Pradaxa百達生

Pradaxa

dabigatran

Manufacturer:

Boehringer Ingelheim

Distributor:

Zuellig
/
Agencia Lei Va Hong
Full Prescribing Info
Contents
Dabigatran etexilate.
Description
Each hard capsule contains 75 mg, 110 mg or 150 mg of dabigatran etexilate (as mesilate).
Excipients/Inactive Ingredients: Capsule content: Tartaric acid, Acacia, Hypromellose, Dimeticone, Talc, Hydroxypropylcellulose.
Capsule shell: Carrageenan, Potassium Chloride, Titanium Dioxide, Indigo Carmine, Hypromellose, Purified water.
Black printing ink: Shellac, Iron Oxide Black, Potassium Hydroxide.
Action
Pharmacotherapeutic group: antithrombotic agents, direct thrombin inhibitors. ATC code: B01AE07.
Pharmacology: Pharmacodynamics: Mechanism of action: Dabigatran etexilate is a small molecule prodrug which does not exhibit any pharmacological activity. After oral administration, dabigatran etexilate is rapidly absorbed and converted to dabigatran by esterase-catalysed hydrolysis in plasma and in the liver. Dabigatran is a potent, competitive, reversible direct thrombin inhibitor and is the main active principle in plasma.
Since thrombin (serine protease) enables the conversion of fibrinogen into fibrin during the coagulation cascade, its inhibition prevents the development of thrombus. Dabigatran inhibits free thrombin, fibrin-bound thrombin and thrombin-induced platelet aggregation.
Pharmacodynamic effects: In vivo and ex vivo animal studies have demonstrated antithrombotic efficacy and anticoagulant activity of dabigatran after intravenous administration and of dabigatran etexilate after oral administration in various animal models of thrombosis.
There is a clear correlation between plasma dabigatran concentration and degree of anticoagulant effect based on phase II studies. Dabigatran prolongs the thrombin time (TT), ECT, and aPTT.
The calibrated quantitative diluted TT (dTT) test provides an estimation of dabigatran plasma concentration that can be compared to the expected dabigatran plasma concentrations. When the calibrated dTT assay delivers a dabigatran plasma concentration result at or below the limit of quantification, an additional coagulation assay such as TT, ECT or aPTT should be considered.
The ECT can provide a direct measure of the activity of direct thrombin inhibitors.
The aPTT test is widely available and provides an approximate indication of the anticoagulation intensity achieved with dabigatran. However, the aPTT test has limited sensitivity and is not suitable for precise quantification of anticoagulant effect, especially at high plasma concentrations of dabigatran. Although high aPTT values should be interpreted with caution, a high aPTT value indicates that the patient is anticoagulated.
In general, it can be assumed that these measures of anti-coagulant activity may reflect dabigatran levels and can provide guidance for the assessment of bleeding risk, i.e. exceeding the 90th percentile of dabigatran trough levels or a coagulation assay such as aPTT measured at trough (for aPTT thresholds see Precautions, Table 17) is considered to be associated with an increased risk of bleeding.
Primary Prevention of Venous Thromboembolism in Orthopaedic Surgery: Steady state (after day 3) geometric mean dabigatran peak plasma concentration, measured around 2 hours after 220 mg dabigatran etexilate administration, was 70.8 ng/mL, with a range of 35.2-162 ng/mL (25th-75th percentile range). The dabigatran geometric mean trough concentration, measured at the end of the dosing interval (i.e. 24 hours after a 220 mg dabigatran dose), was on average 22.0 ng/mL, with a range of 13.0-35.7 ng/mL (25th-75th percentile range).
In a dedicated study exclusively in patients with moderate renal impairment (creatinine clearance, CrCL 30-50 mL/min) treated with dabigatran etexilate 150 mg QD, the dabigatran geometric mean trough concentration, measured at the end of the dosing interval, was on average 47.5 ng/mL, with a range of 29.6 - 72.2 ng/mL (25th-75th percentile range).
In patients treated for prevention of VTEs after hip or knee replacement surgery with 220 mg dabigatran etexilate once daily: the 90th percentile of dabigatran plasma concentrations was 67 ng/mL, measured at trough (20-28 hours after the previous dose) (see Precautions and Overdosage); the 90th percentile of aPTT at trough (20-28 hours after the previous dose) was 51 seconds, which would be 1.3-fold upper limit of normal.
The ECT was not measured in patients treated for prevention of VTEs after hip or knee replacement surgery with 220 mg dabigatran etexilate once daily.
Prevention of stroke and systemic embolism in adult patients with NVAF with one or more risk factors (SPAF): Steady state geometric mean dabigatran peak plasma concentration, measured around 2 hours after 150 mg dabigatran etexilate administration twice daily, was 175 ng/mL, with a range of 117-275 ng/mL (25th-75th percentile range). The dabigatran geometric mean trough concentration, measured at trough in the morning, at the end of the dosing interval (i.e. 12 hours after the 150 mg dabigatran evening dose), was on average 91.0 ng/mL, with a range of 61.0-143 ng/mL (25th-75th percentile range).
For patients with NVAF treated for prevention of stroke and systemic embolism with 150 mg dabigatran etexilate twice daily: the 90th percentile of dabigatran plasma concentrations measured at trough (10-16 hours after the previous dose) was about 200 ng/mL; an ECT at trough (10-16 hours after the previous dose), elevated approximately 3-fold upper limit of normal refers to the observed 90th percentile of ECT prolongation of 103 seconds; an aPTT ratio greater than 2-fold upper limit of normal (aPTT prolongation of about 80 seconds), at trough (10-16 hours after the previous dose) reflects the 90th percentile of observations.
Treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE), and prevention of recurrent DVT and PE in adults (DVT/PE): In patients treated for DVT and PE with 150 mg dabigatran etexilate twice daily, the dabigatran geometric mean trough concentration, measured within 10-16 hours after dose, at the end of the dosing interval (i.e. 12 hours after the 150 mg dabigatran evening dose), was 59.7 ng/mL, with a range of 38.6 - 94.5 ng/mL (25th-75th percentile range). For treatment of DVT and PE, with dabigatran etexilate 150 mg twice daily: the 90th percentile of dabigatran plasma concentrations measured at trough (10-16 hours after the previous dose) was about 146 ng/mL; an ECT at trough (10-16 hours after the previous dose), elevated approximately 2.3-fold compared to baseline refers to the observed 90th percentile of ECT prolongation of 74 seconds; the 90th percentile of aPTT at trough (10-16 hours after the previous dose) was 62 seconds, which would be 1.8-fold compared to baseline.
In patients treated for prevention of recurrent of DVT and PE with 150 mg dabigatran etexilate twice daily no pharmacokinetic data are available.
Clinical efficacy and safety: Ethnic origin: No clinically relevant ethnic differences among Caucasians, African-American, Hispanic, Japanese or Chinese patients were observed.
Clinical trials in Venous Thromboembolism (VTE) prophylaxis following major joint replacement surgery: In 2 large randomized, parallel group, double-blind, dose-confirmatory trials, patients undergoing elective major orthopaedic surgery (one for knee replacement surgery and one for hip replacement surgery) received Pradaxa 75 mg or 110 mg within 1-4 hours of surgery followed by 150 mg or 220 mg once daily thereafter, haemostasis having been secured, or enoxaparin 40 mg on the day prior to surgery and daily thereafter.
In the RE-MODEL trial (knee replacement) treatment was for 6-10 days and in the RE-NOVATE trial (hip replacement) for 28-35 days. Totals of 2,076 patients (knee) and 3,494 (hip) were treated respectively.
Composite of total VTE (including PE, proximal and distal DVT, whatever symptomatic or asymptomatic detected by routine venography) and all-cause mortality constituted the primary end-point for both studies. Composite of major VTE (including PE and proximal DVT, whatever symptomatic or asymptomatic detected by routine venography) and VTE-related mortality constituted a secondary end-point and is considered of better clinical relevance.
Results of both studies showed that the antithrombotic effect of Pradaxa 220 mg and 150 mg were statistically non-inferior to that of enoxaparin on total VTE and all-cause mortality. The point estimate for incidence of Major VTE and VTE related mortality for the 150 mg dose was slightly worse than enoxaparin (Table 1). Better results were seen with the 220 mg dose where the point estimate of Major VTE was slightly better than enoxaparin (Table 1).
The clinical studies have been conducted in a patient population with a mean age > 65 years.
There were no differences in the phase 3 clinical studies for efficacy and safety data between men and women.
In the studied patient population of RE-MODEL and RE-NOVATE (5,539 patients treated), 51 % suffered from concomitant hypertension, 9 % from concomitant diabetes, 9 % from concomitant coronary artery disease and 20 % had a history of venous insufficiency. None of these diseases showed an impact on the effects of dabigatran on VTE-prevention or bleeding rates.
Data for the major VTE and VTE-related mortality endpoint were homogeneous with regards to the primary efficacy endpoint and are shown in Table 1. (See Table 1.)

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Data for the total VTE and all cause mortality endpoint are shown in Table 2. (See Table 2.)

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Data for adjudicated major bleeding endpoints are shown in Table 3 as follows. (See Table 3.)

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Prevention of stroke and systemic embolism in adult patients with NVAF with one or more risk factors: The clinical evidence for the efficacy of dabigatran etexilate is derived from the RE-LY study (Randomized Evaluation of Long-term anticoagulant therapy) a multi-centre, multi-national, randomized parallel group study of two blinded doses of dabigatran etexilate (110 mg and 150 mg twice daily) compared to open-label warfarin in patients with atrial fibrillation at moderate to high risk of stroke and systemic embolism. The primary objective in this study was to determine if dabigatran etexilate was non-inferior to warfarin in reducing the occurrence of the composite endpoint stroke and systemic embolism. Statistical superiority was also analysed.
In the RE-LY study, a total of 18,113 patients were randomized, with a mean age of 71.5 years and a mean CHADS2 score of 2.1. The patient population was 64 % male, 70 % Caucasian and 16 % Asian. For patients randomized to warfarin, the mean percentage of time in therapeutic range (TTR) (INR 2-3) was 64.4 % (median TTR 67 %).
The RE-LY study demonstrated that dabigatran etexilate, at a dose of 110 mg twice daily, is non-inferior to warfarin in the prevention of stroke and systemic embolism in subjects with atrial fibrillation, with a reduced risk of ICH, total bleeding and major bleeding. The dose of 150 mg twice daily reduces significantly the risk of ischemic and haemorrhagic stroke, vascular death, ICH and total bleeding compared to warfarin. Major bleeding rates with this dose were comparable to warfarin. Myocardial infarction rates were slightly increased with dabigatran etexilate 110 mg twice daily and 150 mg twice daily compared to warfarin (hazard ratio 1.29; p=0.0929 and hazard ratio 1.27; p=0.1240, respectively). With improving monitoring of INR the observed benefits of dabigatran etexilate compared to warfarin diminish.
Tables 4-6 display details of key results in the overall population: See Tables 4, 5 and 6.

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Tables 7-9 display results of the primary efficacy and safety endpoint in relevant sub-populations: For the primary endpoint, stroke and systemic embolism, no subgroups (i.e., age, weight, gender, renal function, ethnicity, etc.) were identified with a different risk ratio compared to warfarin. (See Table 7.)

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For the primary safety endpoint of major bleeding there was an interaction of treatment effect and age. The relative risk of bleeding with dabigatran compared to warfarin increased with age. Relative risk was highest in patients ≥ 75 years. The concomitant use of antiplatelets ASA or clopidogrel approximately doubles MBE rates with both dabigatran etexilate and warfarin. There was no significant interaction of treatment effects with the subgroups of renal function and CHADS2 score. (See Table 8.)

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RELY-ABLE (Long term multi-center extension of dabigatran treatment in patients with atrial fibrillation who completed the RE-LY trial): The RE-LY extension study (RELY-ABLE) provided additional safety information for a cohort of patients which continued the same dose of dabigatran etexilate as assigned in the RE-LY trial. Patients were eligible for the RELY-ABLE trial if they had not permanently discontinued study medication at the time of their final RE-LY study visit. Enrolled patients continued to receive the same double-blind dabigatran etexilate dose randomly allocated in RE-LY, for up to 43 months of follow up after RE-LY (total mean follow-up RE-LY + RELY-ABLE, 4.5 years). There were 5897 patients enrolled, representing 49 % of patients originally randomly assigned to receive dabigatran etexilate in RE-LY and 86 % of RELY-ABLE-eligible patients.
During the additional 2.5 years of treatment in RELY-ABLE, with a maximum exposure of over 6 years (total exposure in RELY + RELY-ABLE), the long-term safety profile of dabigatran etexilate was confirmed for both test doses 110 mg b.i.d. and 150 mg b.i.d.. No new safety findings were observed.
The rates of outcome events including, major bleed and other bleeding events were consistent with those seen in RE-LY.
Data from non-interventional studies: A non-interventional study (GLORIA-AF) prospectively collected (in its second phase) safety and effectiveness data in newly diagnosed NVAF patients on dabigatran etexilate in a real-world setting. The study included 4,859 patients on dabigatran etexilate (55% treated with 150 mg bid, 43% treated with 110 mg bid, 2% treated with 75 mg bid). Patients were followed-up for 2 years. The mean CHADS2 and HAS-BLED scores were 1.9 and 1.2, respectively. Mean on-therapy follow-up time was 18.3 months. Major bleeding occurred in 0.97 per 100 patient-years. Life-threatening bleeding was reported in 0.46 per 100 patient-years, intracranial haemorrhage in 0.17 per 100 patient-years and gastrointestinal bleeding in 0.60 per 100 patient-years. Stroke occurred in 0.65 per 100 patient-years.
In addition, in a non-interventional study [Graham DJ et al., Circulation. 2015;131:157-164] in more than 134,000 elderly patients with NVAF in the United States (contributing more than 37,500 patient-years of on-therapy follow-up time) dabigatran etexilate (84 % patients treated with 150 mg bid, 16 % patients treated with 75 mg bid) was associated with a reduced risk of ischemic stroke (hazard ratio 0.80, 95 % confidence interval [CI] 0.67 - 0.96), intracranial haemorrhage (hazard ratio 0.34, CI 0.26 - 0.46), and mortality (hazard ratio 0.86, CI 0.77 - 0.96) and increased risk of gastrointestinal bleeding (hazard ratio 1.28, CI 1.14 - 1.44) compared to warfarin. No difference was found for major bleeding (hazard ratio 0.97, CI 0.88 - 1.07).
These observations in real-world settings are consistent with the established safety and efficacy profile for dabigatran etexilate in the RE-LY study in this indication.
Patients undergoing catheter ablation for atrial fibrillation: A prospective, randomized, open-label, multicenter, exploratory study with blinded, centrally adjudicated endpoint evaluation (RE-CIRCUIT) was conducted in 704 patients who were under stable anticoagulant treatment. The study compared 150 mg twice daily uninterrupted dabigatran etexilate with uninterrupted INR-adjusted warfarin in catheter ablation of paroxysmal or persistent atrial fibrillation. Of the 704 enrolled patients, 317 underwent atrial fibrillation ablation on uninterrupted dabigatran and 318 underwent atrial fibrillation ablation on uninterrupted warfarin. All patients underwent a Trans-oesophageal Echocardiography (TEE) prior to catheter ablation. The primary outcome (adjudicated major bleeding according to ISTH criteria) occurred in 5 (1.6 %) patients in the dabigatran etexilate group and 22 (6.9 %) patients in the warfarin group (risk difference -5.3%; 95% CI -8.4, -2.2; P=0.0009). There was no stroke/systemic embolism/TIA (composite) event in the dabigatran etexilate arm, and one event (TIA) in the warfarin arm from the time of ablation and until 8 weeks post-ablation. This exploratory study showed that dabigatran etexilate was associated with a significant reduction in MBE rate compared with INR-adjusted warfarin in the setting of ablation.
Patients who underwent Percutaneous coronary intervention (PCI) with stenting: A prospective, randomized, open-label, blinded endpoint (PROBE) study (Phase IIIb) to evaluate dual-therapy with dabigatran etexilate (110 mg or 150 mg bid) plus clopidogrel or ticagrelor (P2Y12 antagonist) vs. triple-therapy with warfarin (adjusted to a INR 2.0 - 3.0) plus clopidogrel or ticagrelor and aspirin was conducted in 2725 patients with non valvular atrial fibrillation who underwent a PCI with stenting (RE-DUAL PCI). Patients were randomized to dabigatran etexilate 110 mg bid dual-therapy, dabigatran etexilate 150 mg bid dual-therapy or warfarin triple-therapy. Elderly patients outside of the United States (≥80 years of age for all countries, ≥70 years of age for Japan) were randomly assigned to the dabigatran etexilate 110 mg dual-therapy group or the warfarin triple-therapy group. The primary endpoint was a combined endpoint of major bleeds based on ISTH definition or clinically relevant non-major bleeding event.
The incidence of the primary endpoint was 15.4 % (151 patients) in the dabigatran etexilate 110 mg dual-therapy group as compared with 26.9 % (264 patients) in the warfarin triple-therapy group (HR 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 dabigatran etexilate 150 mg dual-therapy group as compared with 25.7 % (196 patients) in the corresponding warfarin triple-therapy group (HR 0.72; 95% CI 0.58, 0.88; P<0.0001 for non-inferiority and P=0.002 for superiority). As part of the descriptive analysis, TIMI (Thrombolysis In Myocardial Infarction) major bleeding events was lower in both dabigatran etexilate dual-therapy groups than in the warfarin triple-therapy group: 14 events (1.4%) in the dabigatran etexilate 110 mg dual-therapy group as compared with 37 events (3.8%) in the warfarin triple-therapy group (HR 0.37; 95% CI 0.20, 0.68; P=0.002) and 16 events (2.1%) in the dabigatran etexilate 150 mg dual-therapy group as compared with 30 events (3.9%) in the corresponding warfarin triple-therapy group (HR 0.51; 95% CI 0.28, 0.93; P=0.03). Both dabigatran etexilate dual-therapy groups had lower rates of intracranial hemorrhage than the corresponding warfarin triple-therapy group: 3 events (0.3%) in the 110 mg dabigatran etexilate dual-therapy group as compared with 10 events (1.0%) in the warfarin triple-therapy group (HR 0.30; 95% CI 0.08, 1.07; P=0.06) and 1 event (0.1%) in the 150 mg dabigatran etexilate dual-therapy group as compared with 8 events (1.0%) in the corresponding warfarin triple-therapy group (HR 0.12; 95% CI 0.02, 0.98; P=0.047). The incidence of the composite efficacy endpoint of death, thromboembolic events (myocardial infarction, stroke, or systemic embolism) or unplanned revascularization in the two dabigatran etexilate dual-therapy groups combined was non-inferior to the warfarin triple-therapy group (13.7% vs. 13.4% respectively; HR 1.04; 95% CI: 0.84, 1.29; P=0.0047 for non-inferiority). There were no statistical differences in the individual components of the efficacy endpoints between either dabigatran etexilate dual-therapy groups and warfarin triple-therapy.
This study demonstrated that dual-therapy, with dabigatran etexilate and a P2Y12 antagonist, significantly reduced the risk of bleeding vs. warfarin triple-therapy, with non-inferiority for composite of thromboembolic events, in patients with atrial fibrillation who underwent a PCI with stenting.
Treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE) in adults (DVT/PE treatment): The efficacy and safety was investigated in two multi-center, randomised, double blind, parallel-group, replicate studies RE-COVER and RE-COVER II. These studies compared dabigatran etexilate (150 mg bid) with warfarin (target INR 2.0-3.0) in patients with acute DVT and/or PE. The primary objective of these studies was to determine if dabigatran etexilate was non-inferior to warfarin in reducing the occurrence of the primary endpoint which was the composite of recurrent symptomatic DVT and/or PE and related deaths within the 6 month treatment period.
In the pooled RE-COVER and RE-COVER II studies, a total of 5,153 patients were randomised and 5,107 were treated.
The duration of treatment with fixed dose of dabigatran was 174.0 days without coagulation monitoring. For patients randomized to warfarin, the median time in therapeutic range (INR 2.0 to 3.0) was 60.6 %.
The trials, demonstrated that treatment with dabigatran etexilate 150 mg twice daily was non-inferior to the treatment with warfarin (non-inferiority margin for RE-COVER, and RE-COVER II: 3.6 for risk difference and 2.75 for hazard ratio). (See Table 9.)

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Prevention of recurrent deep vein thrombosis (DVT) and pulmonary embolism (PE) in adults (DVT/PE prevention): Two randomized, parallel group, double-blind studies were performed in patients previously treated with anticoagulation therapy. RE-MEDY, warfarin controlled study, enrolled patients already treated for 3 to 12 months with the need for further anticoagulant treatment and RE-SONATE, the placebo controlled study, enrolled patients already treated for 6 to 18 months with Vitamin K inhibitors.
The objective of the RE-MEDY study was to compare the safety and efficacy of oral dabigatran etexilate (150 mg bid) to warfarin (target INR 2.0-3.0) for the long-term treatment and prevention of recurrent, symptomatic DVT and/or PE. A total of 2,866 patients were randomized and 2,856 patients were treated. Duration of dabigatran etexilate treatment ranged from 6 to 36 months (median 534.0 days). For patients randomized to warfarin, the median time in therapeutic range (INR 2.0-3.0) was 64.9 %.
RE-MEDY demonstrated that treatment with dabigatran etexilate 150 mg twice daily was non-inferior to warfarin (non-inferiority margin: 2.85 for hazard ratio and 2.8 for risk difference). (See Table 10.)

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The objective of the RE-SONATE study was to evaluate superiority of dabigatran etexilate versus placebo for the prevention of recurrent symptomatic DVT and/or PE in patients who had already completed 6 to 18 months of treatment with VKA. The intended therapy was 6 months dabigatran etexilate 150 mg twice daily without need for monitoring.
RE-SONATE demonstrated dabigatran etexilate was superior to placebo for the prevention of recurrent symptomatic DVT/PE events including unexplained deaths, with a risk reduction from 5.6 % to 0.4 % (relative risk reduction 92 % based on hazard ratio) during the treatment period (p<0.0001). All secondary and sensitivity analyses of the primary endpoint and all secondary endpoints showed superiority of dabigatran etexilate over placebo.
The study included observational follow-up for 12 months after the conclusion of treatment. After discontinuation of study medication the effect was maintained until the end of the follow-up, indicating that the initial treatment effect of dabigatran etexilate was sustained. No rebound effect was observed. At the end of the follow-up VTE events in patients treated with dabigatran etexilate was 6.9 % vs. 10.7 % among the placebo group (hazard ratio 0.61 (95% CI 0.42, 0.88), p=0.0082). (See Table 11.)

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Clinical trials for the prevention of thromboembolism in patients with prosthetic heart valves: A phase II study examined dabigatran etexilate and warfarin in a total of 252 patients with recent mechanical valve replacement surgery (i.e. within the current hospital stay) and in patients who received a mechanical heart valve replacement more than three months ago. More thromboembolic events (mainly strokes and symptomatic/asymptomatic prosthetic valve thrombosis) and more bleeding events were observed with dabigatran etexilate than with warfarin. In the early post-operative patients, major bleeding manifested predominantly as haemorrhagic pericardial effusions, specifically in patients who started dabigatran etexilate early (i.e. on Day 3) after heart valve replacement surgery (see Contraindications).
Paediatric population: The European Medicines Agency has waived the obligation to submit the results of studies with Pradaxa in all subsets of the paediatric population for the granted indications (see Dosage & Administration for information on paediatric use).
The pharmacokinetics and pharmacodynamics of dabigatran etexilate administered twice daily for three consecutive days (total 6 doses) at the end of standard anticoagulant therapy were assessed in an open-label safety and tolerability study in 9 stable adolescents (12 to < 18 years). All patients received an initial oral dose of 1.71 (± 10%) mg/kg of dabigatran etexilate (80 % of the adult dose of 150 mg/70 kg adjusted for the patient's weight). Based on dabigatran concentrations and clinical assessment, the dose was subsequently modified to a target dose of 2.14 (± 10 %) mg/kg of dabigatran etexilate (100 % of the adult dose adjusted for the patient's weight). In this small number of adolescents, dabigatran etexilate capsules were apparently tolerated with only three mild and transient gastrointestinal adverse events reported by two patients. According to the relatively low exposure, coagulation at 72 hrs (presumed dabigatran trough level at steady state or close to steady state conditions) was only slightly prolonged with aPTT at maximum 1.60 fold, ECT 1.86 fold, and Hemoclot TT (Anti-FIIa) 1.36 fold, respectively. Dabigatran plasma concentrations observed at 72 hrs were relatively low, between 32.9 ng/mL and 97.2 ng/mL at final doses between 100 mg and 150 mg (gMean dose normalized total dabigatran plasma concentration of 0.493 ng/mL/mg).
Pharmacokinetics: After oral administration, dabigatran etexilate is rapidly and completely converted to dabigatran, which is the active form in plasma. The cleavage of the prodrug dabigatran etexilate by esterase-catalysed hydrolysis to the active principle dabigatran is the predominant metabolic reaction. The absolute bioavailability of dabigatran following oral administration of Pradaxa was approximately 6.5 %.
After oral administration of Pradaxa in healthy volunteers, the pharmacokinetic profile of dabigatran in plasma is characterized by a rapid increase in plasma concentrations with Cmax attained within 0.5 and 2.0 hours post administration.
Absorption: A study evaluating post-operative absorption of dabigatran etexilate, 1-3 hours following surgery, demonstrated relatively slow absorption compared with that in healthy volunteers, showing a smooth plasma concentration-time profile without high peak plasma concentrations. Peak plasma concentrations are reached at 6 hours following administration in a postoperative period due to contributing factors such as anaesthesia, GI paresis, and surgical effects independent of the oral medicinal product formulation. It was demonstrated in a further study that slow and delayed absorption is usually only present on the day of surgery. On subsequent days absorption of dabigatran is rapid with peak plasma concentrations attained 2 hours after medicinal product administration.
Food does not affect the bioavailability of dabigatran etexilate but delays the time to peak plasma concentrations by 2 hours.
Cmax and AUC were dose proportional.
The oral bioavailability may be increased by 75 % after a single dose and 37 % at steady state compared to the reference capsule formulation when the pellets are taken without the Hydroxypropylmethylcellulose (HPMC) capsule shell. Hence, the integrity of the HPMC capsules should always be preserved in clinical use to avoid unintentionally increased bioavailability of dabigatran etexilate (see Dosage & Administration).
Distribution: Low (34-35 %) concentration independent binding of dabigatran to human plasma proteins was observed. The volume of distribution of dabigatran of 60-70 L exceeded the volume of total body water indicating moderate tissue distribution of dabigatran.
Biotransformation: Metabolism and excretion of dabigatran were studied following a single intravenous dose of radiolabeled dabigatran in healthy male subjects. After an intravenous dose, the dabigatran-derived radioactivity was eliminated primarily in the urine (85 %). Faecal excretion accounted for 6 % of the administered dose. Recovery of the total radioactivity ranged from 88-94 % of the administered dose by 168 hours post dose.
Dabigatran is subject to conjugation forming pharmacologically active acylglucuronides. Four positional isomers, 1-O, 2-O, 3-O, 4-O-acylglucuronide exist, each accounts for less than 10 % of total dabigatran in plasma. Traces of other metabolites were only detectable with highly sensitive analytical methods. Dabigatran is eliminated primarily in the unchanged form in the urine, at a rate of approximately 100 mL/min corresponding to the glomerular filtration rate.
Elimination: Plasma concentrations of dabigatran showed a biexponential decline with a mean terminal half-life of 11 hours in healthy elderly subjects. After multiple doses a terminal half-life of about 12-14 hours was observed. The half-life was independent of dose. Half-life is prolonged if renal function is impaired as shown in Table 12.
Special populations: Renal insufficiency: In phase I studies the exposure (AUC) of dabigatran after the oral administration of Pradaxa is approximately 2.7-fold higher in volunteers with moderate renal insufficiency (CrCL between 30-50 mL/min) than in those without renal insufficiency.
In a small number of volunteers with severe renal insufficiency (CrCL 10-30 mL/min), the exposure (AUC) to dabigatran was approximately 6 times higher and the half-life approximately 2 times longer than that observed in a population without renal insufficiency (see Dosage & Administration, Contraindications and Precautions). (See Table 12.)

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Additionally, dabigatran exposure (at trough and peak) was assessed in a prospective open label randomized pharmacokinetic study in NVAF patients with severe renal impairment (defined as creatinine clearance [CrCl] 15-30 mL/min) receiving dabigatran etexilate 75 mg twice daily.
This regimen resulted in a geometric mean trough concentration of 155 ng/ml (gCV of 76.9 %), measured immediately before administration of the next dose and in a geometric mean peak concentration of 202 ng/ml (gCV of 70.6 %) measured two hours after the administration of the last dose.
Clearance of dabigatran by haemodialysis was investigated in 7 patients with end-stage renal disease (ESRD) without atrial fibrillation. Dialysis was conducted with 700 mL/min dialysate flow rate, four hour duration and a blood flow rate of either 200 mL/min or 350-390 mL/min. This resulted in a removal of 50 % to 60 % of dabigatran concentrations, respectively. The amount of substance cleared by dialysis is proportional to the blood flow rate up to a blood flow rate of 300 mL/min. The anticoagulant activity of dabigatran decreased with decreasing plasma concentrations and the PK/PD relationship was not affected by the procedure.
The median CrCL in RE-LY was 68.4 mL/min. Almost half (45.8 %) of the RE-LY patients had a CrCL > 50-< 80 mL/min. Patients with moderate renal impairment (CrCL between 30-50 mL/min) had on average 2.29-fold and 1.81-fold higher pre- and post-dose dabigatran plasma concentrations, respectively, when compared with patients without renal impairment (CrCL ≥ 80 mL/min).
The median CrCL in the RE-COVER study was 100.4 mL/min. 21.7 % of patients had mild renal impairment (CrCL > 50 - < 80 mL/min) and 4.5% of patients had a moderate renal impairment (CrCL between 30 and 50 mL/min). Patients with mild and moderate renal impairment had at steady state an average 1.8-fold and 3.6-fold higher pre-dose dabigatran plasma concentrations compared with patients with CrCL > 80 mL/min, respectively. Similar values for CrCL were found in RE-COVER II.
The median CrCL in the RE-MEDY and RE-SONATE studies were 99.0 mL/min and 99.7 mL/min, respectively. 22.9 % and 22.5 % of the patients had a CrCL > 50-< 80 mL/min, and 4.1 % and 4.8 % had a CrCL between 30 and 50 mL/min in the RE-MEDY and RE-SONATE studies.
Elderly patients: Specific pharmacokinetic phase I studies with elderly subjects showed an increase of 40 to 60 % in the AUC and of more than 25 % in Cmax compared to young subjects.
The effect by age on exposure to dabigatran was confirmed in the RE-LY study with an about 31 % higher trough concentration for subjects ≥ 75 years and by about 22 % lower trough level for subjects < 65 years compared to subjects between 65 and 75 years (see Dosage & Administration and Precautions).
Hepatic impairment: No change in dabigatran exposure was seen in 12 subjects with moderate hepatic insufficiency (Child Pugh B) compared to 12 controls (see Dosage & Administration and Precautions).
Body weight: The dabigatran trough concentrations were about 20 % lower in patients with a body weight > 100 kg compared with 50-100 kg. The majority (80.8 %) of the subjects were in the ≥ 50 kg and < 100 kg category with no clear difference detected (see Dosage & Administration and Precautions). Limited clinical data in patients < 50 kg are available.
Gender: Active substance exposure in the primary VTE prevention studies was about 40 % to 50 % higher in female patients and no dose adjustment is recommended. In atrial fibrillation patients females had on average 30 % higher trough and post-dose concentrations. No dose adjustment is required (see Dosage & Administration).
Ethnic origin: No clinically relevant inter-ethnic differences among Caucasian, African-American, Hispanic, Japanese or Chinese patients were observed regarding dabigatran pharmacokinetics and pharmacodynamics.
Pharmacokinetic interactions: In vitro interaction studies did not show any inhibition or induction of the principal isoenzymes of cytochrome P450. This has been confirmed by in vivo studies with healthy volunteers, who did not show any interaction between this treatment and the following active substances: atorvastatin (CYP3A4), digoxin (P-gp transporter interaction) and diclofenac (CYP2C9).
Toxicology: Preclinical safety data: Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity and genotoxicity.
Effects observed in the repeated dose toxicity studies were due to the exaggerated pharmacodynamic effect of dabigatran.
An effect on female fertility was observed in the form of a decrease in implantations and an increase in pre-implantation loss at 70 mg/kg (5-fold the plasma exposure level in patients). At doses that were toxic to the mothers (5- to 10-fold the plasma exposure level in patients), a decrease in foetal body weight and viability along with an increase in foetal variations were observed in rats and rabbits. In the pre- and post-natal study, an increase in foetal mortality was observed at doses that were toxic to the dams (a dose corresponding to a plasma exposure level 4-fold higher than observed in patients).
In lifetime toxicology studies in rats and mice, there was no evidence for a tumorigenic potential of dabigatran up to maximum doses of 200 mg/kg.
Dabigatran, the active moiety of dabigatran etexilate mesilate, is persistent in the environment.
Indications/Uses
Primary prevention of venous thromboembolic events in adult patients who have undergone elective total hip replacement surgery or total 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 prior stroke or transient ischemic attack (TIA); age ≥ 75 years; heart failure (NYHA Class ≥ II); diabetes mellitus; hypertension.
Treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE), and prevention of recurrent DVT and PE in adults.
Dosage/Direction for Use
Posology: Primary Prevention of Venous Thromboembolism in Orthopaedic Surgery: The recommended doses of Pradaxa and the duration of therapy for primary prevention of venous thromboembolism in orthopaedic surgery are shown in Table 13. (See Table 13.)

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For both surgeries, if haemostasis is not secured, initiation of treatment should be delayed. If treatment is not started on the day of surgery then treatment should be initiated with 2 capsules once daily.
Assessment of renal function prior to and during Pradaxa treatment: In all patients and especially in the elderly (>75 years), as renal impairment may be frequent in this age group: Renal function should be assessed by calculating the creatinine clearance (CrCL) prior to initiation of treatment with Pradaxa to exclude patients with severe renal impairment (i.e. CrCL < 30 mL/min) (see Contraindications; Precautions; Pharmacology: Pharmacokinetics under Actions).
Renal function should also be assessed when a decline in renal function is suspected during treatment (e.g. hypovolaemia, dehydration, and in case of concomitant use of certain medicinal products).
The method to be used to estimate renal function (CrCL in mL/min) is the Cockcroft-Gault method.
Missed dose: It is recommended to continue with the remaining daily doses of Pradaxa at the same time of the next day.
No double dose should be taken to make up for missed individual doses.
Discontinuation of Pradaxa: Pradaxa treatment should not be discontinued without medical advice. Patients should be instructed to contact the treating physician if they develop gastrointestinal symptoms such as dyspepsia (see Adverse Reactions).
Switching: Pradaxa treatment to parenteral anticoagulant: It is recommended to wait 24 hours after the last dose before switching from Pradaxa to a parenteral anticoagulant (see Interactions).
Parenteral anticoagulants to Pradaxa: The parenteral anticoagulant should be discontinued and Pradaxa should be started 0-2 hours prior to the time that the next dose of the alternate therapy would be due, or at the time of discontinuation in case of continuous treatment (e.g. intravenous Unfractionated Heparin (UFH)) (see Interactions).
Special populations: Renal impairment: Treatment with Pradaxa in patients with severe renal impairment (CrCL < 30 mL/min) is contraindicated (see Contraindications).
In patients with moderate renal impairment (CrCL 30-50 mL/min), a dose reduction is recommended (see Table 13; Precautions; Pharmacology: Pharmacodynamics under Actions).
Concomitant use of Pradaxa with mild to moderate P-glycoprotein (P-gp) inhibitors, i.e. amiodarone, quinidine or verapamil: Dosing should be reduced as indicated in Table 13 (see also Precautions and Interactions). In this situation Pradaxa and these medicinal products should be taken at the same time.
In patients with moderate renal impairment and concomitantly treated with verapamil, a dose reduction of Pradaxa to 75 mg daily should be considered (see Precautions and Interactions).
Elderly: For elderly patients > 75 years, a dose reduction is recommended (see Table 13; Precautions; Pharmacology: Pharmacodynamics under Actions).
Weight: There is very limited clinical experience in patients with a body weight < 50 kg or > 110 kg at the recommended posology. Given the available clinical and kinetic data no adjustment is necessary (see Pharmacology: Pharmacokinetics under Actions), but close clinical surveillance is recommended (see Precautions).
Gender: No dose adjustment is necessary (see Pharmacology: Pharmacokinetics under Actions).
Paediatric population: There is no relevant use of Pradaxa in the paediatric population for the indication of primary prevention of venous thromboembolic events in patients who have undergone elective total hip replacement surgery or total knee replacement surgery.
Prevention of stroke and systemic embolism in adult patients with NVAF with one or more risk factors (SPAF): Treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE), and prevention of recurrent DVT, and PE in adults (DVT/PE): The recommended doses of Pradaxa in the indications SPAF, DVT and PE are shown in Table 14. (See Table 14.)

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For DVT/PE the recommendation for the use of Pradaxa 220 mg taken as one 110 mg capsule twice daily is based on pharmacokinetic and pharmacodynamic analyses and has not been studied in this clinical setting. See further as follows; Precautions; Interactions; Pharmacology: Pharmacodynamics and Pharmacokinetics under Actions.
In case of intolerability to Pradaxa, patients should be instructed to immediately consult their treating physician in order to be switched to alternate acceptable treatment options for prevention of stroke and systemic embolism associated with atrial fibrillation or for DVT/PE.
Assessment of renal function prior to and during Pradaxa treatment: In all patients and especially in the elderly (>75 years), as renal impairment may be frequent in this age group: Renal function should be assessed by calculating the creatinine clearance (CrCL) prior to initiation of treatment with Pradaxa to exclude patients with severe renal impairment (i.e. CrCL < 30 mL/min) (see Contraindications; Precautions; Pharmacology: Pharmacokinetics under Actions).
Renal function should also be assessed when a decline in renal function is suspected during treatment (e.g. hypovolaemia, dehydration, and in case of concomitant use of certain medicinal products).
Additional requirements in patients with mild to moderate renal impairment and in patients aged over 75 years: Renal function should be assessed during treatment with Pradaxa at least once a year or more frequently as needed in certain clinical situations when it is suspected that the renal function could decline or deteriorate (e.g. hypovolaemia, dehydration, and in case of concomitant use of certain medicinal products).
The method to be used to estimate renal function (CrCL in mL/min) is the Cockcroft-Gault method.
Duration of use: The duration of use of Pradaxa in the indications SPAF, DVT and PE are shown in Table 15. (See Table 15.)

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Missed dose: A forgotten Pradaxa dose may still be taken up to 6 hours prior to the next scheduled dose. From 6 hours prior to the next scheduled dose on, the missed dose should be omitted.
No double dose should be taken to make up for missed individual doses.
Discontinuation of Pradaxa: Pradaxa treatment should not be discontinued without medical advice. Patients should be instructed to contact the treating physician if they develop gastrointestinal symptoms such as dyspepsia (see Adverse Reactions).
Switching: Pradaxa treatment to parenteral anticoagulant: It is recommended to wait 12 hours after the last dose before switching from Pradaxa to a parenteral anticoagulant (see Interactions).
Parenteral anticoagulants to Pradaxa: The parenteral anticoagulant should be discontinued and Pradaxa should be started 0-2 hours prior to the time that the next dose of the alternate therapy would be due, or at the time of discontinuation in case of continuous treatment (e.g. intravenous Unfractionated Heparin (UFH)) (see Interactions).
Pradaxa treatment to Vitamin K antagonists (VKA): The starting time of the VKA should be adjusted based on CrCL as follows: CrCL ≥ 50 mL/min, VKA should be started 3 days before discontinuing Pradaxa; CrCL ≥ 30-< 50 mL/min, VKA should be started 2 days before discontinuing Pradaxa.
Because Pradaxa can impact the International Normalized Ratio (INR), the INR will better reflect VKA's effect only after Pradaxa has been stopped for at least 2 days. Until then, INR values should be interpreted with caution.
VKA to Pradaxa: The VKA should be stopped. Pradaxa can be given as soon as the INR is < 2.0.
Cardioversion (SPAF): Patients can stay on Pradaxa while being cardioverted.
Catheter ablation for atrial fibrillation (SPAF): There are no data available for 110 mg twice daily Pradaxa treatment.
Catheter ablation can be conducted in patients on 150 mg twice daily Pradaxa treatment. Pradaxa treatment does not need to be interrupted (see Pharmacology: Pharmacodynamics under Actions).
Percutaneous coronary intervention (PCI) with stenting (SPAF): Patients with non valvular atrial fibrillation who undergo a PCI with stenting can be treated with Pradaxa in combination with antiplatelets after haemostasis is achieved (see Pharmacology: Pharmacodynamics under Actions).
Special populations: Elderly: For dose modifications in this population see Table 14.
Patients at risk of bleeding: Patients with an increased bleeding risk (see Precautions; Interactions; Pharmacology: Pharmacodynamics and Pharmacokinetics under Actions) should be closely monitored clinically (looking for signs of bleeding or anaemia). Dose adjustment should be decided at the discretion of the physician, following assessment of the potential benefit and risk to an individual patient (see Table 14). A coagulation test (see Precautions) may help to identify patients with an increased bleeding risk caused by excessive dabigatran exposure. When excessive dabigatran exposure is identified in patients at high risk of bleeding, a reduced dose of 220 mg taken as one 110 mg capsule twice daily is recommended. When clinically relevant bleeding occurs, treatment should be interrupted.
For subjects with gastritis, esophagitis, or gastroesophageal reflux, a dose reduction may be considered due to the elevated risk of major gastro-intestinal bleeding (see Table 14 and Precautions).
Renal impairment: Treatment with Pradaxa in patients with severe renal impairment (CrCL < 30 mL/min) is contraindicated (see Contraindications).
No dose adjustment is necessary in patients with mild renal impairment (CrCL 50 - ≤ 80 mL/min). For patients with moderate renal impairment (CrCL 30-50 mL/min) the recommended dose of Pradaxa is also 300 mg taken as one 150 mg capsule twice daily. However, for patients with high risk of bleeding, a dose reduction of Pradaxa to 220 mg taken as one 110 mg capsule twice daily should be considered (see Precautions; Pharmacology: Pharmacokinetics under Actions). Close clinical surveillance is recommended in patients with renal impairment.
Concomitant use of Pradaxa with mild to moderate P-glycoprotein (P-gp) inhibitors, i.e. amiodarone, quinidine or verapamil: No dose adjustment is necessary for concomitant use of amiodarone or quinidine (see Precautions; Interactions; Pharmacology: Pharmacokinetics under Actions).
Dose reductions are recommended for patients who receive concomitantly verapamil (see Table 14 and Precautions and Interactions). In this situation Pradaxa and verapamil should be taken at the same time.
Weight: No dose adjustment is necessary (see Pharmacology: Pharmacokinetics under Actions), but close clinical surveillance is recommended in patients with a body weight < 50 kg (see Precautions).
Gender: No dose adjustment is necessary (see Pharmacology: Pharmacokinetics under Actions).
Paediatric population: There is no relevant use of Pradaxa in the paediatric population for the indication of prevention of stroke and systemic embolism in patients with NVAF.
For the indication DVT/PE, the safety and efficacy of Pradaxa in children from birth to less than 18 years of age have not yet been established. Currently available data are described in Adverse Reactions and Pharmacology: Pharmacodynamics under Actions, but no recommendation on a posology can be made.
Method of administration: Pradaxa is for oral use.
The capsules can be taken with or without food. Pradaxa should be swallowed as a whole with a glass of water, to facilitate delivery to the stomach.
Patients should be instructed not to open the capsule as this may increase the risk of bleeding (see Pharmacology: Pharmacokinetics under Actions; Special precautions for other handling under Cautions for Usage).
Overdosage
Pradaxa doses beyond those recommended expose the patient to increased risk of bleeding.
In case of an overdose suspicion, coagulation tests can help to determine a bleeding risk (see Precautions; Pharmacology: Pharmacodynamics under Actions). A calibrated quantitative dTT test or repetitive dTT measurements allow prediction of the time by when certain dabigatran levels will be reached (see Pharmacology: Pharmacodynamics under Actions), also in case additional measures e.g. dialysis have been initiated.
Excessive anticoagulation may require interruption of Pradaxa treatment. Since dabigatran is excreted predominantly by the renal route adequate diuresis must be maintained. As protein binding is low, dabigatran can be dialysed; there is limited clinical experience to demonstrate the utility of this approach in clinical studies (see Pharmacology: Pharmacokinetics under Actions).
Management of bleeding complications: In the event of haemorrhagic complications, Pradaxa treatment must be discontinued and the source of bleeding investigated. Depending on the clinical situation appropriate supportive treatment, such as surgical haemostasis and blood volume replacement, should be undertaken at the prescriber's discretion.
For situations when rapid reversal of the anticoagulant effect of Pradaxa is required the specific reversal agent (Praxbind, idarucizumab) antagonizing the pharmacodynamic effect of Pradaxa is available (see Precautions).
Coagulation factor concentrates (activated or non-activated) or recombinant Factor VIIa may be taken into account. There is some experimental evidence to support the role of these medicinal products in reversing the anticoagulant effect of dabigatran, but data on their usefulness in clinical settings and also on the possible risk of rebound thromboembolism is very limited. Coagulation tests may become unreliable following administration of suggested coagulation factor concentrates. Caution should be exercised when interpreting these tests. Consideration should also be given to administration of platelet concentrates in cases where thrombocytopenia is present or long acting antiplatelet medicinal products have been used. All symptomatic treatment should be given according to the physician's judgement.
Depending on local availability, a consultation of a coagulation expert should be considered in case of major bleedings.
Contraindications
Hypersensitivity to the active substance or to any of the excipients listed in Description.
Patients with severe renal impairment (CrCL < 30 mL/min).
Active clinically significant bleeding.
Lesion or condition, if considered a significant risk factor for major bleeding. This may include current or recent gastrointestinal ulceration, presence of malignant neoplasms at high risk of bleeding, recent brain or spinal injury, recent brain, spinal or ophthalmic surgery, recent intracranial haemorrhage, known or suspected oesophageal varices, arteriovenous malformations, vascular aneurysms or major intraspinal or intracerebral vascular abnormalities.
Concomitant treatment with any other anticoagulants e.g. unfractionated heparin (UFH), low molecular weight heparins (enoxaparin, dalteparin etc), heparin derivatives (fondaparinux etc), oral anticoagulants (warfarin, rivaroxaban, apixaban etc) except under specific circumstances. These are switching anticoagulant therapy (see Dosage & Administration), when UFH is given at doses necessary to maintain an open central venous or arterial catheter or when UFH is given during catheter ablation for atrial fibrillation (see Interactions).
Hepatic impairment or liver disease expected to have any impact on survival.
Concomitant treatment with the following strong P-gp inhibitors: systemic ketoconazole, cyclosporine, itraconazole, dronedarone and the fixed-dose combination glecaprevir/pibrentasvir (see Interactions).
Prosthetic heart valves requiring anticoagulant treatment (see Pharmacology: Pharmacodynamics under Actions).
Special Precautions
Use of fibrinolytic medicinal products for the treatment of acute ischemic stroke: The use of fibrinolytic medicinal products for the treatment of acute ischemic stroke may be considered if the patient presents with a dTT, ECT or aPTT not exceeding the upper limit of normal (ULN) according to the local reference range.
Patients at high surgical mortality risk and with intrinsic risk factors for thromboembolic events: There are limited efficacy and safety data for Pradaxa available in these patients and therefore they should be treated with caution.
Hip fracture surgery: There is no data on the use of Pradaxa in patients undergoing hip fracture surgery. Therefore treatment is not recommended.
Hepatic impairment: Patients with elevated liver enzymes > 2 ULN were excluded in the main trials. No treatment experience is available for this subpopulation of patients, and therefore the use of Pradaxa is not recommended in this population. Hepatic impairment or liver disease expected to have any impact on survival is contraindicated (see Contraindications).
Interaction with P-gp inducers: Concomitant administration of P-gp inducers is expected to result in decreased dabigatran plasma concentrations, and should be avoided (see Interactions; Pharmacology: Pharmacokinetics under Actions).
Patients with antiphospholipid syndrome: Direct acting Oral Anticoagulants (DOACs) including dabigatran etexilate are not recommended for patients with a history of thrombosis who are diagnosed with antiphospholipid syndrome. In particular for patients that are triple positive (for lupus anticoagulant, anticardiolipin antibodies, and anti-beta 2-glycoprotein I antibodies), treatment with DOACs could be associated with increased rates of recurrent thrombotic events compared with vitamin K antagonist therapy.
Myocardial Infarction (MI): In the phase III study RE-LY (SPAF, see Pharmacology: Pharmacodynamics under Actions) the overall rate of MI was 0.82, 0.81, and 0.64 % / year for dabigatran etexilate 110 mg twice daily, dabigatran etexilate 150 mg twice daily and warfarin, respectively, an increase in relative risk for dabigatran of 29 % and 27 % compared to warfarin. Irrespective of therapy, the highest absolute risk of MI was seen in the following subgroups, with similar relative risk: patients with previous MI, patients ≥ 65 years with either diabetes or coronary artery disease, patients with left ventricular ejection fraction < 40 %, and patients with moderate renal dysfunction. Furthermore a higher risk of MI was seen in patients concomitantly taking ASA plus clopidogrel or clopidogrel alone.
In the three active controlled DVT/PE phase III studies, a higher rate of MI was reported in patients who received dabigatran etexilate than in those who received warfarin: 0.4% vs. 0.2% in the short-term RE-COVER and RE-COVER II studies; and 0.8% vs. 0.1% in the long-term RE-MEDY trial. The increase was statistically significant in this study (p=0.022).
In the RE-SONATE study, which compared dabigatran etexilate to placebo, the rate of MI was 0.1% for patients who received dabigatran etexilate and 0.2% for patients who received placebo.
Active Cancer Patients (DVT/PE): The efficacy and safety have not been established for DVT/PE patients with active cancer.
Effects on ability to drive and use machines: Pradaxa has no or negligible influence on the ability to drive and use machines.
Haemorrhagic risk: Pradaxa should be used with caution in conditions with an increased risk of bleeding or with concomitant use of medicinal products affecting haemostasis by inhibition of platelet aggregation. Bleeding can occur at any site during therapy with Pradaxa. An unexplained fall in haemoglobin and/or haematocrit or blood pressure should lead to a search for a bleeding site.
For situations of life-threatening or uncontrolled bleeding, when rapid reversal of the anticoagulation effect of dabigatran is required, the specific reversal agent (Praxbind, idarucizumab) is available (see Overdosage).
In clinical trials, Pradaxa was associated with higher rates of major gastrointestinal (GI) bleeding. An increased risk was seen in the elderly (≥ 75 years) for the 150 mg twice daily dose regimen. Further risk factors (see also Table 16) comprise co-medication with platelet aggregation inhibitors such as clopidogrel and acetylsalicylic acid (ASA) or non steroidal antiinflammatory drugs (NSAID), as well as the presence of esophagitis, gastritis or gastroesophageal reflux.
Risk factors: Table 16 summarises factors which may increase the haemorrhagic risk. (See Table 16.)

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Limited data is available in patients < 50 kg (see Pharmacology: Pharmacokinetics under Actions).
Precautions and management of the haemorrhagic risk: For the management of bleeding complications, see also Overdosage.
Benefit-risk assessment: The presence of lesions, conditions, procedures and/or pharmacological treatment (such as NSAIDs, antiplatelets, SSRIs and SNRIs, see Interactions), which significantly increase the risk of major bleeding requires a careful benefit-risk assessment. Pradaxa should only be given if the benefit outweighs bleeding risks.
Close clinical surveillance: Close observation for signs of bleeding or anaemia is recommended throughout the treatment period, especially if risk factors are combined (see Table 16). Particular caution should be exercised when Pradaxa is co-administered with verapamil, amiodarone, quinidine or clarithromycin (P-gp inhibitors) and particularly in the occurrence of bleeding, notably in patients having a mild to moderate renal impairment (see Interactions).
Close observation for signs of bleeding is recommended in patients concomitantly treated with NSAIDs (see Interactions).
Discontinuation of Pradaxa: Patients who develop acute renal failure must discontinue Pradaxa (see also Contraindications).
When severe bleedings occur, treatment must be discontinued, the source of bleeding investigated and use of the specific reversal agent Praxbind (idarucizumab) may be considered (see Management of bleeding complications under Overdosage).
Dose reduction: A dose reduction should be either considered or is recommended as indicated in Dosage & Administration.
Use of proton-pump inhibitors: The administration of a proton-pump inhibitor (PPI) can be considered to prevent GI bleeding.
Laboratory coagulation parameters: Although Pradaxa does not in general require routine anticoagulant monitoring, the measurement of dabigatran related anticoagulation may be helpful to detect excessive high exposure to dabigatran 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 inter-test variability (see Pharmacology: Pharmacodynamics under Actions). The International Normalised Ratio (INR) test is unreliable in patients on Pradaxa and false positive INR elevations have been reported. Therefore, INR tests should not be performed.
Table 17 shows coagulation test thresholds at trough that may be associated with an increased risk of bleeding (see Pharmacology: Pharmacodynamics under Actions). (See Table 17.)

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Surgery and interventions: Patients on Pradaxa who undergo surgery or invasive procedures are at increased risk for bleeding. Therefore surgical interventions may require the temporary discontinuation of Pradaxa.
Patients can stay on Pradaxa while being cardioverted. There are no data available for 110 mg twice daily Pradaxa treatment in patients undergoing catheter ablation for atrial fibrillation (see Dosage & Administration). Pradaxa treatment (150 mg twice daily) does not need to be interrupted in patients undergoing catheter ablation for atrial fibrillation (see Dosage & Administration).
Caution should be exercised when treatment is temporarily discontinued for interventions and anticoagulant monitoring is warranted. Clearance of dabigatran in patients with renal insufficiency may take longer (see Pharmacology: Pharmacokinetics under Actions). This should be considered in advance of any procedures. In such cases a coagulation test (see Precautions; Pharmacology: Pharmacodynamics under Actions) may help to determine whether haemostasis is still impaired.
Emergency surgery or urgent procedures: Pradaxa should be temporarily discontinued. When rapid reversal of the anticoagulation effect is required the specific reversal agent (Praxbind, idarucizumab) to Pradaxa is available.
Reversing dabigatran therapy exposes patients to the thrombotic risk of their underlying disease. Pradaxa treatment can be re-initiated 24 hours after administration of Praxbind (idarucizumab), if the patient is clinically stable and adequate haemostasis has been achieved.
Subacute surgery/interventions: Pradaxa should be temporarily discontinued. A surgery / intervention should be delayed if possible until at least 12 hours after the last dose. If surgery cannot be delayed the risk of bleeding may be increased. This risk of bleeding should be weighed against the urgency of intervention.
Elective surgery: If possible, Pradaxa should be discontinued at least 24 hours before invasive or surgical procedures. In patients at higher risk of bleeding or in major surgery where complete haemostasis may be required consider stopping Pradaxa 2-4 days before surgery.
Table 18 summarises discontinuation rules before invasive or surgical procedures. (See Table 18.)

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Spinal anaesthesia/epidural anaesthesia/lumbar puncture: Procedures such as spinal anaesthesia may require complete haemostatic function.
The risk of spinal or epidural haematoma may be increased in cases of traumatic or repeated puncture and by the prolonged use of epidural catheters. After removal of a catheter, an interval of at least 2 hours should elapse before the administration of the first dose of Pradaxa. These patients require frequent observation for neurological signs and symptoms of spinal or epidural haematoma.
Postoperative phase: Pradaxa treatment should be resumed / started after the invasive procedure or surgical intervention as soon as possible provided the clinical situation allows and adequate haemostasis has been established.
Patients at risk for bleeding or patients at risk of overexposure, notably patients with moderate renal impairment (CrCL 30-50 mL/min), should be treated with caution (see Precautions; Pharmacology: Pharmacodynamics under Actions).
Use In Pregnancy & Lactation
Women of childbearing potential: Women of childbearing potential should avoid pregnancy during treatment with Pradaxa.
Pregnancy: There is limited amount of data from the use of Pradaxa in pregnant women.
Studies in animals have shown reproductive toxicity (see Pharmacology: Toxicology: Preclinical safety data under Actions). The potential risk for humans is unknown.
Pradaxa should not be used during pregnancy unless clearly necessary.
Breast-feeding: There are no clinical data of the effect of dabigatran on infants during breast-feeding.
Breast-feeding should be discontinued during treatment with Pradaxa.
Fertility: No human data available.
In animal studies an effect on female fertility was observed in the form of a decrease in implantations and an increase in pre-implantation loss at 70 mg/kg (representing a 5-fold higher plasma exposure level compared to patients). No other effects on female fertility were observed. There was no influence on male fertility. At doses that were toxic to the mothers (representing a 5- to 10-fold higher plasma exposure level to patients), a decrease in foetal body weight and embryofoetal viability along with an increase in foetal variations were observed in rats and rabbits. In the pre- and post-natal study, an increase in foetal mortality was observed at doses that were toxic to the dams (a dose corresponding to a plasma exposure level 4-fold higher than observed in patients).
Adverse Reactions
Summary of the safety profile for 75mg: In actively controlled VTE prevention trials 6,684 patients were treated with 150 mg or 220 mg Pradaxa daily.
The most commonly reported events are bleedings occurring in approximately 14 % of patients; the frequency of major bleeds (including wound site bleedings) is less than 2 %.
Although rare in frequency in clinical trials, major or severe bleeding may occur and, regardless of location, may lead to disabling, life-threatening or even fatal outcomes.
Summary of the safety profile for 110mg: The safety of Pradaxa has been evaluated in ten phase III studies including 23,393 patients exposed to Pradaxa (see Table 19).

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In total, about 9 % of patients treated for elective hip or knee surgery (short-term treatment for up to 42 days), 22 % of patient with atrial fibrillation treated for the prevention of stroke and systemic embolism (long-term treatment for up to 3 years), 14 % of patient treated for DVT/PE and 15 % of patients treated for DVT/PE prevention experienced adverse reactions.
The most commonly reported events are bleedings occurring in approximately 14 % of patients treated short-term for elective hip or knee replacement surgery, 16.6 % in patients with atrial fibrillation treated long-term for the prevention of stroke and systemic embolism, and in 14.4 % of patients treated for DVT/PE. Furthermore, bleeding occurred in 19.4% of patients in the DVT/PE prevention trial RE-MEDY and in 10.5% of patient in the DVT/PE prevention trial RE-SONATE.
Since the patient populations treated in the three indications are not comparable and bleeding events are distributed over several System Organ Classes (SOC), a summary description of major and any bleeding are broken down by indication and given in Tables 22-26 as follows.
Although low in frequency in clinical trials, major or severe bleeding may occur and, regardless of location, may lead to disabling, life-threatening or even fatal outcomes.
Summary of the safety profile for 150mg: The safety of Pradaxa has been evaluated in a pivotal study investigating the prevention of stroke and systemic embolism in patients with atrial fibrillation, in two active controlled DVT/PE treatment trials and in one active controlled DVT/PE prevention trial. In these four phase III trials, 16,709 patients were exposed to Pradaxa (see Table 20).

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In total, 22 % of patient with atrial fibrillation treated for the prevention of stroke and systemic embolism (long-term treatment for up to 3 years), 14 % of patients treated for DVT/PE and 15 % of patients treated for DVT/PE prevention experienced adverse reactions.
The most commonly reported events are bleedings occurring in approximately 16.6 % in patients with atrial fibrillation treated long-term for the prevention of stroke and systemic embolism and in 14.4 % of patients treated for DVT/PE. Furthermore, bleeding occurred in 19.4 % of patients in the DVT/PE prevention trial RE-MEDY and in 10.5 % of patients in the DVT/PE trial RE-SONATE.
Since the patient population treated in the three indications are not comparable and bleeding events are distributed over several System Organ Classes (SOC), a summary description of major and any bleeding are broken down by indication and are provided in Tables 23-26 as follows.
Although low in frequency in clinical trials, major or severe bleeding may occur and, regardless of location, may lead to disabling, life-threatening or even fatal outcomes.
Tabulated list of adverse reactions: Table 21 shows the adverse reactions identified from studies and post-marketing data in the indications primary VTE prevention after hip or knee replacement surgery, prevention of thromboembolic stroke and systemic embolism in patients with atrial fibrillation, DVT/PE treatment and in DVT/PE prevention. They are ranked under headings of System Organ Class (SOC) and frequency using the following convention: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1,000 to < 1/100), rare (≥ 1/10,000 to < 1/1,000), very rare (< 1/10,000), not known (cannot be estimated from the available data). (See Table 21.)

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Description of selected adverse reactions: Bleeding reactions: Due to the pharmacological mode of action, the use of Pradaxa may be associated with an increased risk of occult or overt bleeding from any tissue or organ. The signs, symptoms, and severity (including fatal outcome) will vary according to the location and degree or extent of the bleeding and/or anaemia. In the clinical studies mucosal bleedings (e.g. gastrointestinal, genitourinary) were seen more frequently during long term Pradaxa treatment compared with VKA treatment. Thus, in addition to adequate clinical surveillance, laboratory testing of haemoglobin/haematocrit is of value to detect occult bleeding. The risk of bleedings may be increased in certain patient groups e.g. those patients with moderate renal impairment and/or on concomitant treatment affecting haemostasis or strong P-gp inhibitors (see Haemorrhagic risk under Precautions). Haemorrhagic complications may present as weakness, paleness, dizziness, headache or unexplained swelling, dyspnoea, and unexplained shock.
Known bleeding complications such as compartment syndrome and acute renal failure due to hypoperfusion have been reported for Pradaxa. Therefore, the possibility of haemorrhage is to be considered in evaluating the condition in any anticoagulated patient. A specific reversal agent for dabigatran, idarucizumab, is available in case of uncontrollable bleeding (see Overdosage).
Primary Prevention of Venous Thromboembolism in Orthopaedic Surgery: Table 22 shows the number (%) of patients experiencing the adverse reaction bleeding during the treatment period in the VTE prevention in the two pivotal clinical trials, according to dose. (See Table 22.)

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Prevention of stroke and systemic embolism in adult patients with NVAF with one or more risk factors: Table 23 shows bleeding events broken down to major and any bleeding in the pivotal study testing the prevention of thromboembolic stroke and systemic embolism in patients with atrial fibrillation. (See Table 23.)

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Subjects randomized to Pradaxa 110 mg twice daily or 150 mg twice daily had a significantly lower risk for life-threatening bleeds and intracranial bleeding compared to warfarin [p < 0.05]. Both dose strengths of Pradaxa had also a statistically significant lower total bleed rate. Subjects randomized to 110 mg Pradaxa twice daily had a significantly lower risk for major bleeds compared with warfarin (hazard ratio 0.81 [p=0.0027]). Subjects randomized to 150 mg Pradaxa twice daily had a significantly higher risk for major GI bleeds compared with warfarin (hazard ratio 1.48 [p=0.0005]). This effect was seen primarily in patients ≥ 75 years.
The clinical benefit of dabigatran with regard to stroke and systemic embolism prevention and decreased risk of ICH compared to warfarin is preserved across individual subgroups, e.g. renal impairment, age, concomitant medicinal product use such as anti-platelets or P-gp inhibitors. While certain patient subgroups are at an increased risk of major bleeding when treated with an anticoagulant, the excess bleeding risk for dabigatran is due to GI bleeding, typically seen within the first 3-6 months following initiation of Pradaxa therapy.
Treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE), and prevention of recurrent DVT and PE in adults (DVT/PE treatment): Table 24 shows bleeding events in the pooled pivotal studies RE-COVER and RE-COVER II testing the treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE). In the pooled studies the primary safety endpoints of major bleeding, major or clinically relevant bleeding and any bleeding were significantly lower than warfarin at a nominal alpha level of 5 %. (See Table 24.)

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Bleeding events for both treatments are counted from the first intake of Pradaxa or warfarin after the parenteral therapy has been discontinued (oral only treatment period). This includes all bleeding events, which occurred during Pradaxa therapy. All bleeding events which occurred during warfarin therapy are included except for those during the overlap period between warfarin and parenteral therapy.
Table 25 shows bleeding events in pivotal study RE-MEDY testing prevention of deep vein thrombosis (DVT) and pulmonary embolism (PE). Some bleeding events (MBEs/CRBEs; any bleeding) were significantly lower at a nominal alpha level of 5% in patients receiving Pradaxa as compared with those receiving warfarin. (See Table 25.)

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Table 26 shows bleeding events in pivotal study RE-SONATE testing prevention of deep vein thrombosis (DVT) and pulmonary embolism (PE). The rate of the combination of MBEs/CRBEs and the rate of any bleeding was significantly lower at a nominal alpha level of 5 % in patients receiving placebo as compared with those receiving Pradaxa. (See Table 26.)

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Agranulocytosis and neutropenia: Agranulocytosis and neutropenia have been reported very rarely during post approval use of Pradaxa. Because adverse reactions are reported in the postmarketing surveillance setting from a population of uncertain size, it is not possible to reliably determine their frequency. The reporting rate was estimated as 7 events per 1 million patient years for agranulocytosis and as 5 events per 1 million patient years for neutropenia.
Paediatric population (DVT/PE): In the clinical study 1160.88 in total, 9 adolescent patients (age 12 to < 18 years) with diagnosis of primary VTE received an initial oral dose of dabigatran etexilate of 1.71 (± 10 %) mg/kg bodyweight. Based on dabigatran concentrations as determined by the diluted thrombin time test and clinical assessment, the dose was adjusted to the target dose of 2.14 (± 10%) mg/kg bodyweight of dabigatran etexilate. On treatment 2 (22.1 %) patients experienced mild related adverse events (gastrooesophageal reflux / abdominal pain; abdominal discomfort) and 1 (11.1 %) patient experienced a not related serious adverse event (recurrent VTE of the leg) in the post treatment period > 3 days after stop of dabigatran etexilate.
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 are asked to report any suspected adverse reactions.
Drug Interactions
Transporter interactions: Dabigatran etexilate is a substrate for the efflux transporter P-gp. Concomitant administration of P-gp inhibitors (see Table 27) is expected to result in increased dabigatran plasma concentrations.
If not otherwise specifically described, close clinical surveillance (looking for signs of bleeding or anaemia) is required when dabigatran is co-administered with strong P-gp inhibitors. Dose reductions may be required in combination with some P-gp inhibitors (see Dosage & Administration; Contraindications; Precautions; Pharmacology: Pharmacodynamics under Actions). (See Table 27.)

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Anticoagulants and antiplatelet aggregation medicinal products: There is no or only limited experience with the following treatments 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), thrombolytic medicinal products, and vitamin K antagonists, rivaroxaban or other oral anticoagulants (see Contraindications), and antiplatelet aggregation medicinal products such as GPIIb/IIIa receptor antagonists, ticlopidine, prasugrel, ticagrelor, dextran, and sulfinpyrazone (see Precautions).
From the data collected in the phase III study RE-LY (see Pharmacology: Pharmacodynamics under Actions) it was observed that the concomitant use of other oral or parenteral anticoagulants increases major bleeding rates with both dabigatran etexilate and warfarin by approximately 2.5-fold, mainly related to situations when switching from one anticoagulant to another (see Contraindications). Furthermore, concomitant use of antiplatelets, ASA or clopidogrel approximately doubled major bleeding rates with both dabigatran etexilate and warfarin (see Precautions).
UFH can be administered at doses necessary to maintain a patent central venous or arterial catheter or during catheter ablation for atrial fibrillation (see Contraindications). (See Table 28.)

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Other interactions: See Table 29.

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Interactions linked to dabigatran etexilate and dabigatran metabolic profile: Dabigatran etexilate and dabigatran are not metabolised by the cytochrome P450 system and have no in vitro effects on human cytochrome P450 enzymes. Therefore, related medicinal product interactions are not expected with dabigatran.
Caution For Usage
Special precautions for other handling: When taking Pradaxa capsules out of the blister pack, the following instructions should be followed: One individual blister should be teared off from the blister card along the perforated line.
The backing foil should be peeled off and the capsule can be removed.
The hard capsules should not be pushed through the blister foil.
The blister foil should only be peeled off, when a hard capsule is required.
Incompatibilities: Not applicable.
Storage
Store in the original package in order to protect from moisture. Store below 30°C. Do not remove capsules from blister pack until just before use.
ATC Classification
B01AE07 - dabigatran etexilate ; Belongs to the class of direct thrombin inhibitors. Used in the treatment of thrombosis.
Presentation/Packing
Cap 75 mg (white, opaque cap and white, opaque body of size 2 filled with yellowish pellets; cap is imprinted with the Boehringer Ingelheim company symbol, the body with "R75") x 30's. 110 mg (light blue, opaque cap and light blue, opaque body of size 1 filled with yellowish pellets; cap is imprinted with the Boehringer Ingelheim company symbol, the body with "R110") x 30's. 150 mg (light blue, opaque cap and white, opaque body of size 0 filled with yellowish pellets; cap is imprinted with the Boehringer Ingelheim company symbol, the body with "R150") x 30's.
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