Pradaxa

Dabigatran etexilate.

1 Capsule contains 126.83 mg or 172.95 mg of beta-alanine, N-[[2-[[[4(hexyloxy)carbonyl]amino]iminomethyl] phenyl]amino]methyl]-1-methyl-1H-benzimidazol-5-yl]carbonyl]-N-2-pyridinyl-,ethyl ester, methane-sulfonate, being the methane sulfonic acid salt (corresponding to dabigatran etexilate base form 110 mg or 150 mg).
Excipients/Inactive Ingredients: Tartaric acid, acacia, hypromellose, dimethicone 350, talc, hydroxypropyl cellulose.
HPMC capsule shell: Carrageenan, potassium chloride, titanium dioxide, Indigo Carmine (E132), hypromellose.
Printing ink: Shellac, butyl alcohol, isopropyl alcohol, Iron oxide black (E172), purified water, propylene glycol, anhydrous ethanol, potassium hydroxide, concentrated ammonia solution.

Pharmacotherapy group: oral direct thrombin inhibitor. ATC Code: B01AE07 - dabigatran etexilate.
Pharmacology: 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 also inhibits free thrombin, fibrin-bound thrombin and thrombin-induced platelet aggregation.
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 close correlation between plasma dabigatran concentrations and degree of anticoagulant effect. Dabigatran prolongs the aPTT, ECT and TT.
Clinical trials in primary VTE prevention 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 dabigatran etexilate 75 mg or 110 mg within 1-4 hours of surgery followed by 150 or 220 mg once daily thereafter, haemostasis having been secured, or enoxaparin 40 mg on the day prior to surgery and once 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 2076 patients (knee) and 3494 (hip) were treated respectively.
The results of the knee study (RE-MODEL) with respect to the primary end-point, total including asymptomatic venous thromboembolism (VTE) plus all-cause mortality showed that the antithrombotic effect of both doses of dabigatran etexilate were statistically non-inferior to that of enoxaparin.
Similarly, total including asymptomatic VTE and all-cause mortality constituted the primary end-point for the hip study (RE-NOVATE). Again dabigatran etexilate at both once daily doses was statistically non-inferior to enoxaparin 40 mg daily.
Furthermore in a third randomized, parallel group, double-blind, trial (RE-MOBILIZE), patients undergoing elective total knee surgery received dabigatran etexilate 75 mg or 110 mg within 6-12 hours of surgery followed by 150 mg and 220 mg once daily thereafter. The treatment duration was 12-15 days. In total 2615 patients were randomised and 2596 were treated. The comparator dosage of enoxaparin was 30 mg twice daily according to the US label. In the RE-MOBILIZE trial non-inferiority was not established. There were no statistical differences in bleeding between the comparators.
In addition a randomized, parallel group, double-blind, placebo-controlled phase II study in Japanese patients where dabigatran etexilate 110 mg, 150 mg, and 220 mg was administered at the next day after elective total knee replacement surgery was evaluated. The Japanese study showed a clear dose response relationship for the efficacy of dabigatran etexilate and a placebo like bleeding profile.
In RE-MODEL and RE-NOVATE the randomisation to the respective study medication was done pre-surgery, and in the RE-MOBILIZE and the Japanese placebo controlled trial the randomisation to the respective study medication was done post-surgery. This is of note especially in the safety evaluation of these trials. For this reason the trials are grouped in pre- and post surgery randomised trials in Table 1.
Data for the major VTE and VTE-related mortality end-point and adjudicated major bleeding endpoints are shown in the Table 1 as follows. VTE was defined as the composite incidence of deep vein thrombosis and Pulmonary Embolism. (See Table 1.)

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Clinical trials in prevention of stroke and systemic embolism in patients with atrial fibrillation: 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-center, multi-national, randomized parallel group study of two blinded doses of dabigatran etexilate (110 mg bid and 150 mg bid) compared to open-label warfarin in patients with atrial fibrillation at moderate to high risk of stroke or systemic embolism. The primary objective in this study was to determine if dabigatran was non-inferior to warfarin in reducing the occurrence of the composite endpoint, stroke and systemic embolic events (SEE).
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 population had approximately equal proportions of patients with CHADS₂ score 1, 2 and ≥3. The patient population was 64% male, 70% Caucasian and 16% Asian. RE-LY had a median treatment of 20 months with dabigatran etexilate given as fixed dose without coagulation monitoring. In addition to documented non-valvular atrial fibrillation (AF) e.g., persistent AF or paroxysmal, patients had one of the following additional risk factors for stroke: Previous stroke, transient ischemic attack, or systemic embolism; Left ventricular ejection fraction <40 %; Symptomatic heart failure, ≥ NYHA Class 2; Age ≥ 75 years; Age ≥ 65 years associated with one of the following: diabetes mellitus, coronary artery disease, or hypertension.
The concomitant diseases of patients in this trial included hypertension 79%, diabetes 23% and coronary artery disease (CAD) 28%. 50% of the patient population was VKA naïve defined as less than 2 months total life time exposure. 32% of the population had never been exposed to a VKA. For those patients randomized to warfarin, the time in therapeutic range (INR 2.0 to 3.0) for the trial was a median of 67%. Concomitant medications included ASA (25% of subjects used at least 50% of the time in study), clopidogrel (3.6%), ASA+clopidogrel (2%), NSAIDs (6.3%), beta-blockers (63.4%), diuretics (53.9%), statins (46.4%), ACE-inhibitors (44.6%), angiotensin receptor blockers (26.1%), oral hypoglycemics (17.5%), insulin (5.2%), digoxin (29.4%), amiodarone (11.3%), diltiazem (8.9%), verapamil (5.4%), and proton pump inhibitors (17.8%).
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.
This 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 intracranial hemorrhage and total bleeding. The higher dose of 150 mg twice daily, reduces significantly the risk of ischemic and hemorrhagic stroke, vascular death, intracranial hemorrhage and total bleeding compared to warfarin. The lower dose of dabigatran has a significantly lower risk of major bleeding compared to warfarin.
Figure 1 and Tables 2 - 6 display details of key results. (See Table 2, Figure 1, and Tables 3 and 4.)

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The net clinical benefit (NCB) as measured by the unweighted composite clinical endpoint of stroke, systemic embolism, pulmonary embolism, acute myocardial infarction, vascular deaths, and major bleeds was assessed and is presented as part of Table 5. The yearly event rates for the dabigatran etexilate groups were lower compared to the warfarin group. The risk reduction for this composite endpoint was 8% and 10% for the dabigatran etexilate 110 mg bid and 150 mg bid treatment groups. (See Table 5.)

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There was an increased numeric imbalance in MI events in subjects treated with dabigatran compared to warfarin treated subjects. The reason for this imbalance is unknown. Patients treated with dabigatran who have risk factors for coronary artery disease should be treated according to local guidelines. (See Table 6.)

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The RE-LY extension study (RELY-ABLE) provided additional safety information for a large 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. 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.
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. The composite incidence of MBEs and thromboembolic events (stroke/systemic embolism/TIA) was lower in the dabigatran etexilate arm (5 [1.6%] vs. 23 [7.2%] patients). This exploratory study demonstrated that dabigatran etexilate was associated with a significant reduction in MBE rate compared with INR-adjusted warfarin in the setting of ablation.
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 heart 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 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.
Clinical trials in treatment of acute deep vein thrombosis (DVT) and/or pulmonary embolism (PE): Clinical evidence has demonstrated dabigatran etexilate to be an effective and safe treatment for DVT and/or PE 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 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 acute treatment period.
In the pooled RE-COVER and RE-COVER II studies, a total of 5,153 patients were randomized and 5,107 were treated. The index events at baseline: DVT - 68.5%, PE -22.2%, PE and DVT - 9.1%. The most frequent risk factors were history of DVT and/or PE - 21.5%, surgery/trauma -18.1%, venous insufficiency - 17.6%, and prolonged immobilisation -14.6%. Patients' baseline characteristics: mean age was 54.8 years, males 59.5%, Caucasian 86.1%, Asian 11.8%, blacks 2.1%. The co-morbidities included: hypertension 35.5%, diabetes mellitus 9.0%, CAD 6.8% and gastric or duodenal ulcer 4.1%.
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%. Concomitant medications included vasodilators 28.5%, agents acting on the renin-angiotensin system 24.7%, lipids lowering agents 19.1%, beta-blockers 14.8%, calcium channel blockers 9.7%, NSAIDs 21.7%, aspirin 9.2%, antiplatelet agents 0.7%, P-gp inhibitors 2.0% (verapamil -1.2% and amiodarone -0.4%).
Two trials in patients presenting with acute DVT and/or PE treated initially for at least 5 days of parenteral therapy, RE-COVER and RE-COVER II, demonstrated that treatment with dabigatran etexilate 150 mg twice daily was non-inferior to the treatment with warfarin (p values for non-inferiority: RE-COVER p<0.0001, RECOVER II p=0.0002). Bleeding events (MBEs, MBE/CRBEs and any bleeding) were significantly lower in patients receiving dabigatran etexilate 150 mg twice daily as compared with those receiving warfarin. (See Figure 2 and Table 7.)

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Clinical trials in Prevention of recurrent of deep vein thrombosis (DVT) and/or pulmonary embolism (PE): Clinical evidence has demonstrated dabigatran etexilate to be an effective and safe treatment for recurrent DVT and/or PE. 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. The index events at baseline: DVT - 65.1%, PE - 23.1%, PE and DVT -11.7%. Patients' baseline characteristics: mean age 54.6 years, males 61.0%, Caucasian 90.1%, Asian 7.9%, blacks 2.0%. Co-morbidities included hypertension 38.6 %, diabetes mellitus 9.0%, CAD 7.2 % and gastric or duodenal ulcer 3.8 %. Concomitant medications: agents acting on the renin-angiotensin system 27.9 %, vasodilators 26.7%, lipid lowering agents 20.6%, NSAIDs 18.3%, beta-blockers 16.3%, calcium channel blockers 11.1%, aspirin 7.7%, P-gp inhibitors 2.7% (verapamil 1.2% and amiodarone 0.7%), antiplatelets 0.9%. 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 (p=0.0135 for non-inferiority). Bleeding events (MBEs/CRBEs; any bleeding) were significantly lower in patients receiving dabigatran etexilate as compared with those receiving warfarin.
As in the pooled RE-COVER/RE-COVER II studies, in RE-MEDY concomitant use of P-gp inhibitors was reported by few patients (2.7%); verapamil (1.2%) and amiodarone (0.7%) were the most frequent. In the pooled acute VTE treatment studies, concomitant use of P-gp inhibitors was reported by few patients (2.0%); most frequent were verapamil (1.2% overall) and amiodarone (0.4% overall). (See Figure 3.)

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Table 8 displays details of key results of the RE-MEDY study. (See Table 8.)

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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.
The index events at baseline: DVT 64.5%, PE 27.8%, PE and DVT 7.7%. A total of 1,353 patients were randomized and 1,343 patients treated. Patients' baseline characteristics: mean age 55.8 years, males 55.5%, Caucasian 89.0%, Asian 9.3%, blacks 1.7%. Co-morbidities included hypertension 38.8%, diabetes mellitus 8.0%, CAD 6.0 % and gastric or duodenal ulcer 4.5%. Concomitant medications: agents acting on the renin-angiotensin system 28.7%, vasodilators 19.4%, lipid lowering agents 17.9%, beta-blockers 18.5%, calcium channel blockers 8.9%, NSAIDs 12.1%, aspirin 8.3%, antiplatelets 0.7% and P-gp inhibitors 1.7% (verapamil 1.0% and amiodarone 0.3%).
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 of 92% 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 rates of MBEs and the combination of MBEs/CRBEs were significantly higher in patients receiving dabigatran etexilate as compared with those receiving 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 (0.42, 0.88), p=0.0082). (See Figure 4.)

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Table 9 displays details of key results of the RE-SONATE study. (See Table 9.)

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Other Measures Evaluated: Treatment of acute deep vein thrombosis (DVT) and/or pulmonary embolism (PE) and prevention of recurrent deep vein thrombosis (DVT) and/or pulmonary embolism (PE): In the three active controlled 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.
Liver Function Tests: Treatment of acute deep vein thrombosis (DVT) and/or pulmonary embolism (PE) and prevention of recurrent deep vein thrombosis (DVT) and/or pulmonary embolism (PE): In the active controlled studies RE-COVER, RE-COVER II and RE-MEDY, potential abnormalities of liver function tests (LFT) occurred with a comparable or lower incidence in dabigatran etexilate vs. warfarin treated patients. In RE-SONATE, there was no marked difference between the dabigatran- and placebo groups with regard to possible clinically significant abnormal LFT values.
Pharmacokinetics: After oral administration of dabigatran etexilate in healthy volunteers, the pharmacokinetic profile of dabigatran in plasma is characterized by a rapid increase in plasma concentrations with peak concentration (C_max) attained within 0.5 and 2.0 hours post administration. C_max and the area under the plasma concentration-time curve (AUC) were dose proportional. After C_max, plasma concentrations of dabigatran showed a biexponential decline with a mean terminal half-life of approximately 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. However, half-life is prolonged if renal function is impaired as shown as follows, in Table 10. (See Table 10.)

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The absolute bioavailability of dabigatran following oral administration of dabigatran etexilate as HPMC capsule was approximately 6.5 %.
Food does not affect the bioavailability of dabigatran etexilate but delays the time to peak plasma concentrations by 2 hours.
The oral bioavailability may be increased by about 1.4-fold (+37%) compared to the reference capsule formulation when the pellets are taken without the 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. Therefore, patients should be advised not to open the capsules and taking the pellets alone (e.g. sprinkled over food or into beverages) (see "Dosage & Administration").
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, or at 7 to 9 hours following surgery (BISTRO Ib). It is noted however that contributing factors such as anesthesia, gastrointestinal paresis, and surgical effects will mean that a proportion of patients will experience absorption delay independent of the oral drug formulation. Although this study did not predict whether impaired absorption persists with subsequent doses, 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 drug administration.
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.
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. 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.
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.
Special populations: Renal impairment: The exposure (AUC) of dabigatran after the oral administration of dabigatran etexilate in a phase 1 study was approximately 3-fold higher in volunteers with moderate renal insufficiency (CrCL between 30-50ml/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" and "Contraindications").
Clearance of dabigatran by hemodialysis was investigated in patients with end-stage renal disease (ESRD) without atrial fibrillation. Dialysis was conducted with 700 mL/min dialysate flow rate, four hour duration, a blood flow rate of either 200 mL/min or 350 - 390 mL/min. This resulted in a removal of 50% or 60% of free- or total dabigatran concentrations, respectively. The amount of drug cleared by dialysis is proportional to the blood flow rate up to a blood flow rate of 300ml/min. The anticoagulant activity of dabigatran decreased with decreasing plasma concentrations and the PK/PD relationship was not affected by the procedure.
Prevention of stroke and systemic embolism in patients with non-valvular atrial fibrillation: 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).
Treatment of acute deep vein thrombosis (DVT) and/or pulmonary embolism (PE): The median CrCl in the RE-COVER study was 100.3 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 30-50mL/min). Patients with mild and moderate renal impairment had on average 1.7-fold and 3.4-fold higher steady state dabigatran trough concentrations compared with patients with CrCl > 80 mL/min. Similar values for CrCl were found in RE-COVER II.
Prevention of recurrent deep vein thrombosis (DVT) and/or pulmonary embolism (PE): 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 30-50 mL/min in the RE-MEDY and RE-SONATE studies.
Elderly: Specific pharmacokinetic studies with elderly subjects in phase 1 studies showed an increase of 1.4- to 1.6-fold (+40 to 60%) in the AUC and of more than 1.25-fold (+25 %) in C_max compared to young subjects.
The AUC_τ,ss and C_max,ss in male and female elderly subjects (> 65 y) were approximately 1.9 fold and 1.6-fold higher for elderly females compared to young females and 2.2 and 2.0 fold higher for elderly males than in male subjects of 18 - 40 years of age.
The observed increase of dabigatran exposure correlated with the age-related reduction in creatinine clearance.
The effect by age on exposure to dabigatran was confirmed in the RE-LY study with an about 1.3-fold (+31%) higher trough concentration for subjects ≥ 75 years and by about 22 % lower trough level for subjects <65 years compared to subjects of age between 65 and 75 years.
Hepatic insufficiency: No change in dabigatran exposure was seen in 12 subjects in a phase 1 study with moderate hepatic insufficiency (Child Pugh B) compared to 12 controls.
Primary prevention of venous thromboembolic events in adult patients who have undergone elective total hip replacement surgery or total knee replacement surgery: Patients with moderate and severe hepatic impairment (Child-Pugh classification B and C) or liver disease expected to have any impact on survival or with elevated liver enzymes ≥ 2 Upper Limit Normal (ULN) were excluded in clinical trials.
Prevention of stroke and systemic embolism in patients with non-valvular atrial fibrillation: Patients with active liver disease including but not limited to the persistent elevation of liver enzymes ≥ 2 Upper Limit Normal (ULN), or hepatitis A, B or C were excluded in clinical trials.
Treatment of acute deep vein thrombosis (DVT) and/or pulmonary embolism (PE): Patients with moderate and severe hepatic impairment (Child-Pugh classification B and C) or liver disease expected to have any impact on survival or with elevated liver enzymes ≥ 2 Upper Limit Normal (ULN) were excluded in clinical trials.
Prevention of recurrent deep vein thrombosis (DVT) and/or pulmonary embolism (PE): Patients with moderate and severe hepatic impairment (Child-Pugh classification B and C) or liver disease expected to have any impact on survival or with elevated liver enzymes ≥ 2 Upper Limit Normal (ULN) were excluded in clinical trials.
Body weight: The dabigatran trough concentrations were about 20% lower in patients with a BW > 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. Limited data in patients ≤ 50 kg are available.
Gender: Primary prevention of venous thromboembolic events in adult patients who have undergone elective total hip replacement surgery or total knee replacement surgery: Drug exposure in the primary VTE prevention studies was about 1.4- to 1.5-fold (+40 % to 50 %) higher in female patients. This finding had no clinical relevance.
Prevention of stroke and systemic embolism in patients with non-valvular atrial fibrillation: In atrial fibrillation patients females had on average 1.3-fold (+30 %) higher trough and post-dose concentrations. This finding had no clinical relevance.
Ethnic origin: The pharmacokinetics of dabigatran was investigated in Caucasian and Japanese volunteers after single and multiple doses. Ethnic origin does not affect the pharmacokinetics of dabigatran in a clinically relevant manner.
Limited pharmacokinetic data in black patients are available which suggest no relevant differences.
Pharmacokinetic interactions: In vitro interaction studies did not show any inhibition or induction of cytochrome P450. This has been confirmed by in vivo studies in healthy volunteers, who did not show any interaction between dabigatran etexilate treatment and the following drugs: atorvastatin (CYP3A4) and diclofenac (CYP2C9).
Atorvastatin: When dabigatran etexilate was coadministered with atorvastatin, a CYP3A4 substrate, exposure of atorvastatin, atorvastatin metabolites and of dabigatran were unchanged indicating a lack of interaction.
Diclofenac: When dabigatran etexilate was coadministered with diclofenac, a CYP2C9 substrate, pharmacokinetics of both drugs remained unchanged indicating a lack of interaction between dabigatran etexilate and diclofenac.
P-gp inhibitor / inducer interactions: The pro-drug dabigatran etexilate but not dabigatran is a substrate of the efflux transporter P-glycoprotein (P-gp). Therefore co-medications with P-gp transporter inhibitors and inducers have been investigated.
Co-medication with P-gp inhibitors: Amiodarone: When dabigatran etexilate was coadministered with a single oral dose of 600 mg amiodarone, the extent and rate of absorption of amiodarone and its active metabolite DEA were essentially unchanged. The dabigatran AUC and C_max were increased by about 1.6-fold and 1.5-fold (+60 % and 50 %), respectively.
Prevention of stroke and systemic embolism in patients with non-valvular atrial fibrillation: In the population pharmacokinetics study from RE-LY, no important changes in dabigatran trough levels were observed in patients who received amiodarone (see "Interactions").
Dronedarone: When dabigatran etexilate and dronedarone were given at the same time total dabigatran AUC_0-∞ and C_max values increased by about 2.4-fold and 2.3-fold (+136 % and 125%), respectively, after multiple dosing of 400 mg dronedarone bid, and about 2.1-fold and 1.9-fold (+114% and 87%), respectively, after a single dose of 400 mg. The terminal half-life and renal clearance of dabigatran were not affected by dronedarone. When single and multiple doses of dronedarone were given 2 h after dabigatran etexilate, the increases in dabigatran AUC_0-∞ were 1.3-fold and 1.6 fold, respectively.
Verapamil: When dabigatran etexilate was coadministered with oral verapamil, the C_max and AUC of dabigatran were increased depending on timing of administration and formulation of verapamil.
The greatest elevation of dabigatran exposure was observed with the first dose of an immediate release formulation of verapamil administered one hour prior to dabigatran etexilate intake (increase of C_max by about 2.8-fold (+180%) and AUC by about 2.5-fold (+150%)). The effect was progressively decreased with administration of an extended release formulation (increase of C_max by about 1.9-fold (+90%) and AUC by about 1.7-fold (+70%)) or administration of multiple doses of verapamil (increase of C_max by about 1.6-fold (+60%) and AUC by about 1.5-fold (+50%)). This can be explained by the induction of P-gp in the gut by chronic verapamil treatment.
There was no meaningful interaction observed when verapamil was given 2 hours after dabigatran etexilate (increase of C_max by about 10% and AUC by about 20%). This is explained by completed dabigatran absorption after 2 hours (see "Dosage & Administration").
No data are available for the parenteral application of verapamil; based on the mechanism of the interaction, no meaningful interaction is expected.
Prevention of stroke and systemic embolism in patients with non-valvular atrial fibrillation: In the population pharmacokinetics study from RE-LY, no important changes in dabigatran trough levels were observed in patients who received verapamil (see "Interactions").
Ketoconazole: Systemic ketoconazole increased total dabigatran AUC_0-∞ and C_max values by about 2.4-fold (+138% and 135%), respectively, after a single dose of 400 mg, and about 2.5-fold (+153% and 149%), respectively, after multiple dosing of 400 mg ketoconazole qd. The time to peak, terminal half-life and mean residence time were not affected by ketoconazole.
Clarithromycin: When clarithromycin 500 mg twice daily was administered together with dabigatran etexilate a modest PK-interaction was observed (increased of C_max by about 15 % and AUC by about 19%).
Quinidine: Quinidine was given as 200 mg dose every 2nd hour up to a total dose of 1000 mg. Dabigatran etexilate was given bid over 3 consecutive days, on the 3^rd day either with or without quinidine. Dabigatran AUC_τ,ss and C_max,ss were increased on average by about 1.5-fold (+53 % and 56 %), respectively with concomitant quinidine.
Ticagrelor: When a single dose of 75mg dabigatran etexilate was coadministered simultaneously with a loading dose of 180 mg ticagrelor, the dabigatran AUC and Cmax were increased by 1.73-fold and 1.95-fold (+73% and 95%), respectively. After multiple doses of ticagrelor 90 mg b.i.d. the increase of dabigatran exposure is reduced to 1.56-fold and 1.46-fold (+56% and 46%) for Cmax and AUC, respectively. Concomitant administration of a loading dose of 180 mg ticagrelor and 110 mg dabigatran etexilate (in steady state) increased the dabigatran AUC_τ,ss and by C_max,ss by 1.49-fold and 1.65-fold (+49% and 65%), respectively, compared with dabigatran etexilate given alone. When a loading dose of 180 mg ticagrelor was given 2 hours after 110 mg dabigatran etexilate (in steady state), the increase of dabigatran AUC_τ,ss and C_max,ss was reduced to 1.27-fold and 1.23-fold (+27% and 23%), respectively, compared with dabigatran etexilate given alone. Concomitant administration of 90 mg ticagrelor BID (maintenance dose) with 110 mg dabigatran etexilate increased the adjusted dabigatran AUC_τ,ss and C_max,ss 1.26-fold 1.29-fold, respectively, compared with dabigatran etexilate given alone.
Co-medication with P-gp substrates: Digoxin: When dabigatran etexilate was coadministered with digoxin, a P-gp substrate, no PK-interaction was observed. Neither dabigatran nor the pro-drug dabigatran etexilate is a clinically relevant P-gp inhibitor.
Co-medication with P-gp inducers: Rifampicin: Pre-dosing of the probe inducer rifampicin at a dose of 600 mg qd for 7 days decreased total dabigatran peak and total exposure by 65.5 and 67 %, respectively. The inducing effect was diminished resulting in dabigatran exposure close to the reference by day 7 after cessation of rifampicin treatment. No further increase in bioavailability was observed after another 7 days.
Co-medications with platelet-inhibitors: Acetylsalicylic acid (ASA): The effect of concomitant administration of dabigatran etexilate and acetylsalicylic acid (ASA) on the risk of bleeds was studied in patients with atrial fibrillation in a phase II study in which a randomized ASA coadministration was applied. Based on logistic regression analysis, co-administration of ASA and 150 mg dabigatran etexilate twice daily may increase the risk for any bleeding from 12 % to 18 % and 24% with 81 mg and 325 mg ASA, respectively.
From the data gathered in the phase III study RE-LY it was observed that ASA or clopidogrel co-medication with dabigatran etexilate at dosages of 110 or 150 mg bid may increase the risk of major bleeding. The higher rate of bleeding events by ASA or clopidogrel co-medication was, however, also observed for warfarin.
NSAIDs: NSAIDs given for short-term perioperative analgesia have been shown not to be associated with increased bleeding risk when given in conjunction with dabigatran etexilate. There is limited evidence regarding the use of regular NSAID medication with half-lives of less than 12 hours during treatment with dabigatran etexilate and this has not suggested additional bleeding risk.
Prevention of stroke and systemic embolism in patients with non-valvular atrial fibrillation: NSAIDs increased the risk of bleeding in RE-LY in all treatment groups.
Clopidogrel: In a phase I study in young healthy male volunteers, the concomitant administration of dabigatran etexilate and clopidogrel resulted in no further prolongation of capillary bleeding times (CBT) compared to clopidogrel monotherapy. In addition, dabigatran AUC_τ,ss and C_max,ss and the coagulation measures for dabigatran effect, aPTT, ECT or TT (anti FIIa), or the inhibition of platelet aggregation (IPA) as measure of clopidogrel effect remained essentially unchanged comparing combined treatment and the respective mono-treatments. With a loading dose of 300 or 600 mg clopidogrel, dabigatran AUC_τ,ss and C_max,ss were increased by about 1.3- to 1.4-fold (+30 to 40%) (see previously mentioned subsection on ASA).
Antiplatelets or other anticoagulants: The concomitant use of dabigatran etexilate and antiplatelets or other anticoagulants may increase the risk of bleeding (see "Precautions").
Co-medication with selective serotonin re-uptake inhibitors: SSRIs increased the risk of bleeding in RE-LY in all treatment groups.
Co-medication with gastric pH-elevating agents: The changes in dabigatran exposure determined by population pharmacokinetic analysis caused by PPIs and antacids were not considered clinically relevant because the magnitude of the effect were minor (fractional decrease in bioavailability not significant for antacids and 14.6% for PPIs).
Pantoprazole: When dabigatran etexilate was coadministered with pantoprazole, a decrease in dabigatran area under the plasma concentration - time curve of approximately 30 % was observed. Pantoprazole and other proton-pump inhibitors were co-administered with dabigatran etexilate in clinical trials and no effects on bleeding or efficacy were observed.
Prevention of stroke and systemic embolism in patients with non-valvular atrial fibrillation: In the phase III study, RE-LY, PPI co-medication did not result in lower trough levels and on average only slightly reduced post-dose concentrations (- 11%). Accordingly, PPI co-medication seemed to be not associated with a higher incidence of stroke or SEE, especially in comparison with warfarin, and hence, the reduced bioavailability by pantoprazole co-administration seemed to be of no clinical relevance.
Ranitidine: Ranitidine administration together with dabigatran etexilate had no meaningful effect on the extent of absorption of dabigatran.

110mg Capsule: 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 patients with non-valvular atrial fibrillation.
Treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE), and prevention of recurrent DVT and PE in adults.
150mg Capsule: Prevention of stroke and systemic embolism in patients with non-valvular atrial fibrillation.
Treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE), and prevention of recurrent DVT and PE in adults.

Primary prevention of Venous Thromboembolism (VTE) events in adult patients who have undergone elective knee replacement surgery: The recommended dose of PRADAXA is 220 mg once daily taken as 2 capsules of 110 mg. Treatment should be initiated orally within 1 - 4 hours of completed surgery with a single capsule and continuing with 2 capsules once daily thereafter for a total of 10 days.
Primary prevention of Venous Thromboembolism (VTE) events in adult patients who have undergone elective hip replacement surgery: The recommended dose of PRADAXA is 220 mg once daily taken as 2 capsules of 110 mg. Treatment should be initiated orally within 1 - 4 hours of completed surgery with a single capsule and continuing with 2 capsules once daily thereafter for a total of 28-35 days.
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 of 110 mg once daily.
Prevention of stroke and systemic embolism in patients with non-valvular atrial fibrillation: The recommended daily dose of PRADAXA is 300 mg taken orally as 150 mg hard capsules twice daily.
Treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE), and prevention of recurrent DVT, and PE in adults: The recommended daily dose of PRADAXA is 300mg taken as one 150 mg capsule twice daily following treatment with a parenteral anticoagulant for at least 5 days. The duration of therapy should be individualized after careful assessment of the treatment benefit against the risk of bleeding. Short duration of therapy (at least 3 months) should be based on transient risk factors (eg. recent surgery, trauma, immobilization) and longer durations should be based on permanent risk factors or idiopathic DVT or PE.
SPAF, DVT/PE: For the following groups the recommended daily dose of PRADAXA is 220mg taken as one 110mg capsule twice daily: Patients aged 80 years or above; Patients who receive concomitant verapamil.
For the following groups the daily dose of PRADAXA of 300mg or 220mg should be selected based on an individual assessment of the thromboembolic risk and the risk of bleeding: Patients between 75-80 years; Patients with moderate renal impairment; Patients with gastritis, esophagitis or gastroesophageal reflux; Other patients at increased risk of bleeding.
The recommendation for the use of PRADAXA 220mg taken as one 110mg capsule twice daily is based on pharmacokinetic and pharmacodynamics analyses and has not been studied in this clinical setting.
In case of intolerability to dabigatran, 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 SEE associated with atrial fibrillation or for DVT/PE.
Special patient populations: Renal impairment: Renal function should be assessed by calculating the creatinine clearance (CrCl) prior to initiation of treatment with PRADAXA to exclude patients for treatment with severe renal impairment (i.e. CrCl <30ml/min). There are no data to support use in patients with severe renal impairment (creatinine clearance <30 ml/min). Given the substantial increase in dabigatran exposure observed in this patient population, treatment in this population with PRADAXA is not recommended (see "Contraindications").
While on treatment renal function should be assessed in certain clinical situations when it is suspected that the renal function could decline or deteriorate (such as hypovolemia, dehydration, and with certain comedications, etc).
Dabigatran can be dialysed; there is limited clinical experience to demonstrate the utility of this approach in clinical studies.
Primary prevention of venous thromboembolic events in adult patients who have undergone elective total hip replacement surgery or total knee replacement surgery: In patients with moderate renal impairment (creatinine clearance 30-50 ml/min), there is limited clinical experience. These patients should be treated with caution. The recommended dose is 150 mg taken once daily as 2 capsules of 75 mg (see Precautions and Pharmacology under Actions).
After knee replacement surgery treatment should be initiated orally within 1 - 4 hours of completed surgery with a single capsule and continuing with 2 capsules of 75 mg once daily thereafter for a total of 10 days.
After hip replacement surgery treatment should be initiated orally within 1 - 4 hours of completed surgery with a single capsule and continuing with 2 capsules of 75 mg once daily thereafter for a total of 28-35 days.
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 of 75 mg once daily.
Prevention of stroke and systemic embolism in patients with non-valvular atrial fibrillation; treatment of DVT and PE, and prevention of recurrent DVT and PE in adults: Treatment with PRADAXA in patients with severe renal impairment (CrCL<30mL/min) is contraindicated.
No dose adjustment is necessary in patients with mild renal impairment (CrCL 50 -≤80mL/min). For patients with moderate renal impairment (CrCL 30 - 50mL/min) the recommended dose of PRADAXA is also 300mg taken as one 150mg capsule twice daily. However for patients with high risk of bleeding a dose reduction of PRADAXA to 220mg taken as one 110mg capsule twice daily should be considered. Close clinical surveillance is recommended in patients with renal impairment.
Elderly: Primary prevention of venous thromboembolic events in adult patients who have undergone elective total hip replacement surgery or total knee replacement surgery: As renal impairment may be frequent in the elderly (>75 years), renal function should be assessed by calculating the creatinine clearance (CrCl) prior to initiation of treatment with PRADAXA to exclude patients for treatment with severe renal impairment (i.e. CrCl < 30ml/min). The renal function should also be assessed in certain clinical situations when it is suspected that the renal function could decline or deteriorate (such as hypovolemia, dehydration, and with certain comedications, etc).
In elderly patients (> 75 years) there is limited clinical experience. These patients should be treated with caution. The recommended dose is 150 mg taken once daily as 2 capsules of 75 mg (see Precautions and Pharmacology under Actions).
After knee replacement surgery treatment should be initiated orally within 1 - 4 hours of completed surgery with a single capsule and continuing with 2 capsules once daily thereafter for a total of 10 days.
After hip replacement surgery treatment should be initiated orally within 1 - 4 hours of completed surgery with a single capsule and continuing with 2 capsules once daily thereafter for a total of 28-35 days.
Prevention of stroke and systemic embolism in patients with non-valvular atrial fibrillation; treatment of DVT and PE, and prevention of recurrent DVT and PE: Patients between 75-80 years should be treated with a daily dose of 300mg taken as one 150mg capsule twice daily. A dose of 220mg taken as one 110mg capsule twice daily can be individually considered, at the discretion of the physician, when the thromboembolic risk is low and the bleeding risk is high.
Patients aged 80 years or above should be treated with a daily dose of 220mg taken as one 110mg capsule twice daily due to the increased risk of bleeding in this population.
As renal impairment may be frequent in the elderly (>75 years), renal function should be assessed by calculating the creatinine clearance (CrCl) prior to initiation of treatment with PRADAXA to exclude patients for treatment with severe renal impairment (i.e. CrCl < 30ml/min). The renal function should also be assessed at least once a year in patients treated with PRADAXA or more frequently as needed in certain clinical situations when it is suspected that the renal function could decline or deteriorate (such as hypovolemia, dehydration, and with certain comedications, etc).
Pharmacokinetic studies in older subjects demonstrate an increase in drug exposure in those patients with age-related decline of renal function.
See also dose and administration in renal impairment.
Hepatic impairment: Patients with elevated liver enzymes > 2 upper limit of normal (ULN) were excluded in clinical trials. No treatment experience is available for this subpopulation of patients, and therefore the use of PRADAXA is not recommended in this population (see "Precautions" and "Pharmacology: Pharmacokinetics under Actions"). Hepatic impairment or liver disease expected to have any impact on survival is contraindicated.
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 in patients with a body weight <50kg (see "Precautions").
Gender: Given the available clinical and kinetic data, no dose adjustment is necessary (see "Pharmacology: Pharmacokinetics under Actions").
Post-surgical patients with an increased risk for bleeding: Patients at risk for bleeding or patients at risk of overexposure, notably patients with moderate renal impairment (creatinine clearance 30 - 50 ml/min), should be treated with caution (see Precautions and Pharmacology under Actions).
Children and adolescents: There is no experience in children and adolescents.
PRADAXA is not recommended for use in patients below 18 years due to lack of data on safety and efficacy.
Concomitant use of PRADAXA with strong P-glycoprotein inhibitors, i.e. Amiodarone, Quinidine or Verapamil: Primary prevention of venous thromboembolic events in adult patients who have undergone elective total hip replacement surgery or total knee replacement surgery: Dosing should be reduced to 150 mg PRADAXA taken once daily as 2 capsules of 75mg in patients who concomitantly receive PRADAXA and amiodarone, quinidine or verapamil (see "Interactions").
Treatment initiation with verapamil should be avoided in patients who have undergone major orthopaedic surgery who are already treated with PRADAXA. Simultaneous initiation of treatment with PRADAXA and verapamil should also be avoided.
Treatment with PRADAXA should be initiated orally within 1 - 4 hours of completed surgery with a single capsule of 75 mg and continuing with 2 capsules of 75 mg once daily thereafter for a total of 10 days (following knee replacement surgery) or 28-35 days (following hip replacement surgery).
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 of 75 mg once daily.
Prevention of stroke and systemic embolism in patients with non-valvular atrial fibrillation; treatment of DVT and PE, and prevention of recurrent DVT and PE: No dose adjustment is necessary for concomitant use of amiodarone or quinidine.
Dosing should be reduced to 220mg taken as one 110mg capsule twice daily in patients who receive concomitantly dabigatran etexilate and verapamil. In this situation PRADAXA and verapamil should be taken at the same time.
Patients at risk of bleeding (SPAF/DVT/PE): Patients with an increased risk of bleeding (see Haemorrhagic risk under Precautions and Table 11), 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. A coagulation test 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 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, the dose of 220 mg taken as one 110 mg capsule twice daily may be considered due to the elevated risk of major gastro-intestinal bleeding.
Close clinical surveillance (looking for signs of bleeding or anaemia) is recommended throughout the treatment period, especially if risk factors are combined.
Table 11 summarises factors which may increase the haemorrhagic risk. Also refer to contraindications. (See Table 11.)

Click on icon to see table/diagram/image

The measurement of dabigatran-related anticoagulation may be helpful to avoid excessive high exposure to dabigatran in the presence of additional risk factors.
In patients who are bleeding, an aPTT test may be useful to assist in determining an excess of anticoagulant activity, despite its limited sensitivity. An aPTT > 80 sec at trough, i.e., when the next dose is due, is associated with a higher risk of bleeding (see Monitoring and Laboratory Tests under Precautions).
Should severe bleeding occur, treatment with PRADAXA must be discontinued and the source of bleeding investigated promptly.
Assessment of renal function (SPAF, DVT/PE): In all patients: 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). PRADAXA is contraindicated in patients with severe renal impairment.
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 used to estimate renal function (CrCL in mL/min) during the clinical development of PRADAXA was the Cockcroft-Gault method. The formula is as follows:
For creatinine in μmol/L: See Equation 1:

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For creatinine in mg/dL: See Equation 2:

Click on icon to see table/diagram/image

This method is recommended when assessing patients' CrCL prior to and during PRADAXA treatment.
Switching from PRADAXA treatment to parenteral anticoagulant: Primary prevention of venous thromboembolic events in adult patients who have undergone elective total hip replacement surgery or total knee replacement surgery: It is recommended to wait 24 hours after the last dose before switching from PRADAXA to a parenteral anticoagulant (see Interactions).
Prevention of stroke and systemic embolism in patients with non-valvular atrial fibrillation; treatment of DVT and PE, and prevention of recurrent DVT and PE: It is recommended to wait 12 hours after the last dose before switching from PRADAXA to a parenteral anticoagulant.
Switching from parenteral anticoagulants treatment to PRADAXA: PRADAXA should be given 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 UFH).
Switching from Vit. K antagonists to PRADAXA: Prevention of stroke and systemic embolism in patients with non valvular atrial fibrillation; treatment of DVT and PE, and prevention of recurrent DVT and PE: The Vit. K antagonist should be stopped. PRADAXA can be given as soon as the INR is < 2.0.
Switching from PRADAXA to Vit. K antagonists (VKA): Prevention of stroke and systemic embolism in patients with non-valvular atrial fibrillation: Treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE), and prevention of recurrent DVT, and PE in adults (DVT/PE): As with any short-acting anticoagulant, there is a potential for inadequate anticoagulation when transitioning from PRADAXA to a VKA. It is important to maintain an adequate level of anticoagulation when transitioning patients from one anticoagulant to another. The starting time of the VKA should be adjusted according to the patient's calculated creatinine clearance CrCL as follows: CrCL ≥ 50 ml/min, start VKA 3 days before discontinuing dabigatran etexilate.
CrCL ≥ 30-< 50 ml/min, start VKA 2 days before discontinuing dabigatran etexilate.
In general, after starting VKA therapy, its clinically relevant anticoagulant effect is not readily apparent for at least 2 days, while the full therapeutic effect is achieved in about 5-7 days.
Because PRADAXA can increase 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.
Note that when converting a patient from PRADAXA to vitamin K antagonist therapy, the INR will not reliably reflect the anticoagulant effect of VKA until at least 2 days after discontinuation of PRADAXA. In switching from PRADAXA to VKA, the INR should only be used to assess the anticoagulant effect of the VKA, and not that of PRADAXA, since it is not a valid measure to assess the anticoagulant activity of PRADAXA. The INR is only calibrated and validated for VKA and should not be used for any other anticoagulant, including PRADAXA.
Catheter ablation for atrial fibrillation: Prevention of stroke and systemic embolism in patients with non-valvular atrial fibrillation: Catheter ablation can be conducted in patients on 150 mg twice daily PRADAXA treatment. PRADAXA treatment does not need to be interrupted (see "Pharmacology under Actions").
Cardioversion: Prevention of stroke and systemic embolism in patients with non-valvular atrial fibrillation: Treatment of deep vein thrombosis (DVT) and pulmonary (PE), and prevention of recurrent DVT, and PE in adults (DVT/PE): Patients can stay on PRADAXA while being cardioverted.
Missed dose: Primary prevention of venous thromboembolic events in adult patients who have undergone elective total hip replacement surgery or total knee replacement surgery: Continue with the remaining daily doses of PRADAXA at the same time of the next day. Do not take a double dose to make up for missed individual doses.
Prevention of stroke and systemic embolism in patients with non-valvular atrial fibrillation; treatment of DVT and PE, and prevention of recurrent DVT and PE: 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.
Do not take a double dose to make up for missed individual doses.
Method of administration: PRADAXA hard capsules can be taken with or without food. PRADAXA hard capsules should be swallowed as a whole with a glass of water, to facilitate delivery to the stomach. If gastrointestinal symptoms develop it is recommended to take Pradaxa with a meal and/or a proton pump inhibitor such as pantoprazole. Patients should be instructed not to open the capsule as this may increase the risk of bleeding.

Overdose following administration of PRADAXA may lead to haemorrhagic complications due to its pharmacodynamic properties. Doses of PRADAXA beyond those recommended expose the patient to increased risk of bleeding. In the event of haemorrhagic complications, treatment must be discontinued and the source of bleeding investigated. Since dabigatran is excreted predominantly by the renal route adequate diuresis must be maintained.
Depending on the clinical situation, appropriate standard treatment, e.g. surgical haemostasis as indicated and blood volume replacement, should be undertaken.
For situations when rapid reversal is required the specific reversal agent (PRAXBIND, idarucizumab) antagonising the pharmacodynamics effect of PRADAXA is available (see "Surgery and Interventions, and Pre-operative Phase under Precautions"). In addition, consideration may be given to the use of fresh whole blood or fresh frozen plasma. Coagulation factor concentrations (activated or non-activated) or recombinant Factor VIIa may be taken into account. There is some experimental evidence to support the role of these agents in reversing the anticoagulant effect of dabigatran but their usefulness in clinical settings has not yet been systematically demonstrated. Consideration should also be given to administration of platelet concentrates in cases where thrombocytopenia is present or long acting antiplatelet drugs have been used. All symptomatic treatment has to be given according to the physician's judgement.
As protein binding is low, dabigatran is dialysable, however, there is limited clinical experience in using dialysis in this setting (see "Pharmacology: Pharmacodynamics: Special populations under Actions").

Hypersensitivity to the active substance or to any of the excipients.
Patients with severe renal impairment (CrCl < 30 ml/min) (see "Dosage & Administration").
Active clinically significant bleeding.
Hepatic impairment or liver disease expected to have any impact on survival.
Concomitant treatment with systemic ketoconazole, cyclosporine, itraconazole and dronedarone (see Interactions).
Prosthetic heart valve replacement requiring anticoagulant treatment (see Pharmacology under Actions).
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 anticoagulant agent 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 of switching anticoagulant therapy (see "Dosage & Administration") or when UFH is given at doses necessary to maintain an open central venous or arterial catheter (see "Interactions").

Hepatic impairment: Patients with elevated liver enzymes > 2 ULN were excluded in main trials. No treatment experience is available for this subpopulation of patients, and therefore the use of PRADAXA is not recommended in this population.
Haemorrhagic risk: As with all anticoagulants, PRADAXA should be used with caution in conditions with an increased risk of bleeding. Bleeding can occur at any site during therapy with PRADAXA. An unexplained fall in hemoglobin and/or hematocrit or blood pressure should lead to a search for a bleeding site.
For situation of life-threatening or uncontrolled bleeding, when rapid reversal of the anticoagulation effects of dabigatran is required, the specific reversal agent (PRAXBIND, idarucizumab) is available (see "Surgery and Interventions, and Pre-operative Phase under Precautions" and "Overdosage".)
PRADAXA treatment does not require anticoagulant monitoring. The INR test is unreliable in patients on PRADAXA and false positive INR elevations have been reported. Therefore INR tests should not be performed.
Tests of anticoagulant activity such as thrombin time (TT), ecarin clotting time (ECT) and activated partial thromboplastin time (aPTT) are available to detect excessive dabigatran activity.
Dabigatran related anticoagulation can be assessed by ECT or TT. If ECT or TT is not available, the aPTT test provides an approximation of PRADAXA's anticoagulant activity.
Table 12 shows coagulation test thresholds at trough that may be associated with an increased risk of bleeding. (See Table 12.)

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Prevention of stroke and systemic embolism in patients with non-valvular atrial fibrillation: In atrial fibrillation patients in RE-LY treated with 150 mg bid an aPTT of greater than 2.0 - 3.0 fold of normal range at trough was associated with an increased risk of bleeding.
Close clinical surveillance (looking for signs of bleeding or anaemia) is recommended throughout the treatment period, especially in the following situations that may increase the hemorrhagic risk: diseases associated with an increased risk of bleeding, such as congenital or acquired coagulation disorders, thrombocytopenia or functional platelet defects, active ulcerative gastrointestinal disease, recent biopsy or major trauma, recent intracranial haemorrhage or brain, spinal or ophthalmic surgery, bacterial endocarditis.
Pharmacokinetic studies demonstrated an increase in drug exposure in patients with reduced renal function including age-related decline of renal function. PRADAXA is contraindicated in cases of severe renal impairment (CrCL < 30 mL/min).
Patients who develop acute renal failure should discontinue PRADAXA.
Factors, such as decreased renal function (30 - 50mL/min CrCL), age ≥ 75 years, or strong P-gp-inhibitor comedication are associated with increased dabigatran plasma levels. The presence of one or more than one of these factors may increase the risk of bleeding (see "Dosage & Administration").
The concomitant use of PRADAXA with the following treatments has not been studied and may increase the risk of bleeding: unfractionated heparins (except at doses necessary to maintain patency of central venous or arterial catheter) and heparin derivatives, low molecular weight heparins (LMWH), fondaparinux, desirudin, thrombolytic agents, GPIIb/IIIa receptor antagonists, ticlopidine, dextran, sulfinpyrazone, rivaroxaban, prasugrel, vitamin K antagonists, and the P-gp inhibitors, itraconazole, tacrolimus, cyclosporine, ritonavir, tipranavir, nelfinavir and saquinavir.
The concomitant use of dronedarone increases exposure of dabigatran and is not recommended (see "Pharmacology: Pharmacokinetics: Special populations under Actions").
The concomitant use of ticagrelor increases the exposure to dabigatran and may show pharmacodynamic interaction, which may result in an increased risk of bleeding.
Bleeding risk may be increased in patients concomitantly treated with selective serotonin re-uptake inhibitors (SSRI) or selective serotonin norepinephrine re-uptake inhibitors (SNRIs).
Use of fibrinolytic agents for the treatment of acute ischemic stroke: The use of fibrinolytic agents for the treatment of acute ischemic stroke may be considered if the patient presents with a thrombin time (TT), or Ecarin clotting time (ECT), or activated partial thromboplastin time (aPTT) not exceeding the upper limit of normal (ULN) according to the local reference range.
In situations where there is an increased haemorrhagic risk (e.g. recent biopsy or major trauma, bacterial endocarditis) close observation (looking for signs of bleeding or anaemia) is generally required.
Primary prevention of venous thromboembolic events in adult patients who have undergone elective total hip replacement surgery or total knee replacement surgery: NSAIDs given for short-term perioperative analgesia have been shown not to be associated with increased bleeding risk when given in conjunction with PRADAXA. There is limited evidence regarding the use of regular NSAID medication with half-lives of less than 12 hours during treatment with PRADAXA and this has not suggested additional bleeding risk.
Prevention of stroke and systemic embolism in patients with non-valvular atrial fibrillation: Co-administration of anti-platelet (including ASA and clopidogrel) and NSAID therapies increase the risk of bleeding. Specifically, with concomitant intake of antiplatelets or strong P-gp inhibitors in patients aged ≥75years, the risk of major bleeding, including gastrointestinal bleeding, increases. If bleeding is clinically suspected, appropriate measures such as testing for occult blood in stool, or testing for a drop in hemoglobin is suggested.
Interaction with P-gp inducers: The concomitant use of PRADAXA with the strong P-gp inducer rifampicin reduces dabigatran plasma concentrations. Other P-gp inducers such as St. John`s Wort or carbamazepine are also expected to reduce dabigatran plasma concentrations, and should be co-administered with caution (see "Interactions" and "Pharmacology: Pharmacokinetics: Special populations under Actions").
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 (see also "Pharmacology: Pharmacokinetics under Actions").
Patients can stay on PRADAXA while being cardioverted. PRADAXA treatment (150 mg twice daily) does not need to be interrupted in patients undergoing catheter ablation for atrial fibrillation (see "Dosage & Administration").
In case of emergency surgery or urgent procedures 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 hemostasis has been achieved.
Preoperative Phase: Due to an increased risk of bleeding PRADAXA may be stopped temporarily in advance of invasive or surgical procedures.
Emergency Surgery or Urgent Procedure: The specific reversal agent (PRAXBIND, idarucizumab) of PRADAXA is available for the rapid reversal of the anticoagulation effect (see "Surgery and Interventions" as previously mentioned).
Acute Surgery/Intervention: If an acute intervention is required, PRADAXA should be temporarily discontinued. An acute surgery/intervention should be delayed if possible until at least 12 hours after the last dose. If surgery cannot be delayed there may be an increase in the risk of bleeding.
Elective Surgery/Intervention: 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 hemostasis may be required consider stopping PRADAXA 2-4 days before surgery. Clearance of dabigatran in patients with renal insufficiency may take longer. This should be considered in advance of any procedures (see Table 13 and also "Pharmacology: Pharmacokinetics under Actions"). (See Table 13.)

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PRADAXA is contraindicated in patients with severe renal dysfunction (CrCl <30 mL/min) but should this occur then PRADAXA should be stopped at least 5 days before major surgery.
If an acute intervention is required, 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 there may be an increase in the risk of bleeding. This risk of bleeding should be weighed together with the urgency of intervention.
Patients with moderate renal impairment have an increased exposure to dabigatran. Limited data is available in patients < 50 kg and the elderly. In these situations, PRADAXA should be used with caution and a close clinical surveillance (looking for signs of bleeding or anemia) is required throughout the treatment period. When severe bleedings occur treatment must be discontinued and the source of bleeding investigated. Agents that may enhance the risk of haemorrhage should not be administered concomitantly or should be administered with caution with PRADAXA.
Patients at high surgical mortality risk and with intrinsic risk factors for thromboembolic events: There are limited efficacy and safety data for dabigatran available in these patients and therefore they should be treated with caution.
Spinal anesthesia/epidural anesthesia/lumbar puncture: Procedures such as spinal anesthesia may require complete hemostatic 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 hematoma.
Post Procedural Period: Resume treatment after complete haemostasis is achieved.
Hip fracture surgery: There is no data on the use of PRADAXA in patients undergoing hip fracture surgery. Therefore treatment is not recommended.
Myocardial Infarction (DVT/PE): In the three active controlled 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: No studies on the effects on the ability to drive and use machines have been performed.

Pregnancy: No clinical data on exposed pregnancies are available. The potential risk for humans is unknown.
Women of child-bearing potential should avoid pregnancy during treatment with PRADAXA and when pregnant, women should not be treated with PRADAXA unless the expected benefit is greater than the risk.
Lactation: No clinical data are available. As a precaution, breast-feeding should be stopped.
Fertility: No clinical data available. Non-clinical reproductive studies did not show any adverse effects on fertility or postnatal development of the neonate.

The safety of PRADAXA has been evaluated overall in 38,141 patients in 11 clinical trials; thereof 23,393 PRADAXA patients were investigated.
Primary prevention of venous thromboembolic events in adult patients who have undergone elective total hip replacement surgery or total knee replacement surgery: In the primary VTE prevention trials after elective total hip replacement or total knee replacement surgery, a total of 10,795 patients were treated in 6 controlled studies with at least one dose of dabigatran etexilate (150mg qd, 220mg qd, enoxaparin). 6,684 of the 10,795 patients were treated with 150 mg or 220 mg once daily of dabigatran etexilate. In total, about 9% of patients treated with dabigatran and about 10% of patients treated with enoxaparin for VTE prevention after elective hip or knee surgery (short-term treatment up to 42 days) experienced adverse reactions.
Prevention of stroke and systemic embolism in patients with non-valvular atrial fibrillation: In the RELY trial investigating the prevention of stroke and systemic embolism in patients with atrial fibrillation, a total of 12,042 patients were treated with dabigatran etexilate. Of these 6,059 were treated with 150 mg twice daily of dabigatran etexilate, while 5,983 received doses of 110 mg twice daily.
About 22% of patients with atrial fibrillation treated with dabigatran and about 16% of patients treated with warfarin for the prevention of stroke and systemic embolism (long-term treatment for up to 3 years) experienced adverse events considered related to treatment.
Treatment of acute deep vein thrombosis (DVT) and/or pulmonary embolism (PE): In the acute DVT/PE treatment trials (RE-COVER, RE-COVER II) a total of 2,553 patients were included in the safety analysis for dabigatran etexilate. All patients were treated with dabigatran etexilate 150 mg bid. 14% of patients treated for acute DVT/PE treatment (long-term treatment up to 6 months) experienced adverse reactions.
Prevention of recurrent deep vein thrombosis (DVT) and/or pulmonary embolism (PE): In the recurrent DVT/PE prevention trials (RE-MEDY, RE-SONATE) a total of 2,114 patients were treated with dabigatran etexilate; 552 of the 2,114 patients were rolled over from the RE-COVER trial (acute DVT/PE treatment) into the RE-MEDY trial and are counted in both the acute and recurrent patient totals. All patients were treated with dabigatran etexilate 150 mg bid and 15% of patients treated for recurrent DVT/PE prevention (long-term treatment up to 36 months) experienced adverse reactions.
Bleeding: Bleeding is the most relevant side effect of PRADAXA. Bleeding of any type or severity occurred in approximately 14 % of patients treated short-term for elective hip or knee replacement surgery; in long-term treatment in 16.6 % of patients with atrial fibrillation treated long-term for the prevention of stroke and systemic embolism; and in 14.4% of patients with acute DVT and/or PE. In the recurrent DVT/PE trial RE-MEDY 19.4% and in the RE-SONATE trial 10.5% of patients experienced any bleeding.
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.
Since the patient populations treated with PRADAXA for different indications are not interchangeable, a summary description of major and total bleeding is provided by indication and/or trial in Tables 14, 15 and 16 as follows.
Prevention of VTE after THR or TKR surgery: See Tables 14 and 15.

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Treatment of VTE and Prevention of Recurrent DVT and PE: See Table 16.

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Bleeding events for both treatments are counted from the first intake of dabigatran etexilate or warfarin after the parenteral therapy has been discontinued (oral only treatment period). This includes all bleeding events which occurred during dabigatran therapy. All bleeding events which occurred during warfarin therapy are included except for those during the overlap period between warfarin and parenteral therapy. (See Tables 17 and 18.)

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Prevention of stroke and systemic embolism in AF patients - the RELY trial: In Table 19, the category of major bleeds includes both life-threatening and non-life threatening bleeds. Intracranial bleeds is a subcategory of life-threatening bleeds. Intracranial bleeds include intracerebral (haemorrhagic stroke), subarachnoid and subdural bleeds. For this reason, these events may be counted in multiple categories. (See Table 19.)

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Prevention of stroke and systemic embolism in patients with non-valvular atrial fibrillation: Major bleeding fulfilled one or more of the following criteria: Bleeding associated with a reduction in hemoglobin of at least 20 grams per litre or leading to a transfusion of at least 2 units of blood or packed cells; Symptomatic bleeding in a critical area or organ: intraocular, intracranial, intraspinal or intramuscular with compartment syndrome, retroperitoneal bleeding, intra-articular bleeding or pericardial bleeding.
Major bleeds were classified as life-threatening if they fulfilled one or more of the following criteria: Fatal bleed; symptomatic intracranial bleed; reduction in hemoglobin of at least 50 grams per litre; transfusion of at least 4 units of blood or packed cells; a bleed associated with hypotension requiring the use of intravenous inotropic agents; a bleed that necessitated surgical intervention.
Subjects randomized to dabigatran etexilate 110 mg twice daily and 150mg twice daily had a significantly lower risk for life-threatening bleeds, haemorrhagic stroke and intracranial bleeding compared to warfarin [p< 0.05]. Both dose strengths of dabigatran etexilate had also a statistically significant lower total bleed rate. Subjects randomized to dabigatran etexilate 110mg twice daily had a significantly lower risk for major bleeds compared with warfarin (hazard ratio 0.81, p=0.0027).
Treatment of acute deep vein thrombosis (DVT) and/or pulmonary embolism (PE): The definition of major bleeding events (MBEs) followed the recommendations of the International Society on Thrombosis and Haemostasis. A bleeding event was categorised as an MBE if it fulfilled at least one of the following criteria: Fatal bleeding; Symptomatic bleeding in a critical area or organ, such as intracranial, intraspinal, intraocular, retroperitoneal, intra-articular, or pericardial, or intramuscular with compartment syndrome. In order for bleeding in a critical area or organ to be classified as an MBE it had to be associated with asymptomatic clinical presentation; Bleeding causing a fall in haemoglobin level of 20 g/L (1.24 mmol/L) or more, or leading to transfusion of 2 or more units of whole blood or red cells.
In a pooled analysis of the two pivotal trials (RE-COVER, RE-COVER II) in acute DVT/PE treatment, subjects randomized to dabigatran etexilate had lower rates of the following bleeding events, which were statistically significant: Major bleeding events (hazard ratio 0.60 (0.36, 0.99)); Major or clinically relevant bleeding events (CRBEs) (hazard ratio 0.56 (0.45, 0.71)); Any bleeding events (hazard ratio 0.67 (0.59, 0.77)).
All of which were superior vs. warfarin.
Bleeding events for both treatments are counted from the first intake of dabigatran etexilate or warfarin after the parenteral therapy has been discontinued (oral only treatment period). This includes all bleeding events which occurred during dabigatran therapy. All bleeding events which occurred during warfarin therapy are included except for those during the overlap period between warfarin and parenteral therapy.
Prevention of recurrent deep vein thrombosis (DVT) and/or pulmonary embolism (PE): The definition of MBEs followed the recommendations of the International Society on Thrombosis and Haemostasis. A bleeding in RE-MEDY event was categorised as an MBE if it fulfilled at least one of the following criteria: Fatal bleeding; Symptomatic bleeding in a critical area or organ, such as intracranial, intraspinal, intraocular, retroperitoneal, intra-articular, or pericardial, or intramuscular with compartment syndrome. In order for bleeding in a critical area or organ to be classified as an MBE it had to be associated with asymptomatic clinical presentation; Bleeding causing a fall in haemoglobin level of 20 g/L (1.24 mmol/L) or more, or leading to transfusion of 2 or more units of whole blood or red cells.
In RE-MEDY, patients randomized to dabigatran etexilate had significantly less bleeds compared to warfarin for the following categories: major bleeding events or clinically relevant bleeding events (hazard ratio 0.55 (0.41, 0.72), p<0.0001) and any bleeding events (hazard ratio 0.71 (0.61, 0.83), p<0.0001).
A bleeding event in RE-SONATE was categorised as an MBE if it fulfilled at least one of the following criteria: Fatal bleeding; Associated with a fall in haemoglobin of 2 g/dL or more; Led to the transfusion of ≥2 units packed cells or whole blood; Occurred in a critical site: intracranial, intraspinal, intraocular, pericardial, intra-articular, intramuscular with compartment syndrome, retroperitoneal.
In RE-SONATE, the rates of MBE were low (2 patients with MBEs (0.3%) for dabigatran etexilate vs. 0 patients with MBE (0%) for placebo. The rate of major bleeding events or clinically relevant bleeding events were higher with dabigatran etexilate compared with placebo (5.3% vs. 2.0%).
Clinical Trial Adverse Drug Reactions: Because clinical trials are conducted under very specific conditions the adverse reaction rates observed in the clinical trials may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug. Adverse drug reaction information from clinical trials is useful for identifying drug-related adverse events and for approximating rates.
Prevention of VTE after THR or TKR surgery: See Table 20.

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Treatment of VTE and Prevention of Recurrent DVT and PE: See Table 21.

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Prevention of stroke and systemic embolism in AF patients - RELY trial: See Table 22.

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Gastrointestinal adverse reactions occurred more often with dabigatran etexilate than warfarin. These were related to dyspepsia (including upper abdominal pain, abdominal pain, abdominal discomfort, epigastric discomfort), or gastritis-like symptoms (including GERD, esophagitis, erosive gastritis, gastric haemorrhage, hemorrhagic gastritis, hemorrhagic erosive gastritis, gastrointestinal ulcer).
Gastrointestinal (GI) haemorrhage occurred at a higher frequency with PRADAXA 150 mg bid, compared to warfarin (see Table 22 as previously mentioned). GI adjudicated major bleeds were reported at 1.1, 1.6%, and 1.1% (annualized rates) in the DE 110 mg, DE 150 mg and warfarin groups, respectively. GI life-threatening bleeds occurred with a frequency of 0.6%, 0.8% and 0.5% in the DE 110 mg, DE 150 mg and warfarin groups, respectively. Any GI bleeds occurred with frequency of 5.4%, 5.7% and 3.9% in the DE 110 mg, DE 150 mg and warfarin groups, respectively. The underlying mechanism of the increased rate of GI bleeding has not been established (see Pharmacology: Clinical trials in prevention of stoke and systemic embolism in patients with atrial fibrillation under Actions).
Allergic reactions or drug hypersensitivity including angioedema, urticaria, bronchospasm, rash and pruritus have been reported in patients who received dabigatran etexilate. Rare cases of anaphylactic reactions have also been reported.
Liver Function Tests: In the long-term RELY study, observed abnormalities of liver function tests (LFT) are presented as follows in Table 23. (See Table 23.)

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In the active controlled studies RE-COVER, RE-COVER II and RE-MEDY, potential abnormalities of LFTs occurred with a comparable or lower incidence in dabigatran etexilate vs. warfarin treated patients. In RE-SONATE, there was no marked difference between the dabigatran- and placebo groups with regard to possible clinically significant abnormal LFT values.
Less Common Clinical Trial Adverse Drug Reactions (<1%): Prevention of VTE after THR or TKR surgery (dabigatran 150 mg and 220 mg/day): Blood and lymphatic system: thrombocytopenia.
Gastrointestinal disorders: hemorrhoidal haemorrhage, rectal haemorrhage.
General: bloody discharge, catheter site haemorrhage.
Hepatobiliary disorders: alanine aminotransferase increased, aspartate aminotransferase increased, hepatic enzyme increased, hepatic function abnormal/liver function test abnormal, transaminases increased.
Injury, poisoning and procedural complications: incision site haemorrhage.
Laboratory Investigations: occult blood positive, blood urine present, hematocrit decrease.
Musculoskeletal and cumulative tissue disorders: hemarthrosis.
Respiratory and thoracic system: epistaxis.
Skin and sub-cutaneous tissue: ecchymosis.
Surgical and medical procedures: post-procedural drainage, wound drainage.
Vascular disorders: haemorrhage.
Treatment of VTE and Prevention of Recurrent DVT and PE (dabigatran 150 mg bid): Blood and lymphatic system disorders: anaemia, thrombocytopenia.
Vascular disorders: haematoma, haemorrhage.
Gastrointestinal disorders: diarrhoea, dysphagia, gastrointestinal ulcer (including esophageal ulcer), gastro-esophagitis, gastro-esophageal reflux disease, nausea, vomiting.
Hepatobiliary disorders: hepatic function abnormal.
Musculoskeletal and connective tissue and bone disorders: hemarthrosis.
General disorders and administration site conditions: catheter site haemorrhage, injection site haemorrhage.
Injury, poisoning and procedural complications: incision site haemorrhage, traumatic haemorrhage.
Immune system disorder: anaphylaxis*, angioedema, drug hypersensitivity (bronchospasm*, pruritus, rash, urticaria).
Respiratory disorders: hemoptysis.
Nervous system disorders: intracranial haemorrhage.
* These side effects were not reported in clinical trials as ADRs (AEs only); therefore, a frequency could not be calculated.
Prevention of stroke and systemic embolism in AF patients - the RE-LY trial (dabigatran 110 mg bid and 150 mg bid): Blood and lymphatic system disorders: thrombocytopenia.
Vascular disorders: haematoma, haemorrhage.
Gastrointestinal disorders: gastrointestinal ulcer (including oesophageal ulcer), gastro-esophagitis, gastro-esophageal reflux disease, vomiting, dysphagia.
Hepatobiliary disorders: hepatic function abnormal / liver function test abnormal, hepatic enzyme increased.
Musculoskeletal and connective tissue and bone disorders: haemarthrosis.
Renal and urinary disorders: urogenital haemorrhage.
General disorders and administration site conditions: injection site haemorrhage, catheter site haemorrhage.
Injury, poisoning and procedural complications: incision site haematoma, incision site haemorrhage, traumatic haemorrhage, traumatic hematoma.
Immune system disorder: anaphylaxis, drug hypersensitivity (bronchospasm*, pruritus, rash, urticaria).
Respiratory disorders: haemoptysis.
Nervous system disorders: intracranial haemorrhage.
* These side effects were not reported in clinical trials as ADRs (AEs only).

Interaction studies have only been performed in adults.
Anticoagulants and platelet aggregation agents: Concomitant use of PRADAXA with treatment that interfere with hemostasis or coagulation increases bleeding risk (see Bleeding under Precautions). The following treatments are not recommended concomitantly with PRADAXA: unfractionated heparins and heparin derivatives, low molecular weight heparins (LMWH), fondaparinux, desirudin, thrombolytic agents, GPIIb/IIIa receptor antagonists, clopidogrel, ticlopidine, dextran, sulfinpyrazone and vitamin K antagonists. It should be noted that unfractionated heparin can be administered at doses necessary to maintain a patent central venous or arterial catheter.
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 (see "Pharmacology: Pharmacokinetics: Special populations under Actions").
NSAIDs: NSAIDs given for short-term perioperative analgesia have been shown not to be associated with increased bleeding risk when given in conjunction with dabigatran etexilate. With chronic use in the RE-LY study, NSAIDs increased the risk of bleeding by approximately 50 % on both dabigatran etexilate and warfarin. Therefore, due to the risk of haemorrhage, notably with NSAIDs with elimination halflives >12 hours, close observation for signs of bleeding is recommended.
P-glycoprotein interactions: P-glycoprotein inhibitors: Dabigatran etexilate is a substrate for the efflux transporter P-gp. Concomitant administration of P-gp inhibitors (such as amiodarone, verapamil, quinidine, systemic ketoconazole, dronedarone, ticagrelor and clarithromycin) is expected to result in increased dabigatran plasma concentrations.
Concomitant administration of systemic ketoconazole is contraindicated.
Primary prevention of venous thromboembolic events in adult patients who have undergone elective total hip replacement surgery or total knee replacement surgery: For the concomitant use of P-gp inhibitors and dosing of PRADAXA in the indication, see "Dosage & Administration" and "Pharmacology: Pharmacokinetics: Special populations under Actions".
Prevention of stroke and systemic embolism in patients with non-valvular atrial fibrillation: Treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE), and prevention of recurrent DVT, and PE in adults (DVT/PE): For the P-gp inhibitors listed previously, no dose adjustments are required for PRADAXA in this indication.
Amiodarone is an inhibitor of the efflux transporter P-glycoprotein and dabigatran etexilate a substrate of this transporter. Dabigatran exposure in healthy subjects was increased by 1.6 fold (+60 %) in the presence of amiodarone (see "Pharmacology: Pharmacokinetics: Special populations under Actions"). In view of the long half-life of amiodarone the potential for drug interaction may exist for weeks after discontinuation of amiodarone.
Prevention of stroke and systemic embolism in patients with non-valvular atrial fibrillation: In patients in the RE-LY trial concentrations were increased by no more than 14% and no increased risk of bleeding was observed.
Verapamil: When PRADAXA (150mg) was coadministered with oral verapamil, the C_max and AUC of dabigatran were increased but the magnitude of this change differs, depending on timing of administration and formulation of verapamil (see "Pharmacology: Pharmacokinetics: Special populations under Actions").
Prevention of stroke and systemic embolism in patients with non-valvular atrial fibrillation: In patients in the RE-LY trial concentrations were increased by no more than 21% and no increased risk of bleeding was observed.
Quinidine: Dabigatran exposure in healthy subjects was increased by 1.5 fold (+53 %) in the presence of quinidine (see "Pharmacology: Pharmacokinetics: Special populations under Actions").
Clarithromycin: Dabigatan exposure in healthy subjects was increased by about 19% in the presence of clarithromycine without any clinical safety concern (see "Pharmacology: Pharmacokinetics: Special populations under Actions").
Ketoconazole: Dabigatran exposure was increased by 2.5 fold (+150%) after single and multiple doses of systemic ketoconazole (see "Contraindications" and "Pharmacology: Pharmacokinetics: Special populations under Actions").
Dronedarone: Dabigatran exposure was increased by 2.1 fold (+114%) after single or 2.4 fold (+136%) after multiple doses of dronedarone, respectively (see "Pharmacology: Pharmacokinetics: Special populations under Actions").
Ticagrelor: Dabigatran exposure in healthy subjects was increased by 1.46 fold (+ 46%) in the presence of ticagrelor at steady state or by 1.73 fold (+73%) when a loading dose of ticagrelor was administered simultaneously with a single dose of 75 mg dabigatran etexilate.
Dabigatran steady state exposure in healthy subjects was increased by 1.26 fold (+ 26 %) in the presence of ticagrelor at steady state or by 1.49 fold (+49%) when a loading dose of ticagrelor was administered simultaneously with 110 mg dabigatran etexilate. The increase in exposure was less pronounced when the180 mg ticagrelor loading dose was given two hours after dabigatran intake (+27%).
P-glycoprotein substrate: Digoxin: In a study performed with 24 healthy subjects, when PRADAXA was coadministered with digoxin, no changes on digoxin and no clinical relevant changes on dabigatran exposure have been observed (see "Pharmacology: Pharmacokinetics: Special populations under Actions").
P-glycoprotein inducers: After 7 days of treatment with 600 mg rifampicin qd total dabigatran AUC_0-∞ and C_max were reduced by 67%and 66% compared to the reference treatment, respectively.
The concomitant use with P-gp inducers (e.g., rifampicin, St. John´s wort (Hypericum perforatum), carbamazepine, or phenytoin) reduces exposure to dabigatran and should be avoided (see "Precautions" and "Pharmacology: Pharmacokinetics: Special populations under Actions").

Instruction for Use/Handling: When removing a hard capsule from the blister, note the following instructions: Tear off one individual blister from the blister card along the perforated line; Peel off the backing foil and remove the capsule; The capsule should not be pushed through the blister foil.
Any unused product or waste material should be disposed in accordance with local requirements.

Store below 30°C.
Store in the original package in order to protect from moisture.
Do not put the capsules in pill boxes or pill organizers, unless capsules can be maintained in the original package.
Refer to the packaging for information on shelf-life.

Anticoagulants, Antiplatelets & Fibrinolytics (Thrombolytics)

B01AE07 - dabigatran etexilate ; Belongs to the class of direct thrombin inhibitors. Used in the treatment of thrombosis.

POM

Cap 110 mg [consist of an imprinted hydroxypropylmethylcellulose (HPMC) capsule with light blue opaque cap and light blue opaque body of size 1; the cap is imprinted with the Boehringer Ingelheim company symbol, the body with "R110"; the colour of the imprint is black] x 3 x 10's. 150 mg [consist of an imprinted hydroxypropylmethylcellulose (HPMC) capsule with light blue opaque cap and white opaque body of size 0; the cap is imprinted with the Boehringer Ingelheim company symbol, the body with "R150"; the colour of the imprint is black] x 3 x 10's.