Novoparin injection 80 mg syringe 0.8 ml №2

Author Ольга Кияница

2017-05-11

Amount in a package -
Product form Solution
Manufacturer -
Registration certificate UA/9061/01/01
The main medicament Novoparin
morion code 105139

Novoparin (NOVOPARIN) instructions for use

Composition

active ingredient: sodium enoxaparin; 1 ml of the solution contains sodium enoxaparin with an anti-factor Xa activity of 10,000 IU equivalent to sodium isoxaparin 100 mg

2000 anti-factor Ha IU / 0.2 ml, equivalent to sodium enoxaparin 20 mg

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

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

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

10,000 anti-factor Ha IU / 1.0 mL, equivalent to sodium enoxaparin 100 mg

excipients: water for injection.

Dosage form

Injection.

Basic physical and chemical properties:

colorless or light yellow transparent solution.

Pharmacological group

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

Pharmacological properties

Pharmacodynamics.

Enoxaparin is a low-molecular-weight heparin (LMWH), in which it is separated by antiplatelet and anticoagulant activity of standard heparin. It has a higher anti-factor Xa activity than the anti-factor Iaa, and antithrombin activity (for the enoxaparin the ratio is 3.6).

When used in prophylactic doses, enoxaparin has no significant effect on APTT (activated partial thromboplastin time).

When applying therapeutic doses of the drug, APTT can be prolonged and 1.5-2.2 times higher than the control time of maximum activity. This prolongation reflects residual antithrombin activity.

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

In a large-scale multicenter clinical study, 20,479 patients with acute myocardial infarction with ST-segment elevation after they received fibrinolytic therapy were randomly assigned to receive either enoxaparin as a bolus injection of 3000 anti-factor Ha Me, followed immediately by subcutaneous injection dose 100 anti-factor Ha IU / kg, then 100 subcutaneous injections of 100 anti-factor of Ha IU / kg every 12:00, or for intravenous unfractionated heparin injection in the form of a bolus injection of 60 IU / kg (maximum 4000 IU / kg) followed by a continuous infusion at a dose which was adjusted depending on the parameter activated partial thromboplastin time. Subcutaneous injections of enoxaparin were performed before discharge from the hospital or no more than 8 days (in 75% of cases - not less than 6 days). Half of patients who received heparin, the drug was administered at least 48 hours (in 89.5% of cases ≥ 36 hours). All patients also received acetylsalicylic acid for at least 30 days. The dose of enoxaparin for patients aged ≥75 corrected 0.75 mg / kg (75 anti-factor Ha IU / kg) as a subcutaneous injection every 12:00 without an initial bolus injection.

In the course of the study, 4716 patients (23%) underwent coronary angioplasty on the background of antithrombotic therapy with the use of masked test preparations. Patients did not receive additional doses if less than 8:00 had elapsed from the time of the last subcutaneous injection of enoxaparin before ballooning, or a bolus intravenous injection of enoxaparin at a dose of 0.3 mg / kg (30 anti-factor of Ha IU / kg) if c the time of the last subcutaneous injection of enoxaparin before inflation of the balloon was more than 8:00.

Enoxaparin made it possible to significantly reduce the incidence of events that correspond to primary endpoints (a combined endpoint including recurrence of myocardial infarction and mortality for any reason that occurred during the 30-day follow-up period: 9.9% in the enoxaparin group, compared with 12% in the unfractionated heparin group (a relative risk reduction of 17% (p <0.001).) The incidence of recurrence of myocardial infarction was significantly lower in the enoxaparin group (3.4% compared to 5% <0.001, relative risk reduction -. 31%) Mortality rate was lower in the enoxaparin group, but the difference between the groups was not statistically significant (6.9% compared with 7.5%, p = 0.11).

The advantage of enoxaparin from the point of view of the primary endpoint of the indicator was unconditional irrespective of the subgroup (age, sex, myocardial infarction localization, diabetes or myocardial infarction in the anamnesis, the type of thrombolytics prescribed and the time interval between the appearance of the first clinical signs and the beginning of treatment).

Enoxaparin showed a significant advantage in comparison with unfractionated heparin from the point of view of the primary efficacy criterion as in patients undergoing coronary angioplasty in the 30-day period after enrollment (10.8% compared with 13.9%, 23% reduction in relative risk) , and in patients to whom coronary angioplasty was not performed (9.7% compared to 11.4% for a 15% reduction in relative risk).

The incidence of massive bleeding prior to the 30th day was significantly higher in the enoxaparin group (2.1%) than in the heparin group (1.4%). The incidence of gastrointestinal bleeding was higher in the enoxaparin group (0.5%) than in the heparin group (0.1%), while the rate of intracranial hemorrhage in both groups was similar (0.8% for enoxaparin versus 0 , 7% in the case of heparin).

An analysis of the combined criteria by which clinical benefit was determined showed a statistically significant advantage (p <0.0001) of enoxaparin over unfractionated heparin: a relative risk reduction of 14% in favor of enoxaparin (11% compared to 12.8%) for combined criteria including death, relapse of myocardial infarction and severe bleeding (Tim's criteria) to the 30th day, and 17% (10.1% compared to 12.2%) for combined criteria including death, relapse of myocardial infarction and intracranial hemorrhage s up to the 30th day.

Pharmacokinetics.

Pharmacokinetic parameters of the drug are evaluated by changes in the anti-factor Xa and the anti-factor IIA activity in blood plasma over time in the recommended dose ranges.

Bioavailability. When administered subcutaneously, enoxaparin is absorbed rapidly and almost completely (almost 100%). The maximum activity in the blood plasma is observed between the 3rd and the fourth hour after administration.

This maximum activity (expressed in the anti-factor Xa ME) is 0.18 ± 0.04 (after the administration of 2000 anti-factor Xa ME), 0.43 ± 0.11 (after administration of 4000 anti-factor Xa IU) and 1 , 01 ± 0.14 (after the introduction of 10,000 anti-factor Ha Me).

A bolus intravenous injection of 30 mg (0.3 ml of 3000 anti-factor Ha Me) followed by subcutaneous injection of 1 mg / kg (100 anti-factor of Ha IU / kg) every 12:00 results in the first maximum level of anti-Xa concentration , which is 1.16 IU / ml (n = 16), and the average area under the pharmacokinetic curve corresponding to 88% of the equilibrium level. The equilibrium state is reached on the second day of treatment.

In the recommended dose range, the pharmacokinetics of enoxaparin is linear. Differences in indices between the individual patient and between patients are very small. After repeated subcutaneous administration to healthy volunteers, 40 mg (0.4 ml 4000 anti-factor Xa ME) once a day, the equilibrium state was achieved on the second day, while the average activity of enoxaparin was almost 15% higher than that observed with a single administered. Stable levels of enoxaparin activity are predictable when single doses are administered. After repeated subcutaneous administration of 1 mg / kg (100 anti-factor of Ha IU / kg), the equilibrium state was attained 2 times a day between the third and fourth time, while the average AUC was 65% higher than that observed at single injection, and the maximum and minimum anti-factor Xa activity was 1.2 and 0.52 anti-factor Xa IU / ml, respectively. According to the pharmacokinetic parameters of sodium enoxaparin, this difference in the achievement of the equilibrium state is also expected for the therapeutic range of doses.

The anti-factor Xa activity in plasma after subcutaneous administration is almost 10 times lower than the anti-factor Iaa activity. The average maximum anti-factor Xa activity is observed approximately 3-4 hours after the drug administration, reaching 0.13 anti-factor Ha IU / ml after repeated administration of a dose of 1 mg / kg (100 anti-factor of Ha IU / kg) two times in day.

Distribution. The volume of distribution of enoxaparin sodium according to the anti-factor Xa activity is approximately 5 liters and almost corresponds to the volume of circulating blood.

Metabolism. Metabolism of enoxaparin occurs predominantly in the liver (by desulfatization and depolymerization).

Conclusion. After the administration of the drug, the elimination half-life of anti-factor Xa activity in low-molecular heparins is longer compared to that of unfractionated heparin.

Excretion of enoxaparin Monophasic, with a half-life of approximately 4:00 after a single subcutaneous injection and almost 7:00 with the introduction of repeated doses. For low molecular weight heparins, a faster decrease in the anti-factor Iaa activity in blood plasma is characteristic compared to the anti-factor Xa activity.

Enoxaparin and its metabolites are excreted in the urine (unsaturated mechanism), as well as with bile.

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

High-risk groups

Patients of advanced age. Since this physiological decline in renal function is observed in this age group, the elimination is slower. This does not affect the dosage or mode of administration for prophylactic treatment. In patients aged 75 years, it is very important to systematically monitor kidney function using the Cockcroft formula before starting treatment with LMWH.

Patients with mild and moderate renal insufficiency (creatinine clearance> 30 ml / min). In some cases it may be useful to monitor the anti-factor Xa activity in order to avoid the possibility of an overdose if enoxaparin is used in therapeutic doses.

Indications

  • Prevention of venous thromboembolism in surgical interventions accompanied by moderate and high thrombogenic risk;
  • prevention of deep vein thrombosis in patients on bed rest due to acute therapeutic illnesses: NYHA grade III or IV heart failure, acute respiratory failure, acute infectious or rheumatic disease, with at least one other risk factor for venous thromboembolism;
  • prevention of thrombus formation in the extracorporeal circuit of blood circulation during hemodialysis (the procedure on average lasts until about 4:00)
  • treatment of diagnosed deep vein thrombosis that is accompanied or not accompanied by pulmonary embolism and does not have severe clinical symptoms, with the exception of pulmonary embolism, which requires thrombolytic treatment or surgery
  • treatment of unstable angina and acute myocardial infarction without Q wave in combination with acetylsalicylic acid
  • treatment of acute myocardial infarction with ST elevation / elevation in combination with thrombolytic agents in patients who may continue to use coronary angioplasty, as well as in patients who do not receive this procedure.

Contraindications

For doses of 2000, the anti-factor of Ha Me / 0.2 ml, equivalent to sodium enoxaparin 20 mg

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

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

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

This medicine can not be used in the following cases:

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

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

This medication is generally not recommended in the following cases:

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

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

1. Acetylsalicylic acid in analgesics, antipyretic and anti-inflammatory doses.

2. NSAIDs (NSAIDs) (systemic application).

3. Dextran 40 (parenteral administration).

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

This medication is generally not recommended in the following cases:

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

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

Spinal or epidural anesthesia should not in any case be used for patients undergoing treatment with LMWH.

It is not recommended to apply the drug in the following cases:

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

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

1. Acetylsalicylic acid in analgesics, antipyretic and anti-inflammatory doses.

2. NSAIDs (NSAIDs) (systemic application).

3. Dextran 40 (parenteral administration).

Interaction with other drugs and other interactions

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

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

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

Patients of advanced age (over 65 years).

Unwanted combinations.

With acetylsalicylic acid in analgesic, antipyretic and anti-inflammatory doses (and by analogy - other salicylates): increased risk of bleeding (suppression of salicylates platelet function and damage to the mucous membrane of the digestive tract). It should be used antipyretic, analgesic, not related to salicylates (for example, paracetamol).

With NSAIDs, including ketorolac (systemic use): increased risk of bleeding (suppression of NSAIDs of platelet function and damage to the mucous membrane of the digestive tract). If simultaneous application can not be avoided, careful clinical monitoring should be carried out.

40 With dextran, dipyridamole and sulfinpyrazone (parenteral administration): increased risk of bleeding (inhibition of platelet function dextran 40).

Combinations requiring action.

With oral anticoagulants: increased anticoagulant effect. When replacing heparin oral anticoagulant should enhance the clinical observation.

Combinations to be taken into account.

Since platelet aggregation inhibitors (other than acetylsalicylic acid in analgesic, antipyretic and anti-inflammatory doses NSAIDs): abciximab, acetylsalicylic acid antiplatelet doses in cardiac and neurological indications, beraprost, Klopidrogel, eptifibatide, iloprost, ticlopidine, tirofiban: increased risk of bleeding .

Patients under the age of 65 years.

Combinations to be taken into account.

The combined use of drugs affecting hemostasis different phases, increases the risk of bleeding. Therefore, regardless of the age of the patient should be constant monitoring of the clinical picture and if necessary perform laboratory tests, when to assign prophylactic dose of LMWH simultaneously with oral anticoagulants, antagonists of glycoprotein IIb, / Sha, platelet aggregation inhibitors (abciximab, NSAIDS, acetylsalicylic acid at any dose Klopidrogel, systemic glucocorticosteroids, eptifibatide, iloprost, ticlopidine, tirofiban) and thrombolytic agents.

Features of the application

The drug is not allowed to be administered intramuscularly.

LMWH preparations are not interchangeable, since they differ in molecular weight, unit values of activity against Factor Xa dosing. It is necessary to pay attention to and comply with the specific methods of application recommended for each of the products of low molecular weight heparins.

Precautions for use

Bleeding.

As in treatment with anticoagulants, bleeding may occur (see. Section "Adverse reactions"). In case of bleeding should establish the cause and start the appropriate treatment.

Renal function.

Before treatment, low molecular weight heparin is important to assess renal function, especially in patients aged 75 years, by determining clearance of creatinine using the Cockcroft and last Metrics body weight.

In male patients: creatinine clearance (140 - age) × weight / 0,814 × serum creatinine, where the age is expressed in years, weight - in kg serum creatinine and - in micromoles / liter.

For patients, this formula must be adjusted by multiplying the result by 0.85.

If the serum creatinine is expressed in mg / ml, the resulting value must be multiplied by a factor of 8.8.

Use of NMG in therapeutic doses is contraindicated in patients diagnosed with severe renal failure (creatinine clearance of about 30 ml / min) (see. Section: "Contra ').

Suppression of aldosterone secretion.

Heparin can inhibit the secretion of aldosterone by the adrenal glands, especially in patients with diabetes mellitus, chronic renal failure, pre-existing metabolic acidosis, increased potassium level in blood plasma as well as in patients taking drugs potassium. The risk of hyperkalemia is increased with duration of therapy but is usually counterproductive. In patients with an increased risk of complications of potassium plasma levels must be measured prior to initiation of treatment with heparin and monitor on a regular basis in the future, especially if the treatment is elongated by more than 7 days.

Laboratory parameters.

Control the number of platelets. Heparin-induced thrombocytopenia (HIT).
There is a risk of serious, sometimes thrombogenic heparin-induced thrombocytopenia (which is also observed with unfractionated heparin and less likely - the application LMWH) immune origin - HIT type II (see section "Adverse Reactions.").

Because of the presence of such a risk must determine the number of platelets regardless of therapeutic indications and doses used.

Determining the number of platelets should be carried out before administration or no later than 24 hours after starting treatment, and then - 2 times a week during the treatment period.

If confirmed need long-term treatment in some special cases (e.g., knee surgery, with II and III trimester of pregnancy in women at risk (cm. "Applying during pregnancy and lactation") should be performed on platelet count analysis twice a week during the first month of treatment (high risk period) and 1 times per week until the cessation of treatment.

It is suspected occurrence HIT if the platelet count is less than 150,000 / mm 3, and / or if there is a decrease in platelet count by 30-50% compared with the previous blood analysis. HIT develops mainly from the 5th to the 21th day after the start of heparin treatment (most often occurs around the 10th day).

However, in patients with a history of heparin thrombocytopenia this can occur much earlier. Isolated cases were also observed after 21 days of treatment. Should be taken to identify patients with a history through a detailed survey before treatment.

In addition, the risk of recurrence with repeated use of heparin is observed for many years, and sometimes remains permanently (see. Section "Contraindications").

In all cases, the occurrence of HIT is an emergency that requires consultation with a specialist.

Any significant reduction in the number of platelets (by 30-50% compared with the initial figures) is a warning signal, even if the index has not reached the critical level. If there is a decrease in platelet count, that in all cases, the following measures should be taken:

1) immediate re-holding the platelet count number for confirmation;

2) discontinuing treatment with heparin, if the results confirmed a decrease in platelet count or indicate its increase if other obvious reason for this is not revealed.

To carry out the test for platelet aggregation and n vitro and immunological study of the blood sample must be placed in a test tube with a citrate solution. However, under such conditions, immediate action to be taken, not based on the results of tests on platelet aggregation and n vitro or immunological research, during which there are difficulties, because there are only a few specialized labs that can conduct such tests, and their results can be obtained in the best only a few hours. However, these studies are needed, as they can help diagnose these complications, because the risk of thrombosis with continued treatment with heparin is very high;

3) prevention or treatment of thromboembolic complications associated with HIT.

If continued anticoagulant therapy is important, heparin must be replaced by an antithrombotic agent, refers to chemical groups, for example, sodium or hirudin danaparid assigned therapeutic or prophylactic doses for each patient individually.

Daylight oral anticoagulants may be carried out only after the platelet count returned to normal, since there in the application of oral anticoagulants the risk of worsening of thrombosis.

Replacement of heparin to oral anticoagulants.
There should be more intense monitoring and clinical laboratory tests (prothrombin time, expressed in terms of international normalized ratio (MES) or control effects caused by oral anticoagulants.

Since there is a certain amount of time until the oral anticoagulant reaches the maximum of its actions should continue to heparin in a constant dose for as long as is necessary to MOE in the two series of performance analysis was necessary in the therapeutic range.

Monitoring of anti-factor Xa activity.
Most clinical studies have shown efficacy LMWH were conducted using doses calculated depending on the body weight of the patient and without special monitoring of laboratory parameters, however the utility of laboratory tests in order to evaluate the effectiveness of LMWH has not been determined. However, the monitoring of anti-factor Xa activity may be useful for reducing the risk of bleeding in certain clinical situations, which are often associated with the risk of overdose.

These situations relate primarily to the use of therapeutic indications and LMWH arise because the dose administered to patients with:

  • mild and moderate renal impairment (creatinine clearance - about 30-60 ml / min, calculated by Cockcroft). Because the LMWH appears mainly in the urine, in contrast to standard unfractionated heparin, in any case of renal failure can occur relatively overdose. Severe renal failure is a contraindication to the use of therapeutic doses of LMWH (see Section: "Contra.");
  • significant deviations from the normal body weight (body mass is very small, and even cachexia, obesity);
  • bleeding of unknown etiology.

In contrast, monitoring of laboratory parameters recommended when applying prophylactic doses of LMWH if used in accordance with treatment recommendations (particularly with respect to the duration of the treatment), or during hemodialysis.

To identify possible cumulation heparin upon repeated administration of the drug, it is recommended to carry out, if necessary at the time of blood sampling highest activity formulation (based on the available data), i.e. approximately 4:00 after the third injection, when the drug is administered by subcutaneous, etc. ' injections 2 times a day.

The question of holding repeated studies of anti-factor Xa activity to determine the levels of heparin in the blood, for example, every 2 or 3 days, to be solved individually, depending on the results of previous studies. It should also consider the possibility of adjusting the dose of LMWH.

Anti-factor Xa activity is observed, depending on the type of LMWH and dosing regimens.

According to the information, based on existing data, the mean value (± standard deviation) was observed after seven 4:00 Enoxaparin injections at a dose of 100 anti-factor Xa IU / kg per injection, twice a day, is 1, 2 ± 0, 17 anti-factor Xa IU / ml.

This average value was calculated in clinical trials, during which the study of anti-factor Xa chromogenic activity was conducted (amidolitichnim) method.

Monitoring activated partial thromboplastin time (APTT).
Some LMWHs cause a modest increase in the aPTT. Since the clinical value of this test is not established, there is no need to monitor the treatment from his account.

Spinal / epidural anesthesia in patients receiving prophylactic treatment with LMWH.

Like other anticoagulants LMWH when used during spinal / epidural anesthesia rarely may lead to the appearance of the spinal cord hematoma and prolonged or permanent paralysis.
The risk of spinal hematoma higher in the case with the epidural catheter relative to spinal anesthesia.

The risk of these rare events may increase with prolonged postoperative use of epidural catheters.

If the doctor decides on the appointment of anticoagulants on the background of epidural / spinal anesthesia, observe the extraordinary vigilance and monitored regularly to detect any signs and symptoms of neurological disorders such as pain in the midline of the back, impaired sensory and motor functions (numbness or the weakness of the lower limbs), bowel dysfunction and / or urinary bladder. Patients should be instructed on the need to tell your doctor about the event they have any of the above signs or symptoms. If the suspected signs or symptoms of spinal hematoma, you must start urgent diagnostic and therapeutic measures, including intervention for spinal decompression.

If preoperative treatment with LMWH is necessary (patients, long time bedridden, trauma), and if the benefits of local / regional spinal anesthesia has been carefully weighed, patients who have received prior LMWH injection operation can behave anesthesia, provided that between the injection of heparin and spinal anesthesia has been at least 12.00.
It recommended careful monitoring of the neurological status of the patient, bearing in mind the risk of bruising of the spinal cord.

Almost all patients with LMWH prophylaxis can begin 6-8 hours after anesthesia or removal of a catheter, with the control of neurological status.

It must be particularly careful with simultaneous treatment with other drugs that can affect hemostasis (in particular NSAIDs, acetyl salicylic acid).

Situations, which are accompanied by certain risks.

Supervision of the treatment must be increased in the following cases:

  • liver failure
  • peptic ulcer gastro-intestinal tract, or any other organic lesion with a probability of occurrence of bleeding
  • chorioretinal vascular diseases;
  • after surgery on the brain and / or spinal cord;
  • low back (lumbar) puncture because of the risk of spinal internal bleeding, if possible, of the puncture should be deferred;
  • while taking other drugs affecting hemostasis (cm. 'interaction with other drugs and other types of interactions "section).

Although all the concentrations of different molecular weight heparins are expressed in International Units (IU) of anti-factor Xa activity, their effectiveness is due not only to their anti-factor Xa activity. Replacement of one dosing regimen of LMWH on the other can be dangerous, because each mode has been tested in special clinical studies. Therefore, a great care and adherence to instructions for use of each preparation.

Reservations.

The risk of bleeding.

Recommended dosage regimens (dosage and duration of treatment) should be adhered to.

Non-compliance with these recommendations can lead to bleeding, especially in patients at high risk (elderly patients, patients with kidney failure).

Cases of serious bleeding were observed:

  • in elderly patients, including due to age-related impairment of renal function
  • in patients with renal insufficiency,
  • if the body weight is less than 40 kg;
  • if the therapy is performed longer than the recommended treatment period, which is 10 days
  • at non-fulfillment of therapeutic recommendations, in particular concerning the duration of treatment and the correction of therapeutic doses taking into account the body weight
  • while taking other medications (see "Interaction with other drugs and other interactions").

Injections of enoxaparin, like any other anticoagulant, should be used with caution in conditions characterized by an increased likelihood of bleeding, such as hemostasis disorders, history of ulcer disease, recent ischemic stroke, uncontrolled arterial hypertension, diabetic retinopathy, recent neurosurgical or ophthalmological surgery.

In any case, carefully monitor the condition of elderly patients and / or patients with renal insufficiency, and if treatment lasts more than 10 days.

An analysis of the definition of anti-factor Xa activity in some cases can be useful for detecting the cumulation of the drug (see Section "Features of application").

The risk of heparin-induced thrombocytopenia (HIT).

If the patient receives LMWH (in therapeutic or prophylactic doses), there will be thromboembolic complications:

  • deterioration of the course of thrombosis, the treatment of which is carried out;
  • phlebitis;
  • pulmonary embolism;
  • acute ischemia of lower extremities;
  • myocardial infarction or ischemic stroke,
  • always remember the likelihood of HIT and immediately determine the number of platelets (see section "Features of application").

Procedures for coronary artery revascularization.

To limit the risk of bleeding in patients undergoing angioplasty of the coronary arteries for the treatment of unstable angina, myocardial infarction without Q wave or acute myocardial infarction with ST-segment elevation, the recommended intervals between enoxaparin should be strictly adhered to. It is important to achieve hemostasis at the injection site after angioplasty of the coronary arteries. If special means of closing the vessel (hemostatic devices) are used, the conductor should be removed immediately. In the case of manual compression, the conductor must be removed at 6:00 after the last subcutaneous / in administration of enoxaparin. When continuing treatment with enoxaparin, the next injection should be performed no earlier than 6-8 hours after the removal of the conductor. It is necessary to monitor the site of puncture of the skin for any signs of bleeding or bruising.

The presence of mechanical heart valves made of artificial materials.

The use of enoxaparin for the prevention of thromboembolic complications in patients with mechanical artificial heart valves has not been specifically investigated.

However, in patients with prosthetic heart valves who received enoxaparin for the prevention of thromboembolic complications, in some cases thrombosis was observed.

Pregnant women.

In a clinical study involving pregnant women with mechanical heart valves who received enoxaparin at a dose of 100 anti-factor Xa IU / kg twice daily to reduce the risk of thromboembolic complications, two in eight women developed thrombosis that resulted in valve obstruction and death of mother and child. Also during the post-registration surveillance there were reports of single cases of thrombosis in pregnant women with prosthetic heart valves who received enoxaparin for the prevention of thromboembolic complications. Thus, the risk of thromboembolic complications in these patients may be higher.

Bleeding in elderly people.

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

Renal failure.

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

Low body weight.

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

Monitoring.

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

Lab tests.

In the doses used to prevent venous thromboembolism, sodium enoxaparin did not significantly affect either bleeding time or general blood coagulation assays, nor on platelet aggregation or fibrinogen binding to platelets. In high doses, an increase in APTT (activated partial thromboplastin time) and ABC (activated clotting time) may appear. The increase in APTT and ABC does not correlate linearly with the increased antithrombotic activity of sodium enoxaparin, and thus is not suitable and reliable for monitoring the activity of enoxaparin sodium.

Use during pregnancy and lactation

For doses of 2000, the anti-factor of Ha IU / 0.2 ml, equivalent to sodium enoxaparin 20 mg 4000 anti-factor Ha IU / 0.4 ml, equivalent to sodium enoxaparin 40 mg.

Pregnancy.

Preventive treatment in the first trimester.

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

Therefore, as a precautionary measure, enoxaparin should not be prescribed for preventive purposes to pregnant women in the first trimester.

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

Preventive treatment in the II and III trimesters.

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

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

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

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

The available clinical data are not sufficient to reveal the possible ability of enoxaparin to cause malformations or to exert fetotoxic effects when administered at therapeutic doses during pregnancy, because it is not recommended to apply therapeutic doses of enoxaparin during pregnancy as a preventive measure.

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

Breastfeeding.

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

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

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

Dosing and Administration

1 mg (0.01 ml) of sodium enoxaparin corresponds to approximately 100 units of anti-factor activity of Ha Me. Novoparin should be administered subcutaneously in case of preventive and curative use except for the following cases:

  • application of anticoagulation in the practice of hemodialysis;
  • treatment of patients with ST-segment elevation myocardial infarction who require intravenous bolus administration.

Novoparin is not allowed to be administered intramuscularly. The drug is recommended for use only by adult patients.

The technique of subcutaneous injection. The syringes filled by the manufacturer are ready for immediate use. If necessary, the dose can be adjusted depending on the patient's body weight. To do this, if necessary, before the injection from the syringe, you need to remove the excess amount of the drug. If there is no need to remove the excess amount of the drug, then to avoid the loss of the drug, air bubbles from the syringe should not be eliminated before the injection.

Subcutaneous injection of the drug is best performed when the patient is lying down. Introduce the drug into the subcutaneous fat tissue of the anterolateral or posterolateral surface of the abdominal wall, alternating the right and left sides, using different locations for each injection. Needles need to enter the entire length vertically into the thickness of the fold of the skin, and not at an angle to it, formed between the thumb and forefinger. Skin folding must be maintained throughout the injection. Do not rub the injection site after administration.

The technique of intravenous (bolus) injection / application of acute myocardial infarction with ST segment elevation.

Treatment begins with bolus injection, then immediately subcutaneous injection. To carry out an intravenous bolus from a manufacturer-filled graduated syringe with a preparation that contains 40 mg (0.4 ml 4000 anti-factor Ha MO), 60 mg (0.6 ml 6000 anti-factor Ha MO) or 80 mg (0 8 ml 8000 anti-factor Ha MO), it is necessary to remove the excess amount of the drug so that a dose of 30 mg (0.3 ml of 3000 anti-factor Ha MO) remains in the syringe.

This dose is introduced into the tube of the system for intravenous administration of solutions. Do not mix or inject the drug with other drugs. To remove the remnants of other drugs, and therefore to prevent their mixing with the drug before and after bolus injection, the system should be washed with a sufficient amount of 0.9% sodium chloride solution or 5% glucose solution. Novoparin can be safely administered in a 0.9% solution of sodium chloride or in a 5% solution of glucose.

In a hospital, the drug can be used for:

a dose of 1 mg / kg (100 anti-factor Xa IU / kg) for the first subcutaneous injection to be performed following the intravenous bolus injection, as well as further doses of 1 mg / kg (100 anti-factor Xa IU / kg) that must be administered subcutaneously every 12:00;
receiving a dose of 0.3 mg / kg (30 anti-factor Ha IU / kg) for bolus administration to patients undergoing further coronary angioplasty.
During the treatment period, the number of platelets should be monitored regularly, since there is a risk of heparin-induced thrombocytopenia (HIT).

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

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

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

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

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

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

Operations on the hip, knee joints.

The dose is 40 mg (0.4 ml 4000 anti-factor Ha) 1 time per day.

The dosage regimen, which was investigated, involves the administration of the first injection of 4000 anti-factor Xa IU (complete dose) for 12:00 before the operation or the first injection of 2000 anti-factor Xa IU (half dose) at 2:00 before surgery.

Other situations.

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

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

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

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

Prophylaxis of deep vein thrombosis in patients on bed rest due to acute therapeutic illnesses.

The recommended dose is 40 mg (0.4 ml 4000 anti-factor Ha Me) 1 time per day subcutaneously. Novoparin prescribe a minimum of 6 days, the duration of treatment - no more than 14 days. If the risk of venous thromboembolism is still present, prolonged prophylactic treatment with oral anticoagulants should be undertaken.

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

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

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

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

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

For hemodialysis patients at high risk of bleeding group (especially in dialysis in pre- and postoperative period), or with active bleeding, during the dialysis session can be applied dose of 50 anti-factor Xa IU / kg (double vascular access) or 75 anti-factor Xa IU / kg (one vascular access).

Treatment diagnosed deep vein thrombosis, which is accompanied or not accompanied by pulmonary embolism and does not have severe clinical symptoms.

Any suspicion on the occurrence of deep vein thrombosis should be confirmed by appropriate methods of investigation immediately.

Dosage.

Novoparin administered subcutaneously, intramuscularly, 2 times a day in a dose of 100 anti-factor Xa IU / kg every 12.00. In patients weighing more than 100 kg and less than 40 kgkorrektsiya LMWH dose not studied. NMG may be less effective in patients weighing more than 100 kg, and lead to an increased risk of bleeding in patients weighing less than 40 kg. Therefore, the clinical condition of these patients should be carefully monitored.

Duration of treatment of deep vein thrombosis.

In the treatment with low molecular weight heparin should be as soon as possible go to the use of oral anticoagulants, if there are no contraindications. LMWH treatment duration should not exceed 10 days, including the time required to reach equilibrium coagulants oral, except in those cases where it is difficult to reach an equilibrium state. Therefore, therapy with oral anticoagulants should be initiated as early as possible.

Treatment of unstable angina and myocardial infarction without tooth Q.

The recommended single dose of 1 mg / kg (100 anti-factor Xa IU / kg) subcutaneously every 12:00; simultaneously given acetylsalicylic acid orally (recommended dose: from 75 to 325 mg orally after an initial loading dose of 160 mg).

Duration of treatment - at least 2-8 days prior to the stabilization of the clinical status of the patient.

Treatment of acute myocardial infarction with ST-segment elevation in combination with thrombolytic agents in patients undergoing coronary angioplasty further, as well as in patients who have this procedure is not carried out.

Initial bolus injection preparation carried out in a dose of 30 mg (0.3 ml of 3000 anti-factor Xa IU). Then subcutaneously administered 1 mg / kg (100 anti-factor Xa IU / kg) for 15 minutes, then every 12 o'clock (the first two subcutaneous injections maximum total dose is 10,000 anti-factor Xa IU).

The first dose should be administered at any time within 15 minutes before or 30 minutes after the beginning of thrombolytic therapy.

Recommended treatment duration was 8 days or until the patient is not discharged from the hospital, if hospitalization lasts less than 8 days.

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

Patients undergoing coronary angioplasty:

  • if after the last subcutaneous injection into the balloon inflation was less than 8:00, the additional administration of drug is required;
  • if after the last subcutaneous injection into the balloon inflation has been more than 8:00, it is necessary to carry out an injection bolus of 0.3 mg / kg (30 anti-factor Xa IU / kg) of the drug. To ensure accurate volume administered by injection, it is recommended to dilute the formulation to 300 anti-factor Xa IU / ml (0.3 ml (3000 anti-factor Xa IU) diluted in 10 ml of solvent (0.9% sodium chloride or 5% glucose solution )) (see. table).

Volumes required for injecting when dilution is carried out in patients undergoing coronary angioplasty

Body weight, kg
The required dose of the anti-factor Xa IU
Volume required for injecting, at a dilution to 300 IU / ml (i.e. 0.3 ml (3000 anti-factor Xa IU) Novoparin preparation, diluted in 10 ml solvent)), mL
45
1350
4,5
50
1500
5
55
1650
5.5
60
1800
6th
65
1950
6.5
70
2100
7th
75
2250
7.5
80
2400
8
85
2550
8.5
90
2700
9
95
2850
9.5
100
3000
10

Patients aged 75 years, who were treated for acute myocardial infarction-segment elevation ST, the initial bolus injection is not carried out. Every 12:00 they should subcutaneously administered dose of 0.75 mg / kg (75 anti-factor Xa IU / kg) (only for the first two injections maximum total dose of 75 mg (7500 anti-factor Xa IU).

Children

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

Overdose

Accidental overdose by subcutaneous injection of large doses of low molecular weight heparin can lead to hemorrhagic complications.

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

  • protamine efficiency much lower than the efficiency registered overdose unfractionated heparin;
  • through side reactions (in particular anaphylactic shock) should carefully weigh the risk / benefit ratio for the protamine sulfate.

Neutralization of heparin carried out with slow administration of protamine (hydrochloride or sulfate).

The necessary dose depends protamine:

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

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

However, it is impossible to completely neutralize the anti-factor Xa activity. Furthermore, the neutralization may be temporary due to the absorption characteristics of low molecular weight heparin and as a result it may be necessary to distribute the total calculated dose of protamine into several injections (2-4) for administration within 24 hours.

After hitting a low molecular weight heparin in the stomach severe complications are unlikely, even with large quantities (such cases have been recorded) through a small stomach and intestinal drug absorption.

Adverse reactions

cases of significant bleeding complications have been reported, some of which were fatal. There were intracranial and retroperitoneal hemorrhage. cases of hemorrhagic complications (bleeding), such as hematoma, ecchymosis in the field and in the non-injection site hematoma, wound, hematuria, petechiae, ecchymosis at the injection site were also recorded, epistaxis and gastrointestinal bleeding.

Hemorrhagic manifestations, mainly related to:

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

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

These side reactions cause neurological changes of varying severity, including prolonged paralysis and constant (cm. "Applying Properties").

After subcutaneous administration, the formation of a hematoma at the injection site. cases of pain at the injection site have been reported, other reactions including irritation, swelling at the injection site, increased sensitivity, inflammation and the formation of nodules. This risk is increased if disturbed recommended injection technique or used improper means to carry it out. Inflammatory nodules at the injection site, which extend a few days may be due to inflammation. However, it does not require discontinuation of therapy.

Registered thrombocytosis and thrombocytopenia. There are two types of it:

  • Type I, which is the most common cases, typically moderate (platelet count greater than 100,000 / mm 3) appear in the early stages (before day 5), and do not require the cessation of treatment;
  • AI type, there are rare cases of severe immunoallergic thrombocytopenia - heparin-induced thrombocytopenia (HIT) with thrombosis; In some cases thrombosis was complicated myocardial organ or limb ischemia. Its prevalence little studied (see. "Features of the application" section).

Perhaps asymptomatic and reversible increases in platelet count.

Cases of skin necrosis at application of heparin. They may precede the appearance of purpura or infiltrated and painful erythematous patches. In such cases, you should discontinue therapy immediately.

There were manifestations of systemic allergic reactions (anaphylactic / anaphylactoid reaction) or skin reactions (urticaria, itching, erythema, bullous rashes), which in certain cases can lead to discontinuation of treatment.

As with unfractionated heparin, does not exclude the possibility of the development of osteoporosis in the extension of the treatment.

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

Transient increase in transaminases levels.

Several cases of hyperkalemia development.

There have been cases of vasculitis associated with sensitive skin.

Observed hypereosinophilia separately or simultaneously with the skin reactions that led to discontinuation of treatment.

Very rarely, there have been cases of hyperlipidemia and spontaneous splenic rupture.

Cases of bleeding disorders and anemia.

Shelf life

3 years. Do not use after the expiration date printed on the package

Storage conditions

Keep out of reach of children at a temperature not higher than 25 ° Savanoriu Str original packaging. Do not freeze.

Incompatibility

Do not mix with other drugs.

Packaging

Injection of 100 mg / ml to 20 mg / 0.2 ml; or 40 mg / 0.4 ml; or 60 mg / 0.6 ml; or 80 mg / 0.8 ml; or 100 mg / 1.0 mL prefilled syringes № 2 in the blister in a carton.

Category of leave

On prescription.


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