Description
Pharmacological action of
Pharmacodynamics
Enoxaparin sodium – low molecular weight heparin. The average molecular weight is about 4,500 daltons. In a purified in vitro system, enoxaparin sodium has high activity against coagulation factor Xa (anti-Xa activity of about 100 IU / ml) and low activity against coagulation factor IIa (anti-IIa or antithrombin activity of about 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 (APTT), has practically no effect on platelet aggregation and the level of fibrinogen binding to platelet receptors.
Anti-IIa plasma enoxaparin activity is approximately 10 times lower than anti-Xa activity. The average 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 of body weight – with double administration and 1.5 mg / kg body weight – with a single administration, respectively.
The average maximum anti-Xa plasma activity is observed 3-5 hours after subcutaneous administration of the drug and is approximately 0.2 0.4 1.0 and 1.3 anti-XA IU / ml after subcutaneous administration 20, 40 mg and 1 mg / kg and 1.5 mg / kg, respectively.
Pharmacokinetics
The pharmacokinetics of enoxaparin sodium in these dosing regimens is linear. Variability within and between patient groups is low. After repeated subcutaneous administration of 40 mg of enoxaparin sodium once a day and subcutaneous administration of enoxaparin sodium at a dose of 1.5 mg / kg once a day in healthy volunteers, the equilibrium concentration is reached by day 2, and the area under the pharmacokinetic curve is on average 15% higher than after a single injection. After repeated subcutaneous injections of enoxaparin sodium in a daily dose of 1 mg / kg twice a day, the equilibrium concentration is reached after 3-4 days, and the area under the pharmacokinetic curve is on average 65% higher. than after a single injection and the average maximum concentrations (Cmax) are, respectively, 1.2 IU / ml and 0.52 IU / ml.
The bioavailability of enoxaparin sodium when administered subcutaneously, estimated based on anti-Xa activity, is close to 100%.
The volume of distribution of anti-Xa activity of enoxaparin sodium is approximately 5 L and approaches the volume of blood.
Enoxaparin Sodium is a low-clearance drug. After iv administration for 6 hours at a dose of 1.5 mg / kg body weight, the average anti-Xa clearance in plasma 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.
Withdrawal of the drug is monophasic with a half-life (T1 / 2) of 4 hours (after a single subcutaneous injection) and 7 hours (after repeated administration of the drug).
The excretion of active drug fragments through the kidneys is approximately 10% of the administered dose and the total excretion of active and inactive fragments is approximately 40% of the administered dose.
Elderly patients
Excretion is delayed due to physiological decline in renal function. This change does not affect the dosage and administration regimen during prophylactic therapy if the renal function of such patients remains within acceptable limits, i.e., is slightly reduced.
Before starting treatment with low molecular weight heparins in patients over the age of 75, a systematic examination of renal function is necessary.
Patients with impaired renal function
Enoxaparin sodium clearance decreases in patients with impaired renal function. In patients with severe renal failure (creatinine clearance less than 30 ml / min) with repeated subcutaneous administration, the area under the pharmacokinetic curve in equilibrium increases by 65%.
Hemodialysis patients
Enoxaparin sodium is introduced into the arterial branch of the dialysis system in doses sufficient to prevent coagulation in the system.
Basically, the pharmacokinetic parameters remain unchanged except in cases of overdose, in which the drug enters the general bloodstream and can induce high anti-Xa activity associated with end-stage renal failure.
Overweight patients
In people who are overweight, with subcutaneous administration of the drug, clearance is slightly less.
If you do not adjust the dose taking into account the patient ² ¢s body weight, then after a single subcutaneous injection of 40 mg of enoxaparin sodium anti-Xa activity will be 50% higher in women with body weight less than 45 kg and 27% higher in men with body weight less than 57 kg compared with patients with normal average body weight.
Indications
Prevention of venous thrombosis and embolism during surgical interventions, especially during orthopedic and general surgical operations
prevention of venous thrombosis and embolism in patients on bed rest due to acute therapeutic diseases, including acute heart failure and decompensation of chronic heart failure (NYHA class III or IV), acute respiratory failure, acute infectious diseases, acute stages of rheumatic diseases, combined with one of the risk factors for venous thrombosis (see Special instructions )
treatment of deep vein thrombosis, which is accompanied or not accompanied by pulmonary thromboembolism
prevention of thrombosis in the extracorporeal circulation system during hemodialysis (usually with a session duration of no more than 4 hours)
treatment of unstable angina and myocardial infarction without Q wave in combination with
acetylsalicylic acid treatment of acute myocardial infarction with ST segment elevation in patients, subject to medical treatment or subsequent percutaneous coronary intervention.
Contraindications
Hypersensitivity to enoxaparin sodium, heparin or its derivatives, including other low molecular weight heparins
conditions and diseases at which there is a high risk of bleeding: threatening abortion, cerebral vascular aneurysm or exfoliating aortic aneurysm (except surgery)
hemorrhagic stroke
uncontrolled bleeding
enoxaparin- and heparin-induced thrombocytopenia
not recommended for use in pregnant women with artificial heart valves not effective 18 years and srdlp )
With caution
hemostasis disorders (including hemophilia, thrombocytopenia, hypocoagulation, von Willebrand disease, etc.), spinal puncture (recently transferred)
recent birth
bacterial endocarditis (acute or subacute)
pericarditis or pericardial effusion
renal and / or hepatic insufficiency
intrauterine contraception (IUD)
severe neural trauma) on large surfaces of
, simultaneous administration of drugs that affect the hemostasis system.
There are no data on the clinical use of the drug in the following diseases: active tuberculosis, radiation therapy (recently transferred).
Special instructions
When prescribing the drug for preventive purposes, there was no tendency to increase bleeding. When prescribing the drug for medicinal purposes, there is a risk of bleeding in older patients (especially older than 80 years). Careful monitoring of the patient’s condition is recommended.
Before starting therapy, it is recommended to cancel other drugs that affect the hemostasis system, because of the risk of bleeding (salicylates, acetylsalicylic acid, NSAIDs, including ketorolac, dextran 40, ticlopidine, clopidogrel, glucocorticosteroid drugs, thrombolytics, anticoagulants, anticoagulants, glycoprotein receptors IIb / IIIa), except when strictly indicated. If necessary, the combined use of enoxaparin sodium with these drugs requires careful monitoring of the patient’s condition and monitoring of relevant laboratory parameters.
In patients with impaired renal function, there is a risk of bleeding as a result of increased anti-Xa activity of enoxaparin sodium. Due to the fact that anti-Xa activity increases significantly in patients with severe impaired renal function (creatinine clearance less than 30 ml / min), it is recommended that dose adjustment be performed both for the prophylactic and therapeutic purposes of enoxaparin sodium in such patients. Patients with mild to moderate impaired renal function (creatinine clearance, respectively, 50-80 ml / min or 30-50 ml / min) dose adjustment is not required, but the condition of such patients should be carefully monitored.
With a single subcutaneous injection of enoxaparin sodium at a dose of 40 mg, anti-Xa activity increases 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 people with normal body weight.
The risk of heparin-induced immune thrombocytopenia also exists with low molecular weight heparins. If thrombocytopenia develops, then its symptoms are usually detected between the 5th and 21st days after the initiation of sodium enoxaparin therapy. In this regard, platelet count should be regularly monitored prior to the use of the drug and during its use. In the presence of a confirmed significant decrease in the number of platelets (by 30-50% compared to the baseline), it is necessary to immediately cancel Enixum ® and transfer the patient to another therapy.
Spinal / epidural anesthesia
As with other anticoagulants, cases of neuroaxial hematomas have been described when enoxaparin sodium was used against spinal / epidural anesthesia with the development of persistent or irreversible paralysis. The risk of these phenomena is reduced with the use of enoxaparin sodium at a dose of 40 mg or lower. The risk increases with an increase in the dose of the drug, as well as with the use of penetrating epidural catheters after surgery, or with the concomitant use of additional drugs that have the same effect on hemostasis as NSAIDs (see Interaction with other drugs ). The risk is also increased with traumatic or repeated spinal puncture, as well as in patients who have anamnestic indications of surgery in the spine or spinal deformity.
To reduce the risk of bleeding from the spinal canal with epidural or spinal anesthesia, the pharmacokinetic profile of the drug must be taken into account (see “Pharmacological properties”). Catheter insertion or removal is best done with the low anticoagulant effect of enoxaparin sodium. The installation or removal of the catheter should be carried out 10-12 hours after the application of prophylactic doses of enoxaparin sodium with deep vein thrombosis. In cases where patients receive higher doses of enoxaparin sodium (1 mg / kg 2 times a day or 1, 5 mg / kg once a day), these procedures should be postponed for a longer period of time (24 hours). Subsequent administration of the drug should be carried out no earlier than 2 hours after removal of the catheter.
If the patient is prescribed anticoagulant therapy during spinal / epidural anesthesia, careful careful monitoring of the patient is necessary to identify any neurological symptoms, such as back pain, impaired sensory and motor functions (numbness or weakness in the lower extremities), dysfunction intestines and / or bladder. The patient should be instructed to immediately inform the doctor if the above symptoms occur. Upon detection of symptoms characteristic of a hematoma of the brain stem, urgent diagnosis and treatment is necessary, including, if necessary, then the catheter should not be removed within 6 hours after the last subcutaneous injection of enoxaparin sodium. If it is necessary to continue therapy, then the next calculated dose of enoxaparin sodium should be administered no earlier than 6-8 hours after removal of the catheter. The injection site should be monitored in order to timely detect signs of bleeding and the formation of a hematoma.
Artificial heart valves
Studies on the efficacy and safety of enoxaparin sodium in the prevention of thromboembolic complications in patients with artificial heart valves have not been conducted. Prophylactic doses of enoxaparin sodium are insufficient to prevent artificial valve thrombosis. There were cases of thrombosis of prosthetic heart valves in pregnant women with the use of enoxaparin sodium in therapeutic doses. bedridden
In case of acute infection, acute rheumatic conditions, prophylactic enoxaparin sodium is justified only if the above conditions are combined with one of the following risk factors for venous thrombosis:
age 75 and older,
malignant neoplasms,
embolism and thrombosis history,
obesity,
hormone therapy,
heart failure,
chronic respiratory failure.
Impact on the performance of potentially hazardous activities that require special attention and speed of reactions
There is no evidence of a negative effect of enoxaparin sodium on driving ability and other potentially hazardous activities, requiring increased concentration of attention and speed of psychomotor reactions.
Composition
1 syringe (0.4 ml) contains the active substance enoxaparin sodium 4000 anti-XA ME (40 mg)
excipients: water for injection – up to 0.4 ml.
Dosage and administration of
Enixum ® is administered subcutaneously (deeply), in special cases (see below), into the arterial circuit during a hemodialysis session and intravenously.
The drug can not be administered intramuscularly!
Prevention of venous thrombosis and embolism during surgical interventions, especially during orthopedic and general surgical operations
For patients with a moderate risk of developing thrombosis and embolism (general surgery), the recommended dose of the drug is 20-40 mg once a day subcutaneously.
The first injection is made 2 hours before surgery.
Patients at high risk of developing thrombosis and embolism (orthopedic surgery), the recommended dose of the drug is 40 mg once a day subcutaneously, the first dose is administered 12 hours before surgery or 30 mg 2 times a day with the start of administration 12-24 hours after surgery.
Duration of treatment is an average of 7-10 days. If necessary, therapy can be continued until the risk of developing thrombosis and embolism remains (for example, 40 mg once daily for 5 weeks are used in Enixum ® orthopedics). Peculiarities of prescribing the drug in spinal / epidural anesthesia, as well as in percutaneous coronary angioplasty, are described in the “Special Instructions” section.
Prevention of venous thrombosis and embolism in patients on bed rest due to acute therapeutic diseases
Recommended dose of enoxaparin sodium – 40 mg once daily s / c for 6-14 days.
Treatment of deep vein thrombosis with or without pulmonary thromboembolism
Enixum ® is administered subcutaneously at a rate of 1.5 mg / kg once a day or at a dose of 1 mg / kg twice a day. In patients with complicated thromboembolic disorders, the drug is recommended to be used at a dose of 1 mg / kg twice a day. The duration of treatment is an average of 10 days. It is advisable to immediately start anticoagulant therapy for oral administration, while enoxaparin sodium therapy should be continued until a sufficient anticoagulant effect is achieved. If necessary, control of the anticoagulant effect should be evaluated by anti-Xa activity.
Prevention of thrombosis in the extracorporeal circulatory system during hemodialysis
The dose of enoxaparin sodium is 1 mg / kg body weight. For patients with a high risk of bleeding, the dose should be reduced to 0.5 mg / kg with dual vascular access or 0.75 mg with single vascular access. During hemodialysis, Enixum ® should be introduced into the arterial area of the shunt at the beginning of the hemodialysis session. One dose, as a rule, is enough for a four-hour session, however, if fibrin rings are detected (for example, with longer hemodialysis), you can additionally enter the drug Enixum ® in a dose of 0.5-1 mg / kg.
Treatment of unstable angina pectoris and myocardial infarction without Q wave in combination with
Enixum ® is administered at a dose of 1 mg / kg body weight every 12 hours subcutaneously, with the appointment of acetylsalicylic acid inside at a dose of 100-325 mg once a day. The average duration of treatment is 2-8 days (until the stabilization of the clinical condition of the patient).
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 of enoxaparin sodium at a dose of 30 mg and immediately after it (within 15 minutes) subcutaneous administration of enoxaparin sodium is performed dose of 1 mg / kg (moreover, during the first two subcutaneous injections, 100 mg of enoxaparin sodium can be administered as much as possible). Then, all subsequent subcutaneous doses are administered every 12 hours at the rate of 1 mg / kg body weight (that is, with a body weight of more than 100 kg, the dose may exceed 100 mg).
In persons 75 years of age and older, the initial intravenous bolus is not used. Enoxaparin sodium is administered subcutaneously at a dose of 0.75 mg / kg every 12 hours (moreover, during the first two subcutaneous injections, 75 mg of enoxaparin sodium can be administered as much as possible). Then, all subsequent subcutaneous doses are administered every 12 hours at the rate of 0.75 mg / kg body weight (that is, with a weight of more than 100 kg, the dose may exceed 75 mg).
When combined with thrombolytics (fibrin-specific and fibrin-non-specific), enoxaparin sodium should be administered in the range from 15 minutes before starting thrombolytic therapy to 30 minutes after it. As soon as possible after the detection of acute myocardial infarction with an increase in the ST segment, acetylsalicylic acid should be started at the same time and, if there are no contraindications, it should continue for at least 30 days in doses from 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 hospitalization period is less than 8 days. The bolus administration of enoxaparin sodium should be given through a venous catheter, and enoxaparin sodium should not be mixed or administered with other drugs. 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 a sufficient amount of 0.9% sodium chloride or dextrose solution before and after the intravenous bolus administration of enoxaparin sodium. Enoxaparin sodium can be safely administered with 0.9% sodium chloride solution and 5% dextrose solution.
For bolus administration of 30 mg of enoxaparin sodium in the treatment of acute myocardial infarction with ST segment elevation, 40 mg, 60 mg, 80 mg and 100 mg of syringes are removed from the glass syringes so that only 30 mg is left in them (0.3 ml). A dose of 30 mg can be directly administered intravenously. For intravenous bolus administration of enoxaparin sodium through a venous catheter, pre-filled syringes for subcutaneous administration of the drug without a needle protection device of 40 mg, 60 mg, 80 mg and 100 mg can be used. 20 mg syringes are not used, because they do not have enough drug for the bolus administration of 30 mg of enoxaparin sodium.
In patients undergoing percutaneous coronary intervention, if if the last subcutaneous injection of enoxaparin sodium was performed less than 8 hours before the balloon catheter was introduced into the site of narrowing of the coronary artery, additional administration of enoxaparin sodium is not required. If the last subcutaneous injection of enoxaparin sodium was carried out more than 8 hours before the balloon catheter was inflated, an additional intravenous bolus injection of enoxaparin sodium at a dose of 0.3 mg / kg should be performed.
To increase the accuracy of additional bolus injection of small volumes into a venous catheter during percutaneous coronary interventions, it is recommended to dilute the drug with an 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 solution of enoxaparin sodium with a concentration of 3 mg / ml using a pre-filled syringe, it is recommended to use a container with an infusion solution, from which part of the solution is removed using an ordinary syringe to the required volume. Enoxaparin sodium (the contents of the hypodermic syringe) is injected into the remaining infusion solution.
Side effects
WHO classification of adverse drug reactions by frequency of occurrence:
Very frequent – 1/10 prescriptions ( 10%)
Frequent – 1/100 prescriptions ( 1%, but Infrequent – 1/1000 appointments ( 0, 1%, but Rare – 1/10000 appointments ( 0.01%, but Very rare – less than 1/10000 prescriptions (Frequency is not known – cannot be established on the basis of available data.
Bleeding
Bleeding is possible, especially if there are concomitant risk factors: organic changes with a tendency to bleed, age, renal failure, low body weight and certain drug combinations (see ² ÑInteractions with Other Drugs. ² Ñ) In clinical trials, large bleeding (leading to clinically significant complications and / or concomitant caused by a decrease in hemoglobin of 2 g / l or more and / or requiring transfusion of 2 or more doses of blood components) with the appointment of enoxaparin developed in 4.2% of patients, and in some of these cases were fatal in nature. Point hemorrhages (petechiae), ecchymosis are possible.
Very frequent – bleeding in the prevention of venous thrombosis during surgery and in the treatment of deep vein thrombosis with or without pulmonary embolism.
Frequent – bleeding in the prevention of venous thrombosis in patients on bed rest due to acute therapeutic diseases and in the treatment of unstable angina and myocardial infarction without Q wave.
Infrequent – retroperitoneal hemorrhage or intracranial hemorrhage in the treatment of deep vein thrombosis without thrombosis her.
Rare – retroperitoneal bleeding in the prevention of venous thrombosis in surgical patients and in the treatment of unstable angina and myocardial infarction without tooth Q
In case of bleeding, it is necessary to cancel the drug, establish the cause of bleeding and start appropriate therapy.
When using enoxaparin sodium on the background of spinal / epidural anesthesia and postoperative use of penetrating catheters, cases of neuroaxial hematomas are described (in 0.01-0.1% of cases), which led to neurological disorders of varying severity, including long-lasting or irreversible paralysis (see . “Special instructions”).
Thrombocytopenia and thrombocytosis
A mild, transient asymptomatic thrombocytopenia may develop during the first days after starting therapy.
Very frequent – thrombocytosis in the prevention of venous thrombosis during surgical interventions and in the treatment of deep vein thrombosis with or without pulmonary embolism.
Frequent – thrombocytopenia in the prophylaxis of venous thrombosis during surgical interventions and in the treatment of deep vein thrombosis with or without pulmonary embolism
Infrequent – thrombocytopenia in the prevention of venous thrombosis in patients with bedridden diseases and acute treatment for acute infarction and acute treatment myocardium without Q wave.
In very rare cases (less than 0.01%), the development of autoimmune thrombocytopenia in combination with thrombosis, which sometimes ozhnyalsya myocardial organ or limb ischemia.
Allergic reactions
Frequent – urticaria, itching, redness of the skin.
Rare – anaphylactic and anaphylactoid reactions, allergic vasculitis.
From the skin and reactions at the injection site
Frequent – hematoma, pain at the injection site.
Rare – bullous dermatitis.
Very rare – skin necrosis, which is preceded by the appearance of purpura or infiltrated and painful erythematous plaques. In these cases, drug therapy should be discontinued.
In some cases, at the injection site, the formation of solid inflammatory nodules-infiltrates containing the drug is possible, which disappear after a few days and are not grounds for drug withdrawal.
From the cardiovascular system
Rare – thrombosis of artificial heart valves (usually with inadequate dosage)
Changes in laboratory parameters
Very frequent – asymptomatic and reversible increase in the activity of ² Ñliver ² Ñ transaminases (AST and ALT> 3 times higher than the upper limit of normal values).
Rare – hypoaldosteronism, hyperkalemia (especially in patients with chronic renal failure and diabetes mellitus, metabolic acidosis).
Other
Long-term treatment increases the risk of osteoporosis.
Overdose
Symptoms: hemorrhagic complications in case of accidental overdose with subcutaneous administration of enoxaparin sodium. When ingesting even large doses, absorption of the drug is unlikely.
Treatment: neutralize the effect of enoxaparin sodium by slow intravenous (iv) administration of protamine sulfate (or hydrochloride). Before using protamine sulfate, due to the possibility of side effects (in particular anaphylactic shock), the benefit / risk ratio must be carefully weighed.
1 mg of protamine sulfate neutralizes the anticoagulant effect of 1 mg of enoxaparin sodium if the drug was administered no more than 8 hours before the administration of protamine sulfate.
0.5 mg protamine sulfate neutralizes the anticoagulant effect of 1 mg enoxaparin sodium if it was administered more than 8 hours ago or if a second dose of protamine sulfate is needed.
If, however, 12 hours or more have passed after the administration of enoxaparin sodium, administration of protamine sulfate is not required. However, even with the introduction of large doses of protamine sulfate, anti-Xa, the activity of enoxaparin sodium is not completely neutralized (by a maximum of 60%).
Storage conditions
At a temperature not exceeding 25 ° C. Do not freeze.
Keep out of the reach of children.
Expiration
2 years.
Active ingredient
Sodium enoxaparin
Terms and conditions
prescription
dosage form
injection
