Flenox NEO - instructions for use, dose, side effects, contraindications

One syringe (0.2 ml) contains, as active ingredient enoxaparin sodium 2000 anti-Xa ME (equivalent to 20 mg / 0.2 ml); Excipients: water for injection - up to 0.2 ml.

One syringe (0.4 ml) contains as active ingredient enoxaparin sodium 4000 anti-Xa ME (equivalent to 40 mg / 0.4 mL); Excipients: water for injection - up to 0.4 ml.

One syringe (0.6 ml) contains as active ingredient enoxaparin sodium 6000 anti-Xa ME (equivalent to 60 mg / 0.6 ml); Excipients: water for injection - up to 0.6 ml.

One syringe (0.8 ml) contains as active ingredient enoxaparin sodium 8000 anti-Xa ME (equivalent to 80 mg / 0.8 ml); Excipients: water for injection - up to 0.8 ml.

One syringe (1.0 ml) contains, as active ingredient Enoxaparin sodium 10,000 anti-Xa ME (equivalent to 100 mg / 1 ml); Excipients: water for injection - up to 1.0 ml.

Description:Transparent colorless or light yellow liquid.

Pharmacotherapeutic group:Anticoagulant means of direct action

ATX: & nbsp

B.01.A.B.05 Enoxaparin

Pharmacodynamics:

Enoxaparin sodium is a low molecular weight heparin (LMWH, an average molecular weight of about 4,500 daltons), in which the antithrombotic and anticoagulant effects of standard heparin are not related. It has high activity against the factor Xa of blood coagulation (anti-Xa activity of approximately 100 IU / ml) and low activity with respect to the Co-fold factor (for enoxaparin the ratio of anti-Xa and antithrombin activity is 3.6). This anticoagulant activity acts via antithrombin III (AT-III), providing anticoagulant activity in humans. In addition to anti-Xa /IIand activity, additional anticoagulant and anti-inflammatory properties of enoxaparin sodium have been revealed both in healthy people and patients, and in animal models. This includes AT-1 II dependent inhibition of other coagulation factors as a factor Vila, activation of the release of the tissue factor pathway inhibitor (PTF), as well as a reduction in the release of von Willebrand factor from the vascular endothelium into the bloodstream. These factors provide an anticoagulant effect of sodium enoxaparin as a whole.

When used in prophylactic doses, enoxaparin slightly changes the activated partial thromboplastin time (APTT). At therapeutic doses, APTTV can be increased by 1.5-2.2 times the control time at the peak of activity. This prolongation reflects the residual antithrombin activity.

Anti-IIand plasma activity is about 10 times lower than anti-Xa activity. The average maximum anti-IIand the activity is observed approximately 3-4 hours after subcutaneous administration and reaches 0.13 IU / ml and 0.19 IU / ml after repeated administration of 1 mg / kg of body weight with double administration and 1.5 mg / kg of body weight with a single dose introduction, respectively.

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

Pharmacokinetics:

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

Bioavailability.

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

Bolus intravenous injection 30 mg (0.3 ml; 3000 anti-Xa ME) with further subcutaneous injections of 1 mg / kg (100 anti-Ha IU / kg) every 12 hours leads to the first maximum level of antifactor concentration Xa, which is 1.16 IU / ml, 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 the indices of the individual patient and between patients are rather insignificant. After repeated subcutaneous administration to healthy volunteers, 40 mg (0.4 ml; 4000 anti-Xa ME) Once a day, the equilibrium state was reached on day 2, while the average activity of enoxaparin was almost 15% higher than that observed with a single administration.Stable levels of enoxaparin activity are fairly predictable when single doses are administered. After repeated subcutaneous administration of 1 mg / kg (100 anti-Ha IU / kg) twice a day, an equilibrium state was achieved between 3 and 4 in the afternoon, with the mean AUC was 65% higher than that observed with a single administration, and the maximum and minimum anti-Xa activity was 1.2 and 0.52 anti-Ha IU / ml, respectively. Concerning the pharmacokinetics of enoxaparin sodium, this difference in the achievement of the equilibrium state can also be expected for the therapeutic range of doses.

Distribution.

The volume of distribution of enoxaparin sodium by anti-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 with the formation of low molecular weight substances with very low biological activity

Excretion.

After subcutaneous injection, the half-life of anti-Xa activity in low molecular weight heparins is the most prolonged, compared to that in unfractionated heparins.Elimination of enoxaparin is monophasic, with a half-life of about 4 hours after a single subcutaneous injection and almost 7 hours with repeated doses. For low molecular weight heparins, a faster decline in anti-IIbut activity in plasma compared to anti-Xa activity.

Enoxaparin and its metabolites are excreted in the urine, as well as with bile. Kidney clearance 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.

High-risk groups:

- Elderly patients

Since this physiological decline in renal function is observed in this age group, elimination is slower. This does not affect the dosing or the mode of administration for preventive treatment.

In patients older than 75 years, it is very important to systematically monitor kidney function using the Cockcroft formula before starting treatment with LMWH.

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

In some cases it may be useful to monitor anti-Xa activity in order to avoid overdose,if enoxaparin is used in therapeutic doses. A decrease in the clearance of enoxaparin sodium in renal failure was noted. After repeated subcutaneous administration of 40 mg of enoxaparin sodium, the activity of anti-Xa, represented by the area under the pharmacokinetic curve in mild (creatinine clearance 50-80 ml / min) and moderate (QA 30-50 ml / min), occurs 1 time per day, renal failure. In patients with severe renal insufficiency (CC less than 30 ml / min), the area under the pharmacokinetic curve in the equilibrium state is 65% higher on average with repeated subcutaneous administration of 40 mg of the drug once a day.

- Patients with excessive body weight

In people with overweight with subcutaneous injection of the drug, the clearance is slightly less.

If you do not adjust the dose based on the patient's body weight, then after a single subcutaneous administration of 40 mg of enoxaparin sodium, anti-Xa activity will be 50% higher in women weighing less than 45 kg and 27% higher in men weighing less than 57 kg compared with patients with normal average body weight.

Indications:

- Prevention of venous thrombosis and embolism during surgical interventions, especially in orthopedic and general surgical operations.

- Prevention of venous thrombosis and embolism in patients on bed rest due to acute therapeutic illnesses, including acute heart failure and decompensation of chronic heart failure (III or IV class NYHA), acute respiratory failure, as well as severe acute infections and acute rheumatic diseases in combination with one of the risk factors for venous thrombosis (see "Special instructions").

- Treatment of deep vein thrombosis with pulmonary embolism or without pulmonary arterial thromboembolism.

- Prevention of thrombus formation in the extracorporeal circulation system during hemodialysis (usually with a session duration of no more than 4 hours).

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

- Treatment of acute myocardial infarction with segment elevation ST in patients who are subject to drug treatment or subsequent percutaneous coronary intervention.

Contraindications:

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

- Active large bleeding, as well as conditions and diseases in which there is a high risk of bleeding: threatening abortion, cerebral aneurysms or exfoliating aortic aneurysm (with the exception of surgical procedures), recent hemorrhagic stroke, uncontrolled bleeding, thrombocytopenia in combination with a positive test under conditions in vitro on antiplatelet antibodies in the presence of enoxaparin sodium.

- Children under 18 years of age, as efficacy and safety in this category of patients are not established (see section "Special instructions").

Carefully:

Conditions in which there is a potential risk of bleeding:

- violations of hemostasis (including hemophilia, thrombocytopenia, hypocoagulation, von Willebrand's disease, etc.), severe vasculitis;

- peptic ulcer of stomach or duodenum or other erosive-ulcerative lesions of gastrointestinal tract in anamnesis;

- recent ischemic stroke;

- uncontrolled severe arterial hypertension;

- diabetic or hemorrhagic retinopathy;

- severe diabetes mellitus;

- recent or alleged neurologic or ophthalmic surgery;

- spinal or epidural anesthesia (potential risk of hematoma), spinal puncture (recently transferred);

- recent childbirth;

- endocarditis bacterial (acute or subacute);

- pericarditis or pericardial effusion;

- renal and / or liver failure;

- intrauterine contraception (IUD);

- severe trauma (especially the central nervous system), open wounds on large surfaces;

- simultaneous reception of drugs that affect the hemostasis system;

- heparin-induced thrombocytopenia (in the anamnesis) in combination with or without thrombosis.

There are no data on the clinical use of the drug for the following diseases: active tuberculosis, radiation therapy (recently transferred).

Pregnancy and lactation:

Pregnancy

Information about the fact that sodium enoxaparin penetrates the placental barrier during the second trimester of pregnancy in humans, no. There is no relevant information regarding the first and third trimester of pregnancy.Since there are no adequate and well-controlled studies in pregnant women, and animal studies do not always predict a reaction to sodium enoxaparin during pregnancy in humans, it should be used during pregnancy only when there is an urgent need for its use, established by a doctor .

Breastfeeding period

It is not known whether the unchanged sodium enoxaparin in human milk. Absorption of enoxaparin sodium in the digestive tract in a newborn is unlikely. However, as precautions, breastfeeding women receiving treatment with the drug Flenox® NEO, it should be recommended to interrupt breastfeeding.

Dosing and Administration:

With the exception of special cases (see below, subsections "Treatment of myocardial infarction with segment elevation ST, medicamentous or with the help of percutaneous coronary intervention "and" Prevention of thrombus formation in the system of extracorporeal circulation during hemodialysis "), sodium enoxaparin is injected deeply subcutaneously. Injections should preferably be performed in the patient's "lying" position.When using pre-filled syringes for 20 mg and 40 mg to avoid loss of the drug before the injection, do not remove air bubbles from the syringe. Injections should be performed alternately in the left or right anterolateral or posterolateral surface of the abdomen.

The needle must be inserted at full length, vertically (not sideways), into the skin fold, collected and held until the injection is completed between the thumb and forefinger. Skin fold is released only after the injection is completed.

Do not massage the injection site after injection.

The pre-filled disposable syringe is ready for use.

The drug can not be administered intramuscularly!

Prevention of venous thrombosis and embolism during surgical interventions, especially in orthopedic and general surgical operations.

Patients with a moderate risk of developing thrombosis and embolism (eg, abdominal surgery) the recommended dose of the drug Flenox® NEO is 20 mg once daily subcutaneously. The first injection should be done 2 hours before surgery.

Patients with a high risk of developing thrombosis and embolism (for example, in orthopedic operations,surgical operations in oncology, patients with additional risk factors not related to surgery such as congenital or acquired thrombophilia, malignant neoplasm, bed rest for more than three days, obesity, venous thrombosis in the anamnesis, varicose veins of the lower extremities, pregnancy) the drug is recommended in dose 40 mg once a day, subcutaneously, with the administration of the first dose 12 hours before surgery, or at a dose of 30 mg twice a day with the onset of administration 12-24 hours after surgery.

The duration of treatment with the drug Flenox® NEO averages 7-10 days. If necessary, therapy can be continued as long as there is a risk of developing thrombosis and embolism, and until the patient goes into an outpatient setting.

In orthopedic operations, it may be advisable after the initial therapy to continue treatment by administering the preparation Floenox® NEO at a dose of 40 mg once per day for 3 weeks.

Features of the use of the preparation Flenox® NEO for spinal / epidural anesthesia, as well as for procedures of coronary revascularization are described in the section "Special instructions".

Prevention of venous thrombosis and embolism in patients, who are on a bed rest due to acute therapeutic illnesses

The recommended dose of Flenox® NEO is 40 mg once a day, subcutaneously, for at least 6 days. Therapy should be continued until the patient fully switches to an outpatient schedule (maximum for 14 days).

Treatment of deep vein thrombosis with pulmonary embolism or without pulmonary arterial thromboembolism

The drug is administered subcutaneously at a rate of 1.5 mg / kg body weight once a day or 1 mg / kg body weight twice a day. In patients with complicated thromboembolic disorders, the drug is recommended to be applied at a dose of 1 mg / kg of body weight twice a day.

The average duration of treatment is 10 days. Immediately begin therapy with indirect anticoagulants, while treatment with the drug Flenox® NEO must continue until the therapeutic anticoagulant effect (the values of INR [International Normalized Relations] should be 2.0-3.0).

Prevention of thrombus formation in the extracorporeal circulation system during hemodialysis

The recommended dose of Flenox® NEO is on average 1 mg / kg body weight. At a high risk of bleeding, the dose should be reduced to 0.5 mg / kg of body weight with dual vascular access or up to 0.75 mg / kg of body weight with single vascular access.

When hemodialysis, the preparation Flenox® NEO should be injected into the arterial part of the shunt at the beginning of the hemodialysis session. A single dose, as a rule, is sufficient for a four-hour session, however, if the fibrin rings are detected with a longer hemodialysis, the drug can be additionally administered at a dose of 0.5-1 mg / kg body weight.

Treatment of unstable angina and myocardial infarction without a tooth Q

The preparation Flenox® NEO is administered at a dose of 1 mg / kg body weight every 12 hours, subcutaneously, while using acetylsalicylic acid at a dose of 100-325 mg once daily.

The average duration of therapy is at least 2 days and continues until the patient's clinical condition is stabilized. Usually, the drug is administered from 2 to 8 days.

Treatment of acute myocardial infarction with segment elevation ST, medication or by percutaneous coronary intervention

Treatment begins with a single intravenous bolus administration of enoxaparin sodium at a dose of 30 mg. Immediately after it, subcutaneously injected sodium enoxaparin in a dose of 1 mg / kg body weight. Next, the drug is administered subcutaneously at 1 mg / kg body weight every 12 hours (maximum 100 mg of sodium enoxaparin for each of the first two subcutaneous injections, then 1 mg / kg of body weight for the remaining subcutaneous doses, i.e., with a body weight of more than 100 kg, single dose may exceed 100 mg).

Patients 75 years of age or older do not have an initial intravenous bolus injection. The drug is administered subcutaneously at a dose of 0.75 mg / kg body weight every 12 hours (maximum 75 mg of sodium enoxaparin for each of the first two subcutaneous injections, then 0.75 mg / kg of body weight for the remaining subcutaneous doses, i.e. with a body weight of more than 100 kg, a single dose may exceed 75 mg).

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

The recommended duration of treatment Flenoks® NEO is 8 days or until discharge from the hospital (if hospitalization period lasts at least 8 days).

Intravenous bolus administration of sodium enoxaparin should be performed through a venous catheter. Sodium Enoxaparin should not be mixed or administered together with other medicinal products. In order to avoid the presence in the infusion system traces of other drugs and their interaction with enoxaparin sodium venous catheter should be flushed with a sufficient amount of 0.9% sodium chloride solution or 5% dextrose solution before and after an intravenous bolus of enoxaparin sodium. Sodium Enoxaparin can safely Enter with a 0.9% solution of sodium chloride and 5% solution of dextrose. For the bolus administration of 30 mg of sodium enoxaparin in the treatment of acute myocardial infarction with segment elevation ST from the glass syringe 60 mg, 80 mg and 100 mg remove excess amount of the drug so as to only 30 mg (0.3 ml) was therein. A dose of 30 mg can be directly administered intravenously.

Pre-filled syringes for subcutaneous administration of 60 mg, 80 mg and 100 mg can be used to perform an intravenous bolus injection of enoxaparin sodium through a venous catheter. It is recommended to use 60 mg syringes, as this reduces the amount of drug removed from the syringe. Syringes of 20 mg are not used, since they are not sufficient for bolus administration of 30 mg of enoxaparin sodium. 40 mg syringes are not used, since they do not contain fissions and therefore it is impossible to accurately measure the amount of 30 mg.

In patients undergoing percutaneous coronary intervention, in the event that the last subcutaneous injection of enoxaparin sodium was performed less than 8 hours before the balloon catheter inserted into the narrowing of the coronary artery is inflated, no additional sodium enoxaparin is required. If the last subcutaneous injection of sodium enoxaparin was carried out more than 8 hours before the balloon catheter was inflated, an additional intravenous bolus injection of sodium enoxaparin at a dose of 0.3 mg / kg should be performed. To increase the accuracy of additional intravenous bolus injection of small volumesin a venous catheter for percutaneous coronary interventions, it is recommended to dilute the drug to a concentration of 3 mg / ml. Dilution of the solution is recommended immediately before administration. To obtain a solution of enoxaparin sodium at a concentration of 3 mg / ml with a prefilled syringe of 60 mg, it is recommended to use a container with an infusion solution of 50 ml (ie with 0.9% sodium chloride solution or 5% dextrose solution). 30 ml of the solution is removed from the container with the infusion solution using a conventional syringe. Sodium Enoxaparin (the contents of the syringe for subcutaneous administration of 60 mg) is introduced into the remaining 20 ml of the infusion solution in the containers.

The contents of the container with diluted sodium enoxaparin solution are gently mixed. For administration by means of a syringe, the required volume of the diluted solution of sodium enoxaparin is extracted, which is calculated by the formula:

Volume of reconstituted solution = Body weight of the patient (kg) x 0.1 or using the table below.

Volumes to be administered intravenously after breeding.

Body weight of the patient [kg]	The required dose (0.3 mg / kg) [mg]	The volume of the solution diluted to a concentration of 3 mg / ml
45	13,5	4,5
50	15	5
55	16,5	5,5
60	18	6
65	19,5	6,5
70	21	7
75	22,5	7,5
80	24	8
85	25,5	8,5
90	27	9
95	28,5	9,5
100	30	10

Dosage regimen for specific patient groups

Elderly patients

Except for the treatment of myocardial infarction with segment elevation ST (see above) for all other indications of a reduction in the dose of enoxaparin sodium in elderly patients, if they are not impaired renal function, is not required.

Patients with impaired renal function

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

The dose of sodium enoxaparin is reduced in accordance with the tables presented below, since these patients have an increase in the system exposure (duration of action) of the drug.

When using the drug with a therapeutic purpose, the following correction of the dosing regimen is recommended:

The usual dosing regimen	Dosing regimen for severe renal failure
1 mg / kg body weight subcutaneously 2 times a day	1 mg / kg body weight subcutaneously once a day
1.5 mg / kg body weight subcutaneously once a day	1 mg / kg body weight subcutaneously once a day
Treatment of acute myocardial infarction with segment elevation ST in patients younger than 75 years
Once: bolus intravenous 30 mg plus 1 mg / kg body weight subcutaneously; followed by subcutaneous administration at a dose of 1 mg / kg body weight twice a day (maximum 100 mg for each of the first two subcutaneous injections)	Once: bolus intravenous 30 mg plus 1 mg / kg body weight subcutaneously; followed by subcutaneous administration at a dose of 1 mg / kg body weight once a day (maximum 100 mg only for the first subcutaneous injection)
Treatment of acute myocardial infarction with segment elevation ST in patients 75 years and older
0.75 mg / kg body weight subcutaneously twice a day without an 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 administration (maximum 100 mg only for the first subcutaneous injection)

When using the drug with a prophylactic purpose, it is recommended to correct the dosage regimen shown in the table below.

The usual dosing regimen	Dosing regimen for severe renal failure
40 mg subcutaneously once a day	20 mg subcutaneously once a day
20 mg subcutaneously once a day	20 mg subcutaneously once a day

The recommended dosage adjustment is not used for hemodialysis.

Lungs (creatinine clearance 50-80 ml / min) and moderate (creatinine clearance 30-50 ml / min) renal dysfunction

Dose adjustments are not required, but patients should be under close medical supervision.

Patients with impaired hepatic function

Due to the lack of clinical studies, the preparation Flenox® NEO should be used with caution in patients with impaired hepatic function.

Side effects:

Side effects were classified in 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

There may be bleeding, especially if there are associated risk factors: organic changes with a tendency to bleeding, age, kidney failure, low body weight and some combinations of medications (see section "Interaction with other drugs"). With the development of bleeding, it is necessary to cancel the introduction of the drug, establish the cause of bleeding and begin appropriate therapy.

Very frequent bleeding in the prevention of venous thrombosis, in surgical patients and the treatment of deep vein thrombosis with or without thromboembolism.

Frequent - bleeding in the prevention of venous thrombosis in patients on bed rest and in the treatment of unstable angina, myocardial infarction without a tooth Q and myocardial infarction with segment elevation ST.

Infrequent - retroperitoneal bleeding and intracranial hemorrhage in patients with deep vein thrombosis with or without thromboembolism, as well as with myocardial infarction with segment elevation ST.

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

Thrombocytopenia and thrombocytosis

Very frequent - thrombocytosis (the number of platelets in the peripheral blood is more 400x10⁹/ l) in the prevention of venous thrombosis in surgical patients and the treatment of deep vein thrombosis with or without pulmonary embolism.

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

Infrequent - thrombocytopenia in the prevention of venous thrombosis in patients on bed rest and in the treatment of unstable angina, myocardial infarction without a tooth Q.

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

Immune system disorders

Frequent - allergic reactions.

Rare - anaphylactic and anaphylactoid reactions.

Disturbances from the liver and bile ducts

Very frequent - increased activity of "liver" transaminases more than three times higher than the upper limit of the norm.

Disturbances from the skin and subcutaneous tissues

Frequent - hives, itchy skin, erythema.

Infrequent - bullous dermatitis.

General disorders and disorders at the injection site

Frequent - a hematoma at the injection site, pain at the injection site, edema at the injection site, bleeding, hypersensitivity reactions, inflammation, the formation of seals at the injection site.

Infrequent - irritation at the injection site, necrosis of the skin at the injection site.

Laboratory and instrumental data

Rare - hyperkalemia.

Data, received in the post-registration period

The frequency of unwanted reactions in the received messages is estimated as "the frequency is unknown".

Immune system disorders

Anaphylactic / anaphylactoid reactions, including shock.

Disturbances from the nervous system

Headache.

Vascular disorders

When sodium enoxaparin was applied against the background of spinal / epidural anesthesia or spinal puncture, there were cases of development of spinal hematoma (or neuraxial hematoma). These reactions lead to the development of neurological disorders of varying severity, including permanent or irreversible paralysis (see. The "Special instructions").

Violations from the blood or lymphatic system

Hemorrhagic anemia.

Cases of development of immuno-allergic thrombocytopenia with thrombosis; in some cases, thrombosis was complicated by the development of an infarction of organs or limb ischemia (see section "Special instructions").

Eosinophilia.

Disturbances from the skin and subcutaneous tissues

At the injection site, skin vasculitis, skin necrosis, which is usually preceded by the appearance of purpura or erythematous papules (infiltrated and painful) can develop. In these cases, therapy with Flenox® NEO should be discontinued.Possible formation of solid inflammatory nodules-infiltrates at the site of injection of the drug, which disappear after a few days and are not grounds for discontinuing the drug.

Alopecia.

Disturbances from the liver and bile ducts

Hepatocellular liver damage.

Cholestatic liver damage.

Disturbances from musculoskeletal and connective tissue

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

Overdose:

Symptoms: hemorrhagic complications in case of accidental overdose after subcutaneous administration of significant doses of low molecular weight heparin. The emergence of undesirable consequences after the random intake of low molecular weight heparin by mouth, even in large quantities, is unlikely (no cases have been observed), since the extent of absorption of this substance in the stomach and intestine is negligible.

Treatment: the action of enoxaparin is neutralized by slow intravenous administration of protamine sulfate, but it is taken into account that:

- the effectiveness of protamine sulfate is much lower than that observed with an overdose of unfractionated heparin; Before using protamine sulfate, due to the possibility of adverse events (in particular anaphylactic shock), the benefit / risk ratio should be carefully weighed.

The necessary doses of protamine depend on:

1. of the administered dose of low-molecular heparin (100 anti-heparin units protamine neutralized 100 anti-Ha ME low molecular weight heparin), if sodium enoxaparin was introduced within the last 8 hours;

2. time, which passed after the injection of low-molecular heparin:

- infusion of 50 anti-heparinic protamine units per 100 anti-Xa ME enoxaparin sodium can be carried out if sodium enoxaparin was administered more than 8 hours ago, or if it is necessary to introduce a second dose of protamine;

- if enoxaparin was administered more than 12 hours ago, then there is no need to introduce protamine. The above recommendations are for patients with normal renal function who use repeated doses of the drug.

Nevertheless, it is impossible to completely neutralize the anti-Xa activity of enoxaparin. This neutralization due to the peculiarity of absorption of low molecular weight heparin may be temporary and require the distribution of the total calculated dose of protamine into several injections (2 to 4) that are administered within 24 hours.

Interaction:

Do not mix Phlenox® NEO with other medicines in the same syringe.

When used simultaneously with drugs that affect hemostasis (systemic salicylates, acetylsalicylic acid, non-steroidal anti-inflammatory drugs (including ketorolac), dextran with a molecular weight of 40 kDa, ticlopidine and clopidogrel, systemic glucocorticosteroids, thrombolytics or anticoagulants, other antiplatelet drugs (including glycoprotein antagonists IIb/IIIa) - Increased risk of bleeding (see section "Special instructions").

Special instructions:

Are common

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

Bleeding

As with the use of other anticoagulants, with the introduction of the preparation Flenox® NEO, the development of bleeding of any localization is possible (see section "Side effect"). With the development of bleeding it is necessary to find its source and prescribe the appropriate treatment.

Bleeding in elderly patients

When using the drug Flenox® NEO in preventive doses in elderly patients there was no increased risk of bleeding.

When using the drug in therapeutic doses in elderly patients (especially at the age of 80 years and older) there is an increased risk of bleeding. It is recommended that careful monitoring of the condition of such patients is made (see the section "Pharmacokinetics" and the section "Dosing and Administration", subsection "Patients of advanced age").

Simultaneous use of other drugs, influencing hemostasis

It is recommended that the use of drugs that affect hemostasis (salicylates, including acetylsalicylic acid, non-steroidal anti-inflammatory drugs, including ketorolac; dextran with a molecular mass of 40 kD, ticlopidine, clopidogrel; glucocorticosteroid preparations,thrombolytics, anticoagulants, antiaggregants. including glycoprotein receptor antagonists IIb/IIIa), was discontinued before treatment with enoxaparin sodium, except when their use is necessary. If combinations of sodium enoxaparin with these drugs are shown, careful clinical observation and monitoring of relevant laboratory parameters should be carried out.

Renal insufficiency

In patients with impaired renal function, there is a risk of bleeding as a result of an increase in the systemic exposure of enoxaparin sodium.

In patients with severe renal dysfunction (creatinine clearance less than 30 ml / min), there is a significant increase in exposure to sodium enoxaparin, so it is recommended to dose adjustments for both prophylactic and therapeutic use of the drug. Although dose adjustment is not required in patients with mild to moderate renal impairment (creatinine clearance 30-50 ml / min or 50-80 ml / min), careful monitoring of the condition of such patients is recommended (see sections "Pharmacokinetics" and "Method application and dose ", subsection" Patients with renal insufficiency ").

Low body weight

An increase in the exposure of sodium enoxaparin was noted for its preventive use in women weighing less than 45 kg and for men weighing less than 57 kg, which may lead to an increased risk of bleeding. Recommended careful monitoring of the condition of such patients.

Patients with obesity

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

Control of the number of platelets in the peripheral blood

The risk of developing antibody-mediated heparin-induced thrombocytopenia exists even when low molecular weight heparins are used. If thrombocytopenia develops, it is usually detected between the 5th and 21st days after initiation of sodium enoxaparin therapy. Therefore, it is recommended that the number of platelets in the peripheral blood be monitored regularly before the treatment with Flenox® NEO and during its use.

In the presence of a confirmed significant decrease in the number of platelets (by 30-50% compared with the initial index), it is necessary to immediately cancel sodium enoxaparin and transfer the patient to another therapy.

Spinal / epidural anesthesia

The cases of the appearance of neuroaxial hematomas with the use of the preparation Flenox® NEO with the simultaneous spinal / epidural anesthesia with the development of a long-term or irreversible paralysis are described. The risk of occurrence of these phenomena decreases with the use of the drug in a dose of 40 mg or lower. The risk increases with higher doses of the preparation Flenox® NEO, as well as with the use of permanent catheters after surgery, or with the simultaneous use of additional drugs that affect hemostasis, such as non-steroidal anti-inflammatory drugs (see section "Interaction with other drugs"). The risk also increases with a traumatically performed or repeated spinal puncture or in patients who have a history of referring to the transferred operations in the spine or deformity of the spine.

To reduce the possible risk of bleeding associated with the use of sodium enoxaparin and epidural or spinal anesthesia / analgesia, it is necessary to take into account the pharmacokinetic profile of the drug (see the section "Pharmacokinetics"). It is better to install or remove a catheter with a low anticoagulant effect enoxaparin sodium, but the exact time to achieve a sufficient reduction in the anticoagulant effect in different patients is unknown.

Installation or removal of the catheter should be performed at least 12 hours after the administration of lower doses of the preparation Flenox® NEO (20 mg once daily, 30 mg once or twice daily, 40 mg once a day) and at least , 24 hours after the administration of higher doses of the preparation Flenox® NEO (0.75 mg / kg body weight 2 times a day, 1 mg / kg body weight 2 times a day, 1.5 mg / kg body weight once a day). At these time points, the anti-Xa activity of the drug still continues to be detected, and the time delays are not a guarantee that the development of the neuroaxial hematoma will be avoided. Patients receiving sodium enoxaparin in doses of 0.75 mg / kg body weight 2 times a day or 1 mg / kg body weight 2 times a day, with such a (two-time during the day) dosing regimen, do not enter a second dose,to increase the interval before installing or replacing the catheter. Similarly, consideration should be given to the possibility of delaying the introduction of the next dose of the drug for at least 4 hours, based on an assessment of the benefit / risk ratio (risk of thrombosis and bleeding during the procedure, taking into account the presence of risk factors in patients). However, it is not possible to give clear recommendations on the timing of the next dose of enoxaparin sodium after removal of the catheter. It should be noted that in patients with creatinine clearance less than 30 ml / min, the excretion of sodium enoxaparin is slowed. Therefore, this category of patients should consider doubling the time from catheter removal: at least 24 hours for lower doses of enoxaparin sodium (30 mg once a day) and at least 48 hours for higher doses (1 mg / kg of body weight per day).

If anticoagulant therapy is used as prescribed by the doctor during epidural / spinal anesthesia or lumbar puncture, constant monitoring of the patient is necessary to detect any neurological symptoms such as back pain, impaired sensory and motor functions (numbness or weakness in the lower extremities), violation function of the intestine and / or bladder.The patient should be instructed about the need to inform the doctor immediately if any of the above symptoms occur. When suspected of the symptoms characteristic of the hematoma of the spinal cord, urgent diagnosis and treatment is needed, including, if necessary, decompression of the spinal cord.

Heparin-induced thrombocytopenia

With special care, the drug Flenox® NEO should be used in patients in whom the history of which is known about heparin-induced thrombocytopenia in combination with or without thrombosis.

The risk of developing heparin-induced thrombocytopenia can persist for several years. If anamnesis is presumed to have heparin-induced thrombocytopenia, then platelet aggregation assays in vitro are of limited importance in forecasting the risk of its development. The decision to use the drug Flenox® NEO in this case can be taken only after consultation with the appropriate specialist.

Percutaneous coronary angioplasty

In order to minimize the risk of bleeding associated with invasive vascular instrumental manipulation in the treatment of unstable angina and myocardial infarction without a tooth Q and acute myocardial infarction with segment elevation ST, these procedures should be performed at intervals between the administration of the preparation Flenox® NEO. This is necessary in order to achieve hemostasis after percutaneous coronary intervention. When using a closure device, the introducer of the femoral artery can be removed immediately. When manual (manual) compression is used, the femoral artery introducer should be removed 6 hours after the last intravenous or subcutaneous injection of sodium enoxaparin. If sodium enoxaparin treatment is continued, the next dose should be administered no earlier than 6-8 hours after removal of the femoral artery introducer. It is necessary to monitor the place of introduction of the introducer, in order to detect signs of bleeding and formation of a hematoma in time.

Patients with mechanical heart valves

The use of the preparation Flenox® NEO for the prevention of thrombosis in patients with mechanical mechanical valves of the heart has been studied insufficiently. There are separate reports on the development of thrombosis of heart valves in patients with mechanical heart valves on the background of therapy with enoxaparin sodium for the prevention of thrombosis.The evaluation of these reports is limited due to aggravating factors contributing to the development of thrombosis of artificial heart valves, including the underlying disease, and because of the lack of clinical data.

Pregnant women with mechanical artificial heart valves

The use of the preparation Flenox® NEO for the prevention of thrombosis in pregnant women with mechanical heart valves has been studied insufficiently. In a clinical study of pregnant women with mechanical heart valves using sodium enoxaparin at a dose of 1 mg / kg body weight 2 times a day to reduce the risk of thrombosis and embolism, 2 of 8 women developed thrombi that led to the blocking of the heart valves and to the death of the mother and the fetus.

There are separate post-marketing reports on thrombosis of heart valves in pregnant women with mechanical heart valves treated with enoxaparin for the prevention of thrombosis.

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

Laboratory Tests

In doses used to prevent thromboembolic complications, the preparation Flenox® NEO does not significantly affect bleeding time and blood clotting parameters, as well as platelet aggregation or binding to fibrinogen.

When the dose is raised, the APTT and the activated clotting time can be prolonged. The increase in APTT and the activated clotting time are not in a direct linear relationship with the increase in anticoagulant activity of the drug, so there is no need to monitor them.

Prophylaxis of venous thrombosis and embolism in patients with acute therapeutic diseases, under the established regime

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

- age over 75 years;

- malignant neoplasms;

- thrombosis and embolism in the anamnesis;

- obesity;

- hormonal therapy;

- heart failure;

- chronic respiratory failure.

Children

Safety and efficacy of sodium enoxaparin in children under the age of 18 years have not been established.

Effect on the ability to drive transp. cf. and fur:

Enoxaparin sodium does not affect the ability to drive vehicles and mechanisms.

Form release / dosage:

Solution for injection, 10,000 anti-Ha IU / ml.

Packaging:

0.2 ml (2000 anti-Xa ME) or 0.4 ml (4000 anti-Xa ME) or 0.6 ml (6000 anti-Xa ME) in a glass syringe with a built-in needle and with a protective cap; 2 glass syringes with a built-in needle and with a protective cap in the blister: 1 or 5 blisters together with instructions for medical use are placed in a pack of cardboard.

According to 0.8 ml (8000 anti-Xa ME) in a glass syringe with a built-in needle and with a protective cap; 2 glass syringes with a built-in needle and a protective cap in the blister; 1 blister together with the instruction for medical use is placed in a pack of cardboard.

By 1.0 ml (10,000 anti-Xa ME) in a glass syringe with a built-in needle and with a protective cap; 2 glass syringes with a built-in needle and a protective cap in the blister; 1 blister together with the instruction for medical use is placed in a pack of cardboard.

Storage conditions:

Store in a dark place at a temperature of no higher than 25 ° C. Do not freeze.Keep out of the reach of children.

Shelf life:

2 years.

Do not use after the expiry date printed on the package.

Terms of leave from pharmacies:On prescription

Registration number:LP-004365

Date of registration:06.07.2017

Expiration Date:06.07.2022

The owner of the registration certificate:FARMAK, JSC FARMAK, JSC Ukraine

Manufacturer: & nbsp

FARMAK, PAO Ukraine

Information update date: & nbsp14.09.2017

Illustrated instructions

Instructions

Flenox® NEO (Flenox NEO)