Pradaxa® (Pradaxa®)

Composition Pharmacodynamics Indications Carefully Contraindications Dosing and Administration Side effects Form release / dosage
Read on
Active substanceDabigatran etexilateDabigatran etexilate
Similar drugsTo uncover
  • Pradaxa®
    capsules inwards 
    Boehringer Ingelheim International GmbH     Germany
  • Pradaxa®
    capsules inwards 
    Boehringer Ingelheim International GmbH     Germany
    • Dosage form: & nbsptoapsules
    Composition:

    One capsule contains 86.48 mg, 126.83 mg or 172.95 mg of dabigatran etexylate mesylate, corresponding to 75 mg, 110 mg or 150 mg of dabigatran etexylate.

    Excipients:

    Contents of capsules: acacia gum 4.43 mg, 6.50 mg or 8.86 mg: tartaric acid, coarse-grained 22.14 mg, 32.48 mg or 44.28 mg; tartaric acid, powder 29.52 mg, 43.30 mg or 59.05 mg: tartaric acid, crystalline 36.90 mg, 54.12 mg or 73.81 mg; hypromellose 2.23 mg, 3.27 mg or 4.46 mg; dimethicone 0.04 mg, 0.06 mg or 0.08 mg; talc 17.16 mg, 25.16 mg or 34.31 mg; giprolose (hydroxypropyl cellulose) 17.30 mg, 25.37 mg or 34.59 mg.

    Capsule shell composition: capsule from hypromellose (HPMC) with an overprint in black ink 60 * mg, 70 * mg or 90 * mg.

    Composition of HPMC capsules: carrageenan (E407) 0.2 mg. 0.22 mg or 0.285 mg: potassium chloride 0.27 mg, 0.31 mg or 0.4 mg; titanium dioxide (E171) 3.6 mg, 4.2 mg or 5.4 mg; indigo carmine (E132) 0.036 mg. 0.042 mg or 0.054 mg; dye sunset yellow (E110) 0.002 mg, 0.003 mg or 0.004 mg: hypromellose (hydroxypropylmethylcellulose) 52.9 mg, 61.71 mg or 79.35 mg, water purified 3.0 mg, 3.5 mg or 4.5 mg.

    Composition of black ink (%, wt.)Shellac 24 - 27%, butanol 1 - 3%, isopropanol 1-3%, iron dye black oxide (E172) 24-28%, water purified 15-18%, propylene glycol 3-7%, ethanol 23-26% Ammonia water 1 - 2%, potassium hydroxide 0.05 - 0.1%.

    * Approximate weight of the capsule is 60, 70 or 90 mg.

    Description:

    Capsules 75 mg

    Oblong capsules of hypromellose (hydroxypropylmethylcellulose). The cover is opaque, light blue, the body is an opaque cream color. On the cover there is a symbol of the company Behringer Ingelheim, on the case -R 75. The color of the overprint is black.

    Capsules 110 mg

    Oblong capsules of hypromellose (hydroxypropylmethylcellulose). Cover - opaque light blue, body - opaque cream color. On the cover there is a symbol of the company Behringer Ingelheim, on the case -R 110. The color of the overprint is black.

    Capsules 150 mg

    Oblong capsules of hypromellose (hydroxypropyl methylcellulose), size 0. Cover - opaque light blue, body - opaque cream color. On the cover there is a symbol of the company Behringer Ingelheim, on the case - "R 150. The color of the overprint is black.

    The contents of the capsules are yellowish pellets.

    Pharmacotherapeutic group:Thrombin inhibitor direct
    ATX: & nbsp

    B.01.A.E.07   Dabigatran etexilate

    Pharmacodynamics:Dabigatran etexilate is a low-molecular, non-pharmacologically active precursor of the active form of dabigatran. After oral administration dabigatran etexilate quickly absorbed in the gastrointestinal tract (GIT) and, by hydrolysis catalyzed by esterases, in the liver and blood plasma is converted into dabigatran. Dabigatran is a powerful competitive reversible direct inhibitor of thrombin and the main active substance in the blood plasma.

    As thrombin (serine protease) in the process of coagulation converts fibrinogen into fibrin, suppression of thrombin activity prevents thrombus formation. Dabigatran has an inhibitory effect on free thrombin, thrombin, associated with a fibrin clot, and thrombin-induced platelet aggregation.

    In experimental studies on various models of thrombosis in vivo and ex vivo confirmed antithrombotic effect and anticoagulant activity of dabigatran after intravenous administration and dabigatran etexilate - after oral administration. A direct correlation was found between the concentration of dabigatran in blood plasma and the severity of the anticoagulant effect. Dabigatran extends activated partial thromboplastin time (APTT), ecraryin clotting time (EVS), and thrombin time (TB).

    Prevention of venous thromboembolism (VTE) after endoprosthetics of large joints

    Results of clinical trials in patients undergoing orthopedic surgery - knee and hip joint endoprosthetics - confirmed the preservation of hemostasis parameters and the equivalence of 75 mg or 110 mg dabigatran etexilate application 1-4 hours after surgery and subsequent maintenance dose of 150 or 220 mg once daily for 6-10 days (with surgery on the knee joint) and 28-35 days (on the hip joint), compared with enoxaparin in a dose of 40 mg once a day, which was used the day before and after the operation.

    The equivalence of the antithrombotic effect of dabigatran etexilate is shown when 150 mg or 220 mg is used compared with enoxaparin at a dose of 40 mg per day in assessing the primary endpoint that includes all cases of venous thromboembolism and mortality from any cause.

    Prevention of stroke and systemic thromboembolism in patients with atrial fibrillation

    With a long, average of about 20 months, use in patients with atrial fibrillation and with moderate or high risk of stroke or systemic thromboembolism, it has been shown that dabigatran etexilate in a dose of 110 mg, prescribed 2 times a day, did not concede warfarin on the effectiveness of preventing stroke and systemic thromboembolism in patients with atrial fibrillation; Also in the dabigatran group, there was a decrease in the risk of intracranial bleeding and the overall frequency of bleeding.

    The use of a higher dose of the drug (150 mg twice daily) significantly reduced the risk of ischemic and hemorrhagic strokes, cardiovascular mortality, intracranial bleeding and the overall bleeding frequency compared with warfarin. A smaller dose of dabigatran was characterized by a significantly lower risk of major bleeding compared with warfarin.

    The net clinical effect was assessed by determining the combined endpoint, including the incidence of stroke, systemic thromboembolism, pulmonary thromboembolism, acute myocardial infarction, cardiovascular mortality, and major bleeding.

    The annual frequency 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 etexilatewere observed at a comparable or lower frequency compared with patients receiving warfarin.

    Prophylaxis of thromboembolism in patients with prosthetic heart valves

    In the Phase II clinical trials of dabigatran and warfarin in patients who underwent surgery to replace the heart valve with a mechanical prosthesis (recent operations and operations performed more than 3 months ago), an increase in the incidence of thromboembolism and total bleeding small bleeding) in patients who received dabigatran etexilate. In the early postoperative period, major bleeding was mainly characterized by hemorrhagic effusion to the pericardium, especially in patients to whom dabigatran etexilate was assigned in the early period (on day 3) after surgical replacement of the heart valves.

    Treatment of acute deep vein thrombosis (DVT) and / or pulmonary embolism (PE) and prevention of fatal outcomes caused by these diseases

    Clinical trials in patients with acute DVT and / or PE that initially received parenteral therapy for at least 5 days confirmed that dabigatran etexilate in a dose of 150 mg, administered twice a day, was not inferior to warfarin for effectiveness in reducing the incidence of recurrent symptomatic DVT and / or PE and deaths due to these diseases during the 6-month treatment period. In patients who received dabigatran etexilate. bleeding was significantly less frequent than in patients who received warfarin.

    The incidence of myocardial infarction in all the studies conducted with VTE was low in all treatment groups.

    Indicators of liver function

    In studies using active comparators, possible changes in liver function parameters occurred in patients who received dabigatran etexilate, with comparable or less frequent frequency, than in patients receiving warfarin. In the placebo study, there was no significant difference between the dabigatran and placebo groups for changes in liver function, possibly of clinical significance.

    Prophylaxis of recurrent deep vein thrombosis (DVT) and / or pulmonary embolism (PE) and fatalities caused by these diseases

    Results of clinical studies in patients with recurrent DVT and PE already treated for 3 to 12 months of anticoagulant therapy and in need of its extension, confirmed that treatment with dabigatran etexilate 150 mg twice daily are not inferior to the therapeutic effect of warfarin (p = 0.0135). In patients who received dabigatran etexilate, bleeding was significantly less frequent than in patients who received warfarin.

    In a study comparing dabigatran etexilate with placebo in patients already treated for 6 to 18 months of vitamin K antagonists, it was found that dabigatran superior to placebo in preventing symptomatic recurrent DVT / PE. including cases of death from an unknown cause; reduced risk for the treatment period was 92% (p <0.0001).

    The frequency of myocardial infarction in all ongoing studies with VTE was low in all treatment groups.

    Indicators of liver function

    In studies using active comparators, possible changes in liver function parameters occurred in patients who received dabigatran etexilate. with a comparable or lower frequency than patients who received warfarin. In the placebo study, there was no significant difference between the dabigatran and placebo groups for changes in liver function, possibly of clinical significance.

    Pharmacokinetics:After oral administration of dabigatran etexilate, a rapid dose-dependent increase in plasma concentration and area under the concentration-time curve (AUC) is observed. The maximum concentration of dabigatran etexilate (Cmax) is achieved within 0.5-2 hours.

    After achieving Cmax plasma concentrations of dabigatran are reduced bi-exponentially, the final half-life (T1/2) on average is about 11 hours (in elderly people). The final T1/2 after repeated use of the drug was about 12-14 hours. T1/2 does not depend on the dose. However, in the case of renal dysfunction T1/2 lengthens.

    Absolute bioavailability of dabigatran after taking dabigatran etexilate inside capsules coated with hypromellose shell is about 6.5%.

    Eating does not affect the bioavailability of dabigatran etexilate, however the time to reach Cmax increases by 2 h.

    When dabigatran ethexilate is used without a special capsule shell made of hypromellose, the bioavailability of dabigatran when used without a capsule shell in comparison with the dosage form in capsules can increase by approximately 75% (1.8 times) with a single admission and about 37% (in 1.4 times) in the equilibrium state. Therefore, the integrity of the capsules made of hypromellose should be maintained, given the risk of increasing the bioavailability of dabigatran etexilate, and it is not recommended to open the capsules and apply their contents in pure form (for example, adding to food or drinks) (see "Dosage and Administration").

    When dabigatran etexilate is used after 1-3 h, patients after surgical treatment have a decrease in the absorption rate of the drug compared to healthy volunteers. AUC is characterized by a gradual increase in amplitude without the occurrence of a high peak in plasma concentration. FROMmax in the blood plasma is observed 6 hours after the application of dabigatran etexilate or 7-9 hours after the operation.

    It should be noted that factors such as anesthesia, paresis of the gastrointestinal tract and surgical operation may be important in slowing down absorption, regardless of the dosage form of the drug.Reduction 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 rapidly, with the achievement of Cmax 2 hours after ingestion.

    Metabolism

    After ingestion in the process of hydrolysis under the influence of esterase dabigatran etexilate quickly and completely turns into dabigatran, which is the main active metabolite in the blood plasma. When dabigatran is conjugated, 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 dabigatran content in blood plasma. Traces of other metabolites are detected only when highly sensitive analytical methods are used.

    Distribution

    The volume of distribution of dabigatran is 60-70 liters and exceeds the total volume of water in the body, indicating a moderate distribution of dabigatran in tissues.

    Excretion

    Dabigatran is excreted unchanged, mainly by the kidneys (85%), and only 6% through the digestive tract. It has been established that 88-94% of its dose is excreted from the body 168 hours after the administration of the labeled radioactive preparation.

    Dabigatran has a low ability to bind to blood plasma proteins (34-35%), it does not depend on the concentration of the drug.

    Special patient groups

    Elderly patients

    In elderly people the AUC is higher than in young people, 1.4-1.6 times (by 40-60%), and Cmax - more than 1,25 times (by 25%).

    The observed changes correlated with the age-related decrease in creatinine clearance (CC).

    In elderly women (over 65 years of age), the AUCt, ss and Cmax, ss were approximately 1.9 times and 1.6 times higher than in women of young age (18-40 years), and in elderly men 2.2 and 2.0 times higher than in young men.

    In a study in patients with atrial fibrillation, the effect of age on dabigatran exposure was confirmed: initial dabigatran concentrations in patients> 75 years of age were approximately 1.3 times (31%) higher, and in patients <65 years of age, approximately 22 % lower than in patients aged 65-75 years.

    Impaired renal function

    In volunteers with moderate renal dysfunction (KK - 30-50 ml / min), the value of AUC of dabigatran after ingestion was approximately 3 times greater than in persons with unchanged renal function.

    In patients with severe renal dysfunction (KK - 10-30 ml / min), the values ​​of AUC of dabigatran etexilate and T1/2 increased accordingly in 6 and 2 times, in comparison with similar parameters at persons without infringements of function of kidneys.

    In patients with atrial fibrillation and moderate renal insufficiency (CK 30-50 ml / min), dabigatran concentrations before and after application of the drug were on average 2.29 and 1.81 times higher than in patients without renal dysfunction. In the treatment of acute deep vein thrombosis (DVT) and / or pulmonary embolism (PE) and prevention of fatal outcomes caused by these diseases in patients with mild to moderate renal failure (QA 30-50 ml / min), the basal concentration of dabigatran during the period The steady state of pharmacokinetics was on average 1.7 and 3.4 times higher than in patients with CK> 80 mL / min.

    When using hemodialysis in patients without atrial fibrillation, it was found that the amount of the withdrawn preparation was proportional to the blood flow rate. The dialysis time, with a dialysate flow rate of 700 ml / min, was 4 hours, and the blood flow rate was 200 ml / min or 350-390 ml / min. This resulted in the removal, respectively, of 50% and 60% concentrations of free and common dabigatran.Anticoagulant activity of dabigatran decreased as the concentration in the plasma decreased, the relationship between FC and PD remained unchanged.

    Impaired liver function

    In patients with moderate impaired hepatic function (7-9 points on the Child-Pugh scale), there was no change in the concentration of dabigatran in the blood plasma compared to patients without a violation of liver function.

    Body mass

    In studies, basal concentrations of dabigatran in patients with a body weight> 100 kg were approximately 20% lower than in patients with a body weight of 50-100 kg. Body weight in the majority (80.8%) of patients was> 50 - <100 kg, within this range, no apparent differences in dabigatran concentrations were established. Data for patients with a body weight <50 kg are limited.

    Floor

    The main studies on the prevention of VTE development found that the effect of the drug in women was approximately 1.4-1.5 times (40-50%) higher. In patients with atrial fibrillation, basal concentrations and concentrations after application of the drug were on average 1.3 (30%) higher. The differences were not clinically significant.

    Ethnic groups

    In a comparative study of the pharmacokinetics of dabigatranin Europeans and Japanese, after a single and repeated intake of the drug in the studied ethnic groups, there were no clinically significant differences. Pharmacokinetic studies in patients of the Negroid race are limited, but the available data indicate a lack of significant differences.

    Indications:

    - Prevention of venous thromboembolism in patients after orthopedic surgery;

    - prevention of stroke, systemic thromboembolism and reduction of cardiovascular mortality in patients with atrial fibrillation;

    - treatment of acute deep vein thrombosis (DVT) and / or pulmonary embolism (PE) and prevention of fatal outcomes caused by these diseases;

    - prevention of recurrent deep vein thrombosis (DVT) and / or pulmonary embolism (PE) and deaths caused by these diseases.

    Contraindications:

    - Known hypersensitivity to dabigatran, dabigatran etexilate or any of the excipients;

    - severe degree of renal failure (CC less than 30 ml / min);

    - active clinically significant bleeding, hemorrhagic diathesis, spontaneous or pharmacologically induced hemostasis disorder;

    - organ damage due to clinically significant bleeding, including hemorrhagic stroke within 6 months prior to initiation of therapy;

    - a significant risk of developing large bleeding from existing or recent gastrointestinal ulceration, the presence of malignancies with a high risk of bleeding, recent damage to the brain or spinal cord, recent surgery on the brain or spinal cord or ophthalmic surgery, recent intracranial hemorrhage, the presence or suspicion of varicose-dilated veins esophagus, congenital arteriovenous defects, vascular aneurysms or large intracerebral or intracerebral vascular disorders;

    - simultaneous administration of any other anticoagulants, including unfractionated heparin, low molecular weight heparins (LMWH) (enoxaparin, dalteparin, etc.), heparin derivatives (fondaparinux, etc.), oral anticoagulants (warfarin, rivaroxaban, apixaban , etc.), except for cases when the treatment is switched from or to PRADAX® or when unfractionated heparin is administered at the doses necessary to maintain a central venous or arterial catheter;

    - simultaneous administration of ketoconazole for systemic administration, cyclosporine, itraconazole, tacrolimus and dronedarone;

    - violations of liver function and liver disease, which can affect survival;

    - presence of a prosthetic heart valve;

    - age under 18 years (no clinical data available).

    Carefully:

    In conditions that increase the risk of bleeding:

    - age 75 years and older;

    - moderate decrease in kidney function (KK 30-50 ml / min);

    - simultaneous use of P-glycoprotein inhibitors (except as indicated in the "Contraindications" section);

    - body weight less than 50 kg;

    - simultaneous intake of acetylsalicylic acid, NSAIDs, clopidogrel, selective serotonin reuptake inhibitors and selective norepinephrine reuptake inhibitors, as well as other drugs whose use can disrupt hemostasis;

    - congenital or acquired blood coagulation system diseases;

    - thrombocytopenia or functional defects of platelets;

    - a recent biopsy or extensive trauma;

    - bacterial endocarditis;

    - esophagitis, gastritis or gastroesophageal reflux disease.

    Pregnancy and lactation:

    Data on the use of dabigatran etexilate during pregnancy are absent. The potential risk in humans is unknown.

    In experimental studies, there is no adverse effect on fertility or postnatal development of newborns.

    Women of reproductive age should avoid pregnancy with PRADAX®. When pregnancy occurs, the use of the drug is not recommended, except when the expected benefit exceeds the possible risk.

    If it is necessary to use the drug during breastfeeding, because of the lack of clinical data, it is recommended to stop breastfeeding (as a precaution).

    Dosing and Administration:Capsules should be taken orally, 1 or 2 times a day, regardless of the time of ingestion, with a glass of water to facilitate the passage of the drug into the stomach. Do not open the capsule.

    Special instructions when removing capsules from a blister:

    - tear off one individual blister from the blister pack along the perforation line;

    - remove the capsule from the blister, peeling the foil;

    - Do not squeeze the capsules through the foil.

    Application in adults:

    Prevention of venous thromboembolism (VTE) in patients after orthopedic surgery: the recommended dose is 220 mg once a day (2 capsules of 110 mg).

    In patients with moderate renal impairment in connection with the risk of bleeding the recommended dose is 150 mg once a day (2 capsules of 75 mg).

    Prevention of VTE after arthroplasty of the knee joint: the use of PRADAX should be started 1-4 hours after the completion of the operation with taking 1 capsule (110 mg), followed by increasing the dose to 2 capsules (220 mg) once a day for the next 10 days. If hemostasis is not achieved, treatment should be postponed. If treatment does not start on the day of surgery, therapy should begin with taking 2 capsules (220 mg) once a day.

    Prevention of VTE after hip arthroplasty: the use of PRADAX should be started 1-4 hours after the completion of the operation with 1 capsule (110 mg), followed by a dose increase of 2 capsules (220 mg) once daily for the next 28-35 days. If hemostasis is not achieved, treatment should be postponed. If treatment does not start on the day of surgery, therapy should begin with taking 2 capsules (220 mg) once a day.

    Prevention of stroke, systemic thromboembolism and reduction of cardiovascular mortality in patients with atrial fibrillation: recommended the use of the drug PRADAX in a daily dose of 300 mg (1 capsule of 150 mg 2 times a day). Therapy should last for life.

    Treatment of acute deep vein thrombosis (DVT) and / or pulmonary embolism (PE) and prevention of fatal outcomes caused by these diseases: It is recommended to use PRADAX in a daily dose of 300 mg (1 capsule of 150 mg twice a day) after parenteral treatment with an anticoagulant for at least 5 days. Therapy should last up to 6 months.

    Prophylaxis of recurrent deep vein thrombosis (DVT) and / or pulmonary embolism (PE) and fatalities caused by these diseases: recommended the use of the drug PRADAX in a daily dose of 300 mg (1 capsule of 150 mg 2 times a day). Therapy can last for life, depending on individual risk factors.

    Use in special patient groups

    Use in children

    In patients under 18 years of age, the efficacy and safety of PRADAXA have not been studied, so use in children is not recommended (see "Contraindications").

    Impaired renal function

    Before therapy, in order to avoid prescribing to patients with severe renal dysfunction (CC less than 30 ml / min), it is necessary to first estimate the clearance of creatinine. Due to the lack of data on the use of the drug in patients with severe renal impairment (KK less than 30 ml / min), the use of PRADAX is contraindicated (see section "Contraindications").

    The function of the kidneys should be evaluated during treatment, when there is a suspicion of a possible decrease or deterioration in kidney function (eg, hypovolemia, dehydration, concurrent use of certain medications, etc.).

    In the course of the clinical development of PRADAX as a method for assessing kidney function, a calculation of creatinine clearance by the Coccoft-Gault method was used.

    Dabigatran is excreted during hemodialysis; However, the clinical experience of the use in patients undergoing hemodialysis is limited.

    When using PRADAX for the prevention of venous thromboembolism in patients after orthopedic surgery at moderate violations of kidney function (KK 30-50 ml / min) daily dose should be reduced to 150 mg (2 capsules of 75 mg once a day).

    When using PRADAX with the aim of preventing stroke, systemic thromboembolism and reducing cardiovascular mortality in patients with atrial fibrillation at moderate violations of kidney function (QC 30-50 ml / min) dose adjustment is not required. It is recommended to use the drug in a daily dose of 300 mg (1 capsule 150 mg 2 times a day). Kidney function should be assessed at least once a year.

    When using PRADAX from the purpose of treatment of acute deep vein thrombosis (DVT) and / or pulmonary embolism (PE) and prevention of fatalities, caused by these diseases with CK> 30 ml / min dose adjustment is not required. It is recommended to use the drug in a daily dose of 300 mg (1 capsule 150 mg 2 times a day).

    When using PRADAX with the aim of prevention of recurrent deep vein thrombosis (DVT) and / or pulmonary embolism (PE) and fatalities, caused by these diseases, at moderate violations of kidney function (QC 30-50 ml / min) dose adjustment is not required. It is recommended to use the drug in a daily dose of 300 mg (1 capsule 150 mg 2 times a day). Kidney function should be assessed at least once a year.

    Application in elderly patients

    Due to the fact that increasing the exposure of the drug in elderly patients (over 75 years old) is often due to a decrease in kidney function, the function of the kidneys should be assessed before the drug is administered. Renal function should be assessed at least once a year or more often, depending on the clinical situation. Correction of the dose of the drug should be carried out depending on the severity of violations of kidney function (see "Violation of kidney function").

    Prevention of venous thromboembolism in elderly patients (over 75 years) after orthopedic surgery: application experience is limited. The recommended dose is 150 mg (2 capsules of 75 mg once).

    When using PRADAX in elderly patients over 80 years with the goal of preventing stroke, systemic thromboembolism and reducing cardiovascular mortality in patients with atrial fibrillation The drug PRADAX should be taken in a daily dose of 220 mg (1 capsule of 110 mg twice a day).

    Treatment of acute deep vein thrombosis (DVT) and / or pulmonary embolism (PE) and prevention of deaths caused by these diseases in patients older than 75 years: dose adjustment is not required.It is recommended to use the drug in a daily dose of 300 mg (1 capsule 150 mg 2 times a day).

    Prophylaxis of recurrent deep vein thrombosis (DVT) and / or pulmonary embolism (PE) and deaths caused by these diseases in patients older than 75 years: dose adjustment is not required. It is recommended to use the drug in a daily dose of 300 mg (1 capsule 150 mg 2 times a day).

    Effects of body weight

    Prevention of venous thromboembolism (VTE) in patients after orthopedic surgery: in patients with a body weight of less than 50 kg and more than 110 kg, experience is limited. In accordance with pharmacokinetic and clinical data, dose adjustment is not required. However, it is recommended to observe such patients.

    Prevention of stroke, systemic thromboembolism and reduction of cardiovascular mortality in patients with atrial fibrillation: in accordance with pharmacokinetic and clinical data, dose adjustment is not required. However, patients with a body weight of less than 50 kg are recommended to observe.

    Treatment of acute deep vein thrombosis (DVT) and / or pulmonary embolism (PE) and prevention of fatal outcomes caused by these diseases: dose adjustment is not required depending on body weight.

    Prophylaxis of recurrent deep vein thrombosis (DVT) and / or pulmonary embolism (PE) and fatalities caused by these diseases: dose adjustment is not required depending on body weight.

    Simultaneous use of PRADAXA with active inhibitors of P-glycoprotein (amiodarone, quinidine, verapamil) in order to prevent venous thromboembolism in patients after orthopedic operations:

    When used simultaneously with amiodarone, quinidine or verapamil, the dose of PRADAX should be reduced to 150 mg once a day (2 capsules of 75 mg) (see section "Interaction with other drugs").

    Patients taking PRADAX® after orthopedic surgery are not recommended to start using verapamil at the same time and to connect it to therapy in the future.

    Prevention of stroke, systemic thromboembolism and reduced cardiovascular mortality in patients with atrial fibrillation: dose adjustment is not required, patients are recommended to use the drug in a daily dose of 300 mg (1 capsule of 150 mg 2 times a day).

    Treatment of acute deep vein thrombosis (DVT) and / or thromboembolismpulmonary artery (PE) and prevention of deaths, caused by these diseases: correction of the dose is not required. It is recommended to use the drug in a daily dose of 300 mg (1 capsule 150 mg 2 times a day).

    Prophylaxis of recurrent deep vein thrombosis (DVT) and / or pulmonary embolism (PE) and fatalities, caused by these diseases: correction of the dose is not required. It is recommended to use the drug in a daily dose of 300 mg (1 capsule 150 mg 2 times a 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 the age of 75 years or older, a moderate decrease in renal function (creatinine clearance of 30-50 ml / min), the simultaneous use of P-glycoprotein inhibitors, antiplatelet agents, or an indication of gastro-intestinal bleeding history may increase the risk of bleeding (see ". Special instructions"). Patients with one or more of these risk factors in the physician's discretion, may reduce the daily dose to 220 mg PRADAKSA® (1 intake capsule 110 mg 2 times a day).

    Treatment of acute deep vein thrombosis (DVT) and / or pulmonary embolism (PE) and prevention of fatal outcomescaused by these diseases: the presence of factors such as age 75 or older, a moderate decline in kidney function (QA 30-50 ml / min) or an indication of a history of gastrointestinal hemorrhage may increase the risk of bleeding (see "Special instructions").

    In patients with a single risk factor, dose adjustment is not required. For patients with several risk factors, clinical data are limited. In such patients, the drug should be used only in cases where the expected benefit exceeds the risk of bleeding.

    Prophylaxis of recurrent deep vein thrombosis (DVT) and / or pulmonary embolism (PE) and fatalities caused by these diseases: the presence of factors such as age 75 or older, a moderate decrease in kidney function (QC 30-50 ml / min), or an indication of a history of gastrointestinal hemorrhage may increase the risk of bleeding (see "Special instructions").

    In patients with a single risk factor, dose adjustment is not required. For patients with several risk factors, clinical data are limited.In such patients, the drug should be used only in cases where the expected benefit exceeds the risk of bleeding.

    Transition from the use of PRADAX to the parenteral use of anticoagulants

    Prevention of venous thromboembolism in patients after orthopedic surgery: parenteral administration of anticoagulants should be started 24 hours after the last dose of PRADAX.

    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 the last dose of PRADAX.

    Treatment of acute deep vein thrombosis (DVT) and / or pulmonary embolism (PE) and prevention of fatal outcomes, caused by these diseases: the parenteral use of anticoagulants should be started 12 hours after the last dose of PRADAX.

    Prophylaxis of recurrent deep vein thrombosis (DVT) and / or pulmonary embolism (PE) and fatalities, caused by these diseases: the parenteral use of anticoagulants should be started 12 hours after the last dose of PRADAX.

    Transition from parenteral use of anticoagulants to the use of PRADAX

    The first dose of PRADAX is prescribed instead of the anticoagulant to be canceled in the interval of 0-2 h before the next injection of alternative therapy, or simultaneously with the cessation of a permanent infusion (for example, intravenous use of unfractionated heparin, UFH).

    The transition from the application of vitamin K antagonists to the use of PRADAX

    Prevention of stroke, systemic thromboembolism and reduction of cardiovascular mortality in patients with atrial fibrillation: the use of vitamin K antagonists is discontinued, the use of PRADAX is possible with MNO <2.0.

    Treatment of acute deep vein thrombosis (DVT) and / or pulmonary embolism (PE) and prevention of fatal outcomes, caused by these diseases: the use of vitamin K antagonists is discontinued, the use of PRADAX is possible with MNO <2.0.

    Prophylaxis of recurrent deep vein thrombosis (DVT) and / or pulmonary embolism (PE) and fatalities, caused by these diseases: the use of vitamin K antagonists is discontinued,the use of PRADAX is possible with MNO <2.0.

    The transition from the use of PRADAX to the use of vitamin K antagonists

    Prevention of stroke, systemic thromboembolism and reduction of cardiovascular mortality in patients with atrial fibrillation: with creatinine clearance> 50 ml / min, the use of vitamin K antagonists is possible in 3 days, and with the creatinine clearance of 30-50 ml / min - 2 days before the discontinuation of PRADAX.

    Treatment of acute deep vein thrombosis (DVT) and / or pulmonary embolism (PE) and prevention of fatal outcomes, caused by these diseases: with creatinine clearance> 50 ml / min, the use of vitamin K antagonists is possible in 3 days, and with creatinine clearance of 30-50 ml / min - 2 days before the discontinuation of PRADAX.

    Prophylaxis of recurrent deep vein thrombosis (DVT) and / or pulmonary embolism (PE) and fatalities, caused by these diseases: with creatinine clearance> 50 ml / min, the use of vitamin K antagonists is possible in 3 days, and with creatinine clearance of 30-50 ml / min - 2 days before the discontinuation of PRADAX.

    Cardioversion

    Prevention of stroke, systemic thromboembolism and reduced cardiovascular mortality in patients with atrial fibrillation

    Conducting routine or emergency cardioversion does not require the withdrawal of PRADAX therapy.

    Missing dose

    Prevention of venous thromboembolism in patients after orthopedic surgery: it is recommended to take the usual daily dose of PRADAX at the usual time the next day. In the case of missing individual doses, do not take a double dose of the drug.

    Prevention of stroke, systemic thromboembolism and reduction of cardiovascular mortality in patients with atrial fibrillation: the missed dose of PRADAX can be taken in the event that before taking the next dose of the drug remains 6 hours or more; if the period is less than 6 hours, the missed dose should not be taken. In the case of missing individual doses, do not take a double dose of the drug.

    Treatment of acute deep vein thrombosis (DVT) and / or pulmonary embolism (PE) and prevention of fatal outcomes, caused by these diseases: the missed dose of PRADAX can be taken in the event that before taking the next dose of the drug remains 6 hours or more; if the period is less than 6 hours, the missed dose should not be taken.In the case of missing individual doses, do not take a double dose of the drug.

    Prophylaxis of recurrent deep vein thrombosis (DVT) and / or pulmonary embolism (PE) and fatalities, caused by these diseases: the missed dose of PRADAX can be taken in the event that before taking the next dose of the drug remains 6 hours or more; if the period is less than 6 hours, the missed dose should not be taken. In the case of missing individual doses, do not take a double dose of the drug.

    Side effects:

    Side effects identified with the drug

    - for the prevention of VTE after orthopedic operations;

    - for the prevention of stroke and systemic thromboembolism in patients with atrial fibrillation;

    - for treatment of acute deep vein thrombosis (DVT) and / or pulmonary embolism (PE) and prevention of fatal outcomes caused by these diseases;

    - for the prevention of recurrent deep vein thrombosis (DVT) and / or pulmonary embolism (PE) and fatalities caused by these diseases.

    Classification of adverse reactions according to the frequency of development (number of reported cases / numberpatients): very often - up to 1/10 cases; often from 1/100 to 1/10 cases; rarely from 1/1000 to 1/100 of the cases; it is not known - the side effects from the experience of use can not be estimated on the basis of available data; not applicable - side effect not detected when applied to this indication.

    System-Organ Class / Side Effect

    Indication

    Prevention of stroke, systemic thromboembolism and reduction of cardiovascular mortality in patients with atrial fibrillation

    Prevention of venous thromboembolism in patients after orthopedic surgery

    Treatment of acute deep vein thrombosis (DVT) and / or pulmonary embolism (PE) and prevention of fatalities caused by these diseases

    Prophylaxis of recurrent deep vein thrombosis (DVT) and / or pulmonary embolism (PE) and fatalities caused by these diseases

    Frequency of occurrence

    Disturbances from the hematopoietic and lymphatic system:

    anemia

    often

    infrequently

    infrequently

    rarely

    thrombocytopenia

    infrequently

    rarely

    rarely

    rarely

    Immune system disorders:

    hypersensitivity reactions

    infrequently

    infrequently

    infrequently

    infrequently

    - urticaria

    rarely

    rarely

    rarely

    rarely

    - skin rash

    infrequently

    rarely

    infrequently

    infrequently

    - itchy skin

    infrequently

    rarely

    rarely

    rarely

    bronchospasm

    unknown

    unknown

    unknown

    unknown

    angioedema

    rarely

    rarely

    rarely

    rarely

    anaphylactic reactions

    unknown

    unknown

    unknown

    unknown

    Impaired nervous system:

    intracranial bleeding

    infrequently

    rarely

    rarely

    rarely

    Vascular disorders:

    hematoma

    infrequently

    infrequently

    infrequently

    infrequently

    bleeding

    infrequently

    rarely

    infrequently

    infrequently

    Disorders from the respiratory, thoracic and mediastinal organs:

    nose bleed

    often

    infrequently

    often

    often

    hemoptysis

    infrequently

    rarely

    infrequently

    infrequently

    Disorders from the digestive tract:

    gastrointestinal bleeding

    often

    infrequently

    often

    often

    rectal bleeding

    infrequently

    infrequently

    often

    often

    hemorrhoidal hemorrhage

    infrequently

    infrequently

    rarely

    infrequently

    abdominal pain

    often

    rarely

    infrequently

    infrequently

    diarrhea

    often

    infrequently

    infrequently

    infrequently

    dyspepsia

    often

    rarely

    often

    often

    nausea

    often

    infrequently

    infrequently

    infrequently

    ulceration of the gastrointestinal mucosa, including ulcer of the esophagus

    infrequently

    rarely

    infrequently

    rarely

    gastroesophagitis

    infrequently

    rarely

    infrequently

    infrequently

    gastroesophageal reflux disease

    infrequently

    rarely

    infrequently

    infrequently

    vomiting

    infrequently

    infrequently

    infrequently

    infrequently

    dysphagia

    infrequently

    rarely

    rarely

    rarely

    Disorders from the hepatobiliary system:

    increased activity of "liver" transaminases

    rarely

    infrequently

    infrequently

    infrequently

    abnormal liver function

    infrequently

    often

    infrequently

    infrequently

    hyperbilirubinemia

    rarely

    infrequently

    unknown

    unknown

    Changes in the skin and subcutaneous tissues:

    cutaneous hemorrhagic syndrome

    often

    infrequently

    often

    often

    Musculoskeletal disorders, disorders of connective tissue and bones:

    hemarthrosis

    rarely

    infrequently

    infrequently

    rarely

    Changes in the kidneys and urinary tract:

    urogenital bleeding

    often

    infrequently

    often

    often

    hematuria

    often

    infrequently

    often

    often

    General disorders and changes in the injection site:

    bleeding from the injection site

    rarely

    rarely

    rarely

    rarely

    bleeding from the insertion site of the catheter

    rarely

    rarely

    rarely

    rarely

    Damage, toxicity and complications from the procedures:

    post traumatic bleeding

    rarely

    infrequently

    infrequently

    rarely

    bleeding from the operating room

    rarely

    rarely

    rarely

    rarely

    Additional specific side effects identified in the prevention of venous thromboembolism in patients undergoing orthopedic surgery

    Vascular disorders:

    bleeding from an operating wound

    not applicable

    infrequently

    not applicable

    not applicable

    General disorders and disorders at the site of administration:

    Bloody issues

    not applicable

    rarely

    not applicable

    not applicable

    Damage, toxicity and complications of postoperative treatment:

    hematoma after wound treatment

    not applicable

    infrequently

    not applicable

    not applicable

    bleeding after wound treatment

    not applicable

    infrequently

    not applicable

    not applicable

    anemia in the postoperative period

    not applicable

    rarely

    not applicable

    not applicable

    isolation after a procedure

    not applicable

    infrequently

    not applicable

    not applicable

    secretion from a wound

    not applicable

    infrequently

    not applicable

    not applicable

    Surgical and therapeutic procedures:

    drainage of wound

    not applicable

    rarely

    not applicable

    not applicable

    drainage after wound treatment

    not applicable

    rarely

    not applicable

    not applicable

    Overdose:

    Overdose with PRADAXA can be accompanied by hemorrhagic complications, which is due to the pharmacodynamic features of the drug. When bleeding occurs, the drug is stopped.

    Symptomatic treatment.

    There is no specific antidote.

    Given the main pathway of dabigatran (kidney), it is recommended to provide adequate diuresis.

    Surgical hemostasis is performed and the volume of circulating blood is replenished (BCC).

    It is possible to use fresh whole blood or a freshly frozen plasma transfusion.

    Since dabigatran has a low ability to bind to blood plasma proteins, the drug can be excreted in hemodialysis, but the clinical experience with dialysis is limited in these situations (see section "Pharmacokinetics").

    When an overdose of PRADAX is possible, use of coagulation factor concentrates (activated or non-activated) or recombinant factor VIIa. There are experimental data confirming the effectiveness of these drugs in counteracting the anticoagulant effect of dabigatran, however, no special clinical studies have been performed.

    In the case of thrombocytopenia, or with the use of long-acting antiplatelet agents, the question of the use of platelet mass may be considered.

    For situations where rapid elimination of activity is required, there is a specific antidote of dabigatran (INN: idarutsizumab), which is an antagonist to the pharmacodynamic action of PRADAX.

    Interaction:

    The combined use of PRADAX with drugs that affect hemostasis or a coagulation system, including unfractionated heparin, low molecular weight heparin, acetylsalicylic acid, non-steroidal anti-inflammatory drugs, vitamin K antagonists, can significantly increase the risk of bleeding.

    Pharmacokinetic interactions

    Dabigatran etexilate and dabigatran are not metabolized by enzymes of microsomal liver oxidation, and are neither inducers nor inhibitors of cytochrome P450 isoenzymes activity. Therefore, it is assumed that dabigatran lacks clinically significant pharmacokinetic drug interactions with drugs metabolized by cytochrome P450 isoenzymes.In clinical studies in healthy volunteers, no interactions of dabigatran with atorvastatin (substrate CYP3A4) and diclofenac (substrate CYP2C9) have been identified.

    Interactions with P-glycoprotein inhibitors / inducers: substrate for the transport molecule of P-glycoprotein is a prodrug dabigatran etexilate, but not the dabigatran. Therefore, a study was conducted of the joint application with inhibitors and inducers of the P-glycoprotein transporter. Simultaneous use of inhibitors of P-glycoprotein (amiodarone, verapamil, quinidine, ketoconazole for systemic administration, dronedarone, ticagrelor and clarithromycin) leads to an increase in dabigatran concentration in the blood plasma.

    Simultaneous use with P-glycoprotein inhibitors: simultaneous use with such inhibitors of P-glycoprotein, as ketoconazole for systemic use, ciclosporin, itraconazole, tacrolimus and dronedaron it is contraindicated. Caution should be exercised when concomitant administration with P-glycoprotein inhibitors (eg: amiodarone, quinidine, verapamil and ticagrelor).

    Amiodarone. With the simultaneous use of dabigatran etexilate with a single dose of amiodarone (600 mg) ingested, the degree and rate of absorption of amiodarone and its active metabolite, desethylamiodarone, did not change. The values ​​of AUC and Cmax dabigatran increased by approximately 1.6 and 1.5 times (by 60% and 50%), respectively.

    In a study in patients with atrial fibrillation, the concentration of dabigatran increased by no more than 14%, an increased risk of bleeding was not documented. It is recommended to monitor patients who apply simultaneously amiodarone and dabigatran etexilate with regard to the risk of bleeding, especially in the presence of renal failure (from mild to moderate).

    Dronedaron. After simultaneous application of dabigatran etexilate and dronedarone in a dose of 400 mg once, AUC0-∞ and Cmax dabigatran increase by 2.1 and 1.9 times (by 114% and 87%), respectively, and after repeated application of dronedarone at a dose of 400 mg per day - in 2.4 and 2.3 (by 136% and 125%), respectively . After a single and repeated application of dronedarone 2 hours after taking dabigatran etexilate AUC0-∞ increased by 1.3 and 1.6 times, respectively. Dronedaron did not affect the final T1/2 and renal clearance of dabigatran.Simultaneous use of PRADAX® and dronedarone is contraindicated.

    Tikagrelor. After simultaneous administration of a single dose (75 mg) of dabigatran etexilate with a loading dose of ticagrelor (180 mg), the AUC0-∞ and Cmax dabigatran increase by 1.73 and 1.95 times (by 73% and 95%), respectively. After repeated administration of ticagrelor (90 mg twice daily), this increase in exposure to dabigatran (against AUC0-∞ and Cmax) decreased, respectively, to 1.56 times (up to 56%) and to 1.46 times (to 46%). The concentration of dabigatran in healthy volunteers increased 1.26 times (up to 26%) when administered jointly with ticagrelor in a stationary state or 1.49 times (up to 49%) with the use of a loading dose of ticagrelor with the combined use of dabigatran etexilate taken at a dose of 110 mg twice a day. The increase in concentration was less pronounced if the loading dose (180 mg) of ticagrelor was taken two hours after dabigatran (up to 27%). The simultaneous administration of a loading dose (180 mg) of ticagrelor and 110 mg of dabigatran etexilate (in a steady state) increased AUCt, ss and Cmax, ss dabigatran 1.49 times and 1.65 times (+ 49% and 65%), respectively, compared with taking only dabigatran etexilate.If a loading dose of 180 mg of ticagrelor was given 2 hours after taking 110 mg of dabigatran etexilate (in a steady state), the degree of increase in AUCt, ss and Cmax, ss dabigatran decreased to 1.27-fold and 1.24-fold (+ 27% and 24%), respectively, compared with the intake of only dabigatran etexilate. Co-administration of 90 mg ticagrelor x 2 times a day (maintenance dose) with 100 mg dabigatran etexilate increased the adjusted AUCt, ss and Cmax, ss in 1,26 times and in 1,29 times accordingly in comparison with reception only dabigatran eteksilata.

    Verapamil. With the simultaneous use of dabigatran etexilate with verapamil, administered orally, the Cmax and AUC dibigatran increased depending on the time of application and the dosage form of verapamil.

    The greatest increase in dabigatran effect was observed with the use of the first dose of verapamil in immediate-release dosage form, which was applied 1 hour before dabigatran etexilate (Cmax increased by 180%, and AUC - by 150%). When using the drug form of verapamil with delayed release, this effect progressively decreased (Cmax increased by 90%, and AUC by 70%), as well as with the use of multiple doses of verapamil (Cmax increased by 60%, and AUC by 50%), which can be explained by induction of P-glycoprotein in the digestive tract with prolonged use of verapamil.

    With the use of verapamil 2 hours after dabigatran etexilate, clinically significant interactions were not observed (Cmax increased by 10%, and AUC by 20%), since after 2 h the dabigatran is fully absorbed (see the section "Dosage and Administration").

    In a study in patients with atrial fibrillation, the concentration of dabigatran increased by no more than 21%, an increased risk of bleeding was not reported.

    Data on the interaction of dabigatran etexilate with verapamil administered parenterally are not available; clinically significant interaction is not expected.

    Ketoconazole. Ketoconazole for systemic application after a single appointment in a dose of 400 mg increases AUC0-∞ and dabigatran by approximately 2.4 times (by 138% and 135%), respectively, and after repeated administration of ketoconazole 400 mg daily - approximately 2.5 times (153% and 149%), respectively. Ketoconazole did not affect Tmax and the final T1/2. The simultaneous use of PRADAX® and ketoconazole for systemic use is contraindicated.

    Clarithromycin. With the simultaneous use of clarithromycin in a dose of 500 mg 2 times a day with dabigatran etexilate, there was no clinically significant pharmacokinetic interaction (Cmax increased by 15%, and AUC - by 19%).

    Quinidine. The AUC valuest, ss and Cmax, ss dabigatran with application of 2 times a day in the case of simultaneous administration with quinidine at a dose of 200 mg every 2 hours until the total dose of 1000 mg was increased, on average, by 53% and 56%, respectively. Interaction with itraconazole, tacrolimus and cyclosporine has not been studied, however, from the data in vitro we can expect a similar effect, as well as on the interaction with ketoconazole. The simultaneous use of these inhibitors of P-glycoprotein is contraindicated.

    Simultaneous use with substrates for P-glycoprotein

    Digoxin. In a study of 24 healthy subjects, concomitant administration of PRADAX® with digoxin showed no change in digoxin concentration and clinically significant changes in dabigatran concentration. With simultaneous use of dabigatran etexilate with digoxin, which is a substrate of P-glycoprotein, no pharmacokinetic interaction was observed. Neither dabigatran nor prodrug dabigatran etexilate are not clinically significant inhibitors of P-glycoprotein.

    Simultaneous use with inducers of P-glycoprotein

    The simultaneous administration of PRADAX and P-glycoprotein inducers should be avoided, since co-administration reduces dabigatran exposure (see section "Specific guidance").

    Rifampicin. The preliminary application of the rifampicin test inducer at a dose of 600 mg per day for 7 days resulted in a reduction in the effect of dabigatran. After the withdrawal of rifampicin, this inductive effect decreased, on day 7 the dabigatran effect was close to the baseline level. During the next 7 days, a further increase in the bioavailability of dabigatran was not observed.

    After 7 days of treatment with rifampicin at a dose of 600 mg daily AUC0-∞ and Cmax of total dabigatran were reduced by 67% and 66% compared with reference treatment, respectively.

    It is suggested that other inducers of the P-glycoprotein, such as St. John's wort puffed or carbamazepine, can also reduce the concentration of dabigatran in blood plasma and should be applied with caution.

    Simultaneous use with antiplatelet agents

    The combined use of PRADAX with drugs that affect hemostasis or a coagulation system, including unfractionated heparin, low molecular weight heparin, acetylsalicylic acid, non-steroidal anti-inflammatory drugs, vitamin K antagonists, can significantly increase the risk of bleeding.

    Unfractionated heparin: can be used in the doses necessary to maintain the permeability of the central venous or arterial catheter.

    Acetylsalicylic acid (ASA). The effect of simultaneous use of dabigatran etexilate and ASA on the risk of bleeding was studied in patients with atrial fibrillation in a randomized phase II study with ASA.

    When studying the simultaneous use of dabigatran etexilate 150 mg twice daily and ASA in patients with atrial fibrillation, it was found that the risk of bleeding may increase from 12% to 18% (when using ASA at a dose of 81 mg) and up to 24% (when used ASA in a dose of 325 mg).

    NSAIDs. The NSAIDs used (non-steroidal anti-inflammatory drugs) for short-term analgesia after surgery did not increase the risk of bleeding with simultaneous use with dabigatran etexilate.Long-term use of NSAIDs increased the risk of bleeding by approximately 50%, as with the joint use of dabigatran etexilate. and warfarin.

    It is necessary to carefully monitor the signs of bleeding, in connection with the risk of development when combined with NSAIDs (T1/2 more than 12 hours).

    Low molecular weight heparin: Special studies on the simultaneous use of dabigatran etexilate and low-molecular heparins, such as enoxaparin, have not been conducted.

    24 hours after the 3-day treatment (40 mg once daily) with enoxaparin, exposure to dabigatran was lower than after taking a single dose of 220 mg of dabigatran etexilate.

    High anti-FXa / FII activity was observed after dabigatran etexilate was used with enoxaparin compared with treatment with dabigatran etexilate alone.

    It is believed that this is due to the action of enoxaparin and has no clinical significance. Other tests associated with the anticoagulant effect of dabigatran did not change significantly with the previous treatment with enoxaparin.

    Clopidogrel. It has been established that simultaneous use of dabigatran etexilate and clopidogrel does not lead to an additional increase in the time of capillary bleeding in comparison with clopidogrel monotherapy. In addition, it is shown that the values ​​of AUCt, ss and Cmax,ss dabigatran, and blood clotting parameters that were monitored to evaluate the effect of dabigatran (APTT, echarin coagulation time or thrombin time (anti FIIa), and the degree of inhibition of platelet aggregation (the main indicator of the effect of clopidogrel) during the combined therapy did not change in comparison with the corresponding ones parameters in monotherapy.When using a "loading" dose of clopidogrel (300 or 600 mg), the AUCt, ss and Cmax,ss dabigatran were increased by 30-40%.

    Simultaneous use with drugs, increasing the pH of the contents of the stomach

    The changes in the pharmacokinetic parameters of dabigatran revealed in the course of the population analysis due to the inhibitors of the proton pump and antacid preparations were clinically insignificant, as the degree of expression of these changes was small (the decrease in bioavailability was not significant for antacids, and for proton pump inhibitors it was 14.6%).

    It has been established that the simultaneous use of proton pump inhibitors is not accompanied by a decrease in the dabigatran concentration and, on average, only slightly reduces the concentration of the drug in blood plasma (by 11%).Therefore, the simultaneous use of proton pump inhibitors does not appear to lead to an increase in the incidence of stroke or systemic thromboembolism, especially in comparison with warfarin, and hence a decrease in the bioavailability of dabigatran. caused by the simultaneous use of pantoprazole, probably has no clinical significance.

    Pantoprazole. With the combined use of dabigatran etexilate and pantoprazole, a decrease in the AUC of dabigatran by 30% was observed. Pantoprazole and other proton pump inhibitors have been used in conjunction with dabigatran etexilate in clinical studies, no effect on bleeding risk or efficacy has been observed.

    Ranitidine. Ranitidine when applied simultaneously with dabigatran etexilate did not have a significant effect on the degree of absorption of dabigatran.

    Special instructions:

    Risk of bleeding

    The use of PRADAX, as well as other anticoagulants, is recommended with caution in conditions characterized by an increased risk of bleeding. During therapy with PRADAX®, bleeding of various localizations may develop.Reducing the concentration of hemoglobin and / or hematocrit in the blood, accompanied by a decrease in blood pressure, is the basis for the search for a source of bleeding.

    Treatment with PRADAX does not require monitoring of anticoagulant activity. The test for determining INRs should not be used, since there is evidence of a false overestimation of the INR level.

    To determine the excessive anticoagulant activity of dabigatran, tests should be used to determine thrombin or ECARIN clotting time. In the case where these tests are not available, a test should be used to determine the APTT.

    In the RE-LY study in patients with atrial fibrillation, exceeding the APTT level by 2-3 times the norm border before receiving the next dose of the drug was associated with an increased risk of bleeding.

    In pharmacokinetic studies of PRADAX, it has been shown that in patients with decreased renal function (including in elderly patients) an increase in the exposure of the drug is observed. The use of PRADAX is contraindicated in case of severe renal dysfunction (CK <30 ml / min).

    In the case of acute renal failure, PRADAX should be withdrawn.

    The following factors can lead to an increase in the concentration of dibitran in the plasma: decrease in kidney function (CK 30-50 ml / min), age> 75 years, simultaneous use of an inhibitor of P-glycoprotein. The presence of one or more of these factors may increase the risk of bleeding (see section "Mode of administration and dose").

    The combined use of PRADAX with drugs that affect hemostasis or a coagulation system, including unfractionated heparin, low molecular weight heparin, acetylsalicylic acid, non-steroidal anti-inflammatory drugs, vitamin K antagonists, can significantly increase the risk of bleeding.

    Not studied, but may increase the risk of bleeding concurrent use of the drug PRADAX with the following drugs: fondaparinux sodium, thrombolytic drugs, blockers of glycoprotein GP IIb / IIIa receptor platelets, ticlopidine, dextran, rivaroxaban and P-glycoprotein inhibitors (itraconazole, tacrolimus, ciclosporin, ritonavir, nelfinavir and saquinavir). Risk of bleeding may increase due to pharmacological interaction in patients,simultaneously taking selective serotonin reuptake inhibitors or selective norepinephrine reuptake inhibitors. The risk of bleeding may also increase with simultaneous use of antiplatelet agents and other anticoagulants.

    The combined use of dronedarone and dabigatran is contraindicated (see section "Contraindications").

    Concomitant use of ticagrelor may increase the exposure to dabigatran and may lead to a pharmacodynamic interaction, which could result in increased risk of bleeding.

    Prevention of venous thromboembolism in patients after orthopedic surgery

    It was found that the use of NSAIDs for short-term anesthesia in surgical interventions at the same time with the preparation PRADAKSA not associated with an increased risk of bleeding. There are limited data on the regular use of NSAIDs (having T1/2 less than 12 hours) on the background of treatment with PRADAX, data on the increased risk of bleeding were not received.

    Prevention of stroke, systemic thromboembolism and reduction of cardiovascular mortality in patients with atrial fibrillation

    Simultaneous use of PRADAX, antiplatelet agents (including ASA and clopidogrel) and NSAIDs increase the risk of bleeding. In particular, the simultaneous use of antiplatelet agents or strong P-glycoprotein inhibitors increase the risk of major bleeding, including gastrointestinal bleeding, in patients aged> 75 years. If clinical suspicion of bleeding arises, it is recommended that appropriate studies be conducted, such as occult blood feces or hemoglobin levels (to reduce it).

    The use of fibrinolytic agents may be considered only if the TV performance, the EMU or the aPTT of the patient do not exceed the upper limit of normal local reference range.

    If the risk of bleeding increases (for example, with a recent biopsy or extensive trauma, bacterial endocarditis), monitoring of the patient's condition is required to detect bleeding in time.

    Interaction with inducers of P-glycoprotein

    Application inwardly together with PRADAKSA inductor of P-glycoprotein rifampicin reduced the dabigatran concentration in a plasma.It is suggested that other inducers of the P-glycoprotein, such as St. John's wort puffed or carbamazepine, can also reduce the concentration of dabigatran in blood plasma and should be used with caution (see section "Interaction with other drugs").

    Surgical operations and interventions

    Patients using PRADAX in surgical procedures or invasive procedures increase the risk of bleeding. Therefore, when conducting surgical interventions, PRADAX should be discontinued (see also the section "Pharmacokinetics").

    Preoperative period

    Before carrying out invasive procedures or surgical operations PRADACS preparation is canceled, at least 24 hours prior to their carrying out. In patients with an increased risk of bleeding or before carrying out extensive operations that require complete hemostasis, PRADAX should be discontinued 2-4 days before the operation. In patients with renal insufficiency, the clearance of dabigatran may be prolonged.

    If you cancel the drug, you should consider the following information:

    CK (ml / min)

    T1/2

    Discontinuation of the drug before the planned surgical procedure



    High risk of bleeding or major surgery

    Standard risk

    ≥80

    ~ 13

    For 2 days

    For 24 hours

    ≥50

    ~ 15

    2-3 days

    For 1 -2 days

    <80




    ≥30

    ~ 18

    4 days

    2-3 days

    <50



    (> 48 h)

    This should be taken into account before carrying out any procedures (see also the section "Pharmacokinetics").

    The drug PRADAXA is contraindicated in patients with severe renal dysfunction (CK <30 ml / min), but if the drug is still used, it should be canceled no less than 5 days before the operation.

    In case of necessity of carrying out an emergency surgical intervention, the preparation of PRADAX should be temporarily discontinued. Surgical intervention, if possible, should be performed no earlier than 12 hours after the last administration of PRADAX. If the operation can not be delayed, the risk of bleeding may increase (in the case of cardioversion, see "Method of administration and dose"). In this case, the risk of bleeding and the need for emergency intervention should be assessed.

    Spinal anesthesia / epidural anesthesia / lumbar puncture

    Procedures such as spinal anesthesia may require complete restoration of hemostasis.

    In case of traumatic or repeated spinal puncture and prolonged use of the epidural catheter, the risk of developing spinal bleeding or epidural hematoma may increase. The first dose of PRADAX should be taken no earlier than 2 hours after removal of the catheter. It is necessary to monitor the condition of patients to exclude neurological symptoms, which may be due to cerebrospinal bleeding or epidural hematoma.

    Period after the procedure

    The use of PRADAX can be continued after complete hemostasis.

    In the case of gastrointestinal symptoms, it is recommended to take PRADAXA with food and / or a proton pump inhibitor such as pantoprazole.

    Effect on the ability to drive transp. cf. and fur:The effect of PRADAX® on the ability to drive vehicles and engage in other potentially hazardous activities requiring increased concentration and speed of psychomotor reactions has not been studied, but given that PRADAX® can be associated with an increased risk of bleeding, care should be taken when carrying out such activities.
    Form release / dosage:

    Capsules, 75 mg, 110 mg and 150 mg.

    Packaging:

    10 capsules per blister with perforation from Al / Al foil. 1, 3, 6 blisters in a pack of cardboard with instructions for use.

    For 60 capsules in a bottle of polypropylene, sealed with a plastic screw cap with an autopsy control from the children, with a desiccant.

    One bottle in a pack of cardboard with instructions for use.

    Multi-packaging (for dosages of 110 mg, 150 mg): 10 capsules per blister with perforation from Al / Al. 6 blisters in a pack of cardboard with instructions for use.

    3 packs of cardboard in a polypropylene film.

    Storage conditions:

    Bottle: at a temperature not higher than 25 ° С.

    Keep the bottle tightly sealed, to protect it from moisture.

    After opening the vial, the drug should be used within 4 months.

    Blisters: in a dry place, at a temperature of no higher than 25 ° C.

    Keep out of the reach of children.

    Shelf life:

    3 years.

    Do not use after the expiration date.

    Terms of leave from pharmacies:On prescription
    Registration number:LSR-007065/09
    Date of registration:07.09.2009 / 08.06.2015
    Expiration Date:Unlimited
    The owner of the registration certificate:Boehringer Ingelheim International GmbHBoehringer Ingelheim International GmbH Germany
    Manufacturer: & nbsp
    Representation: & nbspBehringer Ingelheim, LLCBehringer Ingelheim, LLC
    Information update date: & nbsp04.12.2017
    Illustrated instructions
      Instructions
      Up