Pradaxa

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT PRADAXA® (PRADAXA®)

Composition:

Active substance: dabigatran etexilate;

One capsule contains 110 mg of dabigatran etexilate (as mesilate);

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

Capsule shell: carrageenan (E 407), potassium chloride, titanium dioxide (E 171), indigocarmine (E 132), hypromellose, purified water;

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

Pharmaceutical form. Hard capsules.

Main physicochemical properties: elongated hydroxypropylmethylcellulose capsules (size 1) with an opaque light-blue cap bearing the Boehringer Ingelheim company symbol in black and an opaque light-blue body bearing the black marking "R110", containing yellowish pellets.

Pharmacotherapeutic group. Antithrombotic agents. Direct thrombin inhibitors.

ATC code B01A E07.

Pharmacological Properties

Pharmacodynamics

Mechanism of action. Dabigatran etexilate is a low-molecular-weight prodrug that lacks pharmacological activity. After oral administration, dabigatran etexilate is rapidly absorbed and converted to dabigatran via esterase-catalyzed hydrolysis in plasma and the liver. Dabigatran is a potent, competitive, reversible direct thrombin inhibitor and is the primary active substance in plasma.

Since thrombin (a serine protease) mediates the conversion of fibrinogen to fibrin in the coagulation cascade, its inhibition prevents thrombus formation. Dabigatran inhibits both free thrombin and fibrin-bound thrombin, as well as thrombin-induced platelet aggregation.

Pharmacodynamic effects. A clear correlation exists between plasma concentrations of dabigatran and the degree of anticoagulant effect, as demonstrated in phase II studies. Dabigatran prolongs thrombin time (TT), activated partial thromboplastin time (aPTT), and prothrombin time (PT).

The calibrated, diluted thrombin time (dTT) assay provides an approximate estimation of plasma dabigatran concentration, which can be compared with expected levels. If the calibrated, diluted thrombin time (dTT) test result is at or below the lower limit of quantification, additional coagulation tests (TT, aPTT, and PT) should be considered.

The PT test may provide a direct measurement of the activity of direct thrombin inhibitors.

The aPTT test is widely available and provides an approximate indicator of the anticoagulant intensity achieved with dabigatran. However, the aPTT test has limited sensitivity and is not suitable for precise quantitative assessment of anticoagulant effect, especially at high plasma concentrations of dabigatran. Although high aPTT values should be interpreted with caution, they indicate the presence of anticoagulant effect in the patient.

Clinical efficacy and safety. In the RE-LY clinical trial, dabigatran etexilate at a dose of 110 mg twice daily was non-inferior to warfarin in preventing stroke and systemic embolism in adult patients with non-valvular atrial fibrillation (NVAF), with a reduced risk of intracranial hemorrhage, overall bleeding, or major bleeding. The 150 mg twice-daily dose of dabigatran significantly reduced the risk of ischemic and hemorrhagic stroke, cardiovascular mortality, intracranial hemorrhage, and overall bleeding compared to warfarin. The rate of major bleeding with these doses was comparable to that observed with warfarin. The incidence of myocardial infarction with dabigatran etexilate 110 mg and 150 mg twice daily, compared to warfarin, was not significantly increased (risk ratio 1.29; p=0.0929 and risk ratio 1.27; p=0.1240, respectively). A significant positive advantage of dabigatran etexilate over warfarin is improved INR monitoring.

Non-interventional study data

In a non-interventional study (GLORIA-AF), safety and efficacy data were prospectively collected (during phase II) in patients with newly diagnosed non-valvular atrial fibrillation (NVAF) receiving dabigatran etexilate under real-world conditions. The study included 4,859 patients receiving dabigatran etexilate (55% received 150 mg twice daily, 43% received 110 mg twice daily, 2% received 75 mg twice daily). Patients were followed for 2 years. Mean CHADS2 and HAS-BLED scores were 1.9 and 1.2, respectively. The mean treatment observation period was 18.3 months. Major bleeding occurred at a rate of 0.97 events per 100 patient-years. Life-threatening bleeding was recorded at 0.46 events per 100 patient-years, intracranial hemorrhage at 0.17 events per 100 patient-years, and gastrointestinal bleeding at 0.60 events per 100 patient-years. Stroke occurred at a rate of 0.65 events per 100 patient-years.

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

These real-world observations are consistent with the established safety and efficacy profile of dabigatran etexilate from the RE-LY trial when used for the approved indication.

Patients who underwent percutaneous coronary intervention (PCI) with stenting

A prospective, randomized, open-label, blinded-endpoint (PROBE) phase IIIb trial evaluated dual therapy with dabigatran etexilate (110 mg or 150 mg twice daily) plus clopidogrel or ticagrelor (P2Y12 antagonist) versus triple therapy with warfarin (adjusted to INR 2.0–3.0) plus clopidogrel or ticagrelor and aspirin in 2,725 patients with non-valvular atrial fibrillation who underwent PCI with stenting (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 in all countries and ≥70 years in Japan) were randomized to receive dual therapy with dabigatran etexilate 110 mg or triple therapy with warfarin. The primary endpoint was a composite of major bleeding (as defined by the International Society on Thrombosis and Haemostasis [ISTH]) or clinically relevant non-major bleeding.

The rate of the primary endpoint was 15.4% (151 patients) in the dual therapy group receiving dabigatran etexilate 110 mg twice daily versus 26.9% (264 patients) in the triple therapy warfarin group (RR 0.52; 95% CI 0.42, 0.63; P<0.0001 for non-inferiority and P<0.0001 for superiority), and 20.2% (154 patients) in the dual therapy group receiving dabigatran etexilate 150 mg twice daily versus 25.7% (196 patients) in the corresponding triple therapy warfarin group (RR 0.72; 95% CI 0.58, 0.88; P<0.0001 for non-inferiority and P=0.002 for superiority). In descriptive analyses, the rate of TIMI major bleeding (Thrombolysis In Myocardial Infarction) was lower in both dabigatran dual therapy groups compared to the warfarin triple therapy group: 14 events (1.4%) in the 110 mg group versus 37 events (3.8%) in the warfarin group (RR 0.37; 95% CI 0.20, 0.68; P=0.002), and 16 events (2.1%) in the 150 mg group versus 30 events (3.9%) in the corresponding warfarin group (RR 0.51; 95% CI 0.28, 0.93; P=0.03). Both dabigatran dual therapy groups showed lower rates of intracranial hemorrhage compared to the corresponding warfarin triple therapy group: 3 events (0.3%) in the 110 mg group versus 10 events (1.0%) in the warfarin group (RR 0.30; 95% CI 0.08, 1.07; P=0.06), and 1 event (0.1%) in the 150 mg group versus 8 events (1.0%) in the corresponding warfarin group (RR 0.12; 95% CI 0.02, 0.98; P=0.047). For the composite efficacy endpoint of death, thromboembolic events (myocardial infarction, stroke, and systemic embolism), or unplanned revascularization, both dabigatran dual therapy groups collectively were non-inferior to the warfarin triple therapy group (13.7% vs. 13.4%, respectively; RR 1.04; 95% CI 0.84, 1.29; P=0.0047 for non-inferiority). No statistically significant differences were observed in individual components of the efficacy endpoints between either dabigatran dual therapy group and the warfarin triple therapy group.

Clinical studies on thromboembolism prevention in patients with mechanical heart valves

In a clinical trial involving patients who had recently undergone mechanical heart valve replacement (e.g., during hospitalization) and patients who had undergone mechanical valve replacement more than 3 months prior, increased thromboembolic events (primarily strokes and symptomatic or asymptomatic prosthetic valve thrombosis) and higher rates of bleeding were observed with dabigatran etexilate compared to warfarin. In the early postoperative period, major bleeding primarily manifested as hemorrhagic pericardial effusion, particularly in patients who initiated dabigatran etexilate (e.g., on day 3) after heart valve replacement surgery (see section "Contraindications").

Pharmacokinetics

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

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

Absorption. Postoperative absorption of dabigatran etexilate assessed 1–3 hours after surgery was relatively low compared to absorption in healthy volunteers and showed a flat AUC profile without high peak plasma concentrations. Maximum plasma concentration is reached 6 hours after administration in the postoperative period due to concomitant factors such as anesthesia, gastrointestinal paresis, and surgical intervention, regardless of the oral formulation. Additional studies showed that slow and delayed absorption typically occurs only on the day of surgery. In subsequent days, absorption of dabigatran is rapid, with peak plasma concentration achieved within 2 hours after drug administration.

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

Cmax and AUC are dose-proportional.

Oral bioavailability may be increased by 75% after a single dose and by 37% at steady state when pellets are administered without the hydroxypropylmethylcellulose (HPMC) capsule shell. Therefore, the integrity of HPMC capsules must always be maintained during clinical use to prevent unintentional increases in the bioavailability of dabigatran etexilate (see section "Dosage and administration").

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

Metabolism. The metabolism and elimination of dabigatran were studied after administration of a single intravenous dose of radiolabeled dabigatran to healthy male volunteers. After intravenous administration, radiolabeled dabigatran was primarily excreted in urine (85%). Fecal excretion accounted for 6% of the administered dose. Recovery of total radioactivity reached 88–94% within 168 hours after dabigatran administration. Dabigatran undergoes conjugation to form pharmacologically active acylglucuronides. There are four positional isomers: 1-O, 2-O, 3-O, and 4-O-acylglucuronides, each representing less than 10% of total dabigatran in plasma. Traces of other metabolites were detectable only with highly sensitive analytical methods. Dabigatran is primarily excreted unchanged in urine at a rate of approximately 100 mL/min, consistent with glomerular filtration rate.

Elimination

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

Special patient populations

Renal impairment. In phase I studies, exposure (AUC) to dabigatran after oral administration was approximately 2.7-fold higher in adult volunteers with moderate renal impairment (creatinine clearance [CrCl] between 30 and 50 mL/min) compared to volunteers with normal renal function.

In a small number of adult volunteers with severe renal impairment (CrCl 10–30 mL/min), dabigatran exposure (AUC) was approximately 6-fold higher and the elimination half-life approximately twice as long compared to volunteers with normal renal function (see sections "Dosage and administration", "Contraindications", and "Special precautions").

Table 1

Half-life of dabigatran in healthy volunteers and individuals with impaired renal function

Glomerular filtration rate (creatinine clearance), mL/min	Half-life, hours (gCV %; interval)
> 80	13.4 (25.7 %; 11.0–21.6)
> 50–≤ 80	15.3 (42.7 %; 11.7–34.1)
> 30–≤ 50	18.4 (18.5 %; 13.3–23.0)
≤ 30	27.2 (15.3 %; 21.6–35.0)

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

With this dosing regimen, the geometric mean trough concentration, measured immediately before the next dose, was 155 ng/mL (geometric CV 76.9%), and the geometric mean peak concentration, measured two hours after the last dose, was 202 ng/mL (geometric CV 70.6%).

Dabigatran clearance during hemodialysis was studied in 7 adult patients with end-stage renal disease (ESRD) without atrial fibrillation. Dialysis was performed with a dialysate flow 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 concentration, respectively. The amount of substance removed by dialysis is proportional to a blood flow rate of 300 mL/min. The anticoagulant activity of dabigatran decreases with decreasing plasma concentration. The procedure did not affect the pharmacokinetic/pharmacodynamic relationship.

Elderly patients. In a Phase I specific pharmacokinetic study in elderly patients, an increase in AUC of 40% to 60% and Cmax by more than 25% was observed compared to younger patients. The effect of age on dabigatran exposure 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 patients aged 65 to 75 years (see sections "Dosage and administration" and "Special precautions").

Hepatic impairment. No changes in dabigatran exposure were observed in 12 adult patients with moderate hepatic impairment (Child–Pugh class B) compared to 12 control patients (see sections "Dosage and administration" and "Special precautions").

Body weight. Dabigatran concentrations were approximately 20% lower in adult patients with body weight > 100 kg compared to patients with body weight 50–100 kg. The majority (80.8%) of subjects were in the category ≥ 50 kg and < 100 kg, with no clear difference in dabigatran concentration observed (see sections "Dosage and administration" and "Special precautions"). Data for the category of adult patients with body weight < 50 kg are limited.

Sex. Exposure to the active substance in studies on prevention of venous thromboembolic events was 40%–50% higher in female patients; dose adjustment is not recommended. Female patients with atrial fibrillation had on average 30% higher concentrations during and after treatment. Dose adjustment is not recommended (see section "Dosage and administration").

Race. There are no clinically significant ethnic differences in the pharmacokinetics and pharmacodynamics of dabigatran in Caucasian, Black, Hispanic, Japanese, or Chinese patients.

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

Clinical characteristics.

Indications.

Primary prevention of venous thromboembolic events in adult patients who have undergone elective total hip or knee replacement surgery.

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

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

Contraindications.

• Known hypersensitivity to the active substance or to any of the excipients listed in the section "Composition".
• Severe renal impairment (creatinine clearance < 30 mL/min).
• Active clinically significant bleeding.
• Injury or condition considered to be a significant risk factor for massive bleeding, including current or recent gastrointestinal ulceration, presence of malignancies with high bleeding risk, recent trauma to brain or spinal cord, recent surgery on brain or spinal cord or ophthalmological surgery, recent intracranial haemorrhage, known or suspected oesophageal varices, arteriovenous malformations, vascular aneurysms, or significant intraspinal or intracerebral vascular abnormalities.
• 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 under specific circumstances, such as during transition to or from anticoagulant therapy (see section "Method of administration and dosage"), when UFH is used at doses required to maintain patency of a central venous or arterial catheter, or when UF0 is used during catheter ablation for atrial fibrillation (see section "Interaction with other medicinal products and other types of interactions").
• Hepatic impairment or liver disease that may affect survival.
• Concomitant treatment with strong P-gp inhibitors: systemic ketoconazole, cyclosporine, itraconazole, dronedarone, and the fixed-dose combination glecaprevir/pibrentasvir (see section "Interaction with other medicinal products and other types of interactions").
• Mechanical heart valve requiring anticoagulant therapy (see section "Pharmacological properties. Pharmacodynamics").

Interaction with other medicinal products and other types of interactions.

Transporter interactions.

Dabigatran etexilate is a substrate of the efflux transporter P-gp. Concomitant use of P-gp inhibitors (see Table 2) is expected to increase plasma concentrations of dabigatran. Unless otherwise specified, careful clinical monitoring (for signs of bleeding or anaemia) is recommended when dabigatran is used concomitantly with strong P-gp inhibitors. Dose reduction of dabigatran may be required when used in combination with certain P-gp inhibitors (see sections "Method of administration and dosage", "Contraindications", "Special precautions", and subsection "Pharmacodynamics").

Table 2

Transporter interactions

P-gp Inhibitors
Concomitant use is contraindicated (see section «Contraindications»)
Ketoconazole	Ketoconazole increases the total AUC0–∞ and Cmax of dabigatran by 2.38-fold and 2.35-fold, respectively, after a single oral dose of 400 mg, and by 2.53-fold and 2.49-fold, respectively, after multiple oral doses of 400 mg ketoconazole once daily.
Dronedarone	When dabigatran etexilate and dronedarone are used concomitantly, total AUC0–∞ and Cmax values of dabigatran increased approximately 2.4-fold and 2.3-fold, respectively, after multiple doses of 400 mg dronedarone twice daily, and approximately 2.1-fold and 1.9-fold, respectively, after a single 400 mg dose.
Itraconazole and cyclosporine	Based on in vitro data, an effect similar to that with ketoconazole can be expected.
Glecaprevir/ piibrentasvir	Concomitant use of dabigatran etexilate with the fixed-dose combination of P-gp inhibitors glecaprevir/piibrentasvir increases the effect of dabigatran and may increase the risk of bleeding.
Concomitant use is not recommended
Tacrolimus	In vitro studies have shown that tacrolimus has a similar P-gp inhibitory effect as itraconazole and cyclosporine. Clinical studies on the use of dabigatran etexilate with tacrolimus have not been conducted. However, limited clinical data on its use with another P-gp substrate (everolimus) suggest that P-gp inhibition by tacrolimus is weaker than that by strong P-gp inhibitors.
Caution is required during concomitant use (see sections «Dosage and administration» and «Special precautions»)
Verapamil	When dabigatran etexilate (150 mg) and oral verapamil are used concomitantly, Cmax and AUC of dabigatran increase depending on the timing of administration and the formulation of verapamil (see sections «Dosage and administration» and «Special precautions»). The greatest increase in dabigatran exposure was observed when the first dose of immediate-release verapamil was administered one hour before dabigatran etexilate (approximately 2.8-fold increase in Cmax and 2.5-fold increase in AUC). The effect gradually decreased with extended-release verapamil (approximately 1.9-fold increase in Cmax and 1.7-fold increase in AUC) or after multiple doses of verapamil (approximately 1.6-fold increase in Cmax and 1.5-fold increase in AUC). No significant interaction was observed when verapamil was administered 2 hours after dabigatran etexilate (approximately 1.1-fold increase in Cmax and 1.2-fold increase in AUC). This is explained by complete absorption of dabigatran within 2 hours.
Amiodarone	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 desethylamiodarone (DEA) were not substantially altered. AUC and Cmax increased by approximately 1.6-fold and 1.5-fold, respectively. Due to the long elimination half-life of amiodarone, the potential for interaction may persist for several weeks after discontinuation of amiodarone (see sections «Dosage and administration» and «Special precautions»).
Quinidine	Quinidine was administered at a dose of 200 mg every 2 hours to a total dose of 1000 mg. Dabigatran etexilate was administered twice daily for 3 days, on day 3 with or without quinidine. AUCτ,ss and Cmax,ss of dabigatran increased overall by 1.53-fold and 1.56-fold, respectively, when quinidine was co-administered (see sections «Dosage and administration» and «Special precautions»).
Clarithromycin	When clarithromycin (500 mg twice daily) was administered concomitantly with dabigatran etexilate to healthy volunteers, an increase in AUC by approximately 1.19-fold and in Cmax by approximately 1.15-fold was observed.
Ticagrelor	When a single dose of dabigatran etexilate 75 mg was administered concomitantly with the highest initial dose of ticagrelor 180 mg, AUC and Cmax of dabigatran increased by 1.73-fold and 1.95-fold, respectively. After multiple doses of ticagrelor (90 mg twice daily), exposure to dabigatran increased by 1.56-fold and 1.46-fold for Cmax and AUC, respectively. Concomitant administration of the highest initial dose of ticagrelor 180 mg and dabigatran etexilate 110 mg (at steady state) increases AUCτ,ss and Cmax,ss of dabigatran by 1.49-fold and 1.65-fold, respectively, compared to administration of dabigatran etexilate alone. When the 180 mg loading dose of ticagrelor was administered 2 hours after 110 mg of dabigatran etexilate (at steady state), the increases in AUCτ,ss and Cmax,ss of dabigatran were reduced to 1.27-fold and 1.23-fold, respectively, compared to dabigatran etexilate alone. This staggered administration is recommended when initiating ticagrelor at the highest loading dose. Concomitant administration of 90 mg ticagrelor twice daily (maintenance dose) with 110 mg dabigatran etexilate increases AUCτ,ss and Cmax,ss of dabigatran by 1.26-fold and 1.29-fold, respectively, compared to dabigatran etexilate alone.
Posaconazole	Posaconazole also moderately inhibits P-gp but has not been clinically studied. Caution should be exercised when dabigatran etexilate is administered concomitantly with posaconazole.
P-gp Inducers
Concomitant use should be avoided
For example, rifampicin, St. John's wort (Hypericum perforatum), carbamazepine or phenytoin	Concomitant use is expected to reduce dabigatran concentrations. Prior administration of rifampicin 600 mg once daily for 7 days reduces total Cmax and total exposure of dabigatran by 65.5% and 67%, respectively. The inductive effect diminishes, resulting in dabigatran exposure close to baseline, by day 7 after discontinuation of rifampicin. No further increase in bioavailability was observed during the subsequent 7 days.
Protease inhibitors such as ritonavir
Concomitant use is not recommended
For example, ritonavir and its combinations with other protease inhibitors	These agents affect P-gp (both as inhibitors and inducers). They have not been studied and are therefore not recommended for concomitant use with dabigatran etexilate.
P-gp Substrate
Digoxin	In a study involving 24 healthy volunteers, concomitant administration of dabigatran etexilate and digoxin showed no changes in digoxin parameters and no clinically significant changes in dabigatran exposure.

Anticoagulants and antiplatelet medicinal products.

Medicinal products whose therapy has not been investigated or for which experience of use 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), thrombolytics and vitamin K antagonists, rivaroxaban and other oral anticoagulants (see section "Contraindications"), antiplatelet agents such as GPIIb/IIIa receptor antagonists, ticlopidine, prasugrel, ticagrelor, dextran, and sulfinpyrazone (see section "Special precautions for use").

According to data from the RE-LY phase III trial (see subsection "Pharmacodynamics"), concomitant use of other oral or parenteral anticoagulants with dabigatran etexilate and with warfarin increases the incidence of major bleeding by approximately 2.5-fold, primarily during transition from one anticoagulant to another (see section "Contraindications"). In addition, concomitant use of antiplatelet agents, acetylsalicylic acid (ASA) or clopidogrel approximately doubles the rate of major bleeding with both dabigatran etexilate and warfarin (see section "Special precautions for use").

UFH may be administered at doses required to maintain patency of central venous or arterial catheters or during catheter ablation for atrial fibrillation (see section "Contraindications").

Table 3

Interaction with anticoagulants and antiplatelet medicinal products

Non-steroidal anti-inflammatory drugs (NSAIDs)	Short-term use of NSAIDs for perioperative analgesia was not associated with an increased risk of bleeding when used concomitantly with dabigatran etexilate. With long-term use of NSAIDs during the RE-LY study, the risk of bleeding increased by approximately 50% with both dabigatran etexilate and warfarin.
Clopidogrel	In healthy young male volunteers, concomitant administration of dabigatran etexilate and clopidogrel did not prolong capillary bleeding time compared to clopidogrel monotherapy. In addition, AUCτ,ss and Cmax,ss of dabigatran, coagulation parameters assessing the effect of dabigatran, or inhibition of platelet aggregation as an effect of clopidogrel remained unchanged compared to combination therapy and corresponding monotherapies. When 300 mg or 600 mg of clopidogrel were administered, AUCτ,ss and Cmax,ss of dabigatran increased by approximately 30–40% (see section "Special precautions").
Acetylsalicylic acid	Clinical trial data indicate that concomitant use of acetylsalicylic acid (ASA) with dabigatran etexilate at a dose of 150 mg twice daily may increase the risk of any bleeding from 12% to 18% or 24% (with ASA doses of 81 mg or 325 mg, respectively) (see section "Special precautions").
Low molecular weight heparins	Concomitant use of low molecular weight heparins, such as enoxaparin, and dabigatran etexilate has not been studied. After switching from a 3-day treatment with enoxaparin 40 mg once daily, 24 hours after the last enoxaparin dose, exposure to dabigatran was slightly lower than after administration of dabigatran etexilate alone (single dose 220 mg). Higher anti-FXa/FIIa activity was observed after dabigatran etexilate administration following enoxaparin pretreatment compared to dabigatran etexilate treatment alone. This is due to the residual effect of enoxaparin treatment and is not clinically significant. Enoxaparin pretreatment did not significantly affect other anticoagulant tests for dabigatran.

Table 4

Other interactions

Concomitant use of selective serotonin reuptake inhibitors (SSRIs) or serotonin-norepinephrine reuptake inhibitors (SNRIs).
SSRIs and SNRIs	SSRIs and SNRIs increase the risk of bleeding during procedures in all treatment groups.
Substances affecting gastric pH
Pantoprazole	When PRADAXA was administered concomitantly with pantoprazole, a reduction in dabigatran AUC of approximately 30% was observed. Pantoprazole and other proton pump inhibitors (PPIs) were used concomitantly with PRADAXA during clinical trials. Concomitant use of PPIs did not reduce the effectiveness of PRADAXA.
Ranitidine	Concomitant administration of ranitidine and dabigatran etexilate had no clinically significant effect on the extent of dabigatran absorption.

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, interactions between dabigatran and corresponding medicinal products are not expected.

Special precautions for use.

Risk of bleeding. Dabigatran etexilate should be used with caution in conditions associated with a high risk of bleeding or when used concomitantly with medicinal products affecting hemostasis by inhibiting platelet aggregation. Bleeding may occur at any site during treatment. If hemoglobin levels decrease for unexplained reasons and/or hematocrit or arterial blood pressure decreases, the presence of bleeding should be investigated.

In the event of life-threatening or uncontrolled bleeding, when rapid reversal of dabigatran's anticoagulant effect is required, the specific reversal agent idarucizumab is available for administration. Dabigatran is eliminated by hemodialysis. Consideration may be given to the use of fresh whole blood or fresh frozen plasma, coagulation factor concentrates (activated or non-activated), recombinant factor VIIa, platelet concentrates, and other possible options (see section "Overdose").

In clinical trials, the use of dabigatran etexilate was associated with high rates of major gastrointestinal bleeding. The risk was increased in elderly patients (≥75 years) receiving the 150 mg twice-daily dose. Additional risk factors (see also Table 5) include concomitant use with antiplatelet agents such as clopidogrel and acetylsalicylic acid (ASA), or with nonsteroidal anti-inflammatory drugs (NSAIDs), as well as the presence of esophagitis, gastritis, or gastroesophageal reflux.

Risk factors

Table 5

Factors that may increase the risk of bleeding

	Risk factors
Pharmacodynamic and pharmacokinetic factors	Age ≥ 75 years
Factors increasing dabigatran plasma levels	Significant Moderate renal impairment (creatinine clearance 30–50 mL/min). Strong P-gp inhibitors (see sections "Contraindications" and "Interaction with other medicinal products and other forms of interaction"). Concomitant use of mild to moderate P-gp inhibitors (such as amiodarone, verapamil, quinidine and ticagrelor, see section "Interaction with other medicinal products and other forms of interaction"). Minor Low body weight (< 50 kg).
Pharmacodynamic interactions (see section "Interaction with other medicinal products and other forms of interaction")	Acetylsalicylic acid and other platelet aggregation inhibitors such as clopidogrel. NSAIDs. SSRIs or SNRIs. Other medicinal products that may impair hemostasis.
Conditions/procedures associated with bleeding risk	Hereditary or acquired coagulation disorders. Thrombocytopenia or platelet function defects. Recent biopsy or major trauma. Bacterial endocarditis. Esophagitis, gastritis or gastroesophageal reflux.

Data in patients with body weight < 50 kg are limited (see section "Pharmacokinetics").

Precautionary measures and bleeding risk management

For prevention of hemorrhagic complications, see section "Overdose".

Benefit-risk assessment

Injuries, conditions, procedures and/or pharmacological therapies (e.g., NSAIDs, antiplatelet agents, SSRIs and SNRIs; see section "Interaction with other medicinal products and other types of interactions") that significantly increase the risk of major bleeding require careful benefit-risk assessment. Dabigatran etexilate should only be used if benefits outweigh bleeding risks.

Close clinical monitoring

Close clinical monitoring for signs of bleeding or anemia is recommended throughout treatment, especially when multiple risk factors are present (see Table 5 above).

Caution is advised when dabigatran etexilate is used concomitantly with verapamil, amiodarone, quinidine or clarithromycin (P-gp inhibitors), particularly in patients with impaired renal function and in the event of bleeding (see section "Interaction with other medicinal products and other types of interactions").

Close clinical monitoring for signs of bleeding is recommended during concomitant treatment with non-steroidal anti-inflammatory drugs (NSAIDs) (see section "Interaction with other medicinal products and other types of interactions").

Discontinuation of dabigatran etexilate

Patients who develop acute renal failure must discontinue dabigatran etexilate (see section "Contraindications").

In the event of severe bleeding, treatment should be discontinued, the source of bleeding investigated, and consideration given to administration of a specific reversal agent (idarucizumab). Dabigatran is removed by hemodialysis.

Use of proton pump inhibitors (PPIs)

The use of proton pump inhibitors (PPIs) may be considered to prevent gastrointestinal bleeding.

Coagulation laboratory parameters

Although routine anticoagulant monitoring is generally not required with this medicinal product, measuring the anticoagulant effect associated with dabigatran may be useful to identify 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) may provide useful information, but results should be interpreted with caution due to variability between assays (see section "Pharmacodynamics").

The INR (International Normalized Ratio) test is unreliable in patients taking dabigatran etexilate, as false-positive INR elevations have been observed. Therefore, the INR test should not be performed.

Table 6 provides threshold lower values of coagulation tests that may be associated with an increased risk of bleeding (see section "Pharmacodynamics").

Table 6

Threshold values of coagulation tests that may be associated with an increased risk of bleeding

Test	Indications
	Primary prophylaxis of VTE in orthopedic surgery	Stroke and systemic embolism prophylaxis in adult patients with non-valvular atrial fibrillation with one or more risk factors (AF stroke prevention), DVT/PE
PT [ng/mL]	> 67	> 200
aPTT [x-fold upper limit of normal]	data not available	> 3
APTT [x-fold upper limit of normal]	> 1.3	> 2
INR	not required	not required

Use of fibrinolytic agents for the treatment of acute ischaemic stroke

The use of fibrinolytic agents for the treatment of acute ischaemic stroke may be considered if PT, aPTT or ECT results do not exceed the upper limit of normal (ULN) according to local reference values.

Surgery and invasive procedures. Patients receiving dabigatran etexilate who undergo surgical or invasive procedures have an increased risk of bleeding. Therefore, surgical intervention may require temporary discontinuation of dabigatran etexilate.

Patients may continue dabigatran etexilate during cardioversion. Data on the use of dabigatran etexilate 110 mg twice daily in patients with atrial fibrillation undergoing catheter ablation are lacking (see section "Dosage and administration").

Caution should be exercised when temporarily discontinuing treatment for surgical procedures, and monitoring of anticoagulation should be ensured. Dabigatran clearance may be prolonged in patients with renal impairment (see section "Pharmacokinetics"). Caution should be observed with any procedure. In such cases, a coagulation test (see section "Contraindications" and subsection "Pharmacodynamics") may help determine whether haemostasis is impaired.

Emergency surgery or urgent procedures. Dabigatran etexilate should be temporarily discontinued. When rapid reversal of the anticoagulant effect is required, a specific reversal agent, idarucizumab, may be administered. Dabigatran is eliminated by haemodialysis.

Reversal of dabigatran therapy increases the thrombotic risk in patients related to their underlying condition. Dabigatran etexilate may be restarted 24 hours after administration of idarucizumab, provided the patient is clinically stable and adequate haemostasis has been achieved.

Surgery and invasive procedures in subacute settings. Dabigatran etexilate should be temporarily discontinued. Surgical or invasive procedures should be delayed for at least 12 hours after the last dose of dabigatran, if possible. If surgery cannot be delayed, the risk of bleeding may be increased. The risk of bleeding and the urgency of the procedure should be carefully weighed before proceeding.

Planned surgery. If possible, dabigatran etexilate should be discontinued at least 24 hours before invasive or surgical procedures. For patients at increased risk of bleeding or undergoing major surgery where haemostasis may be challenging, discontinuation of dabigatran etexilate 2–4 days prior to surgery should be considered.

Table 7

Guidelines for discontinuation of treatment prior to invasive or surgical procedures

Renal function (creatinine clearance, mL/min)	Expected elimination half-life (hours)	Dabigatran etexilate should be discontinued prior to planned surgical procedures
		High bleeding risk or major surgery	Standard risk
≥ 80	~ 13	2 days before	24 hours before
≥ 50 – < 80	~ 15	2–3 days before	1–2 days before
≥ 30 – < 50	~ 18	4 days before	2–3 days before (> 48 hours)

Spinal anesthesia/epidural anesthesia/lumbar puncture.

Procedures such as spinal anesthesia may require full hemostatic function. The risk of spinal or epidural hematoma may be increased in cases of traumatic or repeated puncture and prolonged postoperative use of epidural catheters. After catheter removal, at least 2 hours should be waited before administering the first dose of dabigatran etexilate. Such patients require careful monitoring for neurological symptoms and signs of spinal or epidural hematoma.

Postoperative phase.

Administration of dabigatran etexilate should be resumed/started after invasive procedures or surgical interventions as soon as the clinical situation allows and adequate hemostasis has been achieved.

Patients at risk of bleeding or patients at risk of excessive effect, especially with impaired renal function (see also Table 5), should be treated with caution (see section "Special precautions for use" and subsection "Pharmacodynamics").

Patients with high mortality risk associated with surgery and hereditary risk factors for thromboembolic events.

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

Surgical intervention for hip fracture.

There are no data on the use of dabigatran etexilate in patients who have undergone surgery for hip fracture; therefore, treatment is not recommended.

Hepatic impairment.

Patients with elevated liver enzymes more than twice the upper limit of normal (ULN) were excluded from the main clinical trials. Due to lack of experience, the use of dabigatran etexilate is not recommended in this patient group. The use of the drug is contraindicated in patients with hepatic insufficiency or liver disease that may affect survival (see section "Contraindications").

Interaction with P-gp inducers.

Concomitant use of P-gp inducers is expected to reduce plasma levels of dabigatran; therefore, concomitant use with this group of medicinal products should be avoided (see section "Interaction with other medicinal products and other forms of interaction" and subsection "Pharmacokinetics").

Patients with antiphospholipid syndrome.

Direct oral anticoagulants (DOACs), including dabigatran etexilate, are not recommended for patients with a history of thrombosis in whom antiphospholipid syndrome has been diagnosed. In particular, in patients with triple positivity (lupus anticoagulant, anti-cardiolipin antibodies, and anti-beta-2-glycoprotein I antibodies), treatment with DOACs may be associated with an increased frequency of recurrent thrombotic events compared to vitamin K antagonist therapy.

Myocardial infarction (MI).

In the phase III RE-LY clinical trial (stroke prevention, see subsection "Pharmacodynamics"), the annual incidence of MI was 0.82%, 0.81%, and 0.64% per year with dabigatran etexilate 110 mg twice daily, dabigatran etexilate 150 mg twice daily, and warfarin, respectively. The relative risk increased by 29% and 27% with dabigatran compared to warfarin. Regardless of therapy, the highest absolute risk of MI was observed in the following subgroups with similar relative risk: patients with a history of myocardial infarction, patients aged ≥65 years with diabetes or coronary artery disease, patients with left ventricular ejection fraction <40%, and patients with moderate renal impairment. Additionally, an increased risk of myocardial infarction was observed in patients receiving concomitant acetylsalicylic acid with clopidogrel or clopidogrel alone.

In three active-controlled phase III studies on DVT/PE, a higher rate of myocardial infarction was observed in patients receiving dabigatran etexilate compared to those receiving warfarin: 0.4% vs. 0.2% in the short-term studies RE-COVER and RE-COVER II, and 0.8% vs. 0.1% in the long-term study RE-MEDY. The increase was statistically significant in these studies (p = 0.022).

According to data from the RE-SONATE study, which compared dabigatran etexilate with placebo, the rate of myocardial infarction was 0.1% in patients receiving dabigatran etexilate and 0.2% in those receiving placebo.

Patients with cancer (DVT/PE).

The efficacy and safety of use in this patient group have not been studied.

Special precautions for use. When removing PRADAXA capsules from the blister pack, the following rules should be observed: separate one individual blister from the other blister along the perforated line; remove the hard capsule from the blister immediately before administration; peel off the foil without pushing the capsule through it.

Use during pregnancy or breastfeeding.

Women of childbearing potential. Women of childbearing potential should avoid pregnancy during treatment with PRADAXA.

Pregnancy. There are no adequate data on the use of PRADAXA in pregnant women. Animal studies have shown reproductive toxicity. The potential risk to pregnant women is unknown. Dabigatran etexilate should not be used during pregnancy except when the expected benefit to the woman outweighs the potential risk to the fetus.

Breastfeeding. There are no clinical data on the effect of dabigatran on breastfed infants. As a precaution, breastfeeding should be discontinued during treatment with PRADAXA.

Fertility. There are no data on the effect on fertility in humans.

In animal studies, an effect on female fertility was observed, including a decrease in the number of implantations and an increase in pre-implantation losses at a dose of 70 mg/kg (plasma exposure level 5 times higher than in humans). No other effects on female fertility were observed. No effects on male fertility were detected. At doses toxic to females (plasma exposure levels 5–10 times higher than in humans), reduced fetal body weight and embryonic viability, along with increased fetal abnormalities, were observed in rats and rabbits. In pre- and postnatal studies, increased intrauterine mortality was observed at doses toxic to females (dose at which plasma exposure was 4 times higher than in humans).

Ability to influence reaction speed when driving or operating machinery.

Dabigatran etexilate has no or negligible effect on the ability to drive or operate machinery.

Dosage and administration.

Primary prophylaxis of venous thromboembolism (hereinafter – VTE) in orthopedic surgery.

The recommended doses of dabigatran etexilate and duration of treatment for primary VTE prophylaxis in orthopedic surgery are presented in Table 8.

Table 8

Recommended doses and duration of treatment for primary VTE prophylaxis in orthopedic surgery

Patient groups	Treatment initiation on the day of surgery, 1–4 hours after completion of surgery	Maintenance dose starting from the first day after surgery	Duration of maintenance dose
Patients after elective knee replacement surgery	1 capsule (110 mg) of dabigatran etexilate	220 mg of dabigatran etexilate once daily: 2 capsules of 110 mg	10 days
Patients after elective hip replacement surgery			28–35 days
Recommended dose reduction
Patients with moderate renal impairment (creatinine clearance CrCL 30–50 mL/min)	1 capsule of 75 mg dabigatran etexilate	150 mg of dabigatran etexilate once daily: 2 capsules of 75 mg	10 days (knee replacement surgery) or 28–35 days (hip replacement surgery)
Patients receiving verapamil*, amiodarone, quinidine concomitantly
Patients aged 75 years and older

*For patients with moderate renal impairment who are also taking verapamil, see "Special patient populations."

For both surgical procedures: if hemostasis has not been achieved, treatment initiation should be delayed. If treatment has not started on the day of surgery, then treatment should be initiated with 2 capsules once daily.

Assessment of renal function before and during dabigatran etexilate therapy

For all patients, and particularly elderly patients (>75 years), as renal impairment may commonly occur in this age group:

• Before initiating dabigatran etexilate therapy, renal function should be assessed by calculating creatinine clearance to exclude patients with severe renal impairment (CrCL < 30 mL/min) (see sections "Contraindications," "Special precautions," and "Pharmacokinetics").
• Renal function should be assessed if there is suspicion of worsening renal function during therapy (e.g., in cases of hypovolemia, dehydration, or concomitant use of certain medicinal products).

The method used to assess renal function (CrCL in mL/min) is the Cockcroft-Gault formula.

Missed dose

It is recommended to continue taking the daily dose of dabigatran etexilate at the usual time on the following day.

A double dose should not be taken to compensate for a missed dose.

Discontinuation of dabigatran etexilate

Dabigatran etexilate treatment must not be discontinued without consulting a physician. Patients should be advised to contact their physician if gastrointestinal symptoms such as dyspepsia occur (see section "Adverse reactions").

Switching from dabigatran etexilate to parenteral anticoagulant therapy

Before switching from dabigatran etexilate to a parenteral anticoagulant, it is recommended to wait 24 hours after the last dose (see section "Interaction with other medicinal products and other forms of interaction").

Switching from parenteral anticoagulant therapy to dabigatran etexilate

Discontinue the parenteral anticoagulant and administer dabigatran etexilate 0–2 hours before the next scheduled dose of the alternative therapy or at the time of discontinuation if continued therapy is required (e.g., intravenous unfractionated heparin) (see section "Interaction with other medicinal products and other forms of interaction").

Special patient populations

Patients with renal impairment

Dabigatran etexilate therapy is contraindicated in patients with severe renal impairment (creatinine clearance < 30 mL/min) (see section "Contraindications").

A reduced dose is recommended for patients with moderate renal impairment (creatinine clearance 30–50 mL/min) (see Table 8 above and sections "Special precautions" and "Pharmacodynamics").

Concomitant use of dabigatran etexilate with P-glycoprotein inhibitors of mild to moderate intensity, such as amiodarone, quinidine, or verapamil

The dose of dabigatran etexilate should be reduced as specified in Table 8 (see also sections "Special precautions" and "Interaction with other medicinal products and other forms of interaction"). In this case, dabigatran etexilate and the mentioned medicinal products should be administered at the same time.

Patients with moderate renal impairment who are taking verapamil should have the dose of dabigatran etexilate reduced to 75 mg once daily (see sections "Special precautions" and "Interaction with medicinal products and other forms of interaction").

Elderly patients

A reduced dose is recommended for elderly patients (>75 years) (see Table 8 above and sections "Special precautions" and "Pharmacodynamics").

Body weight

Clinical experience with use in patients with body weight < 50 kg or > 110 kg at the recommended dosing regimen is limited. Based on available clinical and pharmacokinetic data, dose adjustment is not required (see section "Pharmacokinetics"); however, careful clinical monitoring is recommended (see section "Special precautions").

Sex

Dose adjustment is not required (see section "Pharmacokinetics").

Prevention of stroke and systemic embolism in adult patients with non-valvular atrial fibrillation and one or more risk factors (stroke prevention in NVAF).

Treatment of VTE and PE and prevention of recurrent VTE and PE in adults.

Table 9

Recommended doses for NVAF, VTE, and PE

Recommended dose
Prevention of stroke and systemic embolism in adult patients with non-valvular atrial fibrillation with one or more risk factors (prevention of SE)	The recommended dose of dabigatran etexilate is 300 mg: 1 capsule of 150 mg twice daily
Treatment of VTE and PE and prevention of recurrent VTE and PE in adults (VTE/PE)	The recommended dose of dabigatran etexilate is 300 mg: 1 capsule of 150 mg twice daily after 5 days of parenteral anticoagulant therapy
Recommended dose reduction
Patients aged 80 years and older	The daily dose of dabigatran etexilate is 220 mg: 1 capsule of 110 mg twice daily
Patients receiving verapamil concomitantly
Consider dose reduction
Patients aged 75–80 years	The daily dose of dabigatran etexilate (300 mg or 220 mg) should be determined based on individual assessment of thromboembolic risk and bleeding risk
Patients with moderate renal impairment (CrCL 30–50 mL/min)
Patients with gastritis, esophagitis, or gastroesophageal reflux
Other patients with increased risk of bleeding

In the case of VTE/PE, it is recommended to use 220 mg of dabigatran etexilate: one 110 mg capsule twice daily. This dosage is based on pharmacokinetic and pharmacodynamic analyses and has not been studied under clinical conditions. See the information provided below and sections "Special Warnings and Precautions for Use", "Interaction with Other Medicinal Products and Other Forms of Interaction", "Pharmacodynamics", and "Pharmacokinetics".

In case of hypersensitivity to dabigatran etexilate, patients should be instructed to consult their physician immediately regarding switching to an alternative appropriate therapy for stroke and systemic embolism prevention associated with atrial fibrillation, as well as for the treatment of VTE and PE.

Assessment of renal function before and during dabigatran etexilate treatment

In all patients, and particularly in elderly patients (> 75 years), since renal impairment may frequently occur in patients of this age group:

• Before initiating dabigatran etexilate therapy, renal function should be assessed by calculating creatinine clearance to exclude severe renal impairment (CrCL < 30 mL/min) (see sections "Contraindications", "Special Warnings and Precautions for Use", and "Pharmacokinetics").
• Renal function should be assessed if there is suspicion of worsening renal function during therapy (e.g., in cases of hypovolemia, dehydration, or concomitant use of certain medicinal products).

Additional requirements for patients with mild to moderate renal impairment and patients aged 75 years and older:

• During dabigatran etexilate therapy, renal function should be evaluated at least once a year, or more frequently as needed in certain clinical situations where a decline or worsening of renal function is expected (e.g., in cases of hypovolemia, dehydration, or concomitant use of certain medicinal products).

The method used to assess renal function (CrCL in mL/min) is the Cockcroft-Gault formula.

Table 10

Duration of treatment in NVAF, VTE, and PE

Indications	Treatment duration
VTE	The use of the drug should be long-term
VTE and PE	Treatment duration is determined individually after careful assessment of the benefits of treatment and the risk of bleeding (see section "Special precautions"). Short-term treatment (at least 3 months) should be based on transient risk factors (such as recent surgery, trauma, immobilization), while long-term treatment should be based on permanent risk factors or idiopathic VTE or PE.

Missed dose

A missed dose of dabigatran etexilate may be taken if less than 6 hours have passed before the scheduled time for the next dose. If less than 6 hours remain before the next dose, the missed dose should not be taken.

Do not take a double dose to compensate for a missed dose.

Discontinuation of dabigatran etexilate

Dabigatran etexilate treatment must not be discontinued without medical consultation. Patients should be advised that if gastrointestinal symptoms such as dyspepsia occur, they should contact their physician (see section "Adverse reactions***").

Switching from dabigatran etexilate to a parenteral anticoagulant

Before switching from dabigatran etexilate to a parenteral anticoagulant, it is recommended to wait 12 hours after the last dose (see section "Interaction with other medicinal products and other forms of interactions").

Switching from parenteral anticoagulants to dabigatran etexilate

After discontinuation of a parenteral anticoagulant, dabigatran etexilate should be initiated 0–2 hours before the expected time of the next dose of the parenteral anticoagulant or at the time of discontinuation in continuous therapy (e.g., intravenous unfractionated heparin) (see section "Interaction with other medicinal products and other forms of interactions").

Switching from dabigatran etexilate to vitamin K antagonists (VKAs)

Conditions for switching to VKAs based on CrCl (creatinine clearance):

• CrCl ≥ 50 mL/min: initiate VKA therapy 3 days before discontinuing dabigatran etexilate;
• CrCl ≥ 30 to <50 mL/min: initiate VKA therapy 2 days before discontinuing dabigatran etexilate.

Since dabigatran etexilate may increase the international normalized ratio (INR), the INR will reliably reflect the effect of VKA only 2 days after stopping dabigatran etexilate. Until then, the INR should be interpreted with caution.

Switching from vitamin K antagonists (VKAs) to dabigatran etexilate

Vitamin K antagonists should be discontinued. Dabigatran etexilate may be administered once the international normalized ratio (INR) is < 2.0.

Cardioversion (stroke prevention in AF)

Patients may continue dabigatran etexilate during cardioversion.

Catheter ablation for atrial fibrillation (stroke prevention in AF)

Data on the use of dabigatran etexilate 110 mg twice daily are lacking.

Percutaneous coronary intervention (PCI) with stenting (stroke prevention in AF)

Patients with non-valvular atrial fibrillation who have undergone PCI with stenting may be treated with dabigatran etexilate in combination with antiplatelet agents after hemostasis has been achieved (see section "Pharmacodynamics").

Special patient populations

Elderly patients

For dosage recommendations in this patient group, see Table 9 above.

Patients at risk of bleeding

Patients at increased risk of bleeding (see sections "Special warnings and precautions for use", "Interaction with other medicinal products and other forms of interactions", "Pharmacological properties") should be closely monitored clinically (for signs of bleeding or anemia). Individual dose adjustment may be considered at the physician’s discretion after evaluating the potential benefits and risks for each patient (see Table 9 above). A coagulation test (see section "Special warnings and precautions for use") may help identify patients at increased risk of bleeding due to excessive dabigatran exposure. If excessive dabigatran exposure is detected in patients at high risk of bleeding, a reduced dose of 220 mg (i.e., one 110 mg capsule twice daily) is recommended. In the event of clinically significant bleeding, treatment should be discontinued.

Patients with gastritis, esophagitis, or gastroesophageal reflux disease may be considered for dose reduction due to an increased risk of major gastrointestinal bleeding (see Table 9 above and section "Special warnings and precautions for use").

Renal impairment

Dabigatran etexilate is contraindicated in patients with severe renal impairment (creatinine clearance < 30 mL/min) (see section "Contraindications").

No dose adjustment is required in patients with mild renal impairment (creatinine clearance 50–≤ 80 mL/min). The recommended dose in patients with moderate renal impairment (creatinine clearance 30–50 mL/min) is 300 mg (i.e., one 150 mg capsule twice daily). However, in patients at high risk of bleeding, the dose of dabigatran etexilate may be reduced to 220 mg (i.e., one 110 mg capsule twice daily) (see sections "Special warnings and precautions for use" and "Pharmacokinetics"). Close clinical monitoring is recommended in patients with renal impairment.

Concomitant use of dabigatran etexilate with mild to moderate P-glycoprotein inhibitors, e.g., amiodarone, quinidine, or verapamil

Dose adjustment is not required when dabigatran etexilate is used concomitantly with amiodarone or quinidine (see sections "Special warnings and precautions for use", "Interaction with other medicinal products and other forms of interactions", "Pharmacokinetics").

Patients receiving verapamil concomitantly should have their dose reduced (see Table 9 above and sections "Special warnings and precautions for use" and "Interaction with other medicinal products and other forms of interactions"). In this case, dabigatran etexilate and verapamil should be administered at the same time.

Body weight

No dose adjustment is required (see section "Pharmacokinetics"), but close clinical monitoring is recommended for patients with body weight < 50 kg (see section "Special warnings and precautions for use").

Gender

No dose adjustment is required (see section "Pharmacokinetics").

Method of administration

This medicinal product is administered orally. The capsule may be taken independently of food. The capsule should be swallowed whole with a glass of water to facilitate passage into the stomach. Patients should be advised not to open the capsule, as this may increase the risk of bleeding (see section "Pharmacokinetics").

Paediatric population

There is no justification for the use of PRADAXA in children for the following indications:

• Primary prevention of venous thromboembolic events in patients who have undergone elective total hip or knee replacement surgery;
• Stroke and systemic embolism prevention in patients with non-valvular atrial fibrillation;
• Treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE).

Overdose

Doses of dabigatran etexilate exceeding the recommended dose lead to an increased risk of bleeding.

In case of suspected overdose, a coagulation test may help assess the risk of bleeding (see section "Special warnings and precautions for use" and subsection "Pharmacodynamics"). Calibrated quantitative aPTT or repeated aPTT measurements may help predict when dabigatran levels will reach certain thresholds (see subsection "Pharmacodynamics"). Dialysis may additionally be considered.

Excessive anticoagulant effect may require discontinuation of dabigatran etexilate treatment. Since dabigatran is primarily eliminated via the kidneys, adequate diuresis should be maintained. Due to low plasma protein binding, dabigatran may be removed by dialysis; however, clinical experience with dialysis is limited (see subsection "Pharmacokinetics").

Management of hemorrhagic complications

In the event of hemorrhagic complications, treatment should be discontinued and the source of bleeding identified. Appropriate supportive treatment should be considered as clinically indicated, such as surgical hemostasis or volume replacement, as determined by the physician.

In life-threatening or uncontrolled bleeding where rapid reversal of the anticoagulant effect of dabigatran is required, a specific reversal agent (idarucizumab) with antagonistic effect on the pharmacodynamic action of dabigatran may be administered (see section "Special warnings and precautions for use").

Administration of coagulation factor concentrates (activated or non-activated) or recombinant factor VIIa may be considered. There are some experimental data on the role of these agents in reversing the anticoagulant effect of dabigatran, but clinical evidence of benefit and the potential risk of thromboembolic events upon reversal are very limited. Coagulation tests may become unreliable after administration of the proposed coagulation factor concentrates. Caution should be exercised in interpreting these tests. Caution should also be exercised when administering platelet concentrates in cases of thrombocytopenia or when long-acting antiplatelet agents have been used. Symptomatic treatment should be administered as per physician’s recommendations.

Expert consultation in coagulation may be considered in cases of major bleeding (if such expertise is available).

Adverse reactions.

Summary of safety profile

The safety of dabigatran etexilate has been evaluated in clinical trials involving approximately 64,000 patients, of whom approximately 35,000 patients received treatment with dabigatran etexilate.

Overall, adverse reactions were observed in 9% of patients who underwent elective hip or knee replacement surgery (short-term treatment up to 42 days), in 22% of patients with atrial fibrillation treated for stroke and systemic embolism prevention (long-term treatment for more than 3 years), in 14% of patients treated for DVT/PE, and in 15% of patients treated for prevention of DVT and PE.

The most common adverse reaction was bleeding, observed in approximately 14% of patients receiving short-term treatment following elective hip or knee replacement surgery, in 16.6% of patients with atrial fibrillation receiving long-term treatment for stroke and systemic embolism prevention, and in 14.4% of patients treated for DVT/PE. Additionally, bleeding occurred in 19.4% of patients in the RE-MEDY study for prevention of DVT/PE and in 10.5% of patients in the RE-SONATE study for prevention of DVT/PE.

Since the patient groups treated for the three indications are not comparable and bleeding events are categorized by organ systems, a brief description of major and any bleeding is separated by indication and presented in Tables 12–15.

Although bleeding events were infrequent in clinical studies, they can be massive or severe and, regardless of site, may lead to loss of functional capacity, be life-threatening, or even result in fatal outcomes.

Table 11 lists adverse reactions identified during studies and from post-marketing data for the indications of primary prevention of venous thromboembolism following hip or knee replacement surgery, prevention of stroke and systemic embolism in patients with atrial fibrillation, and treatment and prevention of deep vein thrombosis and pulmonary embolism, by system organ class and frequency. Frequency is defined as: very common (≥1/10),

Common (≥1/100 to <1/10), uncommon (≥1/1000 to <1/100), rare (≥1/10000 to <1/1000), very rare (<1/10000), not known (cannot be estimated from available data). Table 11
Adverse reactions
	Indication / Frequency
System organ class / Adverse reaction	Primary VTE prevention after hip or knee replacement surgery	Prevention of stroke and systemic embolism in patients with atrial fibrillation	Treatment and prevention of deep vein thrombosis/pulmonary embolism
Blood and lymphatic system disorders
anaemia	uncommon	common	uncommon
decreased hemoglobin level	common	uncommon	not known
thrombocytopenia	rare	uncommon	rare
decreased hematocrit	uncommon	rare	not known
neutropenia	not known	not known	not known
agranulocytosis	not known	not known	not known
Immune system disorders
drug hypersensitivity	uncommon	uncommon	uncommon
rash	rare	uncommon	uncommon
pruritus	rare	uncommon	uncommon
anaphylactic reactions	rare	rare	rare
angioedema	rare	rare	rare
urticaria	rare	rare	rare
bronchospasm	not known	not known	not known
Nervous system disorders
intracranial hemorrhage	rare	uncommon	rare
Vascular disorders
hematoma	uncommon	uncommon	uncommon
bleeding	rare	uncommon	uncommon
incision site bleeding	uncommon	-
Respiratory, thoracic and mediastinal disorders
epistaxis	uncommon	common	common
hemoptysis	rare	uncommon	uncommon
Gastrointestinal disorders
gastrointestinal hemorrhage	uncommon	common	common
abdominal pain	rare	common	uncommon
diarrhea	uncommon	common	uncommon
dyspepsia	rare	common	common
nausea	uncommon	common	uncommon
rectal hemorrhage	uncommon	uncommon	common
hemorrhoidal hemorrhage	uncommon	uncommon	uncommon
gastrointestinal ulcer, including esophageal ulcer	rare	uncommon	uncommon
gastroesophagitis	rare	uncommon	uncommon
gastroesophageal reflux disease	rare	uncommon	uncommon
vomiting	uncommon	uncommon	uncommon
dysphagia	rare	uncommon	rare
Hepatobiliary disorders
liver function test abnormal/ hepatic function abnormal	common	uncommon	uncommon
elevation of alanine aminotransferase	uncommon	uncommon	uncommon
elevation of aspartate aminotransferase	uncommon	uncommon	uncommon
elevation of liver enzymes	uncommon	rare	uncommon
hyperbilirubinemia	uncommon	rare	not known
Skin and subcutaneous tissue disorders
skin hemorrhage	uncommon	common	common
alopecia	not known	not known	not known
Musculoskeletal and connective tissue disorders
hemarthrosis	uncommon	rare	uncommon
Renal and urinary disorders
urogenital hemorrhage, including hematuria	uncommon	common	common
General disorders and administration site conditions
injection site hemorrhage	rare	rare	rare
catheter site hemorrhage	rare	rare	rare
blood-stained discharge	rare	-
Injury, poisoning and procedural complications
traumatic hemorrhage	uncommon	rare	uncommon
surgical incision site hemorrhage	rare	rare	rare
postprocedural hematoma	uncommon	-	-
postprocedural hemorrhage	uncommon	-
postoperative anemia	rare	-	-
postprocedural discharge	uncommon	-	-
wound discharge	uncommon	-	-
Surgical and medical procedures
wound drainage	rare	-	-
postprocedural drainage	rare	-	-

Description of selected adverse reactions

Bleeding

Due to its pharmacological mechanism of action, the use of dabigatran etexilate may be associated with an increased risk of occult or overt bleeding, which may occur in any tissues or organs. The symptoms and severity (including fatal outcomes) depend on the location and extent or spread of bleeding and/or anemia. During clinical trials, mucosal bleeding (e.g., gastrointestinal, genitourinary) was observed more frequently with long-term treatment with dabigatran etexilate compared to treatment with VKAs (vitamin K antagonists). Therefore, in addition to adequate clinical monitoring, laboratory tests for hemoglobin/hematocrit levels are important for detecting occult bleeding. The risk of bleeding may increase in certain patient groups, such as patients with moderate renal impairment and/or patients receiving concomitant therapy affecting hemostasis or strong P-gp inhibitors (see section "Special precautions for use": Risk of bleeding). Hemorrhagic complications may present as weakness, pallor, dizziness, headache, unexplained swelling, dyspnea, or unexplained shock.

Serious bleeding complications, such as compartment syndrome, acute kidney injury due to hypoperfusion, and anticoagulant-related nephropathy, have been reported in patients with predisposing risk factors during treatment with dabigatran etexilate. Therefore, the possibility of bleeding should always be considered when evaluating any patient receiving anticoagulant therapy. A specific reversal agent for dabigatran—idarucizumab—is available and can be used in cases of uncontrolled bleeding (see section "Overdose").

Primary prevention of VTE in orthopedic surgery.

Table 12 presents data on the number (%) of patients who experienced bleeding as an adverse reaction during treatment for the indication of primary prevention of venous thromboembolic events in two pivotal clinical trials, specifying the tested doses.

Table 12

Number (%) of patients who experienced bleeding as an adverse reaction

Parameter	Dabigatran etexilate 150 mg once daily N (%)	Dabigatran etexilate 220 mg once daily N (%)	Enoxaparin N (%)
Number of patients	1866 (100.0)	1825 (100.0)	1848 (100.0)
Major bleeding	24 (1.3)	33 (1.8)	27 (1.5)
Any bleeding	258 (13.8)	251 (13.8)	247 (13.4)

Prevention of stroke and systemic embolism in adult patients with atrial fibrillation who have one or more risk factors.

Table 13 presents data on bleeding events, ranging from major to any bleeding, observed during the main study on stroke and systemic embolism prevention in patients with atrial fibrillation.

Table 13

Bleeding events in studies on stroke and systemic embolism prevention in patients with atrial fibrillation

Parameter	Dabigatran etexilate 110 mg twice daily	Dabigatran etexilate 150 mg twice daily	Warfarin
Number of randomized patients	6015	6076	6022
Major bleeding	347 (2.92%)	409 (3.40%)	426 (3.61%)
Intracranial hemorrhage	27 (0.23%)	39 (0.32%)	91 (0.77%)
Gastrointestinal bleeding	134 (1.13%)	192 (1.60%)	128 (1.09%)
Fatal bleeding	26 (0.22%)	30 (0.25%)	42 (0.36%)
Minor bleeding	1566 (13.16%)	1787 (14.85%)	1931 (16.37%)
Any bleeding	1759 (14.78%)	1997 (16.60%)	2169 (18.39%)

In patients randomized to receive dabigatran etexilate at a dose of 110 mg twice daily or 150 mg twice daily, a significantly lower risk of life-threatening bleeding and intracranial hemorrhage was observed compared to patients receiving warfarin [p < 0.05]. Both doses of dabigatran etexilate were also associated with a statistically significantly lower overall incidence of bleeding. In patients randomized to the 110 mg twice-daily dose of dabigatran etexilate, a significantly lower risk of major bleeding was observed compared to those receiving warfarin (risk ratio 0.81 [p = 0.0027]). In patients randomized to the 150 mg twice-daily dose of dabigatran etexilate, a significantly higher risk of major gastrointestinal bleeding was observed compared to those receiving warfarin (risk ratio 1.48 [p = 0.0005]). This effect was predominantly observed in patients aged ≥75 years.

The clinical advantages of dabigatran etexilate in terms of stroke and systemic embolism prevention, as well as reduced risk of intracranial bleeding compared to warfarin, were observed across individual subgroups, including those defined by renal impairment, age, and concomitant use of other medicinal products such as antiplatelet agents or P-gp inhibitors. While certain patient subgroups have an increased risk of major bleeding when using anticoagulants, the excess bleeding risk with dabigatran may be attributable to gastrointestinal bleeding, which may occur within the first 3–6 months after initiation of dabigatran etexilate therapy.

Treatment of DVT and PE and prevention of recurrent DVT and PE in adults (treatment of DVT/PE).

Table 14 presents data on bleeding events observed during the combined main RE-COVER and RE-COVER II studies evaluating treatment of DVT/PE. In the combined studies, the primary safety endpoints of major bleeding, major or clinically relevant non-major bleeding, and any bleeding were significantly lower compared to warfarin at the nominal alpha level of 5%.

Table 14

Bleeding events in the RE-COVER and RE-COVER II studies, which were designed to treat DVT and PE

Parameter	Dabigatran etexilate 150 mg twice daily	Warfarin	Risk ratio compared to warfarin (95 % confidence interval)
Number of patients included in the safety analysis	2456	2462
Major bleeding	24 (1.0 %)	40 (1.6 %)	0.60 (0.36; 0.99)
Intracranial hemorrhage	2 (0.1 %)	4 (0.2 %)	0.50 (0.09; 2.74)
Major gastrointestinal bleeding	10 (0.4 %)	12 (0.5 %)	0.83 (0.36; 1.93)
Bleeding, life-threatening	4 (0.2 %)	6 (0.2 %)	0.66 (0.19; 2.36)
Major bleeding / clinically relevant bleeding	109 (4.4 %)	189 (7.7 %)	0.56 (0.45; 0.71)
Any bleeding	354 (14.4 %)	503 (20.4 %)	0.67 (0.59; 0.77)
Any gastrointestinal bleeding	70 (2.9 %)	55 (2.2 %)	1.27 (0.90; 1.82)

Bleeding events for both treatment methods were assessed after the first administration of dabigatran etexilate or warfarin following the end of parenteral therapy (oral treatment period only). The presented data include all bleeding events observed during dabigatran etexilate administration. For warfarin, all bleeding events were included except those observed during the transition period from parenteral therapy to warfarin.

Table 15 presents data on bleeding events observed during the main RE-MEDY study on prevention of VTE/PE. Some bleeding events (major/clinically relevant; any) at the nominal significance level of 5% were significantly lower in patients receiving dabigatran etexilate compared to those receiving warfarin.

Table 15

Bleeding events in the RE-MEDY study aimed at prevention of VTE and PE

Parameter	Dabigatran etexilate 150 mg twice daily	Warfarin	Risk ratio compared to warfarin (95 % confidence interval)
Number of patients included in the safety analysis	1430	1426
Major bleeding	13 (0.9 %)	25 (1.8 %)	0.54 (0.25; 1.16)
Intracranial hemorrhage	2 (0.1 %)	4 (0.3 %)	Cannot be calculated*
Major gastrointestinal bleeding	4 (0.3 %)	8 (0.5 %)	Cannot be calculated*
Bleeding, life-threatening	1 (0.1 %)	3 (0.2 %)	Cannot be calculated*
Major bleeding / clinically significant bleeding	80 (5.6 %)	145 (10.2 %)	0.55 (0.41; 0.72)
Any bleeding	278 (19.4 %)	373 (26.2 %)	0.71 (0.61; 0.83)
Any gastrointestinal bleeding	45 (3.1 %)	32 (2.2 %)	1.39 (0.87; 2.20)

* Risk ratio was not estimated because no events occurred in either patient group.

Table 16 presents data on bleeding events observed during the main RE-SONATE study on prevention of VTE/PE. The combined rate of major bleeding and clinically relevant bleeding, as well as the rate of any bleeding at the nominal alpha level of 5%, were significantly lower in patients receiving placebo compared to those receiving dabigatran etexilate.

Table 16

Bleeding events in the RE-SONATE study, which was designed to prevent VTE and PE

Parameter	Dabigatran etexilate 150 mg twice daily	Placebo	Relative risk compared to placebo (95% confidence interval)
Number of patients included in the safety analysis	684	659
Major bleeding	2 (0.3%)	0	Cannot be calculated*
Intracranial hemorrhage	0	0	Cannot be calculated*
Major gastrointestinal bleeding	2 (0.3%)	0	Cannot be calculated*
Bleeding, life-threatening	0	0	Cannot be calculated*
Major bleeding / clinically significant bleeding	36 (5.3%)	13 (2.0%)	2.69 (1.43; 5.07)
Any bleeding	72 (10.5%)	40 (6.1%)	1.77 (1.20; 2.61)
Any gastrointestinal bleeding	5 (0.7%)	2 (0.3%)	2.38 (0.46; 12.27)

* Risk ratio was not calculated because no cases were observed in either patient group.

Agranulocytosis and neutropenia

Agranulocytosis and neutropenia have been reported very rarely during treatment with dabigatran etexilate. As these adverse reactions were reported during post-marketing surveillance in a population of unknown size, the exact frequency cannot be reliably determined. The reporting rate was estimated at 7 events per 1 million patient-years for agranulocytosis and 5 events per 1 million patient-years for neutropenia.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorization of the medicinal product is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals and patients, as well as their legal representatives, should report all suspected adverse reactions and lack of efficacy via the automated pharmacovigilance information system at the following link: https://aisf.dec.gov.ua

Shelf life.

3 years.

Storage conditions.

Store in the original packaging to protect from moisture at a temperature not exceeding 25 °C. Keep out of reach and sight of children!

Packaging.

10 capsules in a blister; 6 blisters in a cardboard box.

Prescription status.

Prescription only.

Manufacturer.

Boehringer Ingelheim Pharma GmbH & Co. KG, Germany.

Manufacturer's address.

Binger Strasse 173, 55216 Ingelheim am Rhein, Germany.