Фленокс

General characteristics. Structure:

Active ingredient: эноксапарин sodium;

1 ml of solution contains: 10 000 Anti-ha ME that is equivalent to 100 mg of an enoksaparin of sodium;

2 000 Anti-ha ME/of 0,2 ml that is equivalent an enoksaparina of sodium of 20 mg;

4 000 Anti-ha ml ME/0,4 that is equivalent an enoksaparina of sodium of 40 mg;

6 000 Anti-ha ml ME/0,6 that is equivalent an enoksaparina of sodium of 60 mg;

8 000 Anti-ha ml ME/0,8 that is equivalent an enoksaparina of sodium of 80 mg;

excipients: water for injections.

Pharmacological properties:

Pharmacodynamics. Enoksaparin is a low-molecular heparin (NMG) in which antitrombotichesky and anticoagulating activities of standard heparin are divided.

It has higher Anti-ha activity, than anti-IIA or antithrombic activity (for an enoksaparin the ratio makes 3,6).

At use in preventive doses эноксапарин has no considerable influence on aChTV (the activated partial tromboplastinovy time).

At use of medical doses of drug aChTV it can be prolonged and by 1,5-2,2 times to exceed control time of the maximum activity. This prolongation displays residual antithrombic activity.

Treatment of an acute myocardial infarction with raising of a segment of ST in комбинациис thrombolytic means at patients to whom the subsequent coronary angioplasty, and a takozha at patients to whom this procedure is not carried out is carried out.

In large-scale multicenter clinical trial of 20479 patients with an acute myocardial infarction with raising of a segment of ST after they received fibrinolitic therapy, were randomizirovanno distributed on groups for receiving or an enoksaparin in the form of a bolyusny intravenous injection 3000 Anti-ha of ME after which the dose 100 Anti-ha of ME/kg immediately was subcutaneously entered, subcutaneous injections on 100 Anti-ha of ME/kg each 12 hours, or for administration of intravenous unfractionated heparin in the form of a bolyusny injection of 60 ME/kg (at most 4000 ME/kg) with the subsequent continuous infusion in a dose which was corrected depending on an indicator of the activated partial tromboplastinovy time then were carried out. Subcutaneous injections of an enoksaparin were carried out to an extract from a hospital or no more than 8 days (to 75% of cases – not less than 6 days). To a half of patients who received heparin the drug was administered by not less than 48 hours (in 89,5% of cases ≥ 36 hours). All patients also received aspirin for not less than 30 days. Aged ≥ 75 years modified a dose of an enoksaparin for patients: 0,75 mg/kg (75 Anti-ha ME/kg) in the form of a subcutaneous injection each 12 hours without initial bolyusny intravenous injection.

During the research 4716 (23%) the patient carried out coronary angioplasty against the background of antitrombotichesky therapy using the disguised studied drugs. Patients did not receive additional doses if from the moment of the last subcutaneous injection of an enoksaparin before inflating of a cylinder there passed less than 8 hours, or received a bolyusny intravenous injection of an enoksaparin in a dose of 0,3 mg/kg (30 Anti-ha of ME/kg) if from the moment of the last subcutaneous injection of an enoksaparin before inflating of a cylinder there passed more than 8 hours.

Enoksaparin allowed to reduce considerably the frequency of events which correspond to primary final points (the combined final point which includes a recurrence of a myocardial infarction and mortality for any reason which took place throughout the 30-day period of observation after inclusion in a research: 9,9% in group of an enoksaparin in comparison with 12% in group of unfractionated heparin (decrease in relative risk – 17% (р <0,001)). Frequency of a recurrence of a myocardial infarction was much lower in group of an enoksaparin (3,4% in comparison with 5%, р <0,001, decrease in relative risk – 31%). Mortality was lower in group of an enoksaparin, however distinction between groups was not statistically reliable (6,9% in comparison with 7,5%, р =0,11).

Advantage of an enoksaparin from the point of view of primary final point of an indicator was unconditional irrespective of subgroup (age, sex, localization of a myocardial infarction, diabetes or a myocardial infarction in the anamnesis, type of the appointed trombolitik and a period between emergence of the first clinical signs and an initiation of treatment).

Enoksaparin showed considerable advantage in comparison with unfractionated heparin from the point of view of primary criterion of efficiency as at patients who transferred coronary angioplasty to the 30-day period after inclusion in a research (10,8% in comparison with 13,9%, 23% decrease in relative risk) and at patients to whom coronary angioplasty was not carried out (9,7% in comparison with 11,4%, for 15% decrease in relative risk).

Frequency of developing of massive bleedings till 30th day was authentically higher in group of an enoksaparin (2,1%) in comparison with group of heparin (1,4%). Frequency of gastrointestinal bleedings was higher in group of an enoksaparin (0,5%), than in group of heparin (0,1%) while the frequency of intracraneal hemorrhages in both groups was identical (0,8% in case of an enoksaparin in comparison with 0,7% in case of heparin).

The analysis of the combined criteria by which defined clinical advantage showed statistically significant advantage (р <0,0001) an enoksaparina over unfractionated heparin: decrease in relative risk by 14% in favor of an enoksaparin (11% in comparison with 12,8%) for the combined criteria which included death a recurrence of a myocardial infarction and heavy bleedings (criteria of T_M І) till  30th day, and 17% (10,1% in comparison with 12,2%) for the combined criteria which included death, a recurrence of a myocardial infarction and intracraneal hemorrhage till 30th day.

Pharmacokinetics. Pharmacokinetic parameters of drug are estimated on changes Anti-ha and anti-IIa of activity in plasma in time in the recommended ranges of doses.

Bioavailability.

At hypodermic introduction эноксапарин it is soaked up quickly and almost completely (almost for 100%). The maximum activity in plasma is observed during the period between 3 and 4 hours after introduction.

This maximum activity (expressed in Anti-ha ME) makes 0,18±0,04 (after introduction of 2000 Anti-ha of ME), 0,43 ±0,11 (after introduction 4000 Anti-ha of ME), and 1,01±0,14 (after introduction 10000 Anti-ha of ME).

Bolyusny intravenous injection of 30 mg (0,3 ml; 3000 Anti-ha of ME) with further subcutaneous injections on 1 mg/kg (100 Anti-ha of ME/kg) leads each 12 hours to achievement of the first maximum level of concentration of an anti-factor Ha that makes 1,16 ME/ml (n=16), and an average value of the area under a pharmacokinetic curve that corresponds to 88% of equilibrium level. The equilibrium state is reached for the second day of treatment.

In the recommended range of doses the pharmacokinetics of an enoksaparin is linear. Differences in indicators at the certain patient and between patients quite insignificant. After repeated hypodermic introduction to healthy volunteers of 40 mg (0,4 ml; 4000 Anti-ha of ME) once a day the equilibrium state was reached for the 2nd day, at the same time average activity of an enoksaparin was nearly 15% higher, than that that it was observed at one-time introduction. Stable levels of activity of an enoksaparin are quite predicted at introduction of single doses. After repeated hypodermic introduction 1mg/kg (100 Anti-ha of ME/kg) two times a day, the balanced state was reached during the period between the 3 and 4 day, at the same time average AUC was 65% higher, than that that it was observed at one-time introduction, and activity maximum and minimum Anti-ha made 1,2 and 0,52 Anti-ha of ME/ml respectively. Concerning indicators of pharmacokinetics of an enoksaparin of sodium, this difference in achievement of a balanced state can be expected as well for the therapeutic range of doses.

Anti-ha activity in plasma after hypodermic introduction is nearly 10 times lower, than anti-IIA activity. Average activity maximum Anti-ha is observed approximately in 3-4 hours after a subcutaneous injection, reaching 0,13 anta-Ha ME/ml after repeated introduction of a dose of 1 mg/kg (100 Anti-ha of ME/kg) two times a day.

Distribution.

The volume of distribution of an enoksaparin of sodium on Anti-ha activity makes about 5 l and almost answers the volume of the circulating blood.

Metabolism.

Metabolism of an enoksaparin happens preferential in a liver (by a desulfatization and a depolymerization).

Removal.

After a subcutaneous injection the elimination half-life on Anti-ha activity at low-molecular heparins is the most long, in comparison with this indicator at unfractionated heparins.

Elimination of an enoksaparin monophase, at the same time an elimination half-life makes about 4 hours after one-time hypodermic introduction and nearly 7 hours at introduction of repeated doses. More bystry recession of anti-IIa of activity in plasma in comparison with Anti-ha activity is characteristic of low-molecular heparins.

Enoksaparin and his metabolites are removed with urine (the unsaturated mechanism), and also with bile.

The renal clearance of substances with Anti-ha activity makes 10% of the entered dose, and the general renal excretion of active and inactive metabolites – 40% of a dose.

Groups of the increased risk:

* patients of advanced age:

As in this age category physiological depression of function of kidneys, elimination slower is observed. It does not influence dosing or the introduction mode at preventive treatment.

At patients 75 years very important systematically are more senior to control function of kidneys by means of Kokroft's formula before an initiation of treatment drugs NMG.

* Patients with easy and moderate renal nedostatochnostm. (clearance of creatinine> 30 ml/min.): in some cases there can be useful a carrying out monitoring Anti-ha of activity for the purpose of an exception of a possibility of overdose if эноксапарин it is applied in medical doses.

Pharmaceutical characteristics

 

Main physical and chemical properties. Transparent colourless or light yellow color liquid.

Incompatibility. Not to mix with other medicines.

Indications to use:

- Prevention of venous thrombosis and embolism at orthopedic or all-surgeries;

- prevention of venous tromboembolic episodes at therapeutic patients who are on a bed rest in connection with acute diseases (heart failure ІІІ or class ІV on NYHA classification, respiratory insufficiency, heavy acute infectious process, rheumatic diseases);

- the prevention of a thrombogenesis in the extracorporal blood circulatory system at a hemodialysis;

- treatment of the diagnosed deep vein thrombosis which is followed or is not followed by a thromboembolism of a pulmonary artery, except cases which need performing thrombolytic therapy or surgical intervention;

- treatment of unstable stenocardia and an acute phase of a myocardial infarction without Q tooth in a combination with acetylsalicylic acid.

- treatment of an acute myocardial infarction with rise / элевацией ST segment in a combination with thrombolytic means at patients, which perhaps further use of coronary angioplasty, and also at patients to whom this procedure is not carried out.

Route of administration and doses:

1 mg (0,01 ml) of an enoksaparin of sodium corresponds to about 100 activity units Anti-ha of ME. Фленокс® it is necessary to enter subcutaneously at preventive and medical use except for the following cases:

- use of drug for anti-coagulation in practice of a hemodialysis;

- treatment of patients with a myocardial infarction with an elevation of a segment of ST which need intravenous bolyusny administration.

Фленокс®не it is allowed to enter intramusculary. Drug is recommended for use only for adults.

Technology of hypodermic introduction. The syringes filled with the producer are ready to direct use. If necessary the dose of the drug Flenoks® can be corrected depending on the body weight of the patient. For this purpose in case of need before carrying out an injection it is necessary to remove excess amount of drug from the syringe. If at a distance excess amount of drug there is no need, then in order to avoid loss of drug it is not necessary to eliminate air bubbles from the syringe before an injection.

It is better to carry out a subcutaneous injection of the drug Flenoks® when the patient is in a prone position. Administer the drug in hypodermic fatty tissue of a perednebokovy or posterolateral surface of an abdominal wall, serially, in the left and right side, using different places for each injection. The needle needs to be entered at full length vertically into thickness of a fold of skin which was formed between big and index fingers. The fold of skin needs to be held throughout all introduction of an injection. It is impossible to rub the place of an injection after introduction.

Technology of intravenous (bolyusny) administration / use of the drug Flenoks® for a lecheniyaostry myocardial infarction with raising of a segment of ST:

Treatment is begun with an intravenous bolyusny injection then carry immediately out a subcutaneous injection. For carrying out an intravenous bolus from the graduated syringe filled with the producer with the drug Flenoks® which contains 40 mg (0,4 ml; 4000 Anti-ha ME), 60 mg (0,6 ml; 6000 Anti-ha ME) or 80 mg (0,8 ml; 8000 Anti-ha of ME), it is necessary to remove excess amount of drug that in the syringe there was a dose of 30 mg (0,3 ml; 3000 anti-    Ha ME).

This dose of the drug Flenoks® is entered into a system tube for intravenous administration of solutions. Mixing or simultaneous administration of drug with other medicines is not allowed. For elimination of the remains of other medicines and therefore, for the prevention of their mixing with the drug Flenoks® before carrying out an intravenous bolyusny injection of the drug Flenoks® and after it system it is necessary to wash out enough 0,9% of solution of sodium of chloride or 5% of solution of glucose. Фленокс® it is possible to enter safely into 0,9% solution of sodium of chloride or into 5% glucose solution.

In the conditions of a hospital the drug Flenoks® can be used for:

- receiving a dose of 1 mg/kg (100 Anti-ha ME/kg) for the first subcutaneous injection which needs to be carried out after an intravenous bolyusny injection and also further doses   of 1 mg/kg (100 Anti-ha ME/kg) which it is necessary to enter subcutaneously each 12 hours;

- receiving a dose of 0,3 mg/kg (30 Anti-ha ME/kg) for intravenous bolyusny administration by the patient which carries out the subsequent coronary angioplasty.

During the entire period of treatment it is regularly necessary to control quantity of thrombocytes as there is a risk of emergence the heparin-the induced thrombocytopenia (HIT).

Prevention of venous thrombosis.

At operations at adults with moderate risk of a thrombogenesis (for example in abdominal surgery) and at patients without high risk of a thromboembolism the drug Flenoks® is administered in a dose 20 mg (0,2 ml; 2 000 Anti-ha ME) 1 time a day subcutaneously.

To adult patients with high risk of thromboembolisms (coxofemoral, knee joint operation; operations at oncological patients) Flenoks® enter subcutaneously in a dose 40 mg       (0,4 ml; 4 000 Anti-ha) 1 time a day. In the general surgery the first dose has to be entered in 2 hours prior to an operative measure, in orthopedic surgery the first dose has to be entered in 12 hours prior to an operative measure. Duration of preventive treatment averages 7-10 days. In orthopedics appoint Flenoks® in a dose of 40 mg (0,4 ml; 4 000 Anti-ha) 1 time a day within 4 weeks.

Prevention of venous tromboembolic episodes at the therapeutic patients staying on a bed rest: the recommended dose of the drug Flenoks® makes 40 mg (0,4 ml; 4 000 Anti-ha ME) 1 time a day subcutaneously. Фленокс® appoint a minimum to      6 days, treatment duration no more than 14 days.

Prevention of a thrombogenesis in the extracorporal blood circulatory system when carrying out a hemodialysis: the recommended dose for adults – 1 mg/kg (100 Anti-ha ME/kg) body weights of the patient. Фленокс® enter into the arterial highway of the extracorporal blood circulatory system at the beginning of dialysis session. The anticoagulating effect of this dose, as a rule, is enough for carrying out 4-hour dialysis; at identification of rings of fibrin the additional dose of 0,5-1,0 mg/kg of kg can be entered (50-100 Anti-ha of ME/kg).

For patients with high risk of bleeding the dose of an enoksaparin of sodium has to be lowered to 0,5 mg/kg at double vascular access and to 0,75 mg/kg – at unary access. At emergence of fibrinous rings enter an additional dose from 0,5 mg/kg to           1 mg/kg.

Treatment of a deep vein thrombosis which is followed or is not followed by a thromboembolism of a pulmonary artery, at patients without any serious clinical symptoms: any suspicion on emergence of a deep vein thrombosis should be confirmed immediately by means of the corresponding methods of researches.

Dosing.

Фленокс® appoint subcutaneously 1 time a day in a dose 1,5 mg/kg (150 Anti-ha of ME/kg) or 2 times a day in a single dose of 1 mg/kg (100 Anti-ha of ME/kg) each 12 hours.

Dose adjustment of NMG at patients with body weight more than 100 kg and less than 40 kg was not studied. NMG can be less effective at patients with body weight more than 100 kg and result in the increased risk of developing of bleeding at patients with body weight less than 40 kg. Therefore it is necessary to control a clinical condition of these patients carefully.

Duration of treatment of a deep vein thrombosis.

At treatment it is necessary to pass with low-molecular heparin as soon as possible to reception of peroral anticoagulants if there are no contraindications. Duration of treatment of NMG should not exceed 10 days, including time which is necessary for achievement of an equilibrium state peroral coagulants unless it is heavy to reach a balanced state (see. "Special security measures. Control of quantity of thrombocytes"). Therefore therapy by peroral anticoagulants should be begun as soon as possible.

Treatment of unstable stenocardia and myocardial infarction without Q tooth.

The recommended single dose of the drug Flenoks® makes 1 mg/kg (100 Anti-ha of ME/kg) subcutaneously every 12 hours; at the same time appoint acetylsalicylic acid orally (the recommended doses: from 75 to 325 mg orally after an initial load dose of 160 mg).

Duration of treatment is at least 2-8 days, before clinical stabilization of a condition of the patient.

Treatment of an acute myocardial infarction with raising of a segment of ST in a combination with thrombolytic means at patients to whom the subsequent coronary angioplasty, and also at patients to whom this procedure is not carried out is carried out.

The initial intravenous bolyusny injection of the drug Flenoks® is carried out in a dose of 30 mg   (0,3 ml; 3000 Anti-ha ME). Then subcutaneously enter 1 mg/kg (100 Anti-ha of ME/kg) for 15 minutes, then each 12 hours (for the first two subcutaneous injections the maximum total dose makes 10000 Anti-ha of ME).

The first dose of the drug Flenoks® should be entered in 15 minutes prior to or in 30 minutes after the beginning of thrombolytic therapy at any time.  

The recommended duration of treatment makes 8 days or till that time until the patient is written out from a hospital if hospitalization continues less than 8 days.

The accompanying therapy: after emergence of symptoms it is necessary to begin as soon as possible reception of acetylsalicylic acid and to continue in a dose 75-325 mg a day for not less than 30 days if it is not shown differently.

Patients to whom coronary angioplasty is carried out:

- if since the last hypodermic administration of the drug Flenoks® before inflating of a cylinder there passed less than 8 hours, additional administration of drug is not required;

- if since the last hypodermic administration of the drug Flenoks® before inflating of a cylinder there passed more than 8 hours, it is necessary to carry out an intravenous bolyusny injection of 0,3 mg/kg    (30 Anti-ha of ME/kg) the drug Flenoks®. For ensuring accuracy of volumes which are entered injektsionno it is recommended to dissolve drug to 300 Anti-ha of ME/ml (0,3 ml (3000 anti-     Ha ME) to part in 10 ml of solvent (0,9% of solution of sodium of chloride or 5% of solution of glucose)) (see the table).

Volumes which are necessary for injection introduction when cultivation is carried out for patients to whom coronary angioplasty is carried out

Body weight, kg       Necessary dose, Anti-ha ME      Volume necessary for injection
                                                                                  introductions, at cultivation to 300 ME/ml
                                                                                   (i.e. 0,3 ml (3000 Anti-ha ME) drug
                                                                                        Фленокс®, divorced in 10 ml
                                                                                               solvent)), ml

                                                                                                45 1350 4,5
 
                                         50 1500                                                       5
 
                                                                                                55 1650 5,5

                                         60 1800                                                        6
                                                                                                 65 1950 6,5
                                         70 2100                                                         7
                                                                                                75 2250 7,5
                                         80 2400                                                         8
                                                                                                 85 2550 8,5
                                          90 2700                                                         9
                                                                                                95 2850 9,5
                                        100 3000                                                         10

To patients at the age of 75 years is also more senior which are on treatment concerning an acute myocardial infarction with raising of a segment of ST, the initial intravenous bolyusny injection is not carried out. Each 12 hours they should enter subcutaneously a dose of 0,75 mg/kg (75 Anti-ha of ME/kg) (only for the first two injections the dose maximum totally makes 75 mg (7500 Anti-ha of ME).

Features of use:

Laboratory control.

Control of quantity of thrombocytes.

Heparin-induced Thrombocytopenia (HIT).

There is a risk of emergence serious, sometimes thrombogenic, heparin - the induced thrombocytopenia (which was also observed at use of unfractionated heparin and is much more rare – at use of NMG) an immune origin – type GIT II.

Because of existence of such risk it is necessary to define quantity of thrombocytes irrespective of therapeutic indications and the applied dose.

Determination of quantity of thrombocytes needs to be carried out before administration of drug or not later than in 24 hours after an initiation of treatment, and then – two times a week throughout the entire period of treatment.

It is necessary to suspect emergence of GIT if the quantity of thrombocytes does not exceed 100 000/mm3 and/or if reduction of quantity of thrombocytes by 30-50% in comparison with the previous blood test is observed. GIT develops preferential from 5 to 21st day after an initiation of treatment heparin (most often arises for the 10th day).

However at patients about heparin - the induced thrombocytopenia in the anamnesis this complication can arise and much earlier. Isolated cases were observed as well after the 21st day of treatment. It is necessary to try to reveal patients with such anamnesis by detailed poll before an initiation of treatment. Besides, the risk of emergence of a recurrence at repeated use of heparin is observed for many years, and the unlimited span sometimes lasts.

In all cases emergence of GIT is medical emergency which demands consultation of the specialist.

Any considerable reduction of quantity of thrombocytes (for 30-50% in comparison with initial indicators) is a warning sign even if the indicator did not reach a critical level. If decrease in quantity of thrombocytes is observed, then in all cases the following events have to be held:

1. Immediately repeatedly to carry out calculation of quantity of thrombocytes for receiving confirmation.

2. The treatment termination препаратомФленокс® if the received results confirm decrease in quantity of thrombocytes or point to their increase on condition of lack of other obvious reason.

For test for aggregation of thrombocytes іп vitro and an immunological research the sample of blood needs to be placed in a test tube with citrate solution. However in such conditions urgent measures which need to be carried out are based not on test results on aggregation of thrombocytes іп vitro, and on an immunological research which carrying out is caused by difficulties as there are some specialized laboratories which can carry out such tests, and their results can be received at best only in several hours. Nevertheless, these researches are necessary as they can help to diagnose a similar complication as the risk of developing of thrombosis at treatment continuation by the drug Flenoks® is very high.

3. Prevention or treatment of the tromboembolic episodes connected with GIT.

If continuation of anticoagulating therapy is very important, Flenoks® should replace with antitrombotichesky means which belongs to other chemical group, for example of sodium danaparidy or hirudine and appointed in medical or preventive doses individually for each patient.

Transition to peroral anticoagulants can be carried out only after the quantity of thrombocytes was returned to norm as there is a risk of deterioration in a course of thrombosis at use of peroral anticoagulants.

Heparin replacement with peroral anticoagulants.

It is necessary to conduct more intensive monitoring, laboratory researches (the prothrombin time expressed through the international normalized relation (INR)) or to control the effects caused by peroral anticoagulants.

As there is a certain period until peroral anticoagulant reaches a maximum of the action, it is necessary to continue administration of heparin in an equivalent dose so that MNO in two consistently made analyses remained in necessary therapeutic borders.

Monitoring of an anti-factor Ha activities.

As the majority of clinical researches which showed efficiency of NMG, were conducted using the doses calculated depending on the body weight of the patient and without special monitoring of laboratory indicators, advantage of carrying out laboratory researches for the purpose of assessment of efficiency of NMG it is meanwhile not defined.

However monitoring Anti-ha of activity can be useful to reduction of risk of developing of bleeding in certain clinical situations which are most often connected with risk of overdose.

These situations preferential concern medical indications to use of NMG and arise because of doses which are entered to patients with:
slight and average renal failure (the clearance of creatinine   from about 30 to 60 ml/min. calculated by Kokroft's formula). As NMG is removed preferential with urine, unlike standard unfractionated heparin, at any renal failure there can be a relative overdose. The heavy renal failure is a contraindication to use of NMG (see. "Contraindication");
considerable deviations of body weight from norm (very low body weight, a cachexia or obesity);
bleedings of not clear etiology.

Unlike it, monitoring of laboratory indicators is not recommended at use of preventive doses if NMG is applied according to therapeutic recommendations (in particular concerning treatment duration) or during a hemodialysis.

To reveal possible cumulation of heparin at repeated administration of drug, it is recommended to carry out blood sampling at the moment of the greatest activity of drug (based on the available data), that is approximately in 4 hours after carrying out the third injection if remedy is entered in the form of subcutaneous injections 2 times a day.

Question of carrying out repeated researches Anti-ha activities for the purpose of determination of levels of heparin, for example each 2 or 3 days, it is necessary to solve individually, depending on results of the previous research. It is necessary to consider the possibility of dose adjustment of NMG also.

Anti-ha activity depends on NMG and the modes of dosing.

According to information which is based on the existing data average value                (± a standard deviation) which was observed in 4 hours after 7 injections of an enoksaparin in a dose 100 Anti-ha МЕ/кг/на an injection two times a day made 1,20 ± 0,17 Anti-ha of ME/ml.

This average value was calculated at clinical trials during which studying Anti-ha of activity was carried out by a chromogenic method (amidolytic).

Control of the activated partial tromboplastinovy time (aChTV).

Some NMG cause moderate increase in an indicator of aChTV. As clinical value of this test is not established, there is no need to carry out monitoring of treatment with its account.

• Situations which are followed by a certain risk.

It is necessary to increase control of performing treatment in such cases:

- liver failure;

- a peptic ulcer of digestive tract or any other organic lesion at which developing of bleeding is probable;

- vascular chorioretinal disease;

- after surgical intervention on a head and/or spinal cord;

- a lumbar (lumbar) puncture as there is a risk of internal spinal bleeding. Carrying out a puncture should be postponed at a concomitant use of other drugs which influence a hemostasis (see. "Interaction with other medicines").

Drugs of low-molecular heparins are not interchangeable drugs. Low-molecular heparins differ in the molecular mass, relative values of activity Anti-ha of a factor, dosing. It is necessary to adhere strictly to the routes of administration recommended specifically for each of drugs of low-molecular heparins.

Cautions.

•  Risk of developing of bleeding.

It is necessary to adhere to the recommended dosing modes (a dose and duration of treatment). Non-compliance with these recommendations can lead to developing of bleeding, especially patients have groups of the increased risk (patients of advanced age, patients with a renal failure, etc.).

Cases of serious bleeding were observed:
at patients of advanced age, in a particular owing to age deterioration in function of kidneys;
at patients with a renal failure;
if body weight makes less than 40 kg;

- if therapy is carried out longer than the recommended treatment term which makes 10 days;

- at failure to follow therapeutic recommendations (concerning duration of treatment and correction of medical doses taking into account body weight);
at a concomitant use of other drugs (see. "Interaction with other remedies").

Anyway, it is necessary to control carefully a condition of patients of advanced age and patients with a renal failure, and also if treatment lasts more than 10 days. The analysis on definition Anti-ha of activity in certain cases can be useful to drug cumulation identification.

•  Risk of emergence heparin-the induced thrombocytopenia (HIT).

If the patient who receives NMG (in medical or preventive doses) has a tromboembolic episode:
deterioration in a course of thrombosis which treatment is carried out;
phlebitis;
pulmonary thromboembolism;
acute ischemia of the lower extremities;
myocardial infarction or ischemic stroke, it is always necessary to consider possibility of GIT and to immediately define quantity of thrombocytes.

Precautionary measures at use.

Bleeding.

At drug Flenoks® use, as well as at treatment bleeding can arise anticoagulants. In case of developing of bleeding it is necessary to establish its reason and to begin the corresponding treatment.

Function of kidneys.

Before an initiation of treatment low-molecular heparin it is very important to estimate function of kidneys, in particular at patients at the age of 75 years and is more senior, by determination of clearance of creatinine (Kkr) by means of Kokroft's formula and data of body weight (latest).

At patients is a male: Kkr = (140 - age) × body weight / 0,814 × serumal creatinine where the age is expressed advanced in years, body weight – in kg, and serumal creatinine – in µmol/l.

For patients this formula has to be corrected by multiplication of the received result on 0,85.

If serumal creatinine is expressed in mg/ml, the received value needs to be increased by coefficient 8,8.

Use of NMG is contraindicated to patients with the diagnosed heavy renal failure (clearance of creatinine – about 30 ml/min.) except for cases when patients are on a hemodialysis.

Ability to influence speed of response at control of motor transport or work with other mechanisms

 

Does not influence.

Side effects:

Hemorrhagic manifestations are caused preferential:
concurrent factors of risk: organic lesions at which there is a probability of developing of bleeding, age, a renal failure, small body weight and some combinations of remedies (see. "Contraindications" and "Interaction with other medicines");
failure to follow therapeutic recommendations, namely: duration of treatment and dose adjustment taking into account the body weight of the patient (see. "Cautions").

It was reported about isolated cases of developing of a hematoma of a spinal cord during spinal anesthesia, an analgesia or epidural anesthesia which were carried out after use of low-molecular heparin.

These side effects led to neurologic disorders of various degrees of severity, including long or constant paralysis (see. "Features of use").

Developing of a hematoma in the venue of a subcutaneous injection is possible. This risk increases if the recommended technology of introduction is broken or inappropriate means for its carrying out are used. Owing to an inflammation in the place of an injection there can be firm consolidations which take place in several days. However it does not demand the treatment termination.

It was reported about cases of developing of thrombocytopenia. There are two of its types.

The type I which is most often found usually is moderately severe thrombocytopenia (more than 100 000/mm3) which arises till 5 in the afternoon treatments and does not demand the therapy termination.

The type II is very seldom meeting, serious immunoallergic thrombocytopenia (GIT), its prevalence remains insufficiently studied (see. "Cautions").

Also asymptomatic and reversible increase in quantity of thrombocytes is possible. It was reported about very exceptional cases of emergence of a necrosis of skin in the place of an injection. Emergence of a purpura or infiltrirovanny and painful erythematic plaques can precede emergence of these phenomena. In such cases therapy should be stopped immediately.

Seldom there are allergic manifestations from skin or system reactions which in certain cases led to treatment cancellation. Cases of the vasculitis connected with hypersensitivity of skin were very seldom observed.

As well as in case of use of unfractionated heparins, at prolonged treatment it is impossible to exclude risk of development of osteoporosis.

It was reported about emergence of a hyperpotassemia and tranzitorny increase in level of transaminases.

Interaction with other medicines:

Emergence of a hyperpotassemia at simultaneous use of heparin (low-molecular and unfractionated) with potassium salts, kaliysberegayushchy diuretics, angiotensin-converting enzyme inhibitors, antagonists of angiotensin II, non-steroidal anti-inflammatory drugs, cyclosporines and takrolimusy, Trimethoprimum is possible.

Emergence of a hyperpotassemia can depend on the risk factors connected with the course of a disease. The risk considerably increases when the drugs stated above are used at the same time.

Undesirable combinations:

- with salicylates and acetylsalicylic acid in doses which have anesthetic, febrifugal and antiinflammatory action.

Increase in risk of developing of bleeding (oppression of function of thrombocytes under the influence of salicylates and injury of a mucous membrane of a stomach and duodenum);

- with non-steroidal anti-inflammatory drugs (NPVS) (for system use): increase in risk of developing of bleeding (oppression of function of thrombocytes under the influence of NPVS and injury of a mucous membrane of a stomach and duodenum).

If it is impossible to avoid simultaneous use, it is necessary to carry out careful clinical control of a condition of the patient;

- with the Dextran-40 (parenteral administration):

increase in risk of developing of bleeding (oppression of function of thrombocytes under the influence of the Dextran-40).

Combinations which use demands special precautionary measures:

- use with peroral anticoagulants.

Potentiation of anti-coalugating effect. Clinical monitoring should be strengthened when heparin is replaced with peroral anticoagulants.

Combinations which should be considered:

- use with inhibitors of aggregation of thrombocytes (except acetylsalicylic acid in doses which have anesthetic, febrifugal and antiinflammatory action; NPVS): абсиксимаб, acetylsalicylic acid in doses for anti-aggregation which is applied at cardiological and neurologic diseases, берапрост, клопидогрель, эптифибатид, илопрост, тиклопидин, тирофибан.

The increased risk of developing of bleeding.

Contraindications:

Hypersensitivity to a sodium enoksaparin, heparin or its derivatives, including other low-molecular heparins (NMG);
in the anamnesis serious the type heparin-the induced thrombocytopenia (HIT) II, caused by use of unfractionated or low-molecular heparin (see. "Cautions");
hemorrhagic manifestations or tendency to bleedings in connection with disturbance of a hemostasis (the disseminated intravascular blood coagulation not connected with treatment by heparin (see can be a possible exception. "Features of use");
organic lesion with probability of developing of bleeding;
clinically significant active bleeding;
intracerebral bleeding;
heavy renal failure as there are no relevant data of researches (the clearance of creatinine calculated by Kokroft's formula makes about 30 ml/min., (see. "Features of use"), except for cases when patients are on a hemodialysis).

To patients with a heavy renal failure appoint unfractionated heparin. For calculations by means of Kokroft's formula use the latest these body weights (see. "Features of use).
Patients whom administer the drugs of low-molecular heparins cannot carry out spinal or epidural anesthesia.
Children's age.

Фленокс® it is not recommended to apply in the following situations:

-  in an initial phase of a massive ischemic stroke, with a loss of consciousness or without.

If the stroke is caused by a thromboembolism, then эноксапарин has to be entered within the first 72 hours from the moment of developing of a stroke.

Efficiency of use of medical doses of low-molecular heparins irrespective of the reason is not established yet, to degree of prevalence and clinical weight of a stroke of a brain.
Acute infectious endocarditis (except for some thrombogenic heart diseases).
Easy and moderate severity of a renal failure (clearance of creatinine> 30 and    <60 ml/min.).

It is not recommended применятьв to a combination with such means (see. "Interaction with other medicines"), as:
acetylsalicylic acid in doses which have anesthetic, febrifugal and antiinflammatory action;
non-steroidal anti-inflammatory drugs (NPVS) for system use;
Dextran-40 (parenteral administration).

Overdose:

The accidental overdose after hypodermic introduction of considerable doses of low-molecular heparin, can lead to emergence of hemorrhagic complications. Neutralize action of an enoksaparin slow intravenous administration of protamin of sulfate, but at the same time consider that:

- efficiency of protamin of sulfate is much lower, than that that is observed at overdose of unfractionated heparin;

- before sulfate protamin use because of possibility of the undesirable phenomena (in particular an acute anaphylaxis) it is necessary to weigh carefully a ratio advantage/risk. Neutralization is carried out by slow intravenous administration of protamin (sulfate or a hydrochloride).

Necessary doses of protamin depend from:
1.vvedennoy doses of low-molecular heparin (100 anti-heparin units of protamin neutralize 100 Anti-ha of ME of low-molecular heparin) if эноксапарин sodium it was entered within the last 8 hours;
2.vremeni which passed after an injection of low-molecular heparin:

- infusion of 50 anti-heparin units of protamin on 100 Anti-ha of ME of an enoksaparin of sodium can be carried out if эноксапарин sodium it was entered more than 8 hours ago or if it is necessary to enter the second dose of protamin;

- if эноксапарин it was entered more than 12 hours ago, then there is no need for administration of protamin. The recommendations stated above are intended for patients with normal function of kidneys which apply repeated doses of drug.

Nevertheless, completely it is impossible to neutralize Anti-ha activity of an enoksaparin.

This neutralization because of feature of absorption of low-molecular heparin can be temporary and demand distribution of the general calculated protamin dose to several injections (from 2 to 4) which enter within 24 hours. Emergence of undesirable effects after reception of low-molecular heparin inside, even in large numbers, is improbable (any case was not observed) as extent of absorption of this substance in a stomach and intestines is insignificant.

Use during pregnancy or feeding by a breast

 

Фленокс® it is possible to appoint pregnant only in the presence of strict indications and under strict observation of the doctor. Фленокс® it is not recommended to apply at pregnant women with the fitted a prosthesis heart valves.

Never it is necessary to carry out spinal or epidural anesthesia by the patient during treatment with drugs NMG.

Feeding by a breast. During treatment it is necessary to abstain from feeding by a breast.

Children

 

Do not apply as there are no these corresponding researches.

Special security measures

 

The drug is not allowed to be administered intramusculary. At use of an enoksaparin of sodium careful observation of patients is necessary. It is recommended to define quantity of thrombocytes prior to treatment and throughout all course of treatment.

Monitoring of quantity of thrombocytes is necessary irrespective of indications according to which drug and its dosing is appointed.

Storage conditions:

Period of validity. 2 years. Not to use drug after the termination of the period of validity specified on packaging. To store in the place protected from light at a temperature not above 25 °C. Not to freeze. To store in the place, unavailable to children.

Issue conditions:

According to the recipe

Packaging:

On 0,2 ml, 0,4 ml, 0,6 ml or 0,8 ml in the syringe.

On 1 syringe in the blister. On 1, 2 and 10 blisters (with drug activity 2000 Anti-ha ME, 4000 Anti-ha ME, 6000 Anti-ha ME) and on 1 and 2 blisters (with drug activity 8000 Anti-ha ME) enclosed in a pack.

On 2 syringes in the blister. On 1 and 5 blisters (with drug activity 2000 Anti-ha ME, 4000 Anti-ha ME, 6000 Anti-ha ME) and on 1 blister (with drug activity 8000 Anti-ha ME), enclosed in a pack.