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Active ingredients
Dabigatran etexilate
Release form
Capsules
Composition
Dabigatran etexilate mesilate 86.48 mg, which corresponds to the content of dabigatran etexilate 75 mg. Additional substances: acacia gum - 4.43 mg, tartaric acid, coarse-grained - 22.14 mg, tartaric acid, powder - 29.52 mg, tartaric acid, crystalline - 36.9 mg, hypromellose - 2.23 mg, dimethicone - 0.04 mg, talc - 17.16 mg, hyprolose (hydroxypropylcellulose) - 17.3 mg. Capsule shell composition: hypromellose capsule (HPMC) with overprinted in black ink - 60 * mg. Composition of HPMC capsules: carrageenan (E407) - 0.2 mg, potassium chloride - 0.27 mg, titanium dioxide (E171) - 3.6 mg, indigo carmine (E132) - 0.036 mg, dye sunsets yellow (E110) - 0.002 mg, hypromellose (hydroxypropylmethylcellulose) - 52.9 mg, purified water - 3 mg. The composition of black ink (%, mass.): Shellac - 24-27%, butanol - 1-3%, isopropanol - 1-3%, iron dye black oxide (E172) - 24-28%, purified water - 15-18 %, propylene glycol - 3-7%, ethanol - 23-26%, ammonia water - 1-2%, potassium hydroxide - 0.05-0.1%.
Pharmacological effect
Direct inhibitor of thrombin. Dabigatran etexilate is a low molecular weight, non-pharmacologically active precursor of the active form of dabigatran. After ingestion of dabigatran, etexilate is rapidly absorbed from the gastrointestinal tract and, by hydrolysis catalyzed by esterases, in the liver and blood plasma is converted into dabigatran. Dabigatran is a potent competitive reversible direct inhibitor of thrombin and the main active substance in blood plasma. Since thrombin (serine protease) converts fibrinogen to fibrin in the process of coagulation, the suppression of its activity prevents the formation of a blood clot. Dabigatran inhibits free thrombin, fibrin-binding thrombin and thrombin-induced platelet aggregation. In experimental studies on various models of thrombosis in vivo and ex vivo, the antithrombotic effect and the anticoagulant activity of dabigatran after iv administration and dabigatran etexilate were confirmed after oral administration. A direct correlation between the concentration of dabigatran in the blood plasma and the severity of the anticoagulant effect was established. Dabigatran lengthens APTT, ekarinovo clotting time (EVS) and thrombin time (TV). Prevention of venous thromboembolism (VTE) after endoprosthetics of large joints. Results of clinical studies in patientsthose who underwent orthopedic operations - endoprosthetics of the knee and hip joints - confirmed the retention of hemostasis parameters and the equivalence of dabigatran etexilate in doses of 75 mg or 110 mg 1-4 hours after surgery and the subsequent maintenance dose of 150 mg or 220 mg 1 time / day for 6 10 days (with surgery on the knee joint) and 28-35 days (on the hip joint) compared with enoxaparin at a dose of 40 mg 1 time / day, which was used the day before and after surgery. The equivalence of the antithrombotic effect of dabigatran etexilate was shown when used in doses of 150 mg or 220 mg compared to enoxaparin at a dose of 40 mg / day when assessing the main endpoint, which includes all cases of venous thromboembolism and mortality from any causes. Prevention of stroke and systemic thromboembolism in patients with atrial fibrillation With prolonged, on average about 20 months, use in patients with atrial fibrillation and with moderate or high risk of stroke or systemic thromboembolism, it was shown that dabigatran etexilate at a dose of 110 mg, used 2 times / day, was not inferior to warfarin in terms of the effectiveness of stroke prevention and systemic thromboembolism in patients with atrial fibrillation, and in the dabigatran group, a decrease in the risk of intracranial bleeding was noted and boiling in bleeding. The use of the drug in a higher dose (150 mg 2 times / day) significantly reduced the risk of ischemic and hemorrhagic stroke, cardiovascular death, intracranial bleeding, and general bleeding rate, compared with warfarin. A lower dose of dabigatran was characterized by a significantly lower risk of major bleeding compared with warfarin. The net clinical effect was assessed by determining a combined endpoint, including the incidence of stroke, systemic thromboembolism, pulmonary embolism, acute myocardial infarction, cardiovascular mortality, and major bleeding. The annual incidence of these events in patients who received dabigatran etexilate was lower than in patients who received warfarin. Changes in laboratory parameters of liver function in patients who received dabigatran etexilate were observed with comparable or lower frequency compared with patients receiving warfarin.Thromboembolic prophylaxis in patients with prosthetic heart valves During clinical studies of phase II use of dabigatran and warfarin in patients who underwent surgery to replace a heart valve with a mechanical prosthesis (recently performed operations and surgeries more than 3 months ago), an increase in the incidence of thromboembolism and general the number of bleeding (mainly due to small bleeding) in patients who received dabigatran etexilate. In the early postoperative period, major bleeding was mainly characterized by a hemorrhagic effusion in the pericardium, especially in patients to whom dabigatran etexilate was prescribed in the early period (on day 3) after surgical replacement of the heart valves. Treatment of acute deep vein thrombosis (THV) and / or pulmonary thromboembolism (PE) and prevention of deaths caused by these diseases The results of clinical studies in patients with acute THV and / or PEH who initially received parenteral therapy for at least 5 days, it was confirmed that dabigatran etexilate in a dose of 150 mg, used 2 times / day, was not inferior to warfarin in terms of effectiveness in reducing the frequency of recurrent symptomatic DVT and / or pulmonary embolism and deaths due to these diseases during the 6-month treatment period. In patients who received dabigatran etexilate, bleeding was observed much less frequently than in patients who received warfarin. The incidence of myocardial infarction in all ongoing studies with VTE in all treatment groups was low. Prevention of recurrent DVT and / or pulmonary embolism and deaths caused by these diseases The results of a clinical study in patients with recurrent DVT and pulmonary embolism who had received anticoagulant therapy for 3 to 12 months and needed to continue it, confirmed that treatment with dabigatran etexilate 150 mg 2 times / day was not inferior to the therapeutic effect of warfarin (p = 0.0135). In patients who received dabigatran etexilate, bleeding was observed much less frequently than in patients who received warfarin. In a study comparing dabigatran etexilate with placebo in patients already receiving vitamin K antagonists for 6 to 18 months, it was found that dabigatran was superior to placebo in preventing recurrent symptomatic DVT / TELA, including deaths from an unknown cause, reducing the risk over the period treatment was 92% (less than 0.0001).The incidence of myocardial infarction in all ongoing studies with VTE in all treatment groups was low. Indicators of liver function In studies using active comparison drugs, possible changes in liver function indicators occurred in patients who received dabigatran etexilate, with comparable or lower frequency than in patients who received warfarin. In the study with placebo, there was no significant difference in changes in liver function indicators, which may have clinical significance, between the groups using dabigatran etexilate and placebo.
Pharmacokinetics
Absorption: After oral administration of dabigatran etexilate, a rapid dose-dependent increase in its plasma concentration and AUC is observed. Cmax of dabigatran etexilate is reached within 0.5-2 hours. After reaching Cmax plasma concentrations of dabigatran decrease biexponentially. The absolute bioavailability of dabigatran after ingestion of the drug in capsules coated with hypromellose is about 6.5%. Eating does not affect the bioavailability of dabigatran etexilate, however, the time to achieve Cmax increases by 2 hours. When using dabigatran etexilate without a special capsule shell made of hypromellose, the bioavailability by ingestion may increase by about 1.8 times (75%) compared to drug form in capsules. Therefore, the integrity of capsules made of hypromellose should be maintained, given the risk of increasing the bioavailability of dabigatran etexilate, it is not recommended to open the capsules and use their contents in their pure form (for example, adding to food or drinks). When using dabigatran etexilate after 1-3 hours in patients after surgical treatment, there is a decrease in the rate of absorption of the drug compared with healthy volunteers. AUC is characterized by a gradual increase in amplitude without the appearance of a high peak plasma concentration. Сmax in the blood plasma is observed 6 h after the use of dabigatran etexilate or 7-9 h after the operation. It should be noted that such factors as anesthesia, paresis of the gastrointestinal tract and surgery can be important in slowing the absorption, regardless of the dosage form of the drug. A decrease in the rate of absorption of the drug is usually noted only on the day of surgery.In the following days, the absorption of dabigatran occurs quickly, with the achievement of Cmax 2 hours after it is ingested. Distribution: Vd dabigatran is 60-70 liters and exceeds the volume of the total water content in the body, which indicates a moderate distribution of dabigatran in the tissues. Dabigatran has a low ability to bind to plasma proteins (34-35%), not dependent on the concentration of the drug. Metabolism: After ingestion in the process of hydrolysis under the influence of dabigatran esterase, etexilate quickly and completely turns into dabigatran, which is the main active metabolite in blood plasma. When conjugating dabigatran, 4 isomers of pharmacologically active acylglucuronides are formed: 1-O, 2-O, 3-O, 4-O, each of which is less than 10% of the total content of dabigatran in the blood plasma. Traces of other metabolites are detected only by using highly sensitive analytical methods. Excretion: Dabigatran is excreted unchanged, mainly by the kidneys (85%), and only 6% through the gastrointestinal tract. It was established that after 168 hours after the administration of the labeled radioactive drug, 88-94% of its dose is excreted from the body. The final T1 / 2 after repeated use of the drug was about 12-14 hours. T1 / 2 does not depend on the dose. Pharmacokinetics in special groups of patients Elderly patients: In elderly people, the AUC value is 1.4–1.6 times higher (than in young people), by 1.4–1.6 times (by 40–60%), and Cmax - by more than 1.25 times (by 25%). The observed changes correlated with an age-related decrease in QA. In older women (over 65 years), the AUCt, ss and Cmax, ss values were about 1.9 times and 1.6 times higher than among younger women (18-40 years old), and in older men, 2.2 and 2.0 times higher than that of young men. The study of patients with atrial fibrillation confirmed the effect of age on the exposure of dabigatran: initial concentrations of dabigatran in patients aged ≥75 years were about 1.3 times (31%) higher, and in patients less than 65 years old - about 22% lower, than in patients aged 65-75 years. In elderly patients, the final T1 / 2 averages about 11 hours. Renal dysfunction: In the case of renal impairment, T1 / 2 is lengthened. In volunteers with moderate renal dysfunction (CK 30-50 ml / min), the AUC value of dabigatran after oral administration was approximately 3 times greater than in individuals with unchanged kidney function.In patients with severe impaired renal function (CK 10–30 ml / min), the AUC values of dabigatran etexilate and T1 / 2 increased 6 and 2 times, respectively, compared with those in patients without renal impairment. In patients with atrial fibrillation and moderate renal insufficiency (CC 30-50 ml / min), the AUC of dabigatran before and after the use of the drug was on average 2.29 and 1.81 times greater than in patients without renal dysfunction. In the treatment of acute DVT and / or pulmonary embolism and the prevention of deaths caused by these diseases in patients with mild to moderate renal failure (CK 30-50 ml / min), the basal concentration of dabigatran in the equilibrium state of pharmacokinetics was 1.7 in average and 3.4 times higher than in patients with CC more than 80 ml / min. When using hemodialysis in patients without atrial fibrillation, it was found that the amount of the drug excreted is proportional to the speed of blood flow. The duration of dialysis, with a dialysate flow rate of 700 ml / min, was 4 hours, and a blood flow rate was 200 ml / min or 350-390 ml / min. This resulted in the removal, respectively, of 50% and 60% of the concentrations of free and total dabigatran. The anticoagulant activity of dabigatran decreased with decreasing plasma concentrations, the relationship of pharmacokinetics and pharmacodynamics did not change. Liver dysfunction: In patients with moderately impaired liver function (7–9 points on the Child-Pugh scale), there was no change in the concentration of dabigatran in the blood plasma compared with patients without dysfunction of the liver. Body weight: In studies, basal concentrations of dabigatran in patients weighing more than 100 kg were approximately 20% lower than in patients with a body weight of 50-100 kg. The body weight of most (80.8%) patients was ≥50-less than 100 kg, within this range there were no obvious differences in the concentrations of dabigatran. Data for patients weighing ≤50 kg is limited. Gender: In the main studies on the prevention of the development of VTE, it was found that the effect of the drug in women was about 1.4-1.5 times (40-50%) higher. In patients with atrial fibrillation, basal concentrations and concentrations after using the drug were on average 1.3 (30%) higher. The established differences had no clinical significance.Ethnic groups: In a comparative study of the pharmacokinetics of dabigatran in Europeans and Japanese after a single and repeated administration of the drug in the studied ethnic groups, no clinically significant differences were found. Pharmacokinetic studies in patients of the Negroid race are limited, but available data indicate a lack of significant differences.
Indications
- prevention of venous thromboembolism in patients after orthopedic operations; prevention of stroke, systemic thromboembolism and reduction of cardiovascular mortality in patients with atrial fibrillation; treatment of acute deep vein thrombosis and / or thromboembolism of the arterial artery; and prevention of deaths caused by these diseases — prevention. veins and / or thromboembolism of the pulmonary artery and deaths caused by these diseases.
Contraindications
- severe renal failure (CC less than 30 ml / min) - active clinically significant bleeding, hemorrhagic diathesis, spontaneous or pharmacologically induced hemostasis - organ damage as a result of clinically significant bleeding, including hemorrhagic stroke during the previous 6 months before the start of therapy — significant risk the development of large bleeding from existing or recent ulceration of the gastrointestinal tract, the presence of malignant tumors with a high risk of bleeding, recent head damage th or the spinal cord, recent surgery on the brain or spine, or ophthalmic surgery, recent intracranial hemorrhage, the presence or suspicion of varicose veins of the esophagus, congenital arteriovenous defects, vascular aneurysms or large intravertebral or intracerebral vascular narusheniya- co-administration of any other anticoagulants, including fractional heparin, low molecular weight heparins (including enoxaparin, dalteparin), heparin derivatives (including fondaparinux ), oral anticoagulants (including warfarin, rivaroxaban, apixaban), with the exception of switching treatment with or to the drug Pradaxa; or in the case of using unfractionated heparin in doses necessary to maintain a central venous or arterial catheter — simultaneous administration of ketoconazole for systemic use, cyclosporine,Itraconazole, tacrolimus and dronedarone — abnormal liver function and liver disease that may affect survival — the presence of a prosthetic heart valve — children and adolescents under 18 years of age (no clinical data) —sensitivity to dabigatran or dabigatran etexilate or to one of auxiliary substances With caution, you should use the drug in conditions that increase the risk of bleeding: - age 75 years and older - moderate decrease in kidney function (CC 30-50 ml / min) - simultaneous use P-glycoprotein inhibitors (with the exception of those indicated in the section Contraindications) - body weight less than 50 kg — simultaneous administration of NSAIDs (including acetylsalicylic acid), clopidogrel, selective serotonin reuptake inhibitors and selective noradrenaline reuptake inhibitors, as well as other drugs whose use can disrupt hemostasis — congenital or acquired diseases of the blood coagulation system — thrombocytopenia or functional defects of platelets — a recent biopsy or transfusion Worn extensive traumatic bacterial endokardit- esophagitis, gastritis or gastroesophageal reflux disease.
Dosage and administration
Capsules should be taken orally, 1 or 2 times / day, regardless of the time of meals, with a glass of water to facilitate the passage of the drug in the stomach. Do not open the capsule. To remove the capsules from the blister: - tear up one individual blister from the blister packaging along the perforation line, - remove the capsule from the blister by peeling off the foil, - do not squeeze the capsules through the foil. The drug is prescribed for adults. Prevention of venous thromboembolism (VTE) in patients after orthopedic operations: the recommended dose is 220 mg 1 time / day (2 capsules, 110 mg each). In patients with moderate renal impairment due to the risk of bleeding, the recommended dose is 150 mg 1 time / day (2 capsules, 75 mg each). Prevention of VTE after knee arthroplasty: the use of the drug Pradaxa; should begin after 1-4 hours after completion of the operation with receiving 110 mg (1 caps.), followed by increasing the dose to 220 mg (2 caps.) / day 1 time / day for the next 10 days. If hemostasis is not achieved, treatment should be postponed.If treatment has not begun on the day of surgery, therapy should begin with taking 220 mg (2 capsules) / day 1 time / day. Prevention of VTE after hip arthroplasty: the use of the drug Pradaxa; should begin after 1-4 hours after completion of the operation with a dose of 110 mg (1 capsule), followed by increasing the dose to 220 mg (2 capsules) / day 1 time / day for the next 28-35 days. If hemostasis is not achieved, treatment should be postponed. If treatment has not begun on the day of surgery, therapy should begin with taking 220 mg (2 capsules) / day 1 time / day. Prevention of stroke, systemic thromboembolism and reduction of cardiovascular mortality in patients with atrial fibrillation: the use of the drug Pradaxa is recommended; in a daily dose of 300 mg (1 capsule. 150 mg 2 times / day). Therapy must be continued for life. Treatment of acute DVT and / or pulmonary embolism and prevention of deaths caused by these diseases: the use of the drug Pradaxa is recommended; in a daily dose of 300 mg (1 caps. 150 mg 2 times / day) after parenteral treatment with an anticoagulant for at least 5 days. Therapy should be continued until 6 months. Prevention of recurrent THV and / or pulmonary embolism and deaths caused by these diseases: the use of the drug Pradaxa is recommended; in a daily dose of 300 mg (1 capsule. 150 mg 2 times / day). Therapy can continue for life, depending on the individual risk factors. Use in patients with impaired renal function: Before therapy, in order to avoid administering the drug to patients with severe impaired renal function (CC less than 30 ml / min), it is necessary to preliminarily evaluate CC. In connection with the lack of data on the use of the drug in patients with severely impaired renal function (CC less than 30 ml / min), the use of the drug Pradaxa; contraindicated. Renal function should be assessed in the course of treatment when there is a suspicion of a possible decrease or deterioration of renal function (for example, in case of hypovolemia, dehydration, simultaneous use of certain drugs). During clinical trials of the drug Pradaxa; As a method for assessing kidney function, the calculation of QC using the Cockroft-Gault formula was used. Dabigatran is derived from hemodialysis, but clinical experience with patients undergoing hemodialysis is limited.When using the drug Pradaxa; in order to prevent venous thromboembolism in patients after orthopedic operations with moderate renal impairment (CC 30-50 ml / min), the daily dose should be reduced to 150 mg (2 capsules 75 mg 1 time / day). When using the drug Pradaxa; In order to prevent stroke, systemic thromboembolism and reduce cardiovascular mortality in patients with atrial fibrillation with moderate renal impairment (CC 30-50 ml / min), dose adjustment is not required. The use of the drug is recommended in a daily dose of 300 mg (1 capsule. 150 mg 2 times / day). Renal function should be assessed at least once a year. When using the drug Pradaxa; for the purpose of treating acute DVT and / or PE, and preventing deaths caused by these diseases, dose adjustment is not required in patients with CC greater than 30 ml / min. The use of the drug is recommended in a daily dose of 300 mg (1 capsule. 150 mg 2 times / day). When using the drug Pradaxa; In order to prevent recurrent THV and / or pulmonary embolism and deaths caused by these diseases in patients with moderate renal impairment (CC 30-50 ml / min), dose adjustment is not required. The use of the drug is recommended in a daily dose of 300 mg (1 capsule. 150 mg 2 times / day). Renal function should be assessed at least once a year. Use in elderly patients: Due to the fact that the increase in drug exposure in elderly patients (over 75 years old) is often due to a decrease in kidney function, it is necessary to evaluate kidney function before prescribing the drug. Renal function should be assessed at least once a year or more often, depending on the clinical situation. Dose adjustment of the drug should be carried out depending on the severity of renal dysfunction. Prevention of venous thromboembolism after orthopedic operations in patients over 75 years of age: experience with the use of limited. The recommended dose is 150 mg (2 caps. 75 mg in a single dose). When using the drug Pradaxa; in patients older than 80 years for the prevention of stroke, systemic thromboembolism and reduction of cardiovascular mortality in patients with atrial fibrillation Pradaxa; should be taken in a daily dose of 220 mg (1 capsule. 110 mg 2 times / day). Treatment of acute DVT and / or pulmonary embolism and prevention of deaths caused by these diseases in patients over 75 years of age: dose adjustment is not required. The use of the drug is recommended in a daily dose of 300 mg (1 capsule. 150 mg 2 times / day).Prevention of recurrent THV and / or pulmonary embolism and death caused by these diseases in patients over 75 years of age: dose adjustment is not required. The use of the drug is recommended in a daily dose of 300 mg (1 capsule. 150 mg 2 times / day). Use in children: In patients under the age of 18, the efficacy and safety of the use of the drug Pradaxa; not studied, so the use of the drug in children is not recommended. Patients with different body weight: Prevention of venous thromboembolism after orthopedic operations in patients with a body weight of less than 50 kg and more than 110 kg of experience use is limited. In accordance with the pharmacokinetic and clinical data dose adjustment is not required. However, observation of such patients is recommended. Prevention of stroke, systemic thromboembolism and reduction of cardiovascular mortality in patients with atrial fibrillation: dose adjustment is not required according to pharmacokinetic and clinical data. However, patients weighing less than 50 kg should be monitored. Treatment of acute DVT and / or pulmonary embolism and prevention of deaths caused by these diseases: do not require dose adjustment depending on body weight. Prevention of recurrent THV and / or pulmonary embolism and deaths caused by these diseases: dose adjustment is not required depending on body weight. The simultaneous use of the drug Pradaxa; with active inhibitors of P-glycoprotein (amiodarone, quinidine, verapamil) Prevention of venous thromboembolism after orthopedic operations: with simultaneous use with amiodarone, quinidine or verapamil dose of the drug Pradaxa; should be reduced to 150 mg 1 time / day (2 capsules. 75 mg). Patients taking the drug Pradaxa; after orthopedic operations, it is not recommended to simultaneously begin the use of verapamil and connect it to therapy in the future. Prevention of stroke, systemic thromboembolism and reduction of cardiovascular mortality in patients with atrial fibrillation: dose adjustment is not required, the use of the drug is recommended in a daily dose of 300 mg (1 caps. 150 mg 2 times / day). Treatment of acute DVT and / or pulmonary embolism and prevention of deaths caused by these diseases: dose adjustment is not required. Recommended use of the drug in a daily dose of 300 mg (1 caps.150 mg 2 times / day). Prevention of recurrent THV and / or pulmonary embolism and death caused by these diseases: dose adjustment is not required. The use of the drug is recommended in a daily dose of 300 mg (1 capsule. 150 mg 2 times / day). Use in patients with an increased risk of bleeding: Prevention of stroke, systemic thromboembolism and reduction of cardiovascular mortality in patients with atrial fibrillation: the presence of factors such as age 75 years or older, moderate reduction in renal function (CC 30-50 ml / min), simultaneous use of P-glycoprotein inhibitors, or a history of gastrointestinal bleeding may increase the risk of bleeding. In patients with one or more of these risk factors, at the discretion of the physician, a reduction in the daily dose of Pradaxa may be possible; up to 220 mg (1 capsule. 110 mg 2 times / day). Treatment of acute DVT and / or pulmonary embolism and prevention of deaths caused by these diseases: the presence of such factors as age 75 years or older, a moderate decrease in kidney function (CC 30-50 ml / min) or an indication of a history of gastrointestinal bleeding risk of bleeding. In patients with a single risk factor, dose adjustment is not required. For patients with multiple risk factors, clinical data are limited. In these patients, the drug should be used only in cases where the expected benefit exceeds the risk of bleeding. Prevention of recurrent THV and / or pulmonary embolism and deaths caused by these diseases: the presence of factors such as 75 years or older, a moderate decrease in kidney function (CC 30-50 ml / min) or an indication of a history of gastrointestinal bleeding bleeding. In patients with one risk factor: dose adjustment is not required. For patients with multiple risk factors, clinical data are limited. In these patients, the drug should be used only in cases where the expected benefit exceeds the risk of bleeding. The transition from the use of the drug Pradaxa; to parenteral use of anticoagulants: Prevention of venous thromboembolism in patients after orthopedic operations: parenteral administration of anticoagulants should be started 24 hours after taking the last dose of Pradaxa ;.Prevention of stroke, systemic thromboembolism and reduction of cardiovascular mortality in patients with atrial fibrillation: parenteral use of anticoagulants should be started 12 hours after taking the last dose of Pradaxa ;. Treatment of acute DVT and / or pulmonary embolism and prevention of deaths caused by these diseases: parenteral use of anticoagulants should be started 12 hours after taking the last dose of Pradaxa ;. Prevention of recurrent THV and / or pulmonary embolism and deaths caused by these diseases: parenteral use of anticoagulants should be started 12 hours after taking the last dose of Pradaxa ;. The transition from parenteral use of anticoagulants to the use of the drug Pradaxa ;: The first dose of the drug Pradaxa; appointed instead of the canceled anticoagulant in the range of 0-2 hours before the next injection of alternative therapy, or simultaneously with the cessation of continuous infusion (for example, in / in the use of unfractionated heparin). The transition from the use of vitamin K antagonists to the use of the drug Pradaxa: Prevention of stroke, systemic thromboembolism and reduction of cardiovascular mortality in patients with atrial fibrillation: the use of vitamin K antagonists is stopped, the use of the drug Pradaxa; possible with an MHO less than 2.0. Treatment of acute DVT and / or pulmonary embolism and prevention of deaths caused by these diseases: discontinue the use of vitamin K antagonists, the use of the drug Pradaxa; possible with an MHO less than 2.0. Prevention of recurrent THV and / or pulmonary embolism and deaths caused by these diseases: the use of vitamin K antagonists is stopped, the use of the drug Pradaxa; possible with an MHO less than 2.0. The transition from the use of the drug Pradaxa; for use of vitamin K antagonists: Prevention of stroke, systemic thromboembolism and reduction of cardiovascular mortality in patients with atrial fibrillation: for CC ≥50 ml / min, vitamin K antagonists can be used in 3 days, and for CC 30-50 ml / min - for 2 days before discontinuation of the drug Pradaxa ;. Treatment of acute DVT and / or pulmonary embolism and prevention of deaths caused by these diseases: with CC ≥50 ml / min, vitamin K antagonists can be used for 3 days, and for CC 30-50 ml / min - 2 days before discontinuation of Pradaxa; .Prevention of recurrent THV and / or pulmonary embolism and deaths caused by these diseases: with CC ≥50 ml / min, use of vitamin K antagonists is possible for 3 days, and for CC 30-50 ml / min - 2 days before discontinuation of the drug Pradaxa ;. Cardioversion: Prevention of stroke, systemic thromboembolism and reduction of cardiovascular mortality in patients with atrial fibrillation. Conducting planned or emergency cardioversion does not require discontinuation of therapy with Pradaxa; Missed dose: Prevention of venous thromboembolism in patients after orthopedic operations: it is recommended to take the usual daily dose of Pradaxa; at the usual time the next day. In case of missing individual doses, you should not take a double dose of the drug. Prevention of stroke, systemic thromboembolism and reduction of cardiovascular mortality in patients with atrial fibrillation: a missed dose of Pradaxa; can be taken if 6 hours or more remains before taking the next dose, if the period is less than 6 hours, the missed dose should not be taken. In the case of missing individual doses should not take double