

Allergic reactions:

Skin and injection site reactions

Cardiovascular system disorders: Rare – thrombosis of artificial heart valves (usually with inadequate dosage)

Changes in laboratory parameters:

Other: The risk of osteoporosis increases with prolonged treatment.

Overdose

1 mg of protamine sulfate neutralizes the anticoagulant effect of 1 mg of enoxaparin sodium if the drug was administered no more than 8 h before administration of protamine sulfate.

The 0.5 mg of protamine sulfate will neutralize the anticoagulant effect of 1 mg of enoxaparin sodium if administered more than 8 h before or if a second dose of protamine sulfate is necessary.

If, however, 12 hours or more have elapsed since the administration of enoxaparin sodium, administration of protamine sulfate is not necessary. However, even when large doses of protamine sulfate are administered, the anti-Xa activity of sodium enoxaparin is not completely neutralized (maximum 60%).

Pregnancy use

The spinal or epidural anesthesia should not be performed during the drug treatment. If epidural anesthesia is planned, preventive treatment with Enoxaparin sodium should be discontinued, if possible, at least 12 h before the anesthesia.

Enoxaparin sodium is not recommended for use in pregnant women with prosthetic heart valves. Breastfeeding should be stopped during treatment with Enoxaparin sodium.

Similarities