Pradax than can be replaced. Pradaxa substitute: which is better to choose a generic. Application Precautions

Instructions for use:

Pradaxa is an antithrombotic and anticoagulant drug used in traumatology and orthopedics for the prevention of venous thromboembolism in the postoperative period. Preparations Warfarin, Fenilin and Marcumar are analogues of Pradaxa. Some reviews of Pradax say that this drug is the most effective and modern of all known coagulants.

The drug is produced in hard opaque capsules with a blue cap. Inside the capsules are yellow pellets. Dabigatran etexilate is the main active ingredient of this drug.

Pharmacological action of the drug Pradaxa

The action of the drug is to suppress the activity of thrombin. Dabigatran etexilate is a low molecular weight substance that does not have pharmacological activity. After oral administration, this compound is very rapidly absorbed and hydrolyzed to dabigatran. Dabigatran is an active, competitive, reversible direct thrombin inhibitor. This substance inhibits the activity of fibrin-binding thrombin, free thrombin, and also inhibits platelet aggregation caused by thrombin.

In medical reviews of Pradax, it is said that the effectiveness of this medication is reduced by 20% with a body weight of more than 120 kg. With a body weight of about 48 kg, the effectiveness of the drug increases by 25% (compared to patients with an average body weight).

Indications for the use of Pradaxa

The instructions for Pradaxa indicate that this drug should be prescribed for the prevention of venous or systemic thromboembolism in patients after orthopedic surgery. Pradaxa is sometimes prescribed to patients with atrial fibrillation to reduce cardiovascular mortality rates.

Instructions for use

According to the instructions, Pradaxa in the form of capsules should be taken once or twice a day (regardless of meal times). Do not open the capsules and drink plenty of liquid.

After knee arthroplasty, the medication should be started one to four hours after the operation. Immediately after surgery, it is recommended to take one capsule of the drug per day (110 mg), and then increase the dose to two capsules daily. The course of admission is ten days or 28-35 days (after hip arthroplasty).

Patients with atrial fibrillation should take Pradaxa twice a day at a daily dose of 300 mg.

Contraindications to the use of Pradaxa

According to the instructions, Pradaxa and Pradaxa analogues should not be taken with known hypersensitivity to any of the components of the drug, with severe renal failure, with active clinically significant bleeding, pharmacologically induced or spontaneous disturbance of homeostasis. You should not use the drug for violations of liver function, malignant neoplasms, as well as for intracranial hemorrhage in history, spinal injuries or brain injuries in history, gastrointestinal ulcer, esophageal varicose veins, intracerebral or intraspinal vascular disorders.

The simultaneous use of Pradaxa and antiplatelet agents increases the risk of bleeding three times. The use of this medication in combination with other anticoagulants is contraindicated.

There are no clinical data on the effects of taking this medication in patients under the age of 18 years.

Precautionary measures

Pradaxa and Pradaxa analogues should be used with caution in conditions associated with an increased risk of bleeding. During the period of treatment with the drug, bleeding of various localization may develop. A decrease in the concentration of hematocrit and / or hemoglobin in the blood, which is accompanied by a decrease in blood pressure, is the basis for searching for a source of bleeding.

Side effects of Pradaxa

Many reviews of Pradax say that prolonged use of the drug for prevention is sometimes accompanied by the appearance of urticaria, rash, itching, bronchospasm, diarrhea, abdominal pain, dyspepsia. Sometimes, against the background of taking this medication, thrombocytopenia, anemia, gastroesophageal reflux disease, gastroesophagitis, hyperbilirubinemia, hematuria, urogenital bleeding, skin hemorrhagic syndrome develop.

Pradaxa storage conditions

Pradaxa in vials or blisters is stored at a temperature not exceeding 25°C. The product should be stored for no more than three years. After opening the vial, the drug is recommended to be used within a month.

The drug represents a pharmacological group of drugs that belong to direct anticoagulants. It is used orally in the form of tablets to reduce blood clotting and eliminate the occurrence of a blood clot in various diseases.

Compound

"Pradaksa" is released from pharmacies in the form of capsules for oral administration. Tablets have an oblong shape, a soft shell of a creamy edema. The main active trace element of the drug is dabigatran etexilate.

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The drug is produced in several dosages - 75, 100, 150 milligrams. In addition to the active ingredient, Pradaksa also includes additional substances:

• gum arabic;
• hypromellose;
• liquid silicone;
• wine acid;
• indigo carmine;
• amphoteric oxide of tetravalent titanium;
• carrageenan;
• potassium chloride.

Capsules are distributed in blisters of ten pieces or in plastic bottles of sixty pieces. One package may contain one, three or six blisters.

Pharmacological properties

The active trace element of the drug is considered a direct anticoagulant, which reduces blood clotting. The mechanism of action is due to the fact that the main form of the active substance inhibits thrombin, which is a strain in the form of a serine protease and starts the process of blood coagulation with the transformation of soluble fibrinogen.

After ingestion of the drug, the active microelement is instantly absorbed into the plasma from the intestine. Its pharmacological concentration in the blood is reached two hours after the use of the drug.

The drug is excreted unchanged with urine by the kidneys, the half-life is on average fourteen hours. In patients of retirement age, as well as in the presence of kidney disease with a decrease in their performance, the half-life may increase, which should be taken into account when choosing a dose of the drug.

Indications

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In addition, the drug is used as a preventive measure to prevent pulmonary embolism.

Contraindications

Pradax capsules also have restrictions on use, for example:

In addition, there are a number of prohibitions on the use of Pradaxa, which can provoke bleeding:

Before starting the use of the drug, you should make sure that there are no contraindications.

How to take the drug correctly?

Capsules are used only for adult patients. They are consumed orally, washed down with water, from one to two times a day, regardless of the diet. Before taking the tablets, it is necessary to ensure the integrity of the tablet, since the rate of absorption of the active trace element changes. Dosage and mode of use of the drug directly depend on the disease and certain conditions, for example:

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With kidney disease, which is accompanied by a moderate decrease in their work, the dosage of tablets is reduced to 150 milligrams per day. If prevention of thromboembolic complications in atrial fibrillation is carried out, the dosage is not reduced and is 300 milligrams per day. In patients of retirement age, dosage is adjusted after an assessment of kidney function.

Depending on the appointments, as well as the severity of the age-related decrease in the functional activity of the kidneys, the dosage of Pradaxa can vary between 150-300 milligrams per day. In the event of a concomitant lesion, which can lead to an increased risk of bleeding, the dose is reduced to 220 milligrams per day. With a small weight of the patient (less than 50 kilograms), he is monitored, it is not necessary to adjust the dosage.

Adverse reactions

Negative phenomena against the background of the use of "Pradaksa" can occur from various body systems:

Peculiarities

"Pradaksa" is appointed by the therapist purely individually for each patient in accordance with the indications. The doctor must pay attention to special instructions, which include:

In pharmacies, Pradaksu can only be purchased with a doctor's prescription.

"Pradaksa": analogues

The drug has generics both in composition and spectrum of action, for example:

"Warfarin"

It is a vitamin K antagonist, belongs to the antithrombotic drugs of the group of indirect anticoagulants. Reduces the likelihood of blood clots. It is used in the treatment and prophylaxis of thrombosis, as well as embolism of blood vessels.

"Warfarin" is released from pharmacies in tablet form, 2.5; 3; 5 milligrams. Capsules are distributed in blisters. The active ingredient is warfarin sodium clathrate. "Warfarin" is a cheap analogue of "Pradaksa" (110 mg).

If the patient is prescribed the drug for the first time, the average dosage should be 5 milligrams per day for four days. In the future, based on the patient's condition and indicators, a maintenance dose is prescribed, usually ranging from 2.5 to 7.5 milligrams.

If a person has used the drug before, the first two days the drug is used at a dosage that doubles the known maintenance dosage. Then three days use a maintenance dose. On the fifth day, it is necessary to monitor the indicators and adjust the dosage. The cost of the drug is 180 rubles.

"Fraksiparin"

The drug belongs to direct-acting anticoagulants and is a low molecular weight heparin. Fraxiparine is produced as a solution for subcutaneous use in a disposable syringe, as well as in blisters of 2-5 pieces.

According to the instructions for the Pradaxa analogue, the drug is intended for subcutaneous injections. The dosage of the drug and the duration of therapy are determined by the doctor, depending on the prescriptions and characteristics of the patient's body.

In order to prevent the occurrence of thromboembolism after surgery, 0.3 milliliters of the drug is administered 2-4 hours before surgery, and then for several days once a day, at least a week.

It is not worth using Fraxiparine during pregnancy, since there is no information on admission during this period. If treatment is necessary, the doctor must evaluate the ratio of all risks. The cost of the drug is 3000 rubles.

"Clopidogrel"

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Synthetic drug, which is prescribed for the preventive purposes of diseases of the heart and blood vessels. The medicine is produced in the form of pink capsules.

Each tablet contains 75 milligrams of the active ingredient clopidogrel in the form of hydrogen sulfate.

According to the instructions for use for the Pradaxa analogue, if the patient has an increased risk of bleeding after injury, surgical interventions, then care must be taken when using Clopidogrel. The cost of the medicine varies from 600 to 800 rubles.

The drug is prescribed with extreme caution to patients who have malfunctions in the functioning of the liver in a complex form (according to the instructions for use).

(dabigatran etexilate)

Read this leaflet carefully before you start taking this drug.

• Save the instructions, they may need to be repeated.
• If you have any questions, ask your doctor

This medicine has been prescribed for you personally and should not be passed on to others as it may harm them, even if you have the same symptoms as you.

Registration number:

International non-proprietary name:

Chemical Name:

N-[amino]iminomethyl]phenyl]amino]methyl]-1-methyl-1H-benzimidazol-5-yl-]-N-pyridinyl-b-alanine ethyl ether methanesulfonate

Dosage form:

Compound:

One capsule contains 86.48 mg, 126.83 mg or 172.95 mg of dabigatran etexilate mesylate, which corresponds to 75 mg, 110 mg or 150 mg of dabigatran etexilate.

Excipients:

Capsule content: acacia gum 4.43 mg, 6.50 mg or 8.86 mg; tartaric acid, coarse 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; hyprolose (hydroxypropyl cellulose) 17.30 mg, 25.37 mg or 34.59 mg.

The composition of the capsule shell: hypromellose (HPMC) capsule overprinted with black ink (Colorcon S-1-27797) 60*mg, 70*mg or 90*mg.

CompoundHPMC 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 (hydroxypropyl methylcellulose) 52.9 mg, 61.71 mg or 79.35 mg, purified water 3.0 mg, 3.5 mg or 4.5 mg.

Composition of black inkcolorconS-1-27797, (% wt.): shellac 52.500%, butanol 6.550%, purified water 1.940%, denatured ethanol (methylated alcohol) 0.650%, iron dye black oxide (E172) 33.770%, isopropanol 3.340%, propylene glycol 1.250%.

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

Description:

Capsules 75 mg

Hypromellose (hydroxypropyl methylcellulose) oblong capsules. Lid - opaque, light blue, body - opaque cream color. The Boehringer Ingelheim symbol is printed on the lid and “R 75” on the body. The overprint color is black.

Capsules 110 mg

Hypromellose (hydroxypropyl methylcellulose) oblong capsules. The lid is opaque light blue, the body is opaque cream. The Boehringer Ingelheim symbol is printed on the lid and “R 110” on the body. The overprint color is black.

Capsules 150 mg

Hypromellose (hydroxypropyl methylcellulose) oblong capsules, size 0. Lid - opaque light blue, body - opaque cream. The Boehringer Ingelheim symbol is printed on the lid and “R 150” on the body. The overprint color is black.

The contents of the capsules are yellowish pellets.

Pharmacotherapeutic group:

Pharmacological properties:

Pharmacodynamics:

Dabigatran etexilate is a low molecular weight, pharmacologically inactive precursor to the active form of dabigatran. Following oral administration, dabigatran etexilate is rapidly absorbed from the gastrointestinal tract (GIT) and converted to dabigatran in the liver and plasma by esterase-catalyzed hydrolysis. Dabigatran is a potent competitive reversible direct thrombin inhibitor and the main active substance in plasma.

Since thrombin (serine protease) converts fibrinogen to fibrin during coagulation, inhibition of thrombin activity prevents the formation of a thrombus. Dabigatran has an inhibitory effect on free thrombin, fibrin clot-bound thrombin, and thrombin-induced platelet aggregation.

In experimental studies on various models of thrombosis in vivo and ex vivo, the antithrombotic effect and anticoagulant activity of dabigatran after intravenous administration and dabigatran etexilate after oral administration were confirmed.

A direct correlation has been established between the concentration of dabigatran in blood plasma and the severity of the anticoagulant effect. Dabigatran prolongs activated partial thromboplastin time (APTT), ecarin clotting time (ECT), and thrombin time (TT).

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

The results of clinical studies in patients undergoing orthopedic surgery - knee and hip arthroplasty - confirmed the preservation of hemostasis parameters and the equivalence of using 75 mg or 110 mg of dabigatran etexilate 1-4 hours after surgery and a subsequent maintenance dose of 150 or 220 mg once a day in for 6-10 days (for knee surgery) and 28-35 days (for the hip joint) compared with enoxaparin at a dose of 40 mg 1 time per day, which was used before and after surgery.

The antithrombotic effect of dabigatran etexilate 150 mg or 220 mg was shown to be equivalent to that of enoxaparin 40 mg daily in the primary endpoint, which includes all venous thromboembolic events and all-cause mortality.

Prevention of stroke and systemic thromboembolism in patients with atrial fibrillation

In long-term use, averaging about 20 months, in patients with atrial fibrillation and at moderate or high risk of stroke or systemic thromboembolism, dabigatran etexilate 110 mg given twice daily has been shown to be non-inferior to warfarin in 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 2 times a day) significantly reduced the risk of ischemic and hemorrhagic stroke, cardiovascular death, intracranial bleeding and overall bleeding, compared with warfarin. The lower dose of dabigatran was associated with a significantly lower risk of major bleeding compared with warfarin.

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

The annual incidence of these events in patients treated with dabigatran etexilate was lower than in patients treated with warfarin.

Changes in laboratory parameters of liver function in patients treated with dabigatran etexilate were observed at a comparable or lower frequency compared to patients treated with warfarin.

Pharmacokinetics:

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

After reaching Cmax, plasma concentrations of dabigatran decrease biexponentially, the terminal half-life (T1 / 2) averages about 11 hours (in the elderly). 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 impaired renal function, T1 / 2 lengthens.

The absolute bioavailability of dabigatran following oral administration of dabigatran etexilate in hypromellose-coated capsules is approximately 6.5%.

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

When using dabigatran etexilate without a special capsule shell made from hypromellose, oral bioavailability can increase by about 1.8 times (75%) compared with the dosage form in capsules. Therefore, the integrity of capsules made from hypromellose should be maintained, given the risk of increasing the bioavailability of dabigatran etexilate, and it is not recommended to open the capsules and use their contents in their pure form (for example, adding to food or drinks) (see section "Method of administration and doses").

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. Cmax in blood plasma is observed 6 hours after the use of dabigatran etexilate or 7-9 hours after surgery. It should be noted that factors such as anesthesia, paresis of the gastrointestinal tract and surgery may play a role in slowing 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, absorption of dabigatran is rapid, reaching C max 2 hours after oral administration.

Metabolism

After ingestion, dabigatran etexilate is rapidly and completely converted to dabigatran, which is the main active metabolite in blood plasma, in the process of hydrolysis under the influence of esterase. 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 only detected using highly sensitive analytical methods.

Distribution

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

breeding

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

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

Special patient groups

Elderly patients

In the elderly, the AUC value is 1.4-1.6 times higher than in young people (by 40-60%), and C max is more than 1.25 times (by 25%).

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

In elderly women (over 65 years old), the values ​​of AUC τ, ss and C max , ss were approximately 1.9 times and 1.6 times higher than in young women (18-40 years old), and in elderly men age - 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: baseline concentrations of dabigatran in patients aged ≥75 years were approximately 1.3 times (31%) higher, and in patients aged<65 лет – примерно на 22% ниже, чем у пациентов возрасте 65-75 лет.

Impaired kidney function

In volunteers with moderate renal impairment (CC - 30-50 ml / min), the AUC value of dabigatran after oral administration was approximately 3 times greater than in individuals with unchanged renal function.

In patients with severely impaired renal function (CC - 10-30 ml / min), the AUC values ​​​​of dabigatran etexilate and T1 / 2 increased, respectively, by 6 and 2 times, compared with those in individuals without impaired renal function.

In patients with atrial fibrillation and moderate renal insufficiency (CC 30-50 ml / min), dabigatran concentrations before and after the drug were on average 2.29 and 1.81 times higher than in patients without impaired renal function.

When using hemodialysis in patients without atrial fibrillation, it was found that the amount of excreted drug is proportional to the blood flow rate. The duration of dialysis, 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 of 50% and 60% of free and total dabigatran concentrations, respectively. The anticoagulant activity of dabigatran decreased with decreasing plasma concentrations, the relationship between FC and PD did not change.

Impaired liver function

In patients with moderate hepatic impairment (Child-Pugh score 7-9), there were no changes in plasma concentrations of dabigatran compared with patients without hepatic impairment.

Body mass

In research basal concentrations of dabigatran in patients weighing >100 kg were approximately 20% lower than in patients weighing 50-100 kg. Body weight in the majority (80.8%) of patients was ≥50 -< 100 кг, в пределах этого диапазона явных различий концентраций дабигатрана не установлено. Данные в отношении пациентов с массой тела ≤50 кг ограничены.

In the main studies on the prevention of VTE, it was found that the effect of the drug in female patients was approximately 1.4-1.5 times (40-50%) higher. In patients with atrial fibrillation, basal concentrations and concentrations after the use of 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 black patients are limited, but available data indicate no significant differences.

Indications for use:

Prevention of venous thromboembolism in patients after orthopedic surgery.
Prevention of stroke, systemic thromboembolism and reduction of cardiovascular mortality in patients with atrial fibrillation.

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 violation of hemostasis;
- Damage to organs as a result of clinically significant bleeding, including hemorrhagic stroke within 6 months before the start of therapy;
- Simultaneous administration of ketoconazole for systemic use;
- Impaired liver function and liver disease, which may affect survival;
- Age up to 18 years (no clinical data).

Dosage and administration:

Capsules should be taken orally, 1 or 2 times a day, regardless of the meal time, with water. Do not open the capsule.

Application in adults:

Prevention of venous thromboembolism (VTE) in patients after orthopedic surgery:

In patients with moderate renal impairment due to the risk of bleeding, the recommended dose is 150 mg 1 time per day (2 capsules of 75 mg).

Prevention of VTE after knee arthroplasty: PRADAXA should be started 1-4 hours after the completion of the operation with 1 capsule (110 mg) followed by an increase in dose to 2 capsules (220 mg) once a day for the next 10 days. If hemostasis is not achieved, treatment should be delayed. If treatment is not started on the day of surgery, therapy should be started with 2 capsules (220 mg) once a day.

Prevention of VTE after hip arthroplasty: PRADAXA should be started 1-4 hours after the completion of the operation with 1 capsule (110 mg) followed by an increase in dose to 2 capsules (220 mg) once a day for the next 28-35 days. If hemostasis is not achieved, treatment should be delayed. If treatment is not started on the day of surgery, therapy should be started with 2 capsules (220 mg) once a day.

Application in special groups of patients

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 section "Contraindications").

Impaired kidney function

Before therapy, in order to avoid prescribing the drug to patients with severely impaired renal function (CC less than 30 ml / min), it is necessary to first evaluate creatinine clearance. Due to the lack of data on the use of the drug in patients with heavy impaired renal function (CC less than 30 ml / min), the use of the drug PRADAXA is not recommended (see section "Contraindications").

Renal function should be assessed during treatment when there is a suspicion of a possible decrease or deterioration in renal function (for example, with hypovolemia, dehydration, simultaneous use of certain drugs, etc.).

When applied PRADAXA for the purpose at moderate impaired renal function (CC 30-50 ml / min) the daily dose of the drug should be reduced to 150 mg (2 capsules of 75 mg 1 time per day).

When using PRADAXA for the purpose of prevention of stroke, systemic thromboembolism and reduction of cardiovascular mortality in patients with atrial fibrillation at moderate impaired renal function (CC 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.

Dabigatran is excreted by hemodialysis; however, clinical experience in patients undergoing hemodialysis is limited.

Use in elderly patients

Due to the fact that an increase in drug exposure in elderly patients (over 75 years of age) is often due to a decrease in kidney function, it is necessary to evaluate renal function before prescribing the drug. Renal function should be assessed at least once a year or more frequently, depending on the clinical situation. Dose adjustment of the drug should be carried out depending on the severity of impaired renal function (see "Impaired renal function").

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

When using PRADAXA in elderly patients over 80 years of age to prevent stroke, systemic thromboembolism and reduce cardiovascular mortality in patients with atrial fibrillation PRADAXA should be taken at a daily dose of 220 mg (1 capsule of 110 mg 2 times a day).

Influence of body weight

Dose adjustment is not required depending on body weight.

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

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

Patients taking PRADAXA after orthopedic surgery are not recommended to simultaneously start 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:

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, a moderate decrease in renal function (CC 30-50 ml / min), the simultaneous use of P-glycoprotein inhibitors, or a history of gastrointestinal bleeding may increase the risk of bleeding (see "Special instructions "). In patients with one or more of these risk factors, at the discretion of the physician, it is possible to reduce the daily dose of PRADAXA to 220 mg (taking 1 capsule of 110 mg 2 times a day).

Switching from drug use PRADAXA to parenteral anticoagulants.

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

Prevention of stroke, systemic thromboembolism and reduction of cardiovascular mortality in patients with atrial fibrillation: parenteral anticoagulants should be started 12 hours after the last dose of PRADAXA.

Switching from parenteral anticoagulants to PRADAXA

The first dose of PRADAXA is given in place of the withdrawn anticoagulant 0–2 hours before the next injection of the alternative therapy, or concomitantly with the cessation of a continuous infusion (eg, intravenous unfractionated heparin, UFH).

Switching from vitamin K antagonists to 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 PRADAXA is possible with INR<2,0.

Switching from PRADAXA to vitamin K antagonists

With creatinine clearance ≥50 ml / min, the use of vitamin K antagonists is possible for 3 days, and with creatinine clearance of 30-50 ml / min - 2 days before discontinuation of PRADAXA.

cardioversion

Elective or emergency cardioversion does not require discontinuation of PRADAXA therapy.

Missed Dose

It is recommended that you take your usual daily dose of PRADAXA at ​​your usual time the next day. In 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 PRADAXA can be taken if there are 6 hours or more left before the next dose of the drug; if the period was less than 6 hours, the missed dose should not be taken. In case of missing individual doses, do not take a double dose of the drug.

Side effect:

Side effects identified when using the drug to prevent VTE after orthopedic surgery and for the prevention of stroke and systemic thromboembolism in patients with atrial fibrillation.

Disorders of the hematopoietic and lymphatic system:
anemia, thrombocytopenia.

Immune system disorders:
hypersensitivity reactions, including urticaria, rash and itching, bronchospasm.

Nervous system disorders:
intracranial bleeding.

hematoma, bleeding.

Respiratory, thoracic and mediastinal disorders:
nosebleeds, hemoptysis.

Gastrointestinal disorders:
gastrointestinal bleeding, rectal bleeding, hemorrhoidal bleeding, abdominal pain, diarrhea, dyspepsia, nausea, ulceration of the gastrointestinal mucosa, gastroesophagitis, gastroesophageal reflux disease, vomiting, dysphagia.

Hepatobiliary system disorders:
increased activity of "liver" transaminases, impaired liver function, hyperbilirubinemia.

Skin and subcutaneous tissue changes:
skin hemorrhagic syndrome.

Musculoskeletal disorders, disorders of the connective tissue and bones:
hemarthrosis.

Changes in the kidneys and urinary tract:
urogenital bleeding, hematuria.

General disorders and injection site changes:
bleeding from the injection site, bleeding from the injection site of the catheter.

Damage, toxicity and complications from procedures:
post-traumatic hematoma, bleeding from the site of surgical access.

Additional specific side effects identified in the prevention of venous thromboembolism in patients who underwent orthopedic surgery:

Vascular disorders:
bleeding from the surgical wound.

General disorders and disorders at the injection site:
bloody issues.

Damage, toxicity and complications of postoperative treatment:
hematoma after wound treatment, bleeding after wound treatment, anemia in the postoperative period, discharge from the wound after procedures, secretion from the wound.

Surgical and therapeutic procedures:
wound drainage, drainage after wound treatment.

Overdose:

Overdose when using the drug PRADAXA may be accompanied by hemorrhagic complications, due to the pharmacodynamic characteristics of the drug. If bleeding occurs, the use of the drug is stopped. Symptomatic treatment is shown. There is no specific antidote.

Given the main route of elimination of dabigatran (by the kidneys), it is recommended to ensure adequate diuresis. Surgical hemostasis and replenishment of circulating blood volume (BCV) are performed. Fresh whole blood or transfusion of fresh frozen plasma may be used. Since dabigatran has a low ability to bind to plasma proteins, the drug can be excreted during hemodialysis, however, clinical experience on the use of dialysis in these situations is limited (see the section "Pharmacokinetics").

In case of an overdose of PRADAXA, it is possible to use activated prothrombin complex or recombinant factor VIIa concentrates or coagulation factor II, IX or X concentrates. There is experimental evidence to support the effectiveness of these agents in counteracting the anticoagulant effect of dabigatran, but specific clinical studies have not been conducted.

In the event of thrombocytopenia, or when using long-acting antiplatelet agents, the use of platelet mass may be considered.

Interaction with other drugs:

Co-administration of PRADAXA with medicinal products that affect hemostasis or the coagulation system, including vitamin K antagonists, may significantly increase the risk of bleeding.

Pharmacokinetic interactions

In studies conducted invitro, no inducing or inhibitory effect of dabigatran on cytochrome P450 has been established. In research invivo in healthy volunteers, there was no interaction between dabigatran etexilate and atorvastatin (CYP3A4 substrate) and diclofenac (CYP2C9 substrate).

Interactions with P-glycoprotein inhibitors/inducers:

The substrate for the P-glycoprotein transport molecule is dabigatran etexilate. The simultaneous use of P-glycoprotein inhibitors (amiodarone, verapamil, quinidine, ketoconazole for systemic use or clarithromycin) leads to an increase in the concentration of dabigatran in the blood plasma.

Simultaneous use with P-glycoprotein inhibitors:

Dose selection in the case of the use of the listed P-glycoprotein inhibitors for prevention of stroke, systemic thromboembolism and reduction of cardiovascular mortality in patients with atrial fibrillation not required .

If used for the purpose prevention of venous thromboembolism in patients after orthopedic surgery- see sections "Method of administration and doses" and "Interaction with other drugs".

Amiodarone. Co-administration of dabigatran etexilate with a single oral dose of amiodarone (600 mg) did not alter the extent and rate of absorption of amiodarone and its active metabolite, deethylamiodarone. The AUC and C max values ​​of dabigatran increased 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 increase in the risk of bleeding was not registered.

Dronedarone. Following co-administration of dabigatran etexilate and dronedarone 400 mg as a single dose,

AUC 0-∞ and C max of dabigatran increased by 2.1 and 1.9 times (by 114% and 87%), respectively, and after repeated use of dronedarone at a dose of 400 mg per day - by 2.4 and 2.3 (by 136% and 125%) respectively. After single and multiple doses of dronedarone, 2 hours after taking dabigatran etexilate, AUC 0-∞ increased by 1.3 and 1.6 times, respectively. Dronedarone did not affect the final T1 / 2 and renal clearance of dabigatran.

Verapamil. With the simultaneous use of dabigatran etexilate with oral verapamil, the values ​​of C max and AUC of dabigatran increased depending on the time of use and the dosage form of verapamil.

The greatest increase in the effect of dabigatran was observed when using the first dose of verapamil in the immediate release dosage form, which was used 1 hour before taking dabigatran etexilate (C max increased by 180% and AUC by 150%). With the sustained release formulation of verapamil, this effect was progressively reduced (Cmax increased by 90% and AUC by 70%), as well as with multiple doses of verapamil (Cmax increased by 60% and AUC by 50%) , which may be explained by the induction of P-glycoprotein in the gastrointestinal tract with prolonged use of verapamil.

When using verapamil 2 hours after taking dabigatran etexilate, no clinically significant interactions were observed (C max increased by 10%, and AUC by 20%), since dabigatran is completely absorbed after 2 hours (see section "Method of application and doses").

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

Data on the interaction of dabigatran etexilate with parenteral verapamil are not available; no clinically significant interaction is expected.

Ketoconazole. Systemic ketoconazole after a single dose of 400 mg increases the AUC 0-∞ and C max of dabigatran by about 2.4 times (by 138% and 135%), respectively, and after repeated administration of ketoconazole at a dose of 400 mg per day, by about 2.5 times (by 153% and 149%), respectively. Ketoconazole did not affect T max and final T1 / 2. Simultaneous use of the drug PRADAXA and ketoconazole for systemic use is contraindicated.

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

Quinidine. The values ​​of AUC τ,ss and Cmax,ss of dabigatran when used 2 times a day in the case of simultaneous administration with quinidine at a dose of 200 mg every 2 hours until a total dose of 1000 mg were increased by an average of 53% and 56%, respectively.

Simultaneous use with substrates for P-glycoprotein:

Digoxin. With the simultaneous use of dabigatran etexilate with digoxin, which is a substrate of P-glycoprotein, no pharmacokinetic interaction was observed. Neither dabigatran nor the prodrug dabigatran etexilate are clinically relevant P-glycoprotein inhibitors.

Simultaneous use with P-glycoprotein inducers:

The simultaneous administration of PRADAXA and P-glycoprotein inducers should be avoided, since the combined use leads to a decrease in the effect of dabigatran (see section "Special Instructions").

Rifampicin. Preliminary use of the test inducer rifampicin at a dose of 600 mg daily for 7 days resulted in a decrease in exposure to dabigatran. After discontinuation of rifampicin, this inductive effect decreased; on day 7, the effect of dabigatran was close to baseline. Over the next 7 days, no further increase in the bioavailability of dabigatran was observed.

It is expected that other P-glycoprotein inducers, such as St. John's wort or carbamazepine, may also reduce plasma concentrations of dabigatran and should be used with caution.

Simultaneous use with antiplatelet agents

Acetylsalicylic acid (ASA). When studying the simultaneous use of dabigatran etexilate at a dose of 150 mg 2 times a day and acetylsalicylic acid (ASA) in patients with atrial fibrillation, it was found that the risk of bleeding can increase from 12% to 18% (when using ASA at a dose of 81 mg) and up to 24 % (when using ASA at a dose of 325 mg). ASA or clopidogrel co-administered with dabigatran etexilate 110 mg or 150 mg twice daily has been shown to increase the risk of major bleeding. Bleeding is observed more often also with the simultaneous use of warfarin with ASA or clopidogrel.

NSAIDs. The use of NSAIDs (non-steroidal anti-inflammatory drugs) for short-term analgesia after surgery did not increase the risk of bleeding when used with dabigatran etexilate. The experience of long-term use of NSAIDs, T1 / 2 of which is less than 12 hours, with dabigatran etexilate is limited, there is no evidence of an additional increase in the risk of bleeding.

Clopidogrel. It has been established that the 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 has been shown that the values ​​of AUC τ,ss and C max,ss of dabigatran, as well as blood coagulation parameters that were monitored to assess the effect of dabigatran (APTT, ecarin clotting time or thrombin time (anti FIIa), as well as the degree of inhibition of platelet aggregation (the main indicator of the effect of clopidogrel) during combination therapy did not change compared with the corresponding indicators in monotherapy.When using a "loading" dose of clopidogrel (300 or 600 mg), the AUC t,ss and C max,ss values ​​of dabigatran increased by 30-40 %.

Simultaneous use with drugs that increasepH of stomach contents

Pantoprazole. Co-administration of dabigatran etexilate and pantoprazole resulted in a 30% decrease in dabigatran AUC. Pantoprazole and other proton pump inhibitors have been co-administered with dabigatran etexilate in clinical studies with no effect on bleeding risk or efficacy observed.

Ranitidine. Ranitidine, when co-administered with dabigatran etexilate, did not significantly affect the extent of absorption of dabigatran.

The changes in the pharmacokinetic parameters of dabigatran revealed during the population analysis under the influence of proton pump inhibitors and antacids were clinically insignificant, since the severity 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 concentration of dabigatran and, on average, only slightly reduces the concentration of the drug in the blood plasma (by 11%). Therefore, the concomitant use of proton pump inhibitors does not appear to lead to an increase in the incidence of stroke or systemic thromboembolism, especially when compared with warfarin, and therefore, the decrease in the bioavailability of dabigatran caused by the simultaneous use of pantoprazole is probably not of clinical significance.

Use during pregnancy and during breastfeeding:

There are no data on the use of dabigatran etexilate during pregnancy. The potential risk in humans is unknown.

In experimental studies, no adverse effects on fertility or postnatal development of newborns have been established.

Women of reproductive age should use reliable methods of contraception in order to exclude the possibility of pregnancy during treatment with PRADAXA. When pregnancy occurs, the use of the drug is not recommended, unless the expected benefit outweighs the possible risk.

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

Special instructions:

Risk of bleeding

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

Treatment with PRADAXA does not require monitoring of anticoagulant activity. The test to determine the INR should not be used, since there is evidence of a false increase in the level of INR.

Thrombin or ecarin clotting time tests should be used to detect excessive anticoagulant activity of dabigatran. When these tests are not available, an APTT test should be used.

In a study in patients with atrial fibrillation, an aPTT level exceeding 2-3 times the normal limit before taking the next dose of the drug was associated with an increased risk of bleeding.

In pharmacokinetic studies of PRADAXA, it has been shown that in patients with reduced renal function (including elderly patients), an increase in drug exposure is observed. The use of PRADAXA is contraindicated in case of severe renal dysfunction (CC<30 мл/мин).

In the event of acute renal failure, PRADAXA should be discontinued.

The following factors can lead to an increase in the concentration of dagibatran in plasma: decreased renal function (CC 30-50 ml / min), age ≥75 years, simultaneous use of a P-glycoprotein inhibitor. The presence of one or more of these factors may increase the risk of bleeding (see section "Method of application and dosage").

Co-administration of PRADAXA with the following drugs has not been studied, but may increase the risk of bleeding: unfractionated heparin (excluding doses required to maintain venous or arterial catheter patency) and heparin derivatives, low molecular weight heparins (LMWHs), fondaparinux sodium, thrombolytic drugs, glycoprotein blockers Platelet GP IIb/IIIa receptors, ticlopidine, dextran, rivaroxaban, ticagrelor, vitamin K antagonists and P-glycoprotein inhibitors (itraconazole, tacrolimus, cyclosporine, ritonavir, nelfinavir and saquinavir). The risk of bleeding is increased in patients taking concomitant selective serotonin reuptake inhibitors. Also, the risk of bleeding may increase with the simultaneous use of antiplatelet agents and other anticoagulants.

The combined use of dronedarone and dabigatran is not recommended (see section "Interaction with other medicinal products").

With an increased risk of bleeding (for example, with a recent biopsy or extensive trauma, bacterial endocarditis), the patient's condition is required to be monitored in order to timely detect signs of bleeding.

Prevention of venous thromboembolism in patients after orthopedic surgery

It has been established that the use of NSAIDs for short-term anesthesia in surgical interventions simultaneously with PRADAXA is not accompanied by an increased risk of bleeding. There are limited data on the regular use of NSAIDs (having T1 / 2 less than 12 hours) during treatment with PRADAXA, data on an increased risk of bleeding have not been received.

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

The simultaneous use of PRADAXA, antiplatelet agents (including ASA and clopidogrel) and NSAIDs increases the risk of bleeding.

The use of fibrinolytic drugs should only be considered if the patient's TT, EVS, or APTT values ​​do not exceed the upper limit of normal in the local reference range.

Interaction with inductorsP-glycoprotein

Oral administration of the P-glycoprotein inducer rifampicin with PRADAXA reduced plasma concentrations of dabigatran. It is assumed that other inducers of P-glycoprotein, such as St. John's wort or carbamazepine, can also reduce the concentration of dabigatran in blood plasma and should be used with caution (see section "Interaction with other medicinal products").

Surgical operations and interventions

Patients who use PRADAXA during surgery or invasive procedures have an increased risk of bleeding. Therefore, during surgical interventions, PRADAXA should be discontinued (see also the Pharmacokinetics section).

Preoperative period

Before carrying out invasive procedures or surgical operations, PRADAXA is canceled at least 24 hours before they are performed. In patients with an increased risk of bleeding or before major surgery requiring complete hemostasis, PRADAXA should be discontinued 2-4 days before surgery. In patients with renal insufficiency, the clearance of dabigatran may be prolonged.

When discontinuing the drug, the following information should be considered:

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

PRADAXA is contraindicated in patients with severely impaired renal function (CK<30 мл/мин), но если препарат все же применяют, отменять его следует не менее чем за 5 дней до операции.

If emergency surgery is required, PRADAXA should be temporarily discontinued. Surgical intervention, if possible, should be performed no earlier than 12 hours after the last dose of PRADAXA. If the operation cannot be delayed, the risk of bleeding may increase (in the case of cardioversion, see "Dosage and Administration"). In this case, the ratio of 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 the event of a traumatic or repeated lumbar puncture and prolonged use of an epidural catheter, the risk of spinal bleeding or epidural hematoma may increase. The first dose of PRADAXA should be taken no earlier than 2 hours after catheter removal. It is necessary to monitor the condition of patients to exclude neurological symptoms that may be due to spinal bleeding or epidural hematoma.

The period after the procedure

The use of PRADAXA can be continued after achieving complete hemostasis.

Influence on the ability to drive vehicles and mechanisms:

The effect of PRADAXA on the ability to drive vehicles and engage in other potentially hazardous activities that require increased concentration and speed of psychomotor reactions has not been studied, but given that the use of PRADAXA may be accompanied by an increased risk of bleeding, care should be taken when performing such activities.

Release form:

Capsules 75 mg, 110 mg and 150 mg.

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

60 capsules per bottle made of polypropylene, sealed with a child-proof plastic screw cap, with a desiccant. One bottle in a cardboard box with instructions for use.

Packaging for hospitals (for a dosage of 150 mg): 10 capsules per blister perforated in Al/Al. 6 blisters in a cardboard box with instructions for use. 3 packs of cardboard in a polypropylene film.

Storage conditions:

Vial: at a temperature not exceeding 25°C. Keep the vial tightly closed to protect from moisture.

For 75 mg, 110 mg: after opening the vial, use the drug within 30 days.

For 150 mg: after opening the vial, use the drug within 4 months.

Blisters: in a dry place, at a temperature not exceeding 25°C.

Keep out of the reach of children.

Best before date:

Do not use after the expiration date.

Conditions for dispensing from pharmacies:

On prescription.

Registration certificate holder:

Boehringer Ingelheim International GmbH, Germany
Bingerstrasse 173

Manufacturer:

Boehringer Ingelheim Pharma GmbH & Co.KG, Germany
Germany, 55216 Ingelheim am Rhein,
Bingerstrasse 173

For more information about the drug, as well as to send your claims and information about adverse events, please contact the following address in Russia:

OOO Boehringer Ingelheim
125171, Moscow, Leningradskoe highway, 16A, building 3

Instructions for use. Contraindications and release form.

Instruction
on the medical use of the drug
Pradaxa

Dosage form:

Compound:

One capsule contains 86.48 mg, 126.83 mg or 172.95 mg of dabigatran etexilate mesylate, which corresponds to 75 mg, 110 mg or 150 mg of dabigatran etexilate.

Excipients:
Capsule contents: acacia gum 4.43 mg, 6.50 mg or 8.86 mg; tartaric acid, coarse 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; hyprolose (hydroxypropyl cellulose) 17.30 mg, 25.37 mg or 34.59 mg.

Capsule composition: Hypromellose (HPMC) capsule overprinted with black ink (Colorcon S-1-27797) 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 (hydroxypropyl methylcellulose) 52.9 mg, 61.71 mg or 79.35 mg, purified water 3.0 mg, 3.5 mg or 4.5 mg.

The composition of the black ink Colorcon S-1-27797, (%, wt.): shellac 52.500%, butanol 6.550%, purified water 1.940%, denatured ethanol (methylated alcohol) 0.650%, iron dye black oxide (E172) 33.770%, isopropanol 3.340%, propylene glycol 1.250%.

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

Description:

Capsules 75 mg. Hypromellose (hydroxypropyl methylcellulose) oblong capsules. Lid - opaque, light blue, body - opaque cream color. The Boehringer Ingelheim symbol is printed on the lid and “R 75” on the body. The overprint color is black.

Capsules 110 mg. Hypromellose (hydroxypropyl methylcellulose) oblong capsules. The lid is opaque light blue, the body is opaque cream. The Boehringer Ingelheim symbol is printed on the lid and “R 110” on the body. The overprint color is black.

Capsules 150 mg. Hypromellose (hydroxypropyl methylcellulose) oblong capsules, size 0. Lid - opaque light blue, body - opaque cream. The Boehringer Ingelheim symbol is printed on the lid and “R 150” on the body. The overprint color is black.

The contents of the capsules are yellowish pellets.

Pharmacotherapeutic group:

direct thrombin inhibitor ATC code: B01AE07

Pharmacological properties:

Pharmacodynamics:

Dabigatran etexilate is a low molecular weight, pharmacologically inactive precursor to the active form of dabigatran. Following oral administration, dabigatran etexilate is rapidly absorbed from the gastrointestinal tract (GIT) and converted to dabigatran in the liver and plasma by esterase-catalyzed hydrolysis. Dabigatran is a potent competitive reversible direct thrombin inhibitor and the main active substance in plasma.

Since thrombin (serine protease) converts fibrinogen to fibrin during coagulation, inhibition of thrombin activity prevents the formation of a thrombus. Dabigatran has an inhibitory effect on free thrombin, fibrin clot-bound thrombin, and thrombin-induced platelet aggregation.

In experimental studies on various models of thrombosis in vivo and ex vivo, the antithrombotic effect and anticoagulant activity of dabigatran after intravenous administration and dabigatran etexilate after oral administration were confirmed.

A direct correlation has been established between the concentration of dabigatran in blood plasma and the severity of the anticoagulant effect. Dabigatran prolongs activated partial thromboplastin time (APTT), ecarin clotting time (ECT), and thrombin time (TT).

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

The results of clinical studies in patients undergoing orthopedic surgery - knee and hip arthroplasty - confirmed the preservation of hemostasis parameters and the equivalence of using 75 mg or 110 mg of dabigatran etexilate 1-4 hours after surgery and a subsequent maintenance dose of 150 or 220 mg once a day in for 6-10 days (for knee surgery) and 28-35 days (for the hip joint) compared with enoxaparin at a dose of 40 mg 1 time per day, which was used before and after surgery.

The antithrombotic effect of dabigatran etexilate 150 mg or 220 mg was shown to be equivalent to that of enoxaparin 40 mg daily in the primary endpoint, which includes all venous thromboembolic events and all-cause mortality.

Prevention of stroke and systemic thromboembolism in patients with atrial fibrillation

In long-term use, averaging about 20 months, in patients with atrial fibrillation and at moderate or high risk of stroke or systemic thromboembolism, dabigatran etexilate 110 mg given twice daily has been shown to be non-inferior to warfarin in 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 2 times a day) significantly reduced the risk of ischemic and hemorrhagic stroke, cardiovascular death, intracranial bleeding and overall bleeding, compared with warfarin. The lower dose of dabigatran was associated with a significantly lower risk of major bleeding compared with warfarin.

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

The annual incidence of these events in patients treated with dabigatran etexilate was lower than in patients treated with warfarin.

Changes in laboratory parameters of liver function in patients treated with dabigatran etexilate were observed at a comparable or lower frequency compared to patients treated with warfarin.

Pharmacokinetics:

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

After reaching Cmax, plasma concentrations of dabigatran decrease biexponentially, the terminal half-life (T1 / 2) averages about 11 hours (in the elderly). 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 impaired renal function, T1 / 2 lengthens.

The absolute bioavailability of dabigatran following oral administration of dabigatran etexilate in hypromellose-coated capsules is approximately 6.5%.

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

When using dabigatran etexilate without a special capsule shell made from hypromellose, oral bioavailability can increase by about 1.8 times (75%) compared with the dosage form in capsules. Therefore, the integrity of capsules made from hypromellose should be maintained, given the risk of increasing the bioavailability of dabigatran etexilate, and it is not recommended to open the capsules and use their contents in their pure form (for example, adding to food or drinks) (see section "Method of administration and doses").

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. Cmax in blood plasma is observed 6 hours after the use of dabigatran etexilate or 7-9 hours after surgery. It should be noted that factors such as anesthesia, paresis of the gastrointestinal tract and surgery may play a role in slowing 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, absorption of dabigatran is rapid, reaching Cmax 2 hours after oral administration.

Metabolism

After ingestion, dabigatran etexilate is rapidly and completely converted to dabigatran, which is the main active metabolite in blood plasma, in the process of hydrolysis under the influence of esterase. 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 only detected using highly sensitive analytical methods.

Distribution

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

breeding

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

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

Special patient groups

Elderly patients

In the elderly, the AUC value is 1.4-1.6 times higher than in young people (by 40-60%), and Cmax is more than 1.25 times (by 25%).

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

In elderly women (over 65 years old), the AUCτ,ss and Cmax,ss values ​​were approximately 1.9 times and 1.6 times higher than in young women (18-40 years old), 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: baseline concentrations of dabigatran in patients aged ≥75 years were approximately 1.3 times (31%) higher, and in patients aged<65 лет – примерно на 22% ниже, чем у пациентов возрасте 65-75 лет.

Impaired kidney function

In volunteers with moderate renal impairment (CC - 30-50 ml / min), the AUC value of dabigatran after oral administration was approximately 3 times greater than in individuals with unchanged renal function.

In patients with severely impaired renal function (CC - 10-30 ml / min), the AUC values ​​​​of dabigatran etexilate and T1 / 2 increased, respectively, by 6 and 2 times, compared with those in individuals without impaired renal function.

In patients with atrial fibrillation and moderate renal insufficiency (CC 30-50 ml / min), dabigatran concentrations before and after the drug were on average 2.29 and 1.81 times higher than in patients without impaired renal function.

When using hemodialysis in patients without atrial fibrillation, it was found that the amount of excreted drug is proportional to the blood flow rate. The duration of dialysis, 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 of 50% and 60% of free and total dabigatran concentrations, respectively. The anticoagulant activity of dabigatran decreased with decreasing plasma concentrations, the relationship between FC and PD did not change.

Impaired liver function

In patients with moderate hepatic impairment (Child-Pugh score 7-9), there were no changes in plasma concentrations of dabigatran compared with patients without hepatic impairment.

Body mass

In studies, dabigatran basal concentrations in patients weighing >100 kg were approximately 20% lower than in patients weighing 50-100 kg. Body weight in the majority (80.8%) of patients was ≥50 -< 100 кг, в пределах этого диапазона явных различий концентраций дабигатрана не установлено. Данные в отношении пациентов с массой тела ≤50 кг ограничены.

In the main studies on the prevention of VTE, it was found that the effect of the drug in female patients was approximately 1.4-1.5 times (40-50%) higher. In patients with atrial fibrillation, basal concentrations and concentrations after the use of 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 black patients are limited, but available data indicate no significant differences.

Indications for use:

Prevention of venous thromboembolism in patients after orthopedic surgery.

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 violation of hemostasis;

Organ damage resulting from clinically significant bleeding, including hemorrhagic stroke within 6 months prior to therapy;

Simultaneous administration of ketoconazole for systemic use;

Liver dysfunction and liver disease, which may affect survival;

Age up to 18 years (clinical data are not available).

Dosage and administration:

Capsules should be taken orally, 1 or 2 times a day, regardless of the meal time, with water. Do not open the capsule.

Application in adults:

Prevention of venous thromboembolism (VTE) in patients after orthopedic surgery:

In patients with moderate renal impairment due to the risk of bleeding, the recommended dose is 150 mg 1 time per day (2 capsules of 75 mg).

Prevention of VTE after knee arthroplasty: Pradaxa should be started 1-4 hours after the completion of the operation with 1 capsule (110 mg) followed by an increase in dose to 2 capsules (220 mg) once a day for the next 10 days. If hemostasis is not achieved, treatment should be delayed. If treatment is not started on the day of surgery, therapy should be started with 2 capsules (220 mg) once a day.

Prevention of VTE after hip arthroplasty: Pradaxa should be started 1-4 hours after the completion of the operation with 1 capsule (110 mg) followed by an increase in dose to 2 capsules (220 mg) once a day for the next 28-35 days. If hemostasis is not achieved, treatment should be delayed. If treatment is not started on the day of surgery, therapy should be started with 2 capsules (220 mg) once a day.

Application in special groups of patients

Use in children

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

Impaired kidney function

Before therapy, in order to avoid prescribing the drug to patients with severely impaired renal function (CC less than 30 ml / min), it is necessary to first evaluate creatinine clearance. Due to 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 Pradaxa is not recommended (see section "Contraindications").

Renal function should be assessed during treatment when there is a suspicion of a possible decrease or deterioration in renal function (for example, with hypovolemia, dehydration, simultaneous use of certain drugs, etc.).

When using Pradaxa to prevent venous thromboembolism in patients after orthopedic surgery with moderate renal dysfunction (CC 30-50 ml / min), the daily dose of the drug should be reduced to 150 mg (2 capsules of 75 mg 1 time per day).

When using Pradaxa to prevent stroke, systemic thromboembolism and reduce cardiovascular mortality in patients with atrial fibrillation with moderate renal dysfunction (CC 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.

Dabigatran is excreted by hemodialysis; however, clinical experience in patients undergoing hemodialysis is limited.

Use in elderly patients

Due to the fact that an increase in drug exposure in elderly patients (over 75 years of age) is often due to a decrease in kidney function, it is necessary to evaluate renal function before prescribing the drug. Renal function should be assessed at least once a year or more frequently, depending on the clinical situation. Dose adjustment of the drug should be carried out depending on the severity of impaired renal function (see "Impaired renal function").

When using Pradaxa in elderly patients over 80 years of age to prevent stroke, systemic thromboembolism and reduce cardiovascular mortality in patients with atrial fibrillation, Pradaxa should be taken at a daily dose of 220 mg (1 capsule of 110 mg 2 times a day).

Influence of body weight

Dose adjustment is not required depending on body weight.

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

When used simultaneously with amiodarone, quinidine or verapamil, the dose of Pradaxa should be reduced to 150 mg 1 time per day (2 capsules of 75 mg) (see section "Interaction with other drugs").

Patients taking Pradaxa after orthopedic surgery are not recommended to simultaneously start 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:

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, a moderate decrease in renal function (CC 30-50 ml / min), the simultaneous use of P-glycoprotein inhibitors, or a history of gastrointestinal bleeding may increase the risk of bleeding (see "Special instructions "). In patients with one or more of these risk factors, at the discretion of the physician, it is possible to reduce the daily dose of Pradaxa to 220 mg (taking 1 capsule of 110 mg 2 times a day).

Switching from the use of Pradaxa to parenteral use of anticoagulants.

: parenteral administration of anticoagulants should be started 24 hours after the last dose of Pradaxa.

Prevention of stroke, systemic thromboembolism and reduction of cardiovascular mortality in patients with atrial fibrillation: parenteral anticoagulants should be started 12 hours after the last dose of Pradaxa.

Switching from parenteral anticoagulants to Pradaxa

The first dose of Pradaxa is given in place of the withdrawn anticoagulant 0-2 hours before the next injection of the alternative therapy, or concomitantly with the cessation of a continuous infusion (eg, intravenous unfractionated heparin, UFH).

Switching from vitamin K antagonists to 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 Pradaxa is possible with INR<2,0.

Switching from Pradaxa to Vitamin K Antagonists

With creatinine clearance ≥50 ml / min, the use of vitamin K antagonists is possible for 3 days, and with creatinine clearance of 30-50 ml / min - 2 days before discontinuation of Pradaxa.

cardioversion

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

Elective or emergency cardioversion does not require discontinuation of Pradaxa therapy.

Missed Dose

Prevention of venous thromboembolism in patients after orthopedic surgery

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

The missed dose of PRADAXA can be taken if there are 6 hours or more left before the next dose of the drug; if the period was less than 6 hours, the missed dose should not be taken. In case of missing individual doses, do not take a double dose of the drug.

Side effect:

Side effects identified when using the drug to prevent VTE after orthopedic surgery and to prevent stroke and systemic thromboembolism in patients with atrial fibrillation.

Hematopoietic and lymphatic system disorders: anemia, thrombocytopenia.

Immune system disorders: hypersensitivity reactions including urticaria, rash and itching, bronchospasm.

Nervous system disorders: intracranial bleeding.

Vascular disorders: hematoma, bleeding.

Respiratory, thoracic and mediastinal disorders: epistaxis, hemoptysis.

Gastrointestinal disorders: gastrointestinal bleeding, rectal bleeding, hemorrhoidal bleeding, abdominal pain, diarrhea, dyspepsia, nausea, gastrointestinal mucosal ulceration, gastroesophagitis, gastroesophageal reflux disease, vomiting, dysphagia.

On the part of the hepatobiliary system: increased activity of "liver" transaminases, impaired liver function, hyperbilirubinemia.

Skin and subcutaneous tissue changes: cutaneous hemorrhagic syndrome.

Musculoskeletal disorders, connective tissue and bone disorders: hemarthrosis.

Changes in the kidneys and urinary tract: urogenital bleeding, hematuria.

General disorders and changes at the injection site: bleeding from the injection site, bleeding from the catheter insertion site.

Damage, toxicity and complications from procedures: post-traumatic hematoma, bleeding from the site of surgical access.

Additional specific side effects identified in the prevention of venous thromboembolism in patients who underwent orthopedic surgery:
Vascular disorders: bleeding from the surgical wound.

General disorders and disorders at the injection site: spotting.

Damage, toxicity and complications of postoperative treatment: hematoma after wound treatment, bleeding after wound treatment, anemia in the postoperative period, discharge from the wound after procedures, secretion from the wound.

Surgical and therapeutic procedures: wound drainage, drainage after wound treatment.

Overdose:

Overdose when using Pradaxa may be accompanied by hemorrhagic complications, due to the pharmacodynamic characteristics of the drug. If bleeding occurs, the use of the drug is stopped. Symptomatic treatment is shown. There is no specific antidote.

Given the main route of elimination of dabigatran (by the kidneys), it is recommended to ensure adequate diuresis. Surgical hemostasis and replenishment of circulating blood volume (BCV) are performed. Fresh whole blood or transfusion of fresh frozen plasma may be used. Since dabigatran has a low ability to bind to plasma proteins, the drug can be excreted during hemodialysis, however, clinical experience on the use of dialysis in these situations is limited (see the section "Pharmacokinetics").

In case of an overdose of Pradaxa, it is possible to use activated prothrombin complex concentrates or recombinant factor VIIa or concentrates of coagulation factors II, IX or X. There is experimental evidence to support the effectiveness of these agents in counteracting the anticoagulant effect of dabigatran, but specific clinical studies have not been conducted.

In the event of thrombocytopenia, or when using long-acting antiplatelet agents, the use of platelet mass may be considered.

Interaction with other drugs:

Co-administration of Pradaxa with medicinal products that affect hemostasis or the coagulation system, including vitamin K antagonists, may significantly increase the risk of bleeding.

Pharmacokinetic interactions

In vitro studies have not established an inducing or inhibitory effect of dabigatran on cytochrome P450. In vivo studies in healthy volunteers showed no interaction between dabigatran etexilate and atorvastatin (CYP3A4 substrate) and diclofenac (CYP2C9 substrate).

Interactions with P-glycoprotein inhibitors/inducers:

The substrate for the P-glycoprotein transport molecule is dabigatran etexilate. The simultaneous use of P-glycoprotein inhibitors (amiodarone, verapamil, quinidine, ketoconazole for systemic use or clarithromycin) leads to an increase in the concentration of dabigatran in the blood plasma.

Simultaneous use with P-glycoprotein inhibitors:

Dose selection in the case of the use of the listed P-glycoprotein inhibitors for the prevention of stroke, systemic thromboembolism and the reduction of cardiovascular mortality in patients with atrial fibrillation is not required.

In the case of use for the prevention of venous thromboembolism in patients after orthopedic surgery, see sections "Method of administration and doses" and "Interaction with other drugs."

Amiodarone. Co-administration of dabigatran etexilate with a single oral dose of amiodarone (600 mg) did not alter the extent and rate of absorption of amiodarone and its active metabolite, deethylamiodarone. The AUC and Cmax values ​​of dabigatran increased 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 increase in the risk of bleeding was not registered.

Dronedarone. Following co-administration of dabigatran etexilate and dronedarone 400 mg as a single dose,

AUC0-∞ and Cmax of dabigatran increased by 2.1 and 1.9 times (by 114% and 87%), respectively, and after repeated use of dronedarone at a dose of 400 mg per day, by 2.4 and 2.3 (by 136% and 125%), respectively. After single and multiple doses of dronedarone, 2 hours after taking dabigatran etexilate, AUC0-∞ increased by 1.3 and 1.6 times, respectively. Dronedarone did not affect the final T1 / 2 and renal clearance of dabigatran.

Verapamil. When dabigatran etexilate was co-administered with oral verapamil, the Cmax and AUC of dabigatran increased depending on the time of administration and the dosage form of verapamil.

The greatest increase in the effect of dabigatran was observed with the first dose of verapamil in the immediate release dosage form, which was used 1 hour before taking dabigatran etexilate (Cmax increased by 180% and AUC by 150%). When using the sustained release formulation of verapamil, this effect progressively decreased (Cmax increased by 90% and AUC by 70%), as well as when using multiple doses of verapamil (Cmax increased by 60% and AUC by 50%), which may be due to the induction of P-glycoprotein in the gastrointestinal tract with prolonged use of verapamil.

When using verapamil 2 hours after taking dabigatran etexilate, no clinically significant interactions were observed (Cmax increased by 10%, and AUC by 20%), since dabigatran is completely absorbed after 2 hours (see section "Method of application and doses").

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

Data on the interaction of dabigatran etexilate with parenteral verapamil are not available; no clinically significant interaction is expected.

Ketoconazole. Systemic ketoconazole after a single dose of 400 mg increases the AUC0-∞ and Cmax of dabigatran by about 2.4 times (by 138% and 135%), respectively, and after repeated administration of ketoconazole at a dose of 400 mg per day, by about 2. 5 times (by 153% and 149%), respectively. Ketoconazole did not affect Tmax and final T1 / 2. The simultaneous use of the drug Pradaxa and ketoconazole for systemic use is contraindicated.

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

Quinidine. The values ​​of AUCτ,ss and Cmax,ss of dabigatran when used twice a day in the case of simultaneous administration with quinidine at a dose of 200 mg every 2 hours until a total dose of 1000 mg were increased by an average of 53% and 56%, respectively.

Simultaneous use with substrates for P-glycoprotein:

Digoxin. With the simultaneous use of dabigatran etexilate with digoxin, which is a substrate of P-glycoprotein, no pharmacokinetic interaction was observed. Neither dabigatran nor the prodrug dabigatran etexilate are clinically relevant P-glycoprotein inhibitors.

Simultaneous use with P-glycoprotein inducers:

Simultaneous administration of Pradaxa and P-glycoprotein inducers should be avoided, since the combined use leads to a decrease in the effect of dabigatran (see section "Special Instructions").

Rifampicin. Preliminary use of the test inducer rifampicin at a dose of 600 mg daily for 7 days resulted in a decrease in exposure to dabigatran. After discontinuation of rifampicin, this inductive effect decreased; on day 7, the effect of dabigatran was close to baseline. Over the next 7 days, no further increase in the bioavailability of dabigatran was observed.

It is expected that other P-glycoprotein inducers, such as St. John's wort or carbamazepine, may also reduce plasma concentrations of dabigatran and should be used with caution.

Simultaneous use with antiplatelet agents

Acetylsalicylic acid (ASA). When studying the simultaneous use of dabigatran etexilate at a dose of 150 mg 2 times a day and acetylsalicylic acid (ASA) in patients with atrial fibrillation, it was found that the risk of bleeding can increase from 12% to 18% (when using ASA at a dose of 81 mg) and up to 24 % (when using ASA at a dose of 325 mg). ASA or clopidogrel co-administered with dabigatran etexilate 110 mg or 150 mg twice daily has been shown to increase the risk of major bleeding. Bleeding is observed more often also with the simultaneous use of warfarin with ASA or clopidogrel.

NSAIDs. The use of NSAIDs (non-steroidal anti-inflammatory drugs) for short-term analgesia after surgery did not increase the risk of bleeding when used with dabigatran etexilate. The experience of long-term use of NSAIDs, T1 / 2 of which is less than 12 hours, with dabigatran etexilate is limited, there is no evidence of an additional increase in the risk of bleeding.

Clopidogrel. It has been established that the 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 was shown that the AUCτ,ss and Cmax,ss values ​​of dabigatran, as well as the blood coagulation parameters that were monitored to assess the effect of dabigatran (APTT, ecarin clotting time or thrombin time (anti-FIIa), as well as the degree of inhibition of platelet aggregation (basic the effect of clopidogrel) during combination therapy did not change compared with the corresponding indicators in monotherapy. When using a "loading" dose of clopidogrel (300 or 600 mg), the AUCt,ss and Cmax,ss values ​​of dabigatran increased by 30-40%.

Simultaneous use with drugs that increase the pH of the contents of the stomach

Pantoprazole. Co-administration of dabigatran etexilate and pantoprazole resulted in a 30% decrease in dabigatran AUC. Pantoprazole and other proton pump inhibitors have been co-administered with dabigatran etexilate in clinical studies with no effect on bleeding risk or efficacy observed.

Ranitidine. Ranitidine, when co-administered with dabigatran etexilate, did not significantly affect the extent of absorption of dabigatran.

The changes in the pharmacokinetic parameters of dabigatran revealed during the population analysis under the influence of proton pump inhibitors and antacids were clinically insignificant, since the severity 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 concentration of dabigatran and, on average, only slightly reduces the concentration of the drug in the blood plasma (by 11%). Therefore, the concomitant use of proton pump inhibitors does not appear to lead to an increase in the incidence of stroke or systemic thromboembolism, especially when compared with warfarin, and therefore, the decrease in the bioavailability of dabigatran caused by the simultaneous use of pantoprazole is probably not of clinical significance.

Use during pregnancy and during breastfeeding:

There are no data on the use of dabigatran etexilate during pregnancy. The potential risk in humans is unknown.

In experimental studies, no adverse effects on fertility or postnatal development of newborns have been established.

Women of reproductive age should use reliable methods of contraception in order to exclude the possibility of pregnancy during treatment with Pradaxa. When pregnancy occurs, the use of the drug is not recommended, unless the expected benefit outweighs the possible risk.

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

Special instructions:

Risk of bleeding

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

Treatment with Pradaxa does not require monitoring of anticoagulant activity. The test to determine the INR should not be used, since there is evidence of a false increase in the level of INR.

Thrombin or ecarin clotting time tests should be used to detect excessive anticoagulant activity of dabigatran. When these tests are not available, an APTT test should be used.

In a study in patients with atrial fibrillation, an aPTT level exceeding 2-3 times the normal limit before taking 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 reduced renal function (including elderly patients), there is an increase in drug exposure. The use of Pradaxa is contraindicated in case of severe renal dysfunction (CC<30 мл/мин).

In the event of acute renal failure, Pradaxa should be discontinued.

The following factors can lead to an increase in the concentration of dagibatran in plasma: decreased renal function (CC 30-50 ml / min), age ≥75 years, simultaneous use of a P-glycoprotein inhibitor. The presence of one or more of these factors may increase the risk of bleeding (see section "Method of application and dosage").

Co-administration of Pradaxa with the following drugs has not been studied, but may increase the risk of bleeding: unfractionated heparin (excluding doses required to maintain venous or arterial catheter patency) and heparin derivatives, low molecular weight heparins (LMWHs), fondaparinux sodium, thrombolytic drugs, glycoprotein blockers Platelet GP IIb/IIIa receptors, ticlopidine, dextran, rivaroxaban, ticagrelor, vitamin K antagonists and P-glycoprotein inhibitors (itraconazole, tacrolimus, cyclosporine, ritonavir, nelfinavir and saquinavir). The risk of bleeding is increased in patients taking concomitant selective serotonin reuptake inhibitors. Also, the risk of bleeding may increase with the simultaneous use of antiplatelet agents and other anticoagulants.

The combined use of dronedarone and dabigatran is not recommended (see section "Interaction with other medicinal products").

With an increased risk of bleeding (for example, with a recent biopsy or extensive trauma, bacterial endocarditis), the patient's condition is required to be monitored in order to timely detect signs of bleeding.

Prevention of venous thromboembolism in patients after orthopedic surgery

It has been established that the use of NSAIDs for short-term anesthesia in surgical interventions simultaneously with Pradaxa is not accompanied by an increased risk of bleeding. There are limited data on the regular use of NSAIDs (having T1 / 2 less than 12 hours) during treatment with Pradaxa, data on an increased risk of bleeding have not been received.

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

The simultaneous use of Pradaxa, antiplatelet agents (including ASA and clopidogrel) and NSAIDs increases the risk of bleeding.

The use of fibrinolytic drugs should only be considered if the patient's TT, EVS, or APTT values ​​do not exceed the upper limit of normal in the local reference range.

Interaction with P-glycoprotein inducers

Oral administration of the P-glycoprotein inducer rifampicin with Pradaxa reduced plasma concentrations of dabigatran. It is assumed that other inducers of P-glycoprotein, such as St. John's wort or carbamazepine, can also reduce the concentration of dabigatran in blood plasma and should be used with caution (see section "Interaction with other medicinal products").

Surgical operations and interventions

Patients who use Pradaxa during surgery or invasive procedures have an increased risk of bleeding. Therefore, during surgical interventions, Pradaxa should be discontinued (see also the Pharmacokinetics section).

If emergency surgery is required, Pradaxa should be temporarily discontinued. Surgical intervention, if possible, should be performed no earlier than 12 hours after the last dose of Pradax. If the operation cannot be delayed, the risk of bleeding may increase (in the case of cardioversion, see "Dosage and Administration"). In this case, the ratio of 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 the event of a traumatic or repeated lumbar puncture and prolonged use of an epidural catheter, the risk of spinal bleeding or epidural hematoma may increase. The first dose of Pradaxa should be taken no earlier than 2 hours after catheter removal. It is necessary to monitor the condition of patients to exclude neurological symptoms that may be due to spinal bleeding or epidural hematoma.

The period after the procedure

The use of Pradaxa can be continued when complete hemostasis is achieved.

Influence on the ability to drive vehicles and mechanisms:

The effect of Pradaxa on the ability to drive vehicles and engage in other potentially hazardous activities that require increased concentration and speed of psychomotor reactions has not been studied, but given that the use of Pradaxa may be accompanied by an increased risk of bleeding, care should be taken when performing such activities.

Release form:

Capsules 75 mg, 110 mg and 150 mg.

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

60 capsules per bottle made of polypropylene, sealed with a child-proof plastic screw cap, with a desiccant. One bottle in a cardboard box with instructions for use.

Bingerstrasse 173

Manufacturer:

Boehringer Ingelheim Pharma GmbH & Co.KG, Germany

Germany, 55216 Ingelheim am Rhein,