Dabigatran etexilate Polysan^® (Capsules) Instructions for Use

ATC Code

B01AE07 (Dabigatran etexilate)

Active Substance

Dabigatran etexilate (Rec.INN registered by WHO)

Clinical-Pharmacological Group

Anticoagulant. Direct thrombin inhibitor

Pharmacotherapeutic Group

Antithrombotic agents; direct thrombin inhibitors

Pharmacological Action

Mechanism of action

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

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

Pharmacodynamic effects

Experimental studies on various in vivo and ex vivo thrombosis models have confirmed the antithrombotic effect and anticoagulant activity of dabigatran after intravenous administration and of dabigatran etexilate after oral administration.

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

Prevention of venous thromboembolism (VTE) after major joint replacement

Results of clinical studies in patients who underwent orthopedic surgery (knee and hip replacement) 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 mg or 220 mg once daily for 6-10 days (for knee surgery) and 28-35 days (for hip surgery), compared with enoxaparin at a dose of 40 mg once daily, which was administered pre- and post-operatively.

The antithrombotic effect of dabigatran etexilate at 150 mg or 220 mg was shown to be equivalent to enoxaparin at a dose of 40 mg/day when assessing the primary endpoint, which included all cases of venous thromboembolism and all-cause mortality.

Prevention of stroke and systemic embolism in patients with atrial fibrillation

During long-term use, averaging about 20 months, in patients with atrial fibrillation and with a moderate or high risk of stroke or systemic embolism, it was shown that Dabigatran etexilate at a dose of 110 mg, administered twice daily, was non-inferior to warfarin in efficacy for preventing stroke and systemic embolism in patients with atrial fibrillation; also, in the dabigatran group, a reduced risk of intracranial bleeding and overall bleeding frequency was noted. The use of a higher drug dose (150 mg twice daily) significantly reduced the risk of ischemic and hemorrhagic stroke, cardiovascular mortality, intracranial bleeding, and overall bleeding frequency compared to warfarin. The lower dose of dabigatran was characterized by a significantly lower risk of major bleeding compared to warfarin.

The net clinical effect was assessed by determining the combined endpoint, which included the frequency of stroke, systemic embolism, pulmonary embolism, acute myocardial infarction, cardiovascular mortality, and major bleeding.

The annual frequency of these events in patients receiving Dabigatran etexilate was lower than in patients receiving warfarin.

Changes in liver function laboratory parameters in patients receiving Dabigatran etexilate occurred with comparable or lower frequency compared to patients receiving warfarin.

Further study of dabigatran etexilate in observational studies in patients with atrial fibrillation indicates that the drug’s efficacy and safety profile in clinical practice corresponds to the results of randomized studies.

Results from the prospective randomized RE-CIRCUIT trial demonstrated that performing catheter ablation in patients with paroxysmal or persistent atrial fibrillation receiving continuous dabigatran etexilate at a dose of 150 mg (1 capsule) twice daily is characterized by a lower risk of major bleeding compared to patients undergoing the procedure while on continuous warfarin. No differences were found between the comparison groups regarding the frequency of the combined endpoint, including strokes, systemic embolisms, or transient ischemic attacks.

Results from the open-label randomized RE-DUAL PCI trial demonstrated that the use of dabigatran etexilate at a dose of 150 mg twice daily, or at a dose of 110 mg twice daily in combination with clopidogrel or ticagrelor in patients with non-valvular atrial fibrillation who underwent percutaneous coronary intervention with stenting, is characterized by a lower risk of the primary endpoint (major and clinically relevant bleeding according to the ISTH classification) compared to triple therapy including warfarin in combination with clopidogrel or ticagrelor and acetylsalicylic acid (ASA). Regarding the combined efficacy endpoint, which included death, thromboembolic events (myocardial infarction, stroke, or systemic embolism), or unplanned revascularization, the combined group of patients receiving Dabigatran etexilate (both doses) in combination with clopidogrel or ticagrelor was non-inferior in efficacy to the group of patients receiving triple therapy with warfarin in combination with clopidogrel or ticagrelor and ASA.

Prevention of thromboembolism in patients with prosthetic heart valves

During phase II clinical studies of dabigatran and warfarin in patients who underwent heart valve replacement surgery with a mechanical prosthesis (recent surgeries and surgeries performed more than 3 months prior), an increased frequency of thromboembolism and total number of bleedings (mainly due to minor bleedings) was found in patients receiving Dabigatran etexilate. In the early postoperative period, major bleedings were mainly characterized by hemorrhagic pericardial effusion, especially in patients who were prescribed Dabigatran etexilate early (on day 3) after surgical heart valve replacement.

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

Results of clinical studies in patients with acute DVT and/or PE, who initially received parenteral therapy for at least 5 days, confirmed that Dabigatran etexilate at a dose of 150 mg, administered twice daily, was non-inferior to warfarin in efficacy regarding the reduction in the frequency of recurrent symptomatic DVT and/or PE and cases of death due to these diseases over a 6-month treatment period. Bleedings were noted significantly less frequently in patients receiving Dabigatran etexilate than in patients receiving warfarin.

The frequency of myocardial infarction development in all VTE studies across all treatment groups was low.

Liver function parameters. In studies using active comparators, possible changes in liver function parameters occurred in patients receiving Dabigatran etexilate with comparable or lower frequency than in patients receiving warfarin. In the placebo study, no significant difference was noted between the dabigatran and placebo groups regarding changes in liver function parameters that were potentially clinically significant.

Prevention of recurrent deep vein thrombosis (DVT) and/or pulmonary embolism (PE) and fatal outcomes caused by these diseases

Results of a clinical study in patients with recurrent DVT and PE, who had already received anticoagulant therapy for 3 to 12 months and required its continuation, confirmed that treatment with dabigatran etexilate at a dose of 150 mg twice daily was non-inferior to the therapeutic effect of warfarin (p=0.0135). Bleedings were noted significantly less frequently in patients receiving Dabigatran etexilate than in patients receiving warfarin.

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

The frequency of myocardial infarction development in all VTE studies across all treatment groups was low.

Liver function parameters. In studies using active comparators, possible changes in liver function parameters occurred in patients receiving Dabigatran etexilate with comparable or lower frequency than in patients receiving warfarin. In the placebo study, no significant difference was noted between the dabigatran and placebo groups regarding changes in liver function parameters that were potentially clinically significant.

Preclinical safety data

According to preclinical data, no special risks for humans were identified based on the results of standard pharmacological safety studies, repeated dose toxicity, and genotoxicity.

Effects observed in repeated dose toxicity studies were due to the enhanced pharmacodynamic action of dabigatran.

An effect on female fertility was noted in the form of a decrease in the number of implantations and an increase in pre-implantation losses at a concentration of 70 mg/kg (5 times the human plasma exposure level). At doses toxic to the mother (5-10 times the human plasma exposure level), a decrease in fetal body weight and viability along with an increase in the frequency of fetal developmental abnormalities were noted in rats and rabbits. In a study of effects on pre- and postnatal development, an increase in fetal mortality was noted at doses toxic to females (a dose corresponding to a plasma exposure level 4 times higher than in humans).

In a toxicity study in immature Wistar Han rats, mortality was associated with bleeding at the same systemic exposure levels at which bleeding occurred in adult animals. Mortality in both adult and immature rats is considered to be related to the increased pharmacological activity of dabigatran in conjunction with mechanical impact during drug administration and handling. According to the data from the toxicity study in immature animals, no increased sensitivity regarding toxicity or any toxicity specific to immature animals was identified.

In lifelong toxicological studies in rats and mice, no signs of oncogenic potential of dabigatran were detected when used at doses up to 200 mg/kg (maximum).

Dabigatran, the active substance of dabigatran etexilate mesilate, is stable in the environment.

Pharmacokinetics

After oral administration, Dabigatran etexilate is rapidly and completely converted to dabigatran, which is the active form in plasma. The cleavage of the prodrug dabigatran etexilate via esterase-catalyzed hydrolysis to the active substance dabigatran is the predominant metabolic reaction. The absolute bioavailability of dabigatran after oral administration of dabigatran etexilate was approximately 6.5%.

After oral administration of dabigatran etexilate in healthy volunteers, the pharmacokinetic profile of dabigatran in plasma is characterized by a rapid increase in plasma concentrations with C_max achieved within 0.5 to 2.0 hours after drug intake.

Absorption

A study evaluating the absorption of dabigatran etexilate in the postoperative period 1-3 hours after surgery showed a relatively low absorption rate compared to absorption in healthy volunteers, with AUC characterized by a gradual increase in amplitude without a high plasma concentration peak. C_max in plasma is achieved 6 hours after drug administration in the postoperative period due to the influence of concomitant factors such as anesthesia, gastrointestinal paresis, and the performance of surgery, regardless of the drug formulation. A further study showed that slow and delayed absorption is typically observed only on the day of surgery. On subsequent days, the absorption of dabigatran occurs rapidly, with C_max in plasma reached 2 hours after drug intake.

Food intake does not affect the bioavailability of dabigatran etexilate but delays the time to reach C_max in plasma by 2 hours.

C_max and AUC were dose-proportional.

When orally taking pellets without the hydroxypropyl methylcellulose (HPMC) capsule shell, bioavailability may increase by 75% after a single dose and by 37% at steady state compared to the bioavailability when using the reference capsule formulation. Therefore, the integrity of the HPMC capsules should always be maintained during clinical use to prevent accidental increase in the bioavailability of dabigatran etexilate (see the “Dosage regimen” section).

Distribution

A low (34-35%), concentration-independent degree of dabigatran binding to plasma proteins was observed. The V_d of dabigatran is 60-70 L and exceeds the volume of total body water, indicating moderate distribution of dabigatran in tissues.

Metabolism

The metabolism and excretion of dabigatran were studied after a single intravenous administration of radiolabeled dabigatran to healthy male volunteers. After intravenous administration, radiolabeled dabigatran was excreted mainly by the kidneys (85%). Excretion via the gastrointestinal tract accounted for 6% of the administered dose. It was found that 88-94% of the dose of the radiolabeled drug was excreted from the body 168 hours after administration.

Dabigatran undergoes conjugation to form pharmacologically active acyl glucuronides. There are four positional isomers, 1-O, 2-O, 3-O, 4-O-acyl glucuronide, each accounting for less than 10% of the total dabigatran content in plasma. Traces of other metabolites could only be detected using highly sensitive analytical methods. Dabigatran is excreted mainly unchanged in the urine at a rate of approximately 100 ml/min, which corresponds to the glomerular filtration rate.

Excretion

The plasma concentration of dabigatran decreases biexponentially with a mean terminal T_1/2 of 11 hours in healthy elderly volunteers. After multiple administrations, the terminal T_1/2 was about 12-14 hours. T_1/2 was dose-independent. T_1/2 is prolonged in renal impairment, see “Renal impairment”.

Pharmacokinetics in special patient groups

Renal impairment. In Phase I studies, the exposure (AUC) of dabigatran after oral administration of dabigatran etexilate was approximately 2.7 times higher in volunteers with moderate renal impairment (CrCl 30-50 ml/min) compared to the exposure of dabigatran in volunteers without renal impairment.

In a small number of volunteers with severe renal impairment (CrCl 10-30 ml/min), the exposure (AUC) of dabigatran was approximately 6 times higher, and the T_1/2 was approximately 2 times longer compared to the patient population without renal impairment (see sections “Dosage regimen”, “Contraindications” and “Special instructions”).

Table 1. T_1/2 of total dabigatran in healthy patients and in patients with renal impairment

Furthermore, dabigatran exposure (at trough and at C_max) was assessed in a prospective open-label randomized pharmacokinetic study in patients with non-valvular atrial fibrillation with severe renal impairment (defined as CrCl 15-30 ml/min) who received Dabigatran etexilate 75 mg twice daily. This dosing regimen provided a geometric mean trough concentration of 155 ng/ml (gCV 76.9%) measured immediately before the next dose and a geometric mean C_max of 202 ng/ml (gCV 70.6%) measured 2 hours after the last dose.

The clearance of dabigatran by hemodialysis was investigated in 7 patients with end-stage chronic renal disease (ESRD) without atrial fibrillation. Dialysis was performed with a dialysate flow rate of 700 ml/min, duration of 4 hours, and blood flow rates of 200 ml/min or 350-390 ml/min. This resulted in a reduction of dabigatran concentration by 50-60%, respectively. The amount of drug removed by dialysis is proportional to the blood flow rate at blood flow rates up to 300 ml/min. The anticoagulant activity of dabigatran decreased with the reduction of its plasma concentration, and the procedure did not affect the pharmacodynamic/pharmacokinetic relationships.

The median CrCl in the RE-LY study was 68.4 ml/min. In nearly half (45.8%) of the patients in the RE-LY study, CrCl was >50-<80 ml/min. In patients with moderate renal impairment (CrCl 30-50 ml/min), pre-dose and post-dose plasma concentrations of dabigatran were on average 2.29 times and 1.81 times higher, respectively, compared to patients without renal impairment (CrCl ≥80 ml/min).

The median CrCl in the RE-COVER study was 100.4 ml/min. 21.7% of patients had mild renal impairment (CrCl >50-<80 ml/min), and 4.5% of patients had moderate renal impairment (CrCl 30-50 ml/min). In patients with mild and moderate renal impairment, steady-state pre-dose plasma concentrations of dabigatran were on average 1.8 times and 3.6 times higher, respectively, compared to patients with CrCl >80 ml/min. Similar CrCl values were found in the RE-COVER II study.

The median CrCl in the RE-MEDY and RE-SONATE studies was 99.0 ml/min and 99.7 ml/min, respectively. In 22.9% and 22.5% of patients in the RE-MEDY and RE-SONATE studies, CrCl was >50-<80 ml/min, and in 4.1% and 4.8% of patients, CrCl was from 30 to 50 ml/min.

Elderly patients. In special Phase I pharmacokinetic studies in elderly patients, an increase in AUC of 40%-60% and C_max of more than 25% was observed compared to young patients.

The effect of age on dabigatran exposure was confirmed in the RE-LY study: with an increase in trough plasma concentration (before the next dose) by approximately 31% in patients aged ≥75 years and a decrease by approximately 22% in patients aged <65 years compared to the trough plasma concentration (before the next dose) in patients aged 65 to 75 years (see sections “Dosage Regimen” and “Special Instructions”).

Hepatic impairment. No changes in dabigatran concentration were observed in 12 patients with moderate hepatic insufficiency (Child-Pugh class B) compared to 12 patients in the control group (see sections “Dosage Regimen” and “Special Instructions”).

Body weight. Dabigatran trough plasma concentrations were approximately 20% lower in patients with body weight >100 kg compared to patients with body weight 50-100 kg. The majority (80.8%) of patients were in the body weight category ≥50 kg and <100 kg; within this range, no clear differences in dabigatran concentrations were established (see sections “Dosage Regimen” and “Special Instructions”). Clinical data regarding patients with body weight <50 kg are limited.

Gender. Active substance exposure in primary VTE prevention studies was approximately 40-50% higher in female patients; no dose adjustment is required.

Female patients with atrial fibrillation had trough plasma concentration and peak plasma concentration on average 30% higher. No dose adjustment is required (see section “Dosage Regimen”).

Ethnic groups. No clinically significant ethnic differences in the pharmacokinetics and pharmacodynamics of dabigatran were identified among Caucasian, African American, Hispanic, Japanese, or Chinese patients.

Pharmacokinetic interaction

In vitro interaction studies showed no inhibition or induction of major cytochrome P450 isoenzymes. This was confirmed by in vivo studies in healthy volunteers, which showed no interaction between this drug and the following active substances: atorvastatin (CYP3A4), digoxin (interaction with the P-glycoprotein transporter), and diclofenac (CYP2C9).

Indications

• Primary prevention of venous thromboembolic complications in adult patients (aged 18 years and older) who have undergone elective total hip replacement or total knee replacement;
• Prevention of stroke, systemic thromboembolism, and reduction of cardiovascular mortality in adult patients (aged 18 years and older) with non-valvular atrial fibrillation and one or more risk factors, such as prior stroke or transient ischemic attack (TIA), age ≥75 years, chronic heart failure (≥NYHA functional class II), diabetes mellitus, arterial hypertension, vascular disease (prior myocardial infarction, peripheral artery disease, or atherosclerotic plaque in the aorta);
• Treatment and prevention of recurrence of acute deep vein thrombosis (DVT) and/or pulmonary embolism (PE) and prevention of fatal outcomes caused by these diseases in adult patients (aged 18 years and older).

ICD codes

Dosage Regimen

Capsules

Capsules should be taken orally, 1 or 2 times/day regardless of meals, with a glass of water to facilitate passage into the stomach. The capsule should not be opened.

Primary prevention of venous thromboembolic complications in adult patients (aged 18 years and older) who have undergone elective total hip replacement or total knee replacement

The recommended doses of Dabigatran etexilate Polisan^® and the duration of therapy for the primary prevention of venous thromboembolism in orthopedic surgery are shown in Table 2.

Table 2. Recommended doses and duration of therapy for primary prevention of venous thromboembolism in orthopedic surgery

For the indication: treatment and prevention of recurrence of acute deep vein thrombosis (DVT) and/or pulmonary embolism (PE) and prevention of fatal outcomes caused by these diseases – the recommendation for using the dabigatran etexilate dose of 220 mg (1 capsule of 110 mg twice/day) is based on pharmacokinetic and pharmacodynamic data; clinical trial data are lacking.

Assessment of renal function before and during therapy with Dabigatran etexilate Polisan^®

For all patients, especially the elderly (>75 years), since renal impairment may be frequent in this age group

• Before therapy, to avoid prescribing the drug to patients with severe renal impairment (CrCl <30 ml/min), creatinine clearance should be preliminarily assessed.
• Renal function should be assessed during treatment when a suspected decrease or deterioration of renal function arises (e.g., in hypovolemia, dehydration, concomitant use of certain medications).

Additional requirements for patients with mild and moderate renal impairment and for patients over 75 years

During therapy with Dabigatran etexilate Polisan^®, renal function should be assessed at least once a year or more frequently, depending on the clinical situation, when a suspected decrease or deterioration of renal function arises (e.g., in hypovolemia, dehydration, concomitant use of certain medications).

The Cockcroft-Gault method is used as the method for assessing renal function.

Duration of use

The duration of use of Dabigatran etexilate Polisan^® for stroke prevention in AF (atrial fibrillation), DVT and PE is shown in Table 4.

Table 4. Duration of use for stroke prevention in AF and DVT/PE

Missed dose

A missed dose of Dabigatran etexilate Polisan^® can be taken if 6 hours or more remain until the next dose; if the time is less than 6 hours, the missed dose should not be taken.

In case of missing individual doses, a double dose of the drug should not be taken.

Discontinuation of Dabigatran etexilate Polisan^®

Treatment with Dabigatran etexilate Polisan^® should not be discontinued without medical consultation. Patients should be instructed to contact their treating physician if they develop gastrointestinal symptoms such as dyspepsia.

Changing anticoagulant therapy

Transition from Dabigatran etexilate Polisan^® to parenteral anticoagulants. Parenteral anticoagulants should be started 12 hours after the last dose of Dabigatran etexilate Polisan^® (see section “Drug Interactions”).

Transition from parenteral anticoagulants to Dabigatran etexilate Polisan^®. The first dose of Dabigatran etexilate Polisan^® is administered instead of the discontinued anticoagulant within 0-2 hours before the time of its next scheduled dose or simultaneously with discontinuation in case of continuous administration (e.g., intravenous unfractionated heparin – UFH).

Transition from Dabigatran etexilate Polisan^® to vitamin K antagonists. For CrCl ≥50 ml/min, vitamin K antagonists can be started 3 days, and for CrCl ≥30-<50 ml/min – 2 days before discontinuation of Dabigatran etexilate Polisan^®. Since Dabigatran etexilate may affect INR, INR will better reflect the effect of vitamin K antagonists only at least 2 days after drug discontinuation. Until then, INR values should be interpreted with caution.

Transition from vitamin K antagonists to Dabigatran etexilate Polisan^® . Vitamin K antagonists are discontinued; Dabigatran etexilate Polisan^® can be started when INR <2.0.

Cardioversion

Planned or emergency cardioversion does not require discontinuation of therapy with Dabigatran etexilate Polisan^®.

Catheter ablation for atrial fibrillation

Data on treatment with dabigatran etexilate (1 capsule of 110 mg twice/day) are lacking.

Percutaneous coronary interventions (PCI) with coronary artery stenting

In patients with non-valvular atrial fibrillation who have undergone PCI with coronary artery stenting, Dabigatran etexilate can be used in combination with antiplatelet drugs. Treatment with dabigatran etexilate can be started after hemostasis is achieved (see section “Pharmacological Action”).

Special patient groups

Primary prevention of venous thromboembolic complications in adult patients (aged 18 years and older) who have undergone elective total hip replacement or total knee replacement

Patients with renal impairment

Therapy with Dabigatran etexilate Polisan^® in patients with severe renal impairment (CrCl <30 ml/min) is contraindicated (see section “Contraindications”).

Dose adjustment is recommended for patients with moderate renal impairment (CrCl 30-50 ml/min) (see Table 2 and sections “Special Instructions” and “Pharmacological Action”).

Concomitant use of Dabigatran etexilate Polisan^® with weak or moderate P-glycoprotein (P-gp) inhibitors, e.g., with amiodarone, quinidine, or verapamil: the dose should be reduced as indicated in Table 2 (see also sections “Special Instructions” and “Drug Interactions”). In this situation, Dabigatran etexilate Polisan^® and the specified medications should be taken simultaneously.

In patients with moderate renal impairment who are concomitantly taking verapamil, a reduction of the dabigatran etexilate dose to 75 mg/day should be considered (see sections “Special Instructions” and “Drug Interactions”).

Elderly patients

A reduction in the drug dose is recommended for patients over 75 years of age (see Table 2 and sections “Special Instructions” and “Pharmacological Action”).

Effect of body weight

Clinical experience with patients weighing <50 kg or >110 kg at recommended doses is extremely limited. Given the available clinical and kinetic data, no dose adjustment is required (see section “Pharmacokinetics”), but careful clinical monitoring is recommended (see section “Special Instructions”).

Prevention of stroke, systemic thromboembolism, and reduction of cardiovascular mortality in adult patients (aged 18 years and older) with non-valvular atrial fibrillation and one or more risk factors; treatment and prevention of recurrence of acute deep vein thrombosis (DVT) and/or pulmonary embolism (PE) and prevention of fatal outcomes caused by these diseases in adult patients (aged 18 years and older)

Elderly patients

The principles for selecting the drug dose in elderly patients are indicated in Table 3.

Use in patients with increased bleeding risk

Patients with increased bleeding risk require careful clinical monitoring (for signs of bleeding or anemia) (see sections “Special Instructions” and “Drug Interactions”). The decision on the choice of drug dose is made at the physician’s discretion based on an assessment of the potential benefit and risk for the patients (see Table 2). Assessment of coagulation parameters (see section “Special Instructions”) may help identify patients with an increased risk of bleeding caused by excessive exposure to dabigatran. If patients at high risk of bleeding are found to have excessive dabigatran exposure, a dose reduction to 220 mg (1 capsule of 110 mg twice/day) is recommended. When clinically significant bleeding occurs, treatment should be interrupted.

In patients with gastritis, esophagitis, or gastroesophageal reflux disease, a dose reduction may be considered due to an increased risk of gastrointestinal bleeding (see Table 3 and section “Special Instructions”).

Patients with renal impairment

Therapy with Dabigatran etexilate Polisan^® in patients with severe renal impairment (CrCl <30 ml/min) is contraindicated (see section “Contraindications”).

No dose adjustment is required for patients with mild renal impairment (CrCl 50-≤80 ml/min). For patients with moderate renal impairment (CrCl 30-50 ml/min), the recommended dose of Dabigatran etexilate Polisan^® is also 300 mg (1 capsule of 150 mg twice/day). However, for patients at high risk of bleeding, the possibility of reducing the dose of Dabigatran etexilate Polisan^® to 220 mg (1 capsule of 110 mg twice/day) may be considered (see sections “Special Instructions” and “Pharmacokinetics”). In patients with renal impairment, careful clinical monitoring is recommended.

Concomitant use of Dabigatran etexilate Polisan^® with active P-glycoprotein inhibitors (such as amiodarone, quinidine, verapamil): when used concomitantly with amiodarone or quinidine, no dose adjustment is required (see sections “Special Instructions”, “Drug Interactions” and “Pharmacokinetics”).

A dose reduction is recommended for patients who are concomitantly receiving verapamil (see Table 3 and sections “Special Instructions” and “Drug Interactions”). In this situation, Dabigatran etexilate Polisan^® and verapamil should be taken simultaneously.

Effect of body weight

According to pharmacokinetic and clinical data, no dose adjustment is required. However, clinical monitoring is recommended for patients weighing less than 50 kg.

Children

Dabigatran etexilate Polisan^® is contraindicated in children under 18 years of age.

Adverse Reactions

Tabulated summary of adverse reactions

The frequency of adverse reactions that may occur during therapy is presented using the following gradation: very common (≥1/10), common (≥1/100, <1/10), uncommon (≥1/1000, <1/100), rare (≥1/10000, <1/1000), very rare (<1/10000), unknown (frequency cannot be estimated from available data).

Table 5. Adverse reactions

* These adverse reactions were not reported in clinical trials as adverse reactions (only side effects); therefore, the frequency cannot be calculated.

The calculation of the frequency of adverse reactions is based on post-marketing experience.

Reporting of suspected adverse reactions

It is important to report suspected adverse reactions after drug registration to ensure continuous monitoring of the benefit-risk balance of the drug. Healthcare professionals are encouraged to report any suspected adverse drug reactions through the national adverse reaction reporting system of the member states of the Eurasian Economic Union.

Contraindications

• Hypersensitivity to dabigatran, dabigatran etexilate or to any of the excipients;
• Severe renal failure (CrCl <30 ml/min);
• Active clinically significant bleeding;
• Organ damage due to clinically significant bleeding, including hemorrhagic stroke within 6 months prior to initiation of therapy;
• Presence of conditions associated with an increased risk of major bleeding, including: existing or recent gastrointestinal ulcers, presence of malignancies with a high risk of bleeding, recent brain or spinal cord injury, recent brain or spinal cord surgery or ophthalmic surgery, recent intracranial hemorrhage, presence or suspicion of esophageal varices, congenital arteriovenous malformations, vascular aneurysms, or large intraspinal or intracerebral vascular abnormalities;
• Concomitant use of any other anticoagulants, including unfractionated heparin, low molecular weight heparins (LMWH) (enoxaparin, dalteparin, etc.), heparin derivatives (fondaparinux, etc.), oral anticoagulants (warfarin, rivaroxaban, apixaban, etc.), except when switching treatment to or from Dabigatran etexilate Polisan^® or when using unfractionated heparin in doses necessary to maintain a central venous or arterial catheter or during catheter ablation for atrial fibrillation;
• Concomitant use of potent P-glycoprotein inhibitors: systemic ketoconazole, cyclosporine, itraconazole, tacrolimus and dronedarone;
• Impaired liver function and liver disease that may affect survival;
• Presence of a prosthetic heart valve requiring anticoagulant therapy;
• Pregnancy;
• Breastfeeding period.

With caution

Table 6. Risk factors that may increase the risk of bleeding

Use in Pregnancy and Lactation

Pregnancy

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

Women of reproductive age should avoid becoming pregnant while being treated with Dabigatran etexilate Polisan^®. If pregnancy occurs, the use of the drug is not recommended, except when the expected benefit outweighs the possible risk.

Breastfeeding period

If it is necessary to use the drug during breastfeeding, due to the lack of clinical data, breastfeeding should be discontinued (as a precaution).

Fertility

Experimental studies have not established any adverse effects on fertility or postnatal development of newborns.

Use in Hepatic Impairment

Impaired liver function or liver disease that is expected to affect survival is a contraindication for the use of Dabigatran etexilate Polisan^®.

Use in Renal Impairment

Therapy with Dabigatran etexilate Polisan^® is contraindicated in patients with severe renal impairment (CrCl <30 ml/min). Dose adjustment is recommended in patients with moderate renal impairment (CrCl 30-50 ml/min).

Pediatric Use

Dabigatran etexilate Polisan^® is contraindicated in children under 18 years of age.

Geriatric Use

A dose reduction of the drug is recommended in patients over 75 years of age.

Special Precautions

Risk of bleeding

The use of Dabigatran etexilate Polisan^®, like other anticoagulants, is recommended with caution in conditions characterized by an increased risk of bleeding. During therapy with Dabigatran etexilate Polisan^®, bleeding of various locations may develop. A decrease in hemoglobin and/or hematocrit for unexplained reasons, or a decrease in blood pressure is a reason to search for a source of bleeding.

In situations of life-threatening or uncontrolled bleeding requiring rapid reversal of the anticoagulant effect of dabigatran, the specific antidote idarucizumab is available (see section “Overdose”).

In clinical trials, the use of dabigatran etexilate was associated with an increased incidence of major gastrointestinal (GI) bleeding. An increased risk was observed in elderly patients (≥75 years) taking dabigatran etexilate 150 mg twice daily. Additional risk factors include concomitant use of platelet aggregation inhibitors, e.g., clopidogrel and ASA or NSAIDs, as well as the presence of esophagitis, gastritis or gastroesophageal reflux disease.

Careful clinical monitoring

Careful monitoring for signs of bleeding or anemia is recommended throughout the treatment period, especially if several risk factors are present at once (see section “Special Precautions”). Particular caution should be exercised when Dabigatran etexilate Polisan^® is prescribed concomitantly with verapamil, amiodarone, quinidine or clarithromycin (P-glycoprotein inhibitors) and, in particular, in the event of bleeding, especially in patients with mild or moderate renal impairment (see section “Drug Interactions”).

Careful monitoring for signs of bleeding is recommended in patients concomitantly receiving NSAIDs (see section “Drug Interactions”).

Discontinuation of the drug

If acute renal failure develops, administration of Dabigatran etexilate Polisan^® must be discontinued (see also section “Contraindications”).

If severe bleeding develops, treatment must be discontinued, a search for the source of bleeding initiated, and consideration given to the use of the specific antidote – the drug containing idarucizumab (see section “Overdose”).

Dose reduction

Dose reduction should be considered or recommended as described in the “Dosage Regimen” section.

Use of proton pump inhibitors

Proton pump inhibitors (PPIs) may be prescribed for the prevention of GI bleeding.

Laboratory coagulation parameters

Although Dabigatran etexilate Polisan^® generally does not require regular anticoagulant monitoring, measurement of the anticoagulant effect associated with dabigatran may be useful for detecting excessively high dabigatran exposure in the presence of additional risk factors.

Diluted thrombin time (dTT), ecarin clotting time (ECT) and activated partial thromboplastin time (aPTT) can provide useful information, but their values should be interpreted with caution due to variability in results obtained by different assay methods.

The INR value is unreliable in patients taking Dabigatran etexilate, and cases of false-positive INR elevation have been described. Therefore, INR measurement should not be performed.

Table 7. Threshold values of coagulation tests at the time of minimum drug concentration in blood, which may be associated with an increased risk of bleeding

Spinal anesthesia/epidural anesthesia/lumbar puncture

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

In the case of traumatic or repeated spinal puncture and prolonged use of an epidural catheter, the risk of spinal bleeding or epidural hematoma may increase. The first dose of Dabigatran etexilate Polisan^® should be taken no earlier than 2 hours after catheter removal. Patients should be monitored for neurological symptoms that may be due to spinal bleeding or epidural hematoma.

Postoperative phase

After an invasive procedure/surgery, administration of Dabigatran etexilate Polisan^® should be resumed/initiated as soon as possible, if the clinical situation allows and adequate hemostasis has been achieved.

In patients at risk of bleeding or at risk of excessive drug exposure, especially in patients with moderate renal impairment (CrCl 30-50 ml/min), therapy should be conducted with caution (see section “Pharmacological Action”).

Patients at high risk of surgical mortality and with internal risk factors for thromboembolic complications

Data on the efficacy and safety of dabigatran etexilate in this patient group are limited, so therapy should be conducted with caution.

Surgery for hip fracture

There are no data on the use of dabigatran etexilate in patients undergoing surgery for hip fracture. Therapy is not recommended.

Impaired liver function

Patients with elevated liver enzymes >2 ULN were excluded from the main clinical trials. There is no experience with the use of dabigatran etexilate in this subgroup of patients. Impaired liver function or liver disease that is expected to affect survival is a contraindication for the use of Dabigatran etexilate Polisan^® (see section “Contraindications”).

Interaction with P-glycoprotein inducers

Concomitant use of P-glycoprotein inducers is expected to lead to a decrease in plasma concentrations of dabigatran, and their concomitant use should be avoided (see sections “Pharmacokinetics” and “Drug Interactions”).

Patients with antiphospholipid syndrome

Patients with antiphospholipid syndrome (especially those triple positive for antiphospholipid antibodies) have an increased risk of thromboembolic events. Although the efficacy of dabigatran etexilate has been established for the treatment and prevention of venous thromboembolism, it has not been specifically studied in the subgroup of patients with antiphospholipid syndrome.

Therefore, before using Dabigatran etexilate Polisan^® in patients with antiphospholipid syndrome, all possible treatment options (including standard treatment such as vitamin K antagonists) should be carefully considered.

Patients with active malignant neoplasms (DVT/PE)

The efficacy and safety of dabigatran etexilate for the treatment of DVT/PE in patients with active malignant neoplasms have not been established.

Effect on ability to drive vehicles and operate machinery

The effect of Dabigatran etexilate Polisan^® on the ability to drive vehicles and engage in other potentially hazardous activities requiring increased concentration and speed of psychomotor reactions has not been studied, but given that the use of Dabigatran etexilate Polisan^® may be accompanied by an increased risk of bleeding, caution should be exercised when performing such activities.

Overdose

Symptoms

Doses of Dabigatran etexilate Polisan^® exceeding the recommended ones lead to an increased risk of bleeding in the patient.

Treatment

If an overdose is suspected, coagulation tests may help determine the risk of bleeding (see sections “Pharmacological Action” and “Special Precautions”). A calibrated quantitative test (dTT) or repeated dTT measurements can predict the time when certain levels of dabigatran will be reached (see section “Pharmacological Action”), and dialysis can also be initiated as an additional measure.

Excessive anticoagulation may require temporary discontinuation of treatment with Dabigatran etexilate Polisan^®. Since dabigatran is primarily excreted by the kidneys, adequate diuresis should be maintained. Because the degree of plasma protein binding is low, dabigatran can be removed by dialysis; clinical experience demonstrating the benefit of dialysis in clinical trials is limited (see section “Pharmacokinetics”).

Drug Interactions

Interactions with Transporter Proteins

Dabigatran etexilate is a substrate of the efflux transporter protein P-glycoprotein. Concomitant administration of P-glycoprotein inhibitors is expected to lead to increased plasma concentrations of dabigatran.

Unless otherwise specified, careful clinical monitoring (for signs of bleeding or anemia) is necessary when dabigatran is used concomitantly with potent P-glycoprotein inhibitors. Dose reduction of dabigatran may be required when used concomitantly with certain P-glycoprotein inhibitors (see sections “Pharmacological Action”, “Contraindications”, “Dosage Regimen”, “Special Instructions”).

Table 9. Interactions with Transporter Proteins

Anticoagulants and Medicinal Products that Inhibit Platelet Aggregation

Medicinal products for which therapy has not been studied or experience is limited, and which may increase the risk of bleeding when used concomitantly with dabigatran etexilate: anticoagulants such as unfractionated heparin (UFH), low molecular weight heparins (LMWH) and heparin derivatives (fondaparinux, desirudin), thrombolytic medicinal products and vitamin K antagonists, rivaroxaban or other oral anticoagulants (see section “Contraindications”), as well as medicinal products that inhibit platelet aggregation, such as GPIIb/IIIa receptor antagonists, ticlopidine, prasugrel, ticagrelor, dextran and sulfinpyrazone (see section “Special Instructions”).

Based on data collected in the phase III RE-LY study (see section “Pharmacological Action”), it was noted that concomitant use of other oral or parenteral anticoagulants increased the frequency of major bleeding during treatment with both dabigatran etexilate and warfarin by approximately 2.5 times, mainly when switching from one anticoagulant to another (see section “Contraindications”). In addition, concomitant use of antiplatelet agents, ASA or clopidogrel approximately doubled the frequency of major bleeding during treatment with both dabigatran etexilate and warfarin (see section “Special Instructions”).

UFH can be used in doses necessary to maintain the patency of a central venous or arterial catheter (see section “Contraindications”).

Table 10. Interaction with Anticoagulants and Medicinal Products that Inhibit Platelet Aggregation

Other Interactions

Table 11. Other Interactions

Interactions Related to the Metabolic Profile of Dabigatran Etexilate and Dabigatran

Dabigatran etexilate and dabigatran are not metabolized by the cytochrome P450 system and have no in vitro effect on cytochrome P450 enzymes. Therefore, interaction of dabigatran with relevant medicinal products is not expected.

Storage Conditions

The drug should be stored in the original packaging (blister pack/blister pack in a carton) to protect from moisture at a temperature not exceeding 25°C (77°F).

Shelf Life

Shelf life – 2 years.

Capsules should not be placed in pill organizers, except for those in which they can remain in the original packaging (blister pack).

Dispensing Status

The drug is dispensed by prescription.

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.