Flenox Neo, 10,000 anti-ha me/ml 0.8 ml 2 pcs

Pharmacotherapeutic group: Direct acting anticoagulant

ATC code: B01AB05

Pharmacodynamics:

Enoxaparin sodium is a low molecular weight heparin (HMG average molecular weight about 4500 daltons) which has unrelated antithrombotic and anticoagulant actions of standard heparin. It has high activity against factor Xa clotting (anti-Xa activity of about 100 IU/ml) and low activity against factor Pa clotting (for enoxaparin, the ratio of anti-Xa to antithrombin activity is 36). This anticoagulant activity acts through antithrombin III (AT-III) providing anticoagulant activity in humans.

In addition to anti-Xa/IIa activity, additional anticoagulant and anti-inflammatory properties of enoxaparin sodium have also been identified both in healthy humans and patients and in animal models. These include AT-1 II dependent inhibition of other clotting factors like factor Vila activation of tissue factor pathway inhibitor (TFP) release as well as reduction of Willebrand factor release from the vascular endothelium into the bloodstream. These factors provide the anticoagulant effect of enoxaparin sodium in general.

When used in prophylactic doses enoxaparin slightly changes the activated partial thromboplastin time (APTT). At therapeutic doses, ACTV can be prolonged 15 to 22 times the control time at the peak of activity. This prolongation reflects residual antithrombin activity.

The anti-IIa activity in plasma is about 10 times lower than the anti-Xa activity. Mean maximum anti-IIa activity is observed approximately 3-4 h after subcutaneous administration and reaches 013 IU/ml and 019 IU/ml after repeated administration of 1 mg/kg body weight when administered twice and 15 mg/kg body weight when administered once, respectively.

The mean maximum anti-Xa activity in plasma is observed 3-5 h after subcutaneous administration of the drug and is approximately 02; 04; 10 and 13 anti-Xa IU/ml after subcutaneous administration of 20 40 mg and 1 mg/kg and 15 mg/kg, respectively.

Pharmacokinetics:

The pharmacokinetic parameters of the drug are assessed by changes in anti-Xa and anti-IIa activity in plasma over time in the recommended dose ranges.

Bioavailability.

In subcutaneous administration, enoxaparin is absorbed rapidly and almost completely (almost 100%). Maximum plasma activity is observed between 3 and 4 hours after administration.

A bolus intravenous injection of 30 mg (03 ml; 3000 anti-Xa ME) with further subcutaneous injections of 1 mg/kg (100 anti-Xa ME/kg) every 12 hours results in the first maximal level of antifactor Xa concentration of 116 IU/ml and an average area under the pharmacokinetic curve of 88% of the equilibrium level. The equilibrium state is reached on the second day of treatment.

In the recommended dose range, enoxaparin pharmacokinetics are linear. Differences in values between and among patients are quite small. After repeated subcutaneous administration in healthy volunteers of 40 mg (04 ml; 4000 anti-Xa ME) once daily, equilibrium was reached on day 2, with average enoxaparin activity nearly 15% higher than that observed with a single injection. Stable levels of enoxaparin activity were fairly predictable with single doses. After repeated subcutaneous administration of 1 mg/kg (100 anti-Xa IU/kg) twice daily, equilibrium was reached between day 3 and 4 with a mean AUC 65% higher than that of a single injection and maximal and minimal anti-Xa activity of 12 and 052 anti-Xa IU/ml respectively. Relative to the pharmacokinetic parameters of enoxaparin sodium, this difference in reaching the equilibrium state can also be expected for the therapeutic dose range.

Distribution.

The distribution volume of enoxaparin sodium by anti-Xa activity is approximately 5 L and nearly matches the circulating blood volume.

Metabolism.

The metabolism of enoxaparin occurs primarily in the liver by desulfatization and depolymerization to form low molecular weight substances with very low biological activity

Excretion.

After subcutaneous injection, the elimination half-life for anti-Xa activity is longest for low-molecular-weight heparins compared to that of unfractionated heparins. Enoxaparin elimination is monophasic, with a half-life of about 4 hours after a single subcutaneous injection and almost 7 hours when repeated doses are administered. Low molecular weight heparins are characterized by a faster decline of anti-IIa activity in plasma compared to anti-Xa activity.

Enoxaparin and its metabolites are excreted with urine and bile. Renal clearance of substances with anti-Xa activity is 10% of the administered dose and total renal excretion of active and inactive metabolites is 40% of the dose.

Higher risk groups:

– Elderly patients

Because there is a physiologic decline in renal function in this age group, elimination is slower. This does not affect the dosing or administration regimen for prophylactic treatment.

In patients over 75 years of age, it is very important to systematically monitor renal function with the Cockcroft formula before starting treatment with LMWH drugs.

Patients with mild to moderate renal impairment (creatinine clearance > 30 mL/min)

In individual cases it may be useful to monitor anti-Kha activity to rule out the possibility of overdose if enoxaparin is used in therapeutic doses. Decreased clearance of enoxaparin sodium has been noted in renal failure. After repeated subcutaneous administration of 40 mg of Enoxaparin sodium once daily there is an increase of anti-Xa activity represented by the area under pharmacokinetic curve in mild (creatinine clearance (CK) 50-80 ml/min) and moderate (CK 30-50 ml/min) renal insufficiency. In patients with severe renal insufficiency (CKR less than 30 ml/min) the area under pharmacokinetic curve at equilibrium is, on average, 65% higher with repeated subcutaneous administration of 40 mg of the drug once daily.

– Overweight patients

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 mass less than 45 kg and 27% higher in men with a body mass less than 57 kg compared to patients of normal average body mass.

Indications

– Prevention of venous thrombosis and embolism in surgical interventions, especially in orthopedic and general surgical procedures.

Prevention of venous thrombosis and embolism in bed-ridden patients due to acute therapeutic diseases including acute heart failure and decompensation of chronic heart failure (class III or IV NYHA) acute respiratory failure as well as in severe acute infections and acute rheumatic diseases in combination with one of the risk factors of venous thrombosis (see “Special Indications. “Special Indications”).

– Treatment of deep vein thrombosis with or without pulmonary embolism.

– Prevention of thrombosis in the extracorporeal circulation system during hemodialysis (usually when the session is no longer than 4 hours).

– Treatment of unstable angina and myocardial infarction without Q-wave in combination with acetylsalicylic acid.

Treatment of acute ST-segment elevation myocardial infarction in patients undergoing drug treatment or subsequent percutaneous coronary intervention.

Active ingredient

Composition

How to take, the dosage

Except in special cases (see subsections “Treatment of ST-segment elevation myocardial infarction by medication or percutaneous coronary intervention” and “Prevention of thrombosis in extracorporeal circulation during hemodialysis” below), enoxaparin sodium is injected deep subcutaneously. Injections should preferably be performed in the “supine” position of the patient. When using pre-filled 20 mg and 40 mg syringes, air bubbles should not be removed from the syringe before injection to avoid loss of product. Injections should be given alternately on the left or right anterolateral or posterolateral surface of the abdomen.

The needle must be inserted full length vertically (not laterally) into the skin fold gathered and held between the thumb and forefinger until the injection is complete. The skin fold is not released until the injection is complete.

The injection site should not be massaged after the injection.

The pre-filled disposable syringe is ready for use.

The product must not be injected intramuscularly!

Prevention of venous thrombosis and embolism in surgical procedures, especially orthopedic and general surgical procedures.

In patients at moderate risk of thrombosis and embolism (e.g., abdominal surgeries), the recommended dose of Flenox® NEO is 20 mg once daily subcutaneously. The first injection should be given 2 hours before surgery.

.

Patients at high risk of thrombosis and embolism (e.g., orthopedic, oncology, surgery, patients with additional non-surgical risk factors such as congenital or acquired thrombophilia, malignant neoplasm treatment (treatment mode more than three days obesity venous thrombosis in anamnesis varicose veins of lower limbs pregnancy) the preparation is recommended in a dose of 40 mg once a day subcutaneously with the first dose administered 12 hours before the surgical intervention or in a dose of 30 mg twice a day with the first dose administered 12-24 hours after surgery.

The duration of treatment with Flenox® NEO is 7-10 days on average. If necessary, therapy may be continued as long as the risk of thrombosis and embolism persists and as long as the patient remains ambulatory.

In orthopedic surgeries, it may be appropriate to continue treatment after initial therapy with Flenox® NEO at a dose of 40 mg once daily for 3 weeks.

The specifics of Flenox® NEO administration during spinal/epidural anesthesia as well as during coronary revascularization procedures are described in section “Cautionary Note”.

Prevention of venous thrombosis and embolism in bed-ridden patients with acute medical conditions

The recommended dose of Flenox® NEO is 40 mg once daily subcutaneously for at least 6 days. The therapy should be continued until the patient is fully transitioned to outpatient treatment (for a maximum of 14 days).

The treatment of deep vein thrombosis with or without pulmonary embolism

The drug is administered subcutaneously at a rate of 15 mg/kg body weight once daily or 1 mg/kg body weight twice daily. In patients with complicated thromboembolic disorders the drug is recommended at a dose of 1 mg/kg body weight twice daily.

The duration of treatment is on average 10 days. Therapy with indirect anticoagulants should be started immediately and treatment with Flenox® NEO should be continued until therapeutic anticoagulant effect has been achieved (INR value [International Normalized Ratio] should be 20-30).

Prevention of thrombosis in the extracorporeal circulation system during hemodialysis

The recommended dose of Flenox® NEO averages 1 mg/kg body weight. If there is a high risk of bleeding, the dose should be reduced to 05 mg/kg body weight for dual vascular access or 075 mg/kg body weight for single vascular access.

In hemodialysis, Flenox® NEO should be administered to the arterial shunt site at the beginning of the hemodialysis session. One dose is usually sufficient for a four-hour session; however, if fibrin rings are detected during longer hemodialysis, an additional dose at a rate of 05-1 mg/kg body weight may be administered.

The treatment of unstable angina and myocardial infarction without Q-wave

Flenox® NEO is given at a rate of 1 mg/kg body weight every 12 hours subcutaneously while concomitant administration of 100-325 mg of acetylsalicylic acid once daily.

The average duration of therapy is at least 2 days and continues until the patient’s clinical condition stabilizes. Usually the drug lasts from 2 to 8 days.

The treatment of acute ST-segment elevation myocardial infarction is medication-assisted or by percutaneous coronary intervention

The treatment begins with a single intravenous bolus injection of enoxaparin sodium at a dose of 30 mg. Immediately thereafter, enoxaparin sodium is administered subcutaneously at a dose of 1 mg/kg of body weight. Subsequently the drug is given by subcutaneous injection of 1 mg/kg of body weight every 12 hours (maximum 100 mg of enoxaparin sodium for each of the first two subcutaneous injections, then 1 mg/kg of body weight for the remaining subcutaneous doses, i.e. single dose may exceed 100 mg if body weight exceeds 100 kg).

In patients 75 years of age and older, the initial intravenous bolus injection is not used. The drug is administered subcutaneously at a dose of 075 mg/kg of body weight every 12 hours (maximum of 75 mg of enoxaparin sodium for each of the first two subcutaneous injections then 075 mg/kg of body weight for the remaining subcutaneous doses i.e. if body weight over 100 kg the single dose may exceed 75 mg).

When combined with thrombolytics (fibrin-specific and fibrin-nonspecific), enoxaparin sodium should be administered between 15 minutes before thrombolytic therapy and up to 30 minutes after it. As soon as possible after detection of acute ST-segment elevation myocardial infarction, patients should be simultaneously prescribed acetylsalicylic acid and if there are no contraindications, the administration of acetylsalicylic acid (in doses of 75-325 mg) should be continued daily for at least 30 days.

The recommended duration of treatment with Flenox® NEO is 8 days or until discharge from hospital (if less than 8 days).

The intravenous bolus injection of sodium enoxaparin should be given via a venous catheter. 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 infusion system and their interaction with sodium enoxaparin, the venous catheter should be flushed with sufficient amounts of 09% sodium chloride solution or 5% dextrose solution before and after intravenous bolus injection of sodium enoxaparin. Enoxaparin sodium can be administered safely with 09% 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 60 mg, 80 mg, and 100 mg glass syringes are discarded so that only 30 mg (03 ml) remains. The 30 mg dose can be directly administered intravenously.

Pre-filled 60 mg, 80 mg and 100 mg hypodermic syringes may be used for intravenous bolus injection of enoxaparin sodium via a venous catheter. The 60 mg syringe is recommended because it reduces the amount of product removed from the syringe. The 20 mg syringe is not used because it does not contain enough preparation for a 30 mg bolus of Enoxaparin sodium. The 40 mg syringe is not used because it has no graduations and therefore cannot be used to accurately measure the 30 mg.

In patients undergoing percutaneous coronary intervention, if the last subcutaneous injection of sodium enoxaparin was given less than 8 hours before the balloon catheter inserted into the coronary artery constriction is inflated, no additional injection of sodium enoxaparin 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 03 mg/kg should be given. To improve the accuracy of additional intravenous bolus injection of small volumes into the venous catheter during percutaneous coronary interventions, it is recommended to dilute the drug to a concentration of 3 mg/ml. Dilution of the solution is recommended immediately prior to administration. To obtain enoxaparin sodium solution with a concentration of 3 mg/ml using a pre-filled syringe 60 mg, it is recommended to use a container with 50 ml infusion solution (i.e. with 09% sodium chloride solution or 5% dextrose solution). From the container with the infusion solution using a normal syringe extract and remove 30 ml of the solution. Enoxaparin sodium (60 mg hypodermic syringe) is injected into the remaining 20 ml of the infusion solution in the container.

The contents of the container with the diluted sodium enoxaparin solution are stirred gently. A syringe is used to extract the desired volume of the diluted enoxaparin sodium solution, which is calculated using the formula:

Volume of diluted solution = Patient body weight (kg) x 01 or using the table below.

The volumes to be administered intravenously after dilution.

Patient body weight[kg]

The required dose (03 mg/kg) [mg]

Volume of solution diluted to a concentration of 3 mg/ml required to administer

The dose required/p>

45

135

45

50

15

5

55

165

18

6

65

7

75

225

75

80

85

255

85

30

Dosing regimen in special patient groups

Patients in the elderly

Except for treatment of ST-segment elevation myocardial infarction (see above) for all other indications, dosage reduction of enoxaparin sodium is not required in elderly patients if they do not have renal impairment.

Patients with impaired renal function

Severe renal impairment (creatinine clearance less than 30 mL/min)

The dose of sodium enoxaparin is reduced according to the tables below because these patients have increased systemic exposure (duration of action) to the drug.

The following dosing adjustments are recommended when using the drug for therapeutic purposes:

The normal dosing regimen

The dosing regimen for severe renal impairment

1 mg/kg body weight subcutaneously 2 times daily

1 mg/kg body weight subcutaneously 1 time per day

15 mg/kg body weight subcutaneously once daily

1 mg/kg body weight subcutaneously once daily

Treatment of acute ST-segment elevation myocardial infarction in patients younger than 75 years

Once: 30 mg bolus intravenous plus 1 mg/kg body weight subcutaneously; followed by a subcutaneous dose of 1 mg/kg body weight twice daily (maximum 100 mg for each of the first two subcutaneous injections)

Once: A bolus intravenous injection of 30 mg plus 1 mg/kg body weight subcutaneously; followed by a subcutaneous injection of 1 mg/kg body weight once daily (maximum 100 mg for the first subcutaneous injection only)

/p>

Treatment of acute ST-segment elevation myocardial infarction in patients 75 years and older

075 mg/kg body weight subcutaneously twice daily without initial intravenous bolus injection (maximum 75 mg for each of the first two subcutaneous injections)

1 mg/kg body weight subcutaneously once daily without initial intravenous bolus injection (maximum 100 mg for the first subcutaneous injection only)

When using the drug for prophylactic purposes, dosing adjustments shown in the table below are recommended.

The usual dosing regimen

Dosing regimen for severe renal failure

40 mg subcutaneously once daily

20 mg subcutaneously once daily

20 mg subcutaneously once daily

20 mg subcutaneously once daily

The recommended dosing regimen adjustment is not applicable in hemodialysis.

Mild (creatinine clearance 50-80 ml/min) and moderate (creatinine clearance 30-50 ml/min) impaired renal function

Dose adjustment is not required but patients should be under close medical supervision.

Patients with hepatic impairment

In the absence of clinical studies, Flenox® NEO should be used with caution in patients with hepatic impairment.

Interaction

Do not mix Flenox® NEO with other medications in the same syringe.

Concomitant use with drugs which affect hemostasis (systemic salicylates acetylsalicylic acid non-steroidal anti-inflammatory drugs (including ketorolac) 40 kDa dextran ticlopidine and clopidogrel systemic glucocorticosteroid thrombolytics or anticoagulants other antiplatelet agents (including glycoprotein IIb/IIIa antagonists).

Special Instructions

General

Low molecular weight heparins are not interchangeable, since they differ in production process, molecular weight, specific anti-Xa activity, dosing units and dosing regimen, which are associated with differences in their pharmacokinetics and biological activity (antithrombin activity and interaction with platelets). Therefore, it is necessary to strictly follow the recommendations for the use of each drug belonging to the class of low molecular weight heparins.

Bleeding

As with other anticoagulants when administering Flenox® NEO bleeding of any localization is possible (see section “Side effects”). If bleeding develops, it is necessary to find its source and prescribe an appropriate treatment.

Bleeding in elderly patients

When Flenox® NEO is used in prophylactic doses in elderly patients, there is no increased risk of bleeding.

There is an increased risk of bleeding when using the drug in therapeutic doses in elderly patients (especially those aged 80 years and older). Close monitoring of these patients is recommended (see section “Pharmacokinetics” and section “Administration and doses”, subsection “Elderly patients”).

The concomitant use of other drugs that affect hemostasis

The use of drugs that affect hemostasis (salicylates including acetylsalicylic acid non-steroidal anti-inflammatory drugs including ketorolac is recommended; dextran with a molecular weight of 40 kDa ticlopidine clopidogrel; glucocorticosteroid drugs thrombolytics anticoagulants antiaggregants. including glycoprotein IIb/IIIa receptor antagonists) have been discontinued prior to treatment with enoxaparin sodium unless their use is necessary. If combinations of sodium enoxaparin with these drugs are indicated, close clinical observation and monitoring of relevant laboratory parameters should be performed.

Renal failure

In patients with impaired renal function, there is a risk of bleeding due to increased systemic exposure to enoxaparin sodium.

In patients with severe renal impairment (creatinine clearance less than 30 ml/min) there is a significant increase of sodium enoxaparin exposure, therefore it is recommended that dosage adjustment is performed both during prophylactic and therapeutic use of the drug. Although it is not required to perform dose adjustment in patients with mild to moderate renal dysfunction (creatinine clearance 30-50 ml/min or 50-80 ml/min) it is recommended to perform close monitoring of these patients (see sections “Pharmacokinetics” and “Dosage and administration” subsection “Patients with renal insufficiency”).

Low body weight

There has been increased exposure to enoxaparin sodium when used prophylactically in women with a body weight less than 45 kg and in men with a body weight less than 57 kg, which may lead to an increased risk of bleeding. Close monitoring of such patients is recommended.

Patients with obesity

Patients with obesity have an increased risk of thrombosis and embolism. The safety and efficacy of enoxaparin sodium at prophylactic doses in obese patients (BMI greater than 30 kg/m2) is not fully defined and there is no general consensus on dose adjustment. These patients should be closely monitored for signs and symptoms of thrombosis and embolism.

Peripheral blood platelet count monitoring

The risk of antibody-mediated heparin-induced thrombocytopenia also exists with low molecular weight heparins. If thrombocytopenia develops, it is usually detected between day 5 and 21 after the start of therapy with enoxaparin sodium. Therefore, it is recommended to monitor the peripheral blood platelet count before and during treatment with Flenox® NEO at regular intervals.

If a significant decrease in platelet count is confirmed (30-50% compared to baseline), enoxaparin sodium should be stopped immediately and the patient transferred to another therapy.

Spinal/epidural anesthesia

There have been reports of neuroaxial hematomas when Flenox® NEO is used concomitantly with spinal/epidural anesthesia with development of long-standing or irreversible paralysis. The risk of these phenomena is reduced when using the drug at a dose of 40 mg or less. The risk increases when using higher doses of Flinox® NEO and when using indwelling catheters after surgery or when concomitant use of additional drugs affecting hemostasis such as nonsteroidal anti-inflammatory drugs (see section “Interaction with other medicinal products”). Risk also increases with traumatic or repeated spinal tap or in patients with a history of spinal surgery or spinal deformity.

In order to reduce the possible risk of bleeding associated with the use of enoxaparin sodium and epidural or spinal anesthesia/analgesia, the pharmacokinetic profile of the drug should be considered (see section “Pharmacokinetics”). Catheter placement or removal is best performed when the anticoagulant effect of enoxaparin sodium is low; however, the exact time to achieve sufficient reduction of anticoagulant effect in different patients is unknown.

The insertion or removal of a catheter should be performed at least 12 h after administration of lower doses of Flenox® NEO (20 mg once daily. 30 mg once or twice daily 40 mg once daily) and at least 24 h after administration of higher doses of Flenox® NEO (0.75 mg/kg body weight 2 times daily 1 mg/kg body weight 2 times daily 15 mg/kg body weight once daily). At these time points, anti-Xa activity of the drug is still detectable and time delays are no guarantee that neuroaxial hematoma development will be avoided. Patients receiving enoxaparin sodium at doses of 075 mg/kg body weight twice daily or 1 mg/kg body weight twice daily on this (twice daily) dosing regimen should not be given a second dose to extend the interval before catheter placement or replacement. Similarly, consideration should be given to delaying the administration of the next dose by at least 4 h based on a benefit/risk assessment (risk of thrombosis and bleeding during the procedure, taking into account patients’ risk factors). However, it is not possible to give a clear recommendation on the timing of the next dose of sodium enoxaparin after catheter removal. Note that in patients with a creatinine clearance of less than 30 ml/min, excretion of sodium enoxaparin slows down. Therefore, in this category of patients, consideration should be given to doubling the time from catheter removal: at least 24 h for lower doses of sodium enoxaparin (30 mg once daily) and at least 48 h for higher doses (1 mg/kg body weight daily).

If anticoagulant therapy is prescribed by a physician during epidural/spinal anesthesia or lumbar puncture, the patient should be monitored continuously for any neurologic symptoms such as back pain sensory and motor function impairment (numbness or weakness in the lower extremities) bowel and/or bladder function impairment. The patient should be instructed to inform the physician immediately if the above symptoms occur. Urgent diagnosis and treatment, including decompression of the spinal cord if symptoms characteristic of a spinal hematoma are suspected.

Heparin-induced thrombocytopenia

Flenox® NEO should be used with particular caution in patients with a history of heparin-induced thrombocytopenia with or without thrombosis.

The risk of heparin-induced thrombocytopenia may persist for several years. If a history of heparin-induced thrombocytopenia is suspected, in vitro platelet aggregation tests are of limited value in predicting risk. The decision to use Flenox® NEO in this case should only be made after consultation with an appropriate specialist.

Prescapular coronary angioplasty

. In order to minimize the risk of bleeding associated with invasive vascular instrumentation in the treatment of unstable angina and myocardial infarction without Q wave and acute ST-segment elevation myocardial infarction, these procedures should be performed in intervals between Flenox® NEO injections. This is necessary to achieve hemostasis after percutaneous coronary intervention. If a femoral artery intraductor is used, the femoral artery intraductor can be removed immediately. If manual compression is used, the femoral artery intromedullary tube should be removed 6 h after the last intravenous or subcutaneous injection of sodium enoxaparin. If treatment with sodium enoxaparin is continued, the next dose should not be administered before 6-8 hours after removal of the femoral artery intraductor. It is necessary to monitor the place of insertion of the introducer in order to detect timely signs of bleeding and hematoma formation.

Patients with mechanical heart valves

The use of Flenox® NEO for prophylaxis of thrombosis in patients with mechanical heart valves has not been well studied. There are isolated reports of heart valve thrombosis in patients with mechanical heart valves on therapy with enoxaparin sodium for prophylaxis of thrombosis. The evaluation of these reports is limited because of aggravating factors contributing to the development of artificial heart valve thrombosis, including underlying disease, and because of insufficient clinical data.

Pregnant women with mechanical artificial heart valves

The use of Flenox® NEO for the prevention of thrombosis in pregnant women with mechanical artificial heart valves has not been well studied. In a clinical study of pregnant women with mechanical heart valves, when enoxaparin sodium was administered at a dose of 1 mg/kg body weight twice daily to reduce the risk of thrombosis and embolism, 2 of 8 women developed thromboses which resulted in heart valve block and death to mother and fetus.

There have been anecdotal post-marketing reports of heart valve thrombosis in pregnant women with mechanical artificial heart valves treated with enoxaparin to prevent thrombosis.

Pregnant women with mechanical artificial heart valves have a high risk of thrombosis and embolism.

Laboratory tests

In doses used for thromboembolic prevention, Flenox® NEO has no significant effect on bleeding time and clotting parameters or on platelet aggregation or binding to fibrinogen.

Additional doses may lengthen the ACTV and activated clotting time. Increase of ACTV and activated clotting time are not in direct linear relation to increase of anticoagulant activity of the drug, so there is no need to monitor them.

The prophylaxis of venous thrombosis and embolism in patients with acute therapeutic conditions on an infusion regimen

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

– age greater than 75 years;

– malignant neoplasms;

– history of thrombosis and embolism;

– obesity;

– hormone therapy;

– heart failure;

– chronic respiratory failure.

Children

The safety and effectiveness of enoxaparin sodium in children under the age of 18 years has not been established.

Enoxaparin sodium has no effect on the ability to operate vehicles and machinery.

Contraindications

– Hypersensitivity to enoxaparin sodium heparin or its derivatives including other low molecular weight heparins.

– Active major bleeding as well as conditions and diseases with a high risk of bleeding: Threatened abortion cerebral vascular aneurysm or dissecting aortic aneurysm (unless surgical intervention is performed for this purpose) recent hemorrhagic stroke uncontrolled bleeding thrombocytopenia in combination with a positive in vitro test for antiplatelet antibodies in the presence of enoxaparin sodium.

– Children under 18 years of age because efficacy and safety have not been established in this patient population (see section “Special Precautions”).

Conditions with potential risk of bleeding:

– hemostasis disorders (including hemophilia thrombocytopenia hypocoagulation Willebrand’s disease, etc.

– history of gastric or duodenal ulcers or other erosive-ulcerative lesions of the gastrointestinal tract;

– recent ischemic stroke;

– uncontrolled severe arterial hypertension;

– diabetic or hemorrhagic retinopathy;

– severe diabetes mellitus;

– recent or suspected neurologic or ophthalmologic surgery;

– spinal or epidural anesthesia (potential risk of hematoma) spinal tap (recent);

– recent childbirth;

– bacterial endocarditis (acute or subacute);

– pericarditis or pericardial effusion;

– renal and/or hepatic insufficiency;

– intrauterine contraception (IUI);

– severe trauma (especially central nervous system) open wounds on large surfaces;

– concomitant administration of drugs affecting the hemostatic system;

– heparin-induced thrombocytopenia (history) in combination with or without thrombosis.

There are no data on the clinical use of the drug in the following diseases: active tuberculosis radiation therapy (recent).

Side effects

Side effects were classified according to frequency as follows: very frequent (≥ 1/10) frequent (≥ 1/100 – < 1/10) infrequent (≥ 1/1000 – < 1/100) rare (≥ 1/10000 – < 1/1000) very rare (< 1/10000).

Bleeding

Bleeding may occur especially in the presence of concomitant risk factors: organic changes with propensity for bleeding age renal insufficiency low body weight and some combinations of drugs (see section “Interaction with other medicinal products”). If bleeding develops, the drug administration should be stopped to determine the cause of bleeding and initiate an appropriate therapy.

Bleeding during prophylaxis of venous thrombosis in surgical patients and treatment of deep vein thrombosis with or without thromboembolism is very common.

Frequent – Bleeding in prophylaxis of venous thrombosis in bed rest and treatment of unstable angina of myocardial infarction without Q wave and myocardial infarction with ST-segment elevation.

Infrequent – retroperitoneal bleeding and intracranial bleeding in patients treated for deep vein thrombosis with or without thromboembolism and ST-segment elevation myocardial infarction.

Rarely, retroperitoneal bleeding in the prevention of venous thrombosis in surgical patients and in the treatment of angina of myocardial infarction without Q-wave.

Thrombocytopenia and thrombocytosis

Very common – thrombocytosis (peripheral blood platelet count greater than 400×109/L) in the prevention of venous thrombosis in surgical patients and the treatment of deep vein thrombosis with or without pulmonary embolism.

Frequent – thrombocytopenia in the treatment of patients with acute myocardial infarction with ST-segment elevation. Thrombocytopenia in prevention of venous thrombosis in surgical patients and treatment of deep vein thrombosis with or without pulmonary embolism and in acute ST-segment elevation myocardial infarction.

Infrequent – thrombocytopenia in prophylaxis of venous thrombosis in bed-ridden patients and in treatment of unstable angina of myocardial infarction without Q-wave.

Very rare – immune-allergic thrombocytopenia in the treatment of patients with acute ST-segment elevation myocardial infarction.

Immune system disorders

Frequent – allergic reactions.

Rare – anaphylactic and anaphylactoid reactions.

Hepatic and biliary tract disorders

Very frequent – increased activity of “hepatic” transaminases more than three times the upper limit of normal.

Skin and subcutaneous tissue disorders

Frequent – urticaria skin itching erythema.

Infrequent – bullous dermatitis.

General disorders and disorders at the injection site

Frequent – bruising at the injection site pain at the injection site swelling at the injection site bleeding hypersensitivity reactions inflammation formation of lumps at the injection site.

Infrequent – irritation at the injection site skin necrosis at the injection site.

Laboratory and instrumental data

Rare – hyperkalemia.

Post-registration data

The frequency of adverse reactions in the reports received was rated as “frequency unknown”.

Immune system disorders

Anaphylactic/anaphylactoid reactions including shock.

Nervous system disorders

Headache.

Vascular disorders

In cases of spinal hematoma (or neuroaxial hematoma) have been reported when using enoxaparin sodium against a background of spinal/epidural anesthesia or spinal tap. These reactions have led to the development of neurological disorders of varying severity, including persistent or irreversible paralysis (see section “Special Precautions”).

Disorders of the blood or lymphatic system

Hemorrhagic anemia.

In cases of development of immune-allergic thrombocytopenia with thrombosis; in some cases thrombosis has been complicated by the development of organ infarction or limb ischemia (see section “Special Precautions”).

Eosinophilia.

Skin and subcutaneous tissue disorders

Skin vasculitis necrosis may develop at the injection site and is usually preceded by purpura or erythematous papules (infiltrated and painful). In these cases, therapy with Flenox® NEO should be discontinued. Solid inflammatory nodules-infiltrates may form at the injection site of the drug which disappear after a few days and are not a reason for discontinuation of the drug.

Alopecia.

Hepatic and biliary tract disorders

Hepatocellular liver disease.

Cholestatic liver damage.

Skeletal, muscular and connective tissue disorders

Osteoporosis in long-term therapy (more than three months).

Overdose

Symptoms: hemorrhagic complications of accidental overdose after subcutaneous administration of significant doses of low molecular weight heparin. The occurrence of adverse effects after accidental ingestion of low molecular weight heparin, even in large quantities, is unlikely (no cases have been observed) because the degree of absorption of this substance in the stomach and intestine is insignificant.

Treatment: the effect of enoxaparin is neutralized by slow intravenous administration of protamine sulfate, but note that:

– the efficacy of protamine sulfate is much lower than that observed in an overdose of unfractionated heparin; before using protamine sulfate because of the possibility of adverse events (particularly anaphylactic shock), the benefit/risk ratio should be carefully weighed.

The required doses of protamine depend on:

1. The dose of low molecular weight heparin administered (100 anti-heparin units of protamine will neutralize 100 anti-Xa ME of low molecular weight heparin) if enoxaparin sodium has been administered within the last 8 hours;

2. The time elapsed since the injection of the low molecular weight heparin:

– An infusion of 50 anti-heparin units of protamine per 100 anti-Ha ME of enoxaparin sodium may be given if enoxaparin sodium was injected more than 8 hours ago or if a second dose of protamine must be given;

– If enoxaparin was injected more than 12 hours ago, no protamine injection is necessary. The above recommendations are for patients with normal renal function who are using repeat doses of the drug.

However, it is not possible to completely neutralize the anti-Xa activity of enoxaparin. This neutralization, due to the nature of absorption of low molecular weight heparin, may be temporary and requires distribution of the total calculated dose of protamine into several injections (2 to 4) that are administered over a 24-hour period.

Pregnancy use

Pregnancy

There is no evidence that enoxaparin sodium crosses the placental barrier in humans during the second trimester of pregnancy. There is no relevant information regarding the first and third trimesters of pregnancy. Because there are no adequate and well-controlled studies in pregnant women, and animal studies do not always predict the response to enoxaparin sodium administration in humans during pregnancy, it should be used during pregnancy only when there is an urgent need for its use as determined by a physician.

Breastfeeding

It is not known whether unchanged enoxaparin sodium is excreted into human breast milk. Absorption of enoxaparin sodium into the gastrointestinal tract in the infant is unlikely. However, as a precautionary measure, lactating women treated with Flenox® NEO should be advised to interrupt breastfeeding.

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