Pradaxa hard capsules 110 mg blister No. 60

Instructions for Pradaxa hard capsules 110 mg blister No. 60

Composition

active ingredient: dabigatran etexilate;

1 capsule contains dabigatran etexilate (as mesylate) 110 mg;

excipients: acacia, tartaric acid, hypromellose, dimethicone, talc, hydroxypropylcellulose;

capsule shell: carrageenan (E 407), potassium chloride, titanium dioxide (E 171), indigo carmine (E 132), hypromellose, purified water;

inscription on the capsule in black ink SW-9008: shellac, butyl alcohol, isopropyl alcohol, black iron oxide (E 172), purified water, propylene glycol (E 1520), anhydrous ethyl alcohol, concentrated ammonium solution, potassium hydroxide.

Dosage form

The capsules are hard.

Main physicochemical properties: oblong capsules made of hydroxypropylmethylcellulose (size 1) with an opaque light blue cap with a black Boehringer Ingelheim company symbol and an opaque light blue capsule body with a black symbol “R110”, containing yellowish pellets.

Pharmacotherapeutic group

Antithrombotic agents. Direct thrombin inhibitors. ATX code B01A E07.

Pharmacological properties

Pharmacodynamics

Mechanism of action: Dabigatran etexilate is a low molecular weight prodrug that does not exhibit pharmacological activity. After oral administration, dabigatran etexilate is rapidly absorbed and converted to dabigatran by esterase-catalyzed hydrolysis in plasma and liver. Dabigatran is a potent competitive, reversible direct thrombin inhibitor and the main active substance in plasma.

Since thrombin (a serine protease) activates the conversion of fibrinogen to fibrin in the blood coagulation system, its inhibition prevents the development of a thrombus. Dabigatran inhibits free thrombin, fibrin-bound thrombin, and thrombin-induced platelet aggregation.

Pharmacodynamic effects: There is a clear correlation between dabigatran plasma concentrations and the degree of anticoagulant effect in phase II studies. Dabigatran prolongs thrombin time (TT), partial thromboplastin time (PT), and partial thromboplastin time (PTT).

The quantitative calibrated diluted thrombin time (cDT) test provides an approximate value of the dabigatran plasma concentration that can be compared with the expected one. If the calibrated diluted thrombin time (cDT) test result is at or below the limit of quantification, additional coagulation tests (CT, PTT and APTT) should be considered.

The CBC can provide a direct measurement of the activity of direct thrombin inhibitors.

The aPTT test is widely used and provides an approximate measure of the anticoagulant intensity achieved by dabigatran. However, the aPTT test has limited sensitivity and is not suitable for precise quantification of the anticoagulant effect, especially at high plasma concentrations of dabigatran. Although high aPTT values should be interpreted with caution, they are indicative of an anticoagulant effect in the patient.

Clinical efficacy and safety. In clinical trials, dabigatran etexilate 110 mg twice daily was shown to be non-inferior to warfarin in the prevention of stroke and systemic embolism in adult patients with nonvalvular atrial fibrillation (NAF) at low risk of intracerebral hemorrhage, systemic bleeding, or major bleeding. Dabigatran 150 mg twice daily significantly reduced the risk of ischemic and hemorrhagic stroke, vascular death, intracerebral hemorrhage, and systemic bleeding compared with warfarin. The incidence of major bleeding at these doses was comparable to that of warfarin. The incidence of myocardial infarction with dabigatran etexilate 110 mg and 150 mg twice daily compared with warfarin was practically not increased (hazard ratio 1.29; p = 0.0929 and hazard ratio 1.27; p = 0.1240, respectively). A significant positive effect of dabigatran etexilate compared with warfarin is the improvement of INR monitoring.

Data from non-interventional studies

A non-interventional study (GLORIA-AF) prospectively (during the second phase) collected safety and efficacy data in patients with newly diagnosed non-valvular atrial fibrillation (NAF) treated with dabigatran etexilate in real-life settings. The study included 4859 patients treated with dabigatran etexilate (55% received a dose of 150 mg twice daily, 43% - 110 mg twice daily, 2% - 75 mg twice daily). Patients were followed for 2 years. The mean CHADS2 and HAS-BLED scores were 1.9 and 1.2, respectively. The mean follow-up period during treatment was 18.3 months. Major bleeding occurred in 0.97 cases per 100 patient-years. Life-threatening bleeding was reported in 0.46 cases per 100 patient-years, intracranial bleeding in 0.17 cases per 100 patient-years, and gastrointestinal bleeding in 0.60 cases per 100 patient-years. Stroke was observed in 0.65 cases per 100 patient-years.

In addition, during a non-interventional study [Graham DJ et al., Circulation. 2015;131:157–164] in more than 134,000 elderly patients with nonvalvular atrial fibrillation (NAF) in the United States (equivalent to more than 37,500 patient-years of observation on therapy), dabigatran etexilate (84% of patients receiving 150 mg twice daily, 16% of patients receiving 75 mg twice daily) was associated with a reduced risk of ischemic stroke (hazard ratio 0.80; 95% confidence interval [CI] 0.67–0.96), intracranial hemorrhage (hazard ratio 0.34; CI 0.26–0.46), and mortality (hazard ratio 0.86; CI 0.77–0.96), as well as an increased risk of gastrointestinal bleeding (hazard ratio 1.28; CI 1.14–1.44) compared with warfarin. There was no difference in the risk of major bleeding (hazard ratio 0.97; CI 0.88–1.07).

Patients who underwent percutaneous coronary angioplasty (PCA) with stenting

A prospective, randomized, open-label, blinded phase IIIb trial (PROBE) was conducted to evaluate dual therapy with dabigatran etexilate (110 mg or 150 mg twice daily) plus clopidogrel or ticagrelor (a P2Y12 antagonist) compared with triple therapy with warfarin (adjusted to an INR of 2.0–3.0) plus clopidogrel or ticagrelor and aspirin in 2725 patients with nonvalvular atrial fibrillation undergoing percutaneous coronary intervention (RE-DUAL PCI). Patients were randomized to dual therapy with dabigatran etexilate 110 mg twice daily, dual therapy with dabigatran etexilate 150 mg twice daily, or triple therapy with warfarin. Elderly patients outside the United States (aged 80 years or older for all countries and 70 years or older for Japan) were randomized to dual therapy with dabigatran etexilate 110 mg or warfarin. The primary endpoint was a composite endpoint of major bleeding based on ISTH (International Society on Thrombosis and Hemostasis) or clinically significant minor bleeding.

The primary endpoint was achieved in 15.4% (151 patients) in the dual therapy group with dabigatran etexilate 110 mg compared with 26.9% (264 patients) in the triple therapy group with warfarin (HR 0.52; 95% CI 0.42, 0.63; P<0.0001 for non-inferiority and P<0.0001 for superiority) and in 20.2% (154 patients) in the dual therapy group with dabigatran etexilate 150 mg compared with 25.7% (196 patients) in the corresponding triple therapy group with warfarin (HR 0.72; 95% CI 0.58, 0.88; P<0.0001 for non-inferiority and P=0.002 for higher efficiency). In a descriptive analysis, the incidence of major bleeding according to the TIMI (thrombolysis in myocardial infarction) scale was lower in both dual therapy groups with dabigatran etexilate than in the triple therapy group with warfarin: 14 events (1.4%) in the dual therapy group with dabigatran etexilate 110 mg compared with 37 events (3.8%) in the triple therapy group with warfarin (HR 0.37; 95% CI 0.20, 0.68; P=0.002) and 16 events (2.1%) in the dual therapy group with dabigatran etexilate 150 mg compared with 30 events (3.9%) in the corresponding triple therapy group with warfarin (HR 0.51; 95% CI 0.28, 0.93; P=0.03). Both dual therapy groups with dabigatran etexilate had a lower incidence of intracranial hemorrhage than the corresponding triple therapy group with warfarin: 3 events (0.3%) in the dual therapy group with dabigatran etexilate 110 mg compared with 10 events (1.0%) in the triple therapy group with warfarin (HR 0.30; 95% CI 0.08, 1.07; P=0.06) and 1 event (0.1%) in the dual therapy group with dabigatran etexilate 150 mg compared with 8 events (1.0%) in the corresponding triple therapy group with warfarin (HR 0.12; 95% CI 0.02, 0.98; P=0.047). The combined efficacy endpoint of death, thromboembolic events (myocardial infarction, stroke, and systemic embolism) or unplanned revascularization was noninferior to the warfarin triple therapy group in both dabigatran etexilate dual therapy groups (13.7% vs. 13.4%, respectively; HR 1.04; 95% CI 0.84, 1.29; P=0.0047 for noninferiority). There were no statistical differences in the individual components of the efficacy endpoints between either dabigatran etexilate dual therapy group and the warfarin triple therapy group.

Clinical trials on the prevention of thromboembolism in patients with mechanical heart valves

In clinical studies in patients who had recently undergone mechanical heart valve replacement surgery (e.g. during inpatient treatment) and patients who had undergone mechanical heart valve replacement surgery more than 3 months previously, an increase in thromboembolic complications (mainly strokes and prosthetic valve thrombosis with clinical manifestations and/or asymptomatic) and more bleeding events were observed with dabigatran etexilate compared to warfarin. In patients in the early postoperative period, massive bleeding mainly manifests itself as hemorrhagic exudate in the pericardial cavity, especially in patients who started dabigatran etexilate (e.g. on day 3) after heart valve replacement surgery (see section "Contraindications").

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

After oral administration of dabigatran etexilate, the pharmacokinetic profile of dabigatran in plasma is characterized by a rapid increase in concentration, reaching Cmax 0.5–2 hours after administration.

Absorption. The postoperative absorption of dabigatran etexilate, assessed in a study 1–3 hours after surgery, was relatively low compared to that in healthy volunteers and showed a flat AUC profile without high peak plasma concentrations. Maximum plasma concentrations are reached 6 hours after administration in the postoperative period due to concomitant factors such as anesthesia, gastrointestinal paresis and surgery, regardless of the oral formulation of the drug. An additional study showed that slow and delayed absorption is usually observed only on the day of surgery. On subsequent days, absorption of dabigatran is rapid, with peak plasma concentrations reached 2 hours after administration.

Food does not affect the bioavailability of dabigatran etexilate, but delays the time to reach maximum plasma concentration by 2 hours.

Cmax and AUC were dose proportional.

Oral bioavailability can be increased by 75% after a single dose and by 37% at steady state compared to the capsule formulation when pellets are used without hydroxypropyl methylcellulose (HPMC) in the capsule shell. Therefore, the integrity of HPMC capsules should always be maintained during clinical use to avoid an unintended increase in the bioavailability of dabigatran etexilate (see section 4.2).

Distribution: Low (34–35%), concentration-independent binding of dabigatran to human plasma proteins was observed. The volume of distribution of dabigatran, 60–70 L, exceeded the total body fluid volume, indicating moderate tissue distribution of dabigatran.

Biotransformation. The metabolism and elimination of dabigatran were studied after a single intravenous dose of radiolabeled dabigatran to healthy male volunteers. After intravenous administration, radioactive dabigatran was mainly excreted in the urine (85%). Faecal excretion accounted for 6% of the administered dose. Recovery of initial radioactivity to 88–94% occurred 168 hours after dabigatran administration. Dabigatran is conjugated to form pharmacologically active acylglucuronides. There are four positional isomers, 1-O, 2-O, 3-O, 4-O-acylglucuronides, each accounting for less than 10% of total dabigatran in plasma. Traces of other metabolites could only be detected by highly sensitive analytical methods. Dabigatran is mainly excreted unchanged in the urine at a rate of approximately 100 ml/min, which corresponds to the glomerular filtration rate.

Breeding

Dabigatran plasma concentrations decline biexponentially with a mean terminal half-life of 11 hours in healthy elderly volunteers. After multiple doses, the terminal half-life was approximately 12–14 hours. The half-life was independent of dose. The half-life is prolonged with decreasing renal function (see Table 1).

Special patient groups.

Renal impairment: In phase I studies, the distribution (AUC) of dabigatran after oral administration was approximately 2.7 times higher in volunteers with moderate renal impairment (creatinine clearance (CrCl) 30-50 ml/min) compared to that in volunteers without renal impairment. In a small number of volunteers with severe renal impairment (creatinine clearance (CrCl) 10-30 ml/min), the distribution (AUC) of dabigatran was approximately 6 times higher and the half-life approximately 2 times longer compared to that in volunteers without renal impairment (see sections 4.2, 4.3 and 4.4).

Table 1. Dabigatran half-life depending on renal function

In addition, dabigatran exposure (at trough and peak) was evaluated in a prospective, open-label, randomized pharmacokinetic study in patients with non-valvular atrial fibrillation and severe renal impairment (creatinine clearance (CrCl) 15–30 mL/min) receiving dabigatran etexilate 75 mg twice daily.

The clearance of dabigatran during hemodialysis was studied in 7 patients with end-stage renal disease (ESRD) without atrial fibrillation. Dialysis was performed at a dialysate rate of 700 mL/min for 4 hours and a blood flow rate of either 200 mL/min or 350–390 mL/min. This resulted in a 50% and 60% reduction in dabigatran concentrations, respectively. The amount of material removed by dialysis is proportional to a blood flow rate of 300 mL/min. The anticoagulant activity of dabigatran decreases with decreasing plasma concentrations. The procedure did not affect the pharmacodynamic/pharmacokinetic relationship.

Elderly patients: In a phase I dedicated pharmacokinetic study, an increase in AUC from 40% to 60% and Cmax of more than 25% was observed in elderly patients compared to young patients. The effect of age on the disposition of dabigatran was confirmed in the RE-LY study: approximately 31% higher concentrations in patients ≥ 75 years and approximately 22% lower in patients < 65 years compared to those in patients aged 65 to 75 years (see sections 4.2 and 4.4).

Hepatic impairment: No changes in the disposition of dabigatran were observed in 12 patients with moderate hepatic impairment (Child-Pugh class B) compared to 12 control patients (see sections 4.2 and 4.4).

Body weight: Dabigatran concentrations were approximately 20% lower in patients with a body weight of >100 kg compared to those in patients with a body weight of 50–100 kg. The majority (80.8%) of volunteers were in the ≥50 kg and <100 kg categories with no clear difference in dabigatran concentrations (see sections 4.2 and 4.4). Limited data are available for patients with a body weight of <50 kg.

Gender. The distribution of the active substance in studies on the prevention of venous thromboembolic complications was 40%-50% higher in female patients; no dose adjustment is recommended. Female patients with atrial fibrillation had on average 30% higher concentrations during and after administration. No dose adjustment is recommended (see section "Method of administration and dosage").

Race: There are no clinically relevant inter-ethnic differences in the pharmacokinetics and pharmacodynamics of dabigatran in patients of Caucasian, Negroid, Hispanic, Japanese or Chinese origin.

Pharmacokinetic interactions: In vitro interaction studies have shown no inhibition or induction of the major cytochrome P450 isoenzymes. This was confirmed by in vitro studies in healthy volunteers, in which no interactions were observed between dabigatran and active substances such as atorvastatin (CYP3A4), digoxin (P-gp transporter interaction) and diclofenac (CYP2C9).

Indication

Primary prevention of venous thromboembolic complications in patients who have undergone major orthopedic surgery for hip or knee replacement.

Prevention of stroke and systemic embolism in adult patients with non-valvular atrial fibrillation (NAF) with one or more risk factors such as: previous stroke or transient ischemic attack (TIA), age ≥ 75 years, heart failure (New York Heart Association (NYHA) class ≥ II), diabetes mellitus or hypertension.

Treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE) and prevention of recurrent DVT and PE in adults.

Contraindication

Known hypersensitivity to dabigatran or dabigatran etexilate or to any of the excipients. Severe renal impairment (creatinine clearance < 30 ml/min). Active clinically significant bleeding. Injury or condition considered to be a significant risk factor for major bleeding, including current or recent gastrointestinal ulcer, presence of malignant tumours with high risk of bleeding, recent brain or spinal cord injury, spinal cord or ophthalmic surgery, recent intracerebral haemorrhage, known or suspected oesophageal varices, arteriovenous malformations, vascular aneurysms or significant intraspinal or intracerebral vascular pathologies.

Concomitant use of any anticoagulant medicinal product, such as unfractionated heparin (UFH), low molecular weight heparins (enoxaparin, dalteparin, etc.), heparin derivatives (fondaparinux, etc.), oral anticoagulants (warfarin, rivaroxaban, apixaban, etc.), except in specific circumstances, in particular cases of switching from or to anticoagulant therapy (see section "Method of administration and dosage"), when UFH is used in doses necessary to maintain a patent central venous or arterial catheter, or when UFH is used during catheter ablation for atrial fibrillation (see section "Interaction with other medicinal products and other types of interactions").

Liver dysfunction or liver disease, which may affect survival.

Concomitant treatment with the following strong P-gp inhibitors: systemic ketoconazole, ciclosporin, itraconazole, dronedarone and the fixed-dose combination of glecaprevir/pibrentasvir (see section “Interaction with other medicinal products and other forms of interaction”).

Artificial heart valve requiring anticoagulant therapy.

Interaction with other medicinal products and other types of interactions

Transporter interactions.

Dabigatran etexilate is a substrate for the P-gp transporter. Concomitant use of P-gp inhibitors (see Table 2) is expected to increase dabigatran plasma concentrations. Unless otherwise indicated, close clinical monitoring (for signs of bleeding or anaemia) is recommended when dabigatran is used concomitantly with strong P-gp inhibitors. A dose reduction of dabigatran may be required when used in combination with some P-gp inhibitors (see sections 4.2, 4.4, and 5.1).

Table 2. Transporter interactions

When dabigatran etexilate was co-administered with a single 600 mg dose of amiodarone, the extent and rate of absorption of amiodarone and its active metabolite diethanolamine (DEA) were not significantly altered. The area under the concentration-time curve (AUC) and Cmax were increased approximately 1.6-fold and 1.5-fold, respectively. Given the long half-life of amiodarone, the potential for interaction may persist for several weeks after discontinuation of amiodarone (see sections 4.2 and 4.4).

Quinidine was administered at a dose of 200 mg every 2 hours up to a total dose of 1000 mg. Dabigatran etexilate was administered twice daily for 3 days, with or without quinidine on day 3. The AUCτ,ss and Cmax,ss of dabigatran were increased overall by 1.53-fold and 1.56-fold, respectively, when quinidine was administered concomitantly (see sections 4.2 and 4.4).

Anticoagulants and drugs that counteract platelet aggregation.

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

Limited data from the RE-LY study in patients with atrial fibrillation suggest that concomitant use of other oral or parenteral anticoagulants with dabigatran etexilate and warfarin increases the incidence of major bleeding by approximately 2.5-fold, mainly when switching from one anticoagulant to another (see section 4.3).

UFH can be used in doses necessary to maintain a patent central venous or arterial catheter or during catheter ablation for atrial fibrillation (see section "Contraindications").

Table 3. Interaction with anticoagulants and antiplatelet agents

In young healthy male volunteers, concomitant administration of dabigatran etexilate and clopidogrel did not prolong capillary bleeding time compared to clopidogrel alone. In addition, dabigatran AUCτ,ss and Cmax,ss and the effect of dabigatran on platelet aggregation inhibition remained unchanged compared to those of combination therapy and the respective monotherapy. When 300 mg or 600 mg of clopidogrel were administered, dabigatran AUCτ,ss and Cmax,ss were increased by approximately 30-40% (see section 4.4).

Research data suggest that concomitant use of acetylsalicylic acid (ASA) with dabigatran etexilate at a dose of 150 mg twice daily may increase the risk of major bleeding from 12% to 18% or 24% (at a dose of ASA 81 mg or 325 mg, respectively) (see section "Special warnings and precautions for use").

Table 4. 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 effect on cytochrome P450 enzymes in vitro. Therefore, no interactions of dabigatran etexilate or dabigatran with these medicinal products are expected.

Application features

Bleeding risk. PRADAXA should be used with caution in conditions with a high risk of bleeding or in the case of concomitant use of medicinal products that affect haemostasis by inhibiting platelet aggregation. Bleeding may occur at any site during treatment with PRADAXA. In case of unexplained decreases in haemoglobin and/or haematocrit or blood pressure, bleeding should be investigated.

In life-threatening or uncontrolled bleeding situations where rapid reversal of the anticoagulant effect is required, the specific reversal agent PRAXBIND (idarucizumab) is available for prescription.

In clinical trials, PRADAXA was associated with high rates of major gastrointestinal bleeding. An increased risk was observed in elderly patients (≥ 75 years) at 150 mg twice daily. Additional risk factors (see also Table 5) include concomitant use with platelet aggregation inhibitors such as clopidogrel and acetylsalicylic acid (ASA) or nonsteroidal anti-inflammatory drugs (NSAIDs), as well as the presence of oesophagitis, gastritis or gastroesophageal reflux disease.

Risk factors

Table 5. Factors that may increase the risk of bleeding

Pharmacodynamic interactions (see section “Interaction with other medicinal products and other types of interactions”)

Pharmacodynamic and kinetic factors

Age ≥ 75 years

Factors that increase dabigatran plasma levels

Significant Moderate renal insufficiency (creatinine clearance 30–50 ml/min). Strong P-gp inhibitors (see sections “Contraindications” and “Interaction with other medicinal products and other types of interactions”). Concomitant use of mild to moderate P-gp inhibitors (such as amiodarone, verapamil, quinidine and ticagrelor, etc.) Specifications Characteristics Active ingredient Dabigatran etexilate Adults Can ATC code B AGENTS AFFECTING THE BLOOD SYSTEM AND HEMOPOIESIS; B01 ANTITHROMBOTIC AGENTS; B01A ANTITHROMBOTIC AGENTS; B01A E Direct thrombin inhibitors; B01A E07 Dabigatran etexilate Country of manufacture Germany Diabetics It is impossible. Dosage 110 мг Drivers Can For allergies It is impossible. For children It is impossible. Form Capsules Method of application Inside, solid Nursing It is impossible. Pregnant It is impossible. Primary packaging blister Producer Boehringer Ingelheim Quantity per package 60 pcs Trade name Pradaxa Vacation conditions By prescription Reviews There are no reviews for this product. + Add review Write a review Pradaxa hard capsules 110 mg blister No. 60 My mark: Continue There are no reviews for this product, be the first to leave your review. Answers & questions Add your question and we will answer as soon as possible. + Ask a question Ask a question Add your question and we will answer as soon as possible. * Your question Continue No questions about this product, be the first and ask your question. You are watched new Sold out Toridip 20 tablets 20 mg No. 30 Распродано 0 399.30 грн. 1 664.40 грн. Add to Cart