Pradaxa

Active substance:

dabigatran etexilate mesylate;

Excipients:

acacia gum;

coarse-grained tartaric acid;

tartaric acid powder;

crystalline tartaric acid;

hypromellose;

dimethicone;

talc;

hyprolose (hydroxypropyl cellulose);

Sheath:

Hypromellose capsule (HPMC) overprinted with black ink (Colorcon S-1-27797);

HPMC capsules:

carrageenan; potassium chloride; titanium dioxide; indigo carmine (E132); dye sunset sunset yellow (E110); hypromellose (hydroxypropyl methylcellulose), purified water;

Composition of black ink Colorcon S-1-27797, (%, mass.) :

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%

Pradaxa has an anticoagulant effect.

Pharmacodynamics

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

Since thrombin (serine protease) converts fibrinogen into fibrin during coagulation, inhibition of thrombin activity prevents thrombus formation. Dabigatran has an inhibitory effect on free thrombin, thrombin associated with fibrin clot, 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 was established between the concentration of dabigatran in blood plasma and the severity of the anticoagulant effect. Dabigatran prolongs activated partial thromboplastin time (APTT), ecarinic clotting time (EVT), and thrombin time (TB).

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

The results of clinical studies in patients who underwent orthopedic surgery - arthroplasty of the knee and hip joints - 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 within 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 equivalence of the antithrombotic effect of dabigatran etexilate at 150 mg or 220 mg versus enoxaparin at a dose of 40 mg per day was shown in assessing the main endpoint, which includes all cases of venous thromboembolism and mortality from any cause.

Prevention of stroke and systemic thromboembolism in patients with atrial fibrillation

With prolonged, on average about 20 months, use in patients with atrial fibrillation and with a moderate or high risk of stroke or systemic thromboembolism, it was shown that dabigatran etexilate at a dose of 110 mg, prescribed 2 times a day, was not inferior to warfarin in terms of the effectiveness of preventing stroke and systemic thromboembolism in patients with atrial fibrillation; also in the dabigatran group there was a decrease in the risk of intracranial bleeding and the overall frequency of bleeding. The use of a higher dose of the drug (150 mg 2 times a day) significantly reduced the risk of ischemic and hemorrhagic strokes, cardiovascular death, intracranial bleeding and the overall frequency of 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 combined 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 receiving dabigatran etexilate were observed with a comparable or lower frequency compared with patients receiving warfarin.

Pharmacokinetics

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

After reaching C _max,  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 case of renal dysfunction, T1 / 2 is lengthened.

The absolute bioavailability of dabigatran after taking dabigatran etexilate orally in capsules coated with hypromellose is about 6.5%.

Food intake does not affect the bioavailability of dabigatran etexilate, however, the time to reach C _max  increases by 2 hours.

When dabigatran etexilate is used without a special capsule shell made of hypromellose, oral bioavailability can increase by about 1.8 times (75%) compared to the dosage form in capsules. Therefore, the integrity of the 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 pure form (for example, by adding to food or drinks) (see section "Dosage and Administration").

When using dabigatran etexilate after 1-3 hours in patients after surgery, there is a decrease in the rate of absorption of the drug in comparison with healthy volunteers. AUC is characterized by a gradual increase in amplitude without the appearance of a high peak in plasma concentration. C _max  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, gastrointestinal paresis and surgery may be important 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, the absorption of dabigatran occurs quickly, with the achievement of C _max  2 hours after its ingestion.

Metabolism

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

Distribution

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

Withdrawal

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

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

Special patient groups

Elderly patients

In elderly people, the AUC 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 the age-related decrease in creatinine clearance (CC).

In elderly women (over 65 years old), the AUC values _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 exposure to dabigatran was confirmed: the initial concentrations of dabigatran in patients aged ≥75 years were approximately 1.3 times (31%) higher, and in patients aged

Impaired renal function

In volunteers with moderate renal impairment (CC - 30-50 ml / min), the AUC value of dabigatran after oral administration was approximately 3 times higher 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 by a factor of 6 and 2, respectively, compared with those in individuals without renal impairment.

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

When using hemodialysis in patients without atrial fibrillation, it was found that the amount of drug excreted 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 the free and total dabigatran concentrations, respectively. The anticoagulant activity of dabigatran decreased with decreasing plasma concentrations; the relationship between PK and PD did not change.

Liver dysfunction

In patients with moderate hepatic impairment (7-9 points on the Child-Pugh scale), there were no changes in the concentration of dabigatran in 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 in the majority (80.8%) of patients was ≥50 - <100 kg, within this range, no clear differences in dabigatran concentrations were found. Data for patients weighing ≤50 kg are limited.

Floor

In the main studies on the prevention of the development 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 drug use were, on average, 1.3 (30%) higher. The differences found 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 the available data indicate no significant differences.

Prevention of venous thromboembolism in patients after orthopedic surgery;

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

• Known hypersensitivity to dabigatran, dabigatran etexilate or to any of the excipients;
• Severe renal failure (CC less than 30 ml / min);
• Active clinically significant bleeding, hemorrhagic diathesis, spontaneous or pharmacologically induced hemostasis disorder;
• Organ damage as a result of clinically significant bleeding, including hemorrhagic stroke within 6 months before starting therapy;
• Concomitant administration of ketoconazole for systemic use;
• Liver dysfunction and liver disease that can affect survival;
• Age up to 18 years (no clinical data).

Disturbances from the hematopoietic and lymphatic system: anemia, thrombocytopenia.

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

Nervous system disorders: intracranial bleeding.

Vascular disorders: hematoma, bleeding.

Respiratory, chest and mediastinal disorders: epistaxis, hemoptysis.

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

Disturbances from the hepatobiliary system: increased activity of "hepatic" transaminases, impaired liver function, hyperbilirubinemia.

Changes in the skin and subcutaneous tissues: 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 surgical site.

Vascular disorders: bleeding from the surgical wound.

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

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

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

The combined use of the drug PRADAXA with drugs that affect hemostasis or the coagulation system, including vitamin K antagonists, can significantly increase the risk of bleeding.

Pharmacokinetic interactions

In studies conducted in vitro, no inducing or inhibitory effect of dabigatran on cytochrome P450 has been established. In in vivo studies 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.

Concomitant use with P-glycoprotein inhibitors:

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

In case of application for the prevention of venous thromboembolism in patients after orthopedic surgery - see the sections "Dosage and Administration" and "Interaction with other medicinal products".

Amiodarone. With the simultaneous use of dabigatran etexilate with a single dose of amiodarone (600 mg) taken orally, the degree and rate of absorption of amiodarone and its active metabolite, desethylamiodarone, did not change. The AUC and C _max  values ​​of dabigatran increased by approximately 1.6 and 1.5 times (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 recorded.

Dronedarone. After the simultaneous use of dabigatran etexilate and dronedarone at a dose of 400 mg once,

AUC _0-∞  and C _{max of}  dabigatran increase 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 a single and multiple use of dronedarone 2 hours after taking dabigatran etexilate, AUC _0-∞  increased 1.3 and 1.6 times, respectively. Dronedarone did not affect the endpoint T1 / 2 and the renal clearance of dabigatran.

Verapamil. With the simultaneous use of dabigatran etexilate with oral verapamil, the C _max  and AUC values ​​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 with the use of the first dose of verapamil in an immediate-release dosage form, which was applied 1 hour before taking dabigatran etexilate (C _max  increased by 180%, and AUC - by 150%). When using the sustained-release dosage form of verapamil, this effect progressively decreased (C _max  increased by 90%, and AUC - by 70%), as well as when using multiple doses of verapamil (C _max  increased by 60%, and AUC - by 50%) , which can 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 after 2 hours dabigatran is completely absorbed (see section "Dosage and Administration").

In a study in patients with atrial fibrillation, the concentration of dabigatran increased by no more than 21%; no increased risk of bleeding was recorded.

There are no data on the interaction of dabigatran etexilate with parenteral verapamil; no clinically significant interaction is expected.

Ketoconazole. Ketoconazole for systemic use after a single administration at a dose of 400 mg increases the AUC _0-∞  and C _{max of}  dabigatran by approximately 2.4 times (by 138% and 135%), respectively, and after repeated administration of ketoconazole at a dose of 400 mg per day, approximately in 2.5 times (153% and 149%), respectively. Ketoconazole did not affect T _max  and endpoint T1 / 2. The simultaneous use of the drug PRADAX 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 C _{max, ss of}  dabigatran when applied twice a day in case of simultaneous administration with quinidine at a dose of 200 mg every 2 hours until a total dose of 1000 mg was reached increased on average by 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 significant P-glycoprotein inhibitors.

Simultaneous use with inducers of P-glycoprotein:

Avoid the simultaneous administration of the drug PRADAX and inducers of P-glycoprotein, since the combined use leads to a decrease in the effect of dabigatran (see section "Special instructions").

Rifampicin. Preliminary administration of the test inducer rifampicin at a dose of 600 mg per day for 7 days resulted in a decrease in the exposure to dabigatran. After discontinuation of rifampicin, this inductive effect decreased; on day 7, the effect of dabigatran was close to the initial level. No further increase in the bioavailability of dabigatran was observed over the next 7 days.

It is assumed that other P-glycoprotein inducers, such as St. John's wort or carbamazepine, may also reduce plasma dabigatran concentrations 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). It has been shown that ASA or clopidogrel, used concomitantly with dabigatran etexilate at a dose of 110 mg or 150 mg 2 times a day, may increase the risk of major bleeding. Bleeding is also more common with the simultaneous use of warfarin with ASA or clopidogrel.

NSAIDs. The NSAIDs (non-steroidal anti-inflammatory drugs) used for short-term analgesia after surgery did not increase the risk of bleeding when used concomitantly 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 are no data on an additional increase in the risk of bleeding.

Clopidogrel. It was found 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 AUC values _{τ, ss}  and C _{max, ss of}  dabigatran, as well as the blood coagulation parameters that were monitored to assess the effect of dabigatran (APTT, ecarinic 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 the "loading" dose of clopidogrel (300 or 600 mg), the values ​​of AUC _{t, ss}  and C _{max, ss} dabigatran increased by 30-40%.

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

Pantoprazole. With the combined use of dabigatran etexilate and pantoprazole, a 30% decrease in the AUC of dabigatran was observed. Pantoprazole and other proton pump inhibitors have been co-administered with dabigatran etexilate in clinical trials with no effect on bleeding risk or efficacy.

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

The changes in the pharmacokinetic parameters of dabigatran revealed in the course of 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 was found 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 simultaneous use of proton pump inhibitors, apparently, does not lead to an increase in the frequency of stroke or systemic thromboembolism, especially in comparison with warfarin, and, therefore, a decrease in the bioavailability of dabigatran caused by the simultaneous use of pantoprazole,

Capsules should be taken orally, 1 or 2 times a day, regardless of meal time, with water.

The capsule should not be opened.

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

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

In case of an overdose of PRADAX, it is possible to use concentrates of the activated prothrombin complex or recombinant factor VIIa or concentrates II, IX or X of coagulation factors. There is experimental data confirming the effectiveness of these agents in countering the anticoagulant effect of dabigatran, however, no special clinical studies have been carried out.

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

Capsules