Pradaxa capsules 150mg №180

Latin name

PRADAXA

Active substance

Dabigatran etexilate

Release form

capsules

Owner / Registrar

BOEHRINGER INGELHEIM INTERNATIONAL, GmbH

Pharmacological group

Anticoagulant. Direct thrombin inhibitor

Mechanism of action

Direct inhibitor of thrombin. Dabigatran etexilate is a low molecular weight, non-pharmacologically active precursor of the active form of dabigatran. After ingestion of dabigatran, etexilate is rapidly absorbed from the gastrointestinal tract and, by hydrolysis catalyzed by esterases, in the liver and blood plasma is converted into dabigatran. Dabigatran is a potent competitive reversible direct inhibitor of thrombin and the main active substance in blood plasma.

Since thrombin (serine protease) converts fibrinogen to fibrin in the process of coagulation, the suppression of its activity prevents the formation of a blood clot. Dabigatran inhibits free thrombin, fibrin-binding thrombin and thrombin-induced platelet aggregation.

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

A direct correlation between the concentration of dabigatran in the blood plasma and the severity of the anticoagulant effect was established. Dabigatran lengthens APTT, ekarinovo clotting time (EVS) and thrombin time (TV).

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

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

The equivalence of the antithrombotic effect of dabigatran etexilate was shown when used in doses of 150 mg or 220 mg compared to enoxaparin at a dose of 40 mg / day when assessing the main endpoint, which includes all cases of venous thromboembolism and mortality from any causes.

Prevention of stroke and systemic thromboembolism in patients with atrial fibrillation

With a long, on average about 20 months, use in patients with atrial fibrillation and with moderate or high risk of stroke or systemic thromboembolism, it was shown that dabigatran etexilate at a dose of 110 mg, used 2 times / day, was not inferior to Warfarin in terms of the effectiveness of stroke prevention and systemic thromboembolism in patients with atrial fibrillation; similarly, in the dabigatran group, a decrease in the risk of intracranial bleeding and overall bleeding rates was observed. The use of the drug in a higher dose (150 mg 2 times / day) significantly reduced the risk of ischemic and hemorrhagic stroke, cardiovascular death, intracranial bleeding, and general bleeding rate, compared with warfarin. A lower dose of dabigatran was characterized by a significantly lower risk of major bleeding compared with warfarin.

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

The annual incidence of these events in patients who received dabigatran etexilate was lower than in patients who received warfarin.

Changes in laboratory parameters of liver function in patients who received dabigatran etexilate were observed with comparable or lower frequency compared with patients receiving warfarin.

Prevention of thromboembolism in patients with prosthetic heart valves

During clinical studies of phase II use of dabigatran and warfarin in patients undergoing surgery to replace the heart valve with a mechanical prosthesis (recent operations and surgeries performed more than 3 months ago), an increase in the frequency of thromboembolism and total bleeding was detected (mainly due to small bleeding ) in patients receiving dabigatran etexilate.In the early postoperative period, major bleeding was mainly characterized by a hemorrhagic effusion in the pericardium, especially in patients to whom dabigatran etexilate was prescribed in the early period (on day 3) after surgical replacement of the heart valves.

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

The results of clinical studies in patients with the presence of acute DVT and / or pulmonary embolism who initially received
parenteral therapy for at least 5 days confirmed that dabigatran etexilate in a dose of 150 mg, used 2 times / day, was not inferior to warfarin in terms of effectiveness in reducing the frequency of recurrent
symptomatic DVT and / or pulmonary embolism and deaths due to these diseases over a period of 6 months
treatment period. In patients who received dabigatran etexilate, bleeding was less frequent than in patients with dabigatran etexilate.
patients receiving warfarin.

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

Prevention of recurrent DVT and / or pulmonary embolism and death caused by these diseases

The results of a clinical study in patients with recurrent DVT and PE, who had already received anticoagulant therapy for 3 to 12 months and who needed to continue it, confirmed that treatment of dabigatran etexilate with a dose of 150 mg 2 times / day was not inferior to the therapeutic effect of warfarin (p = 0.0135). In patients who received
dabigatran etexilate, bleeding was observed much less frequently than in patients receiving warfarin.

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

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

Liver function indicators

In studies using active comparison drugs, possible changes in liver function parameters occurred in patients who received dabigatran etexilate, with comparable or lower frequency than in patients who received warfarin.In the study with placebo, there was no significant difference in changes in liver function indicators, which may have clinical significance, between the groups using dabigatran etexilate and placebo.

Pharmacokinetics

Suction

After ingestion of dabigatran etexilate, a rapid dose-dependent increase in its plasma concentration and AUC is observed. C_max dabigatran etexilate is reached within 0.5-2 hours.

After reaching C_max plasma concentrations of dabigatran decrease biexponentially. The absolute bioavailability of dabigatran after ingestion of the drug in capsules coated with hypromellose is about 6.5%.

Meal does not affect the bioavailability of dabigatran etexilate, however, the time to reach C_max increases by 2 hours

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

When using dabigatran etexilate after 1-3 hours in patients after surgical treatment, there is a decrease in the rate of absorption of the drug compared with healthy volunteers. AUC is characterized by a gradual increase in amplitude without the appearance of a high peak plasma concentration. WITH_max in the blood plasma observed after 6 h after application of dabigatran etexilate or 7-9 h after surgery.

It should be noted that such factors as anesthesia, paresis of the gastrointestinal tract and surgery can be important in slowing the absorption, regardless of the dosage form of the drug. A decrease in the rate of absorption of the drug is usually noted only on the day of surgery. In the following days, the absorption of dabigatran occurs quickly, with the achievement of C_max 2 hours after ingestion.

Distribution

V_d dabigatran is 60-70 liters and exceeds the volume of the total water content in the body, which indicates a moderate distribution of dabigatran in the tissues.

Dabigatran has a low ability to bind to plasma proteins (34-35%), independent of the concentration of the drug.

Metabolism

After ingestion in the process of hydrolysis under the influence of dabigatran esterase, etexilate quickly and completely turns into dabigatran, which is the main active metabolite in blood plasma. When conjugating dabigatran, 4 isomers of pharmacologically active acylglucuronides are formed: 1-O, 2-O, 3-O, 4-O, each of which is less than 10% of the total content of dabigatran in the blood plasma. Traces of other metabolites are detected only by using highly sensitive analytical methods.

Removal

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

Final t_1/2 after repeated use of the drug was about 12-14 hours. T_1/2 independent of dose

Pharmacokinetics in Special Patient Groups

Elderly patients

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

The observed changes correlated with an age-related decrease in QA.

In older women (over 65) AUC values_{t ss} and C_{max, ss} were about 1.9 times and 1.6 times higher than among younger women (18-40 years old), and in older men - 2.2 and 2.0 times higher than among younger men. The study of patients with atrial fibrillation confirmed the effect of age on the exposure of dabigatran: initial concentrations of dabigatran in patients aged ≥75 years were about 1.3 times (31%) higher, and in patients aged <65 years - about 22% lower than in patients aged 65-75 years.

Elderly patients end T_1/2 on average is about 11 hours.

Renal dysfunction

In case of impaired renal function T_1/2 lengthened.

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

In patients with severe impaired renal function (CC 10-30 ml / min) AUC values ​​of dabigatran etexilate and T_1/2 increased respectively 6 and 2 times, compared with similar indicators in individuals without impaired renal function.

In patients with atrial fibrillation and moderate renal insufficiency (CC 30-50 ml / min), the AUC of dabigatran before and after the use of the drug was on average 2.29 and 1.81 times greater than in patients without renal dysfunction.In the treatment of acute DVT and / or pulmonary embolism and the prevention of deaths caused by these diseases in patients with mild to moderate renal failure (CK 30-50 ml / min), the basal concentration of dabigatran in the equilibrium state of pharmacokinetics was 1.7 in average and 3.4 times higher than in patients with CC> 80 ml / min.

When using hemodialysis in patients without atrial fibrillation, it was found that the amount of the drug excreted is proportional to the speed of blood flow. The duration of dialysis, with a dialysate flow rate of 700 ml / min, was 4 h, and the blood flow rate was 200 ml / min or 350-390 ml / min. This resulted in the removal, respectively, of 50% and 60% of the concentrations of free and total dabigatran. The anticoagulant activity of dabigatran decreased with decreasing plasma concentrations, the relationship of pharmacokinetics and pharmacodynamics did not change.

Liver dysfunction

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

Body mass

In studies, basal concentrations of dabigatran in patients weighing> 100 kg were approximately 20% lower than in patients weighing 50-100 kg. The body weight of the majority (80.8%) of patients was ≥50- <100 kg, within this range there are no clear differences in the concentrations of dabigatran. Data for patients weighing ≤50 kg is limited.

Floor

In the main studies on the prevention of the development of VTE, it was found that the effect of the drug in women was about 1.4-1.5 times (40-50%) higher. In patients with atrial fibrillation, basal concentrations and concentrations after using the drug were on average 1.3 (30%) higher. The established differences had no clinical significance.

Ethnic groups

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

Indications

- prevention of venous thromboembolism in patients after orthopedic operations;

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

- treatment of acute deep vein thrombosis and / or thromboembolism
pulmonary artery disease and the prevention of deaths caused by these diseases;

- prevention of recurrent deep vein thrombosis and / or thromboembolism of the pulmonary artery and deaths,
caused by these diseases.

Contraindications

- renal failure severe (CC <30 ml / min);

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