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ENOXAPARINE-PHARMEX injection 10,000 anti-XA ME / 1ml

Instruction manual

For medical use of the drug




Active substance: enoxaparin;

1 ml of the solution contains 10,000 anti-XA ME, which is equivalent to 100 mg of enoxaparin sodium;

30,000 anti-Xa IU / 3 ml is equivalent to 300 mg of enoxaparin sodium;

excipients: benzyl alcohol, water for injection.

Dosage form.


Basic physical and chemical properties: clear, colorless or yellowish solution.

Pharmacotherapeutic group.

Antithrombotic agents. heparin group. code atx b01a b05.

Pharmacological properties.


Enoxaparin is a low molecular weight heparin in which the antithrombotic and anticoagulant effects of standard heparin are unrelated. It is characterized by a higher anti-Xa activity than anti-Pa and prothrombin activity. For enoxaparin, the ratio of these two activities is 3.6.

In prophylactic doses, it has no significant effect on activated partial thromboplastin time (aPTT).

At the peak of the activity of therapeutic doses, aPTT can be 1.5–2.2 times the control time. This extension indicates residual antithrombin activity.

Treatment of acute myocardial infarction with ST segment elevation in combination with a thrombolytic agent in patients for whom subsequent use of coronary angioplasty is possible.

In a large multicenter clinical trial, 20479 patients with acute ST segment elevated myocardial infarction, after they received fibrinolytic therapy, were randomly assigned to receive or enoxaparin as a bolus intravenous injection of 3000 anti-XA IU followed by emergency subcutaneous administration of 100 anti -Xa IU / kg, and then subcutaneous injection of 100 anti-XA IU / kg every 12 hours, or for the introduction of intravenous unfractionated heparin as a bolus injection of 60 IU / kg (maximum 4000 IU / kg) with after uyuschey constant infusion dose, which was adjusted for activated partial thromboplastin time (APTT). Subcutaneous injections of enoxaparin were administered before discharge from the hospital or not more than 8 hours (75% for at least 6 days). Half of the patients receiving heparin, the drug was administered for at least 48 hours (in 89.5% of cases 36 hours). All patients also received aspirin for at least 30 days. The dose of enoxaparin for patients aged 75 years was adjusted: 75 IU / kg as a subcutaneous injection every 12 hours without an initial bolus intravenous injection.

During the study, 4716 (23%) patients underwent coronary angioplasty with antithrombotic therapy using masked test drugs. Patients did not receive additional doses if less than 8 hours elapsed from the last subcutaneous injection of enoxaparin to inflate the balloon, or received a bolus intravenous injection of enoxaparin, 30 anti-XA IU / kg, if more than 8 has passed since the last subcutaneous injection of enoxaparin to inflate the balloon hours.

Enoxaparin significantly reduced the frequency of primary end events (combined end event, including recurrence of myocardial infarction and mortality for any reason that occurred within a 30-day period after enrollment in the study: 9.9% in the enoxaparin group compared to 12% in the unfractionated heparin group (reduction in relative risk - 17% (p

The advantage of enoxaparin in terms of the primary endpoint was unconditional regardless of the subgroup: age, gender, localization of myocardial infarction, history of diabetes or myocardial infarction, type of thrombolytic prescribed and the interval between the first clinical signs and the start of treatment.

Enoxaparin showed a significant advantage over unfractionated heparin in terms of the primary performance criterion as in patients undergoing coronary angioplasty in the 30-day period after enrollment in the study (10.8% compared with 13.9%, 23% reduction in relative risk) , and in patients who did not use coronary angioplasty (9.7% compared with 11.4%, a 15% decrease in relative risk).

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

An analysis of the combined criteria by which clinical benefit was measured showed a statistically significant advantage (pTIMI) up to the 30th day, and 17% (10.1% compared with 12.2%) for the combined criteria consisting of mortality, recurrence of myocardial infarction and intracranial hemorrhage until the 30th day.


The pharmacokinetic parameters of enoxaparin were evaluated by the duration of the plasma anti-Xa period and anti-IIA activity at the recommended doses (validated amidolytic methods) after single and repeated subcutaneous injections and after a single intravenous injection.

Bioavailability. Enoxaparin, administered subcutaneously, is rapidly and almost completely absorbed (about 100%). The maximum plasma activity is observed 3-4 hours after administration. This maximum activity (expressed in anti-XA ME) is 0.18 ± 0.04 (after 2000 anti-XA ME), 0.43 ± 0.11 (after 4000 anti-XA ME) with prophylactic treatment and 1.01 ± 0.14 (after 10,000 anti-XA ME) with therapeutic therapy.

A bolus intravenous injection of 3,000 anti-XA IU followed by subcutaneous injections of 100 anti-XA IU / kg every 12 hours provided a maximum concentration of antifactor Xa levels of 1.16 IU / ml (n = 16) and an average exposure of 88 % equilibrium level. An equilibrium level is reached on the second day of treatment.

Within the recommended doses, the pharmacokinetics of enoxaparin is linear. Intrapersonal and interpersonal variability is low. After repeated subcutaneous injections to healthy volunteers of 4000 anti-XA ME once a day, the equilibrium state is reached on the 2nd day, while the average activity of enoxaparin is approximately 15% higher than after a single dose. The level of enoxaparin activity in equilibrium is well predicted in a single dose pharmacokinetics. After repeated subcutaneous administration of 100 anti-XA IU / kg 2 times a day, the equilibrium level is reached on the 3-4th day with an average exposure of about 65% higher than after a single dose, and at the maximum and minimum levels of anti- Xa activity equal to 1.2 and 0.52 anti-XA IU / ml, respectively. Based on the pharmacokinetics of enoxaparin sodium, this difference in the saturation stage is predictable and is within the therapeutic range. Plasma anti-Pa activity after subcutaneous administration is about 10 times lower than anti-Xa activity. The average maximum anti-11a activity is observed approximately 3-4 hours after subcutaneous injection and reaches 0.13 anti-Pa ME / ml with repeated doses of 100 anti-XA ME / kg 2 times a day.

Pharmacokinetic interactions between enoxaparin and a thrombolytic agent with simultaneous administration were not observed.

Distribution. The volume of distribution of anti-Xa activity of enoxaparin is about 5 liters and is close to the volume of blood.

Metabolism. Enoxaparin is metabolized mainly in the liver (desulfation, depolymerization).

After subcutaneous administration, the half-life of anti-Xa activity is lower in low molecular weight heparins than in unfractionated heparins. Enoxaparin is characterized by monophasic elimination with a half-life of about 4 hours after one subcutaneous dose and about 7 hours after repeated administration.

In low molecular weight heparin, a decrease in plasma anti-Pa activity occurs faster than anti-Xa activity.Enoxaparin and its metabolites are excreted by the kidneys (unsaturated mechanism) and with bile. The renal clearance of fragments with anti-Xa activity is about 10% of the administered dose, and the total renal excretion of active and inactive substances is 40% of the dose.

High risk groups.

Patients of advanced age. Excretion is slow due to physiologically reduced renal function in this group. This change does not affect the dosage and administration regimen during prophylactic therapy if the renal function of such patients remains within acceptable limits, that is, when it is only slightly reduced. Before starting treatment with low molecular weight heparin (LMWH) for patients over 75 years of age, it is necessary to systematically examine the function of the kidneys according to the Cockroft formula (see section "Features of use").

Patients with mild or moderate renal failure (creatinine clearance 30 ml / min). In some cases, it may be useful to monitor the activity of the circulating antifactor Xa to prevent overdose if enoxaparin is used for therapeutic purposes (see section "Peculiarities of use").

Hemodialysis. Low molecular weight heparin is introduced into the arterial branch of the dialysis system in doses sufficient to prevent blood coagulation in the system. Pharmacokinetic parameters remain unchanged, with the exception of cases of overdose, in which the drug enters the general bloodstream and can cause high anti-Xa activity associated with end-stage renal failure.

Clinical characteristics.


  • Prevention of venous thromboembolism with moderate or high risk surgical interventions; prevention of blood coagulation in the extracorporeal circulatory system during the hemodialysis procedure (usually with a duration of 4 hours or less); treatment of diagnosed deep vein thrombosis, with or without pulmonary thromboembolism and without severe clinical symptoms, with the exception of pulmonary thromboembolism, which requires treatment with a thrombolytic drug or surgery; treatment of unstable angina pectoris and acute myocardial infarction without q wave in combination with acetylsalicylic acid; treatment of acute myocardial infarction with st segment elevation in combination with a thrombolytic agent in patients for whom further use of coronary angioplasty is possible.


Regardless of the dose (therapeutic or prophylactic) enoxaparin cannot be used in such cases:

  • hypersensitivity to enoxaparin, heparin or its derivatives, including other low molecular weight heparins (LMWH);
  • history of severe heparin-induced thrombocytopenia (HIT) type II caused by unfractionated or low molecular weight heparin (see section "Features of use");
  • bleeding or bleeding tendency associated with impaired hemostasis (an exception may be disseminated intravascular coagulation, if it is not associated with heparin treatment (see section "Peculiarities of use"));
  • organic organ damage with a tendency to bleeding;
  • active bleeding of a clinically significant degree;
  • children under 3 years of age due to benzyl alcohol content. Such patients should be prescribed unfractionated heparin. In preterm infants, with the administration of drugs containing benzyl alcohol, respiratory disturbance such as shortness of breath syndrome (metabolic acidosis, neurological disorders, pauses in breathing, etc.) was observed.

Enoxaparin cannot be used in therapeutic doses in such cases:

- intracerebral hemorrhage;

- an active ulcer of the stomach or duodenum;

- severe renal failure (creatinine clearance of 30 ml / min according to the Cockroft formula), except in some cases in patients undergoing dialysis - due to a lack of relevant data.

Patients with severe renal failure should be prescribed unfractionated heparin.

For calculation according to the Cockcroft formula, you need to know the patient’s body weight according to the latest definitions (see section "Peculiarities of use").

In no case should spinal or epidural anesthesia be used by patients undergoing treatment for LMWH.

Patients receiving heparin for treatment, and not for prevention, do not use local regional anesthesia during planned surgical interventions.

It is not recommended to use this drug in therapeutic doses in such cases:

  • acute acute ischemic stroke of the brain with or without loss of consciousness. If the stroke is caused by an embolism, enoxaparin should not be used in the first 72 hours. The effectiveness of therapeutic doses of LMWH has not yet been determined, regardless of the cause, degree and severity of the clinical manifestations of ischemic stroke;
  • acute infectious endocarditis (except for some embologic heart complications);
  • mild or moderate renal failure (creatinine clearance 30-60 ml / min).

In addition, therapeutic doses of enoxaparin are generally not recommended for patients, regardless of their age, in combination with such drugs (see section "Interaction with other drugs and other types of interactions"):

  • acetylsalicylic acid in painkillers, antipyretic and anti-inflammatory doses;
  • non-steroidal anti-inflammatory drugs (NSAIDs) (systemic use);
  • dextran 40 (parenteral administration).

Enoxaparin in prophylactic doses is not recommended in such cases:

  • patients with severe renal failure (creatinine clearance of 30 ml / min according to the Cockroft formula, see the section "Features of use");
  • in the first 24 hours after intracerebral hemorrhage.

In addition, enoxaparin in prophylactic doses is not recommended for patients over 65 years of age in combination with such drugs (see section "Interaction with other drugs and other types of interactions"):

  • acetylsalicylic acid in painkillers, antipyretic and anti-inflammatory doses;
  • NSAIDs (systemic use);
  • dextran 40 (parenteral administration).

Special security measures.

Although the concentrations of various low molecular weight heparins are determined in international units (IU) of anti-ha activity, their effectiveness is determined not only by their anti-ha activity. it is dangerous to replace one dosing regimen of nmg with another, since each regimen was substantiated by specific clinical studies. therefore, with the use of each drug, special care should be taken and special instructions for use should be followed.


Risk of bleeding. It is necessary to observe the recommended modes of administration (dose and duration of treatment). Failure to follow these recommendations can lead to bleeding, in particular in patients at high risk (elderly patients, with renal failure, etc.).

Cases of severe bleeding have been reported in elderly patients, in particular due to a decrease in renal function that occurs with age; in patients with renal failure; in patients with body weight below 40 kg; during treatment, the duration of which exceeded the recommended average duration of 10 days, if the therapeutic recommendations are not followed (in particular, regarding the duration of treatment and dose adjustment according to body weight during treatment); with simultaneous use with drugs that increase the risk of bleeding (seesection “Interaction with other drugs and other types of interactions”).

Enoxaparin injections, like any other anticoagulant, should be used with caution in conditions for which there is an increased likelihood of bleeding, such as hemostasis, a history of peptic ulcer, recent ischemic stroke, uncontrolled arterial hypertension, diabetic retinopathy, recent neurosurgery or ophthalmic surgery.

In any case, elderly patients, patients with renal failure, as well as patients whose treatment lasts more than 10 days, should be under special supervision.

In some cases, a quantitative determination of anti-Xa activity may be useful for detecting the accumulation of the drug (see section "Features of use").

Risk of heparin-induced thrombocytopenia (HIT). You should always assume the possibility of developing GIT and urgently determine the level of platelets (see section "Features of use").

With the development of such thrombolytic complications in a patient who receives LMWH (in therapeutic or prophylactic doses):

exacerbation of thrombosis, the treatment of which is carried out;


embolism of the lungs;

acute ischemia of the lower extremities;

myocardial infarction or cerebral stroke.

Mechanical prostheses of heart valves. The use of enoxaparin for the prevention of thromboembolic complications in patients with mechanical prosthesis of heart valves has not been separately studied. However, several individual cases of thrombosis have been reported in patients with mechanical prosthetic heart valves who received enoxaparin to prevent thromboembolic complications.

Pregnancy: in a clinical study involving pregnant women with mechanical prosthetic heart valves who received 100 anti-XA ME enoxaparin / kg 2 times a day to reduce the risk of thromboembolic complications, two out of eight women developed thrombosis, which caused valve obstruction, which led to death of mother and fetus. In addition, isolated cases of thrombosis in pregnant women with mechanical prosthetic heart valves receiving enoxaparin for the prevention of thromboembolic complications were reported during post-registration surveillance of the drug.

Therefore, in such patients, the risk of thromboembolic complications is increased.

Interaction with other drugs and other types of interactions.

Certain drugs or therapeutic classes can contribute to the development of hyperkalemia: potassium salts, potassium-sparing diuretics, angiotensin-converting enzyme inhibitors (APFs), angiotensin ii inhibitors, non-steroidal anti-inflammatory drugs (NSAIDs), heparins (low molecular weight or non-fractionated heparin, tacriminoprimin, heparin, and tacrimin.

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

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

Patients under 65 years of age receiving therapeutic doses of LMWH and elderly patients (from 65 years old)

Unwanted combinations. With acetylsalicylic acid in painkillers, antipyretic and anti-inflammatory doses (by extrapolation and other salicylates): increased risk of bleeding (salicylate inhibition of platelet function and damage to the mucous membrane of the digestive tract). Use antipyretic, analgesics that are not related to salicylates (e.g. paracetamol).

With non-steroidal anti-inflammatory drugs (NSAIDs) (systemic use): increased risk of bleeding (inhibition of NSAIDs platelet function and damage to the mucous membrane of the digestive tract).If simultaneous use cannot be avoided, careful clinical observation should be made.

With dextran 40 (parenteral administration): increased risk of bleeding (inhibition of platelet function by 40 dextran).

Combinations requiring preventive measures.

With oral anticoagulants: increased anticoagulant effect. When replacing heparin with an oral anticoagulant, clinical observation should be strengthened.

Combinations requiring careful use.

With platelet aggregation inhibitors (other than acetylsalicylic acid in painkillers, antipyretic and anti-inflammatory doses; NSAIDs): absiximab, acetylsalicylic acid in antiplatelet doses for cardiological and neurological indications, beraprost, clopidrogel, erytrophybrophytibibid, elevated erythrobin tibibatide.

Patients under 65 years of age receiving prophylactic doses of LMWH

Combinations requiring careful use.

The combined use of drugs that affect different phases of hemostasis increases the risk of bleeding. Thus, regardless of the patient’s age, continuous monitoring of the clinical picture should be carried out and, if necessary, laboratory tests should be performed when prophylactic doses of LMWH are prescribed simultaneously with oral anticoagulants, platelet aggregation inhibitors (absiximab, NSAIDs, any dose of acetylsalicylic acid, clopidrogel, systemic glucocorticosteroids , eptifibatid, iloprost, ticlopidine, tirofiban) and thrombolytic agents.

Features of the application.

Precautions for use.

Bleeding. As with all anticoagulants, bleeding may occur (see section “Adverse Reactions”). With the development of bleeding, its cause should be determined and appropriate treatment prescribed.

Kidney function. Before starting treatment with low molecular weight heparin, renal function should be assessed, in particular in patients over 75 years of age, by determining creatinine clearance using the Cockcroft-Gault formula, using data from the last measurement of body weight:

  • for male patients: KK = (140 - age) x body weight / (0.814 x serum creatinine), where age is expressed in years, body weight - in kg, and serum creatinine - in micromol / l;
  • for women, the result obtained by the formula is multiplied by 0.85.
  • if serum creatinine is expressed in mg / ml, the indicator is multiplied by a factor of 8.8.

The use of therapeutic doses of LMWH for patients with diagnosed severe renal failure (creatinine clearance of 30 ml / min) is contraindicated.

Suppression of aldosterone secretion. Heparin can inhibit adrenal secretion of aldosterone, especially in patients with diabetes mellitus, chronic renal failure, metabolic acidosis, elevated levels of potassium in the blood plasma, as well as in patients taking potassium preparations. The risk of hyperkalemia increases with the duration of therapy. In patients with an increased risk of this complication, the level of potassium in the blood plasma should be measured before starting treatment with heparin and regularly monitored in the future, especially if treatment lasts more than 7 days.

Laboratory indicators.

Platelet control.

Heparin-induced thrombocytopenia (GIT). There is a risk of developing severe, sometimes thrombogenic, heparin-dependent thrombocytopenia (which was registered in connection with the use of unfractionated heparin and less often in connection with LMWH) of immunological origin, which is called type II HIT (see also the section “Adverse reactions”).

In connection with this risk, the determination of platelet count is mandatory regardless of the therapeutic indications and the dose administered.

The platelet count must be determined before the introduction of the drug or no later than within 24 hours from the start of treatment, and then 2 times a week during treatment with a standard duration.

If in some cases (for example, surgery on the hip joint, II and III trimesters of pregnancy with a high risk (see section "Use during pregnancy and lactation")), long-term treatment is required, then during the first month of treatment (the period of greatest risk ) platelet count is determined 2 times a week, then 1 time per week until treatment is discontinued.

The presence of GIT should be assumed if the platelet count is below 100,000 / mm3 and / or if between two consecutive determinations a decrease in platelet count by 30–50% is observed. In general, GIT develops 5-21 days after the start of heparin treatment (most cases occur 10 days later).

However, in patients with a history of heparin-induced thrombocytopenia, this complication can occur much earlier, some cases were reported after 21 days. Thus, patients with such a history should be systematically identified, conducting detailed interviews with patients before starting treatment. In addition, the risk of relapse upon resumption of heparin treatment may persist for several years or even for an unlimited time (see section "Contraindications").

In all cases, GIT is a critical condition and requires a specialist opinion.

Any significant decrease in platelet count (30–50% relative to baseline) is a warning sign even before this indicator reaches a critical level. In all cases of platelet reduction, it is necessary:

1) urgently check the platelet count;

2) stop treatment with heparin, if the result confirms a drop in platelet count and there is no other obvious reason for this phenomenon.

A blood sample is taken into a citrate tube for in vitro platelet aggregation tests and immunological tests. However, in such conditions, urgent measures are not taken based on the results of in vitro platelet aggregation tests or immunological analysis, since such tests are carried out in the usual manner only in some specialized laboratories, and the results, at best, are ready only after a few hours. Nevertheless, these tests are necessary to diagnose complications, since with continued treatment with heparin, the risk of developing thrombosis is very high;

3) to prevent or treat thrombotic complications associated with GIT.

If there is a need to continue anticoagulant therapy, heparin should be replaced with an antithrombotic agent of another group, for example, sodium danaparoid or hirudin, which are prescribed in therapeutic or prophylactic doses for each case separately. Replacement with an oral anticoagulant is possible only after normalization of the platelet level due to the risk of exacerbation of thrombosis under the influence of oral anticoagulants.

Replacing heparin with oral anticoagulants. Clinical observation should be strengthened and the frequency of laboratory tests (prothrombin time expressed as INR) should be increased to monitor the effects of oral anticoagulants.

Due to the existence of a period preceding the development of the maximum effect of an oral coagulant, heparin treatment should be carried out in a constant dose for a time sufficient to maintain INR in the interval between two consecutive analyzes desired for this therapeutic indication.

Control of anti-Xa activity. Since most of the clinical studies that demonstrated the effectiveness of LMWH were carried out using a dose calculated on the basis of body weight without special laboratory control, the need for laboratory tests to determine the effectiveness of treatment for LMWH has not been established. However, in certain clinical conditions, which are often associated with an overdose risk, monitoring of anti-Xa activity may be useful in controlling the risk of bleeding.

In connection with the doses that are prescribed, such cases mainly relate to medical indications for the use of LMWH for patients:

  • with mild to moderate renal failure (creatinine clearance of 30-60 ml / min according to the Cockcroft formula). Since, unlike standard unfractionated heparin, LMWH is excreted mainly by the kidneys, any renal failure can cause a relative overdose. Severe renal failure is a contraindication to the use of LMWH in therapeutic doses (see section "Contraindications"); -
  • with very high or low body weight (thinness or even cachexia, obesity);
  • with bleeding of an unknown etiology.

On the contrary, laboratory monitoring is not recommended in the case of prophylactic doses, if the treatment of LMWH is carried out according to therapeutic recommendations (in particular, according to the duration of treatment), as well as during hemodialysis.

To identify possible accumulation of heparin after repeated administration, it is recommended, if necessary, to take blood for analysis at the peak of activity (according to available data, that is, 4 hours after the third injection with subcutaneous injection of the drug 2 times a day).

The need for repeated analyzes of anti-Xa activity to determine the level of heparin in the blood, for example, every 2-3 days, is decided individually, depending on the results of the preliminary analysis. It may also be necessary to adjust the dose of LMWH.

Certain anti-Xa activity varies depending on the type of LMWH and the dosage regimen.

Note: based on the available data, the average indicator (± standard deviation) observed 4 hours after the 7th injection of enoxaparin, which was administered at a dose of 100 anti-XA IU / kg / injection 2 times a day, is 1.20 ± 0.17 anti-XA ME / ml.

This average value was observed during clinical studies on the quantitative determination of anti-Xa activity by the chromogenic (amidolytic) method.

Activated partial thromboplastin time (aPTT). Some LMWH moderate increases in APTT. Since the clinical significance of this indicator has not been proven, there is no need to use this test to monitor treatment.

Spinal / epidural anesthesia in patients with prophylactic treatment of LMWH. As with other anticoagulants, with the use of NMH, infrequent cases of spinal hematomas were recorded with spinal / epidural anesthesia, which caused prolonged or permanent paralysis. The risk of developing spinal hematoma is higher with epidural anesthesia with a catheter than with spinal anesthesia. The risk of such infrequent changes increases with prolonged use of epidural catheters in the postoperative period. In the case when the doctor decides on the appointment of anticoagulants during epidural / spinal anesthesia, vigilance and frequent monitoring are necessary to detect any signs of neurological disorders, such as midline pain, impaired sensory and motor functions (numbness or weakness of the lower limbs), intestinal and / or bladder dysfunction. Patients should be instructed to immediately inform their doctor of any of the above symptoms. If spinal hematoma is suspected, urgent diagnostic and therapeutic measures should be initiated, including spinal cord decompression intervention.

If postoperative treatment of LMWH is required (prolonged bed rest, trauma) and if the benefits of local / regional spinal anesthesia are carefully weighed, patients who received an LMWH injection in the postoperative period can be anesthetized provided that heparin and spinal anesthesia have passed not less than 12 hours.

Strict neurological monitoring is recommended because of the risk of spinal hematoma.

In almost all patients, prophylactic treatment of LMWH can be started 6–8 hours after anesthesia or after removal of the catheter, providing neurological control.

Particular care should be taken when administering the drug simultaneously with other drugs that affect hemostasis (especially non-steroidal anti-inflammatory drugs, aspirin).

The conditions associated with special risk (it is necessary to strengthen monitoring of the course of treatment):

liver failure;

gastrointestinal ulcers or other organic lesions with a history of bleeding;

vascular obstruction