Pradaxa

Pradaxa

dabigatran

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Boehringer Ingelheim
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Contents
Dabigatran etexilate.
Description
1 capsule contains 86.48 mg, 126.83 mg or 172.95 mg of dabigatran etexilate mesilate corresponding to dabigatran etexilate base form 75 mg, 110 mg or 150 mg.
Excipients/Inactive Ingredients: Tartaric acid, acacia, hypromellose, dimethicone, talc, hydroxypropyl cellulose.
HPMC capsule shell: Carragenan, potassium chloride, titanium dioxide, Sunset Yellow (E110), Indigo Carmin (E132), hypromellose.
Printing ink: Shellac, butyl alcohol, isopropyl alcohol, Iron oxide black (E172), purified water, propylene glycol, ethanol anhydrous, potassium hydroxide, concentrated ammonia solution.
Action
Pharmacotherapeutic Group: Oral direct thrombin inhibitor. ATC Code: B01AE07-dabigatran exilate.
Pharmacology: General: 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.
The calibrated quantitative diluted TT (dTT) test provides an estimation of dabigatran plasma concentration that can be compared to the expected dabigatran plasma concentrations. When the calibrated dTT assay delivers a dabigatran plasma concentration result at or below the limit of quantification, an additional coagulation assay such as TT, ECT or aPTT should be considered.
The ECT can provide a direct measure of the activity of direct thrombin inhibitors.
The aPTT test is widely available and provides an approximate indication of the anticoagulation intensity achieved with dabigatran. However, the aPTT test has limited sensitivity and is not suitable for precise quantification of anticoagulant effect, especially at high plasma concentrations of dabigatran. Although high aPTT values should be interpreted with caution, a high aPTT value indicates that the patient is anticoagulated.
In general, it can be assumed that these measures of anti-coagulant activity may reflect dabigatran levels and can provide guidance for the assessment of bleeding risk, i.e. exceeding the 90th percentile of dabigatran trough levels or a coagulation assay such as aPTT measured at trough (for aPTT thresholds see Precautions, Table 11) is considered to be associated with an increased risk of bleeding.
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 Table 11. 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 SEE in adult patients with NVAF with one or more risk factors (SPAF): 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.
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.
Tables 2-4 display details of key results: See Tables 2, 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 3. 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. Other components evaluated included all hospitalizations which had statistically significant fewer hospitalizations at dabigatran etexilate 110 mg bid compared to warfarin (7% risk reduction, 95% CI 0.87, 0.99, p=0.021). (See Tables 5 and 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 RELY trial. Patients were eligible for the RELY-ABLE trial if they had not permanently discontinued study medication at the time of their final RELY study visit. Enrolled patients continued to receive the same double-blind dabigatran etexilate dose randomly allocated in RELY, for up to 43 months of follow up after RELY (total mean follow-up RELY + RELY-ABLE, 4.5 years). There were 5897 patients enrolled, representing 49% of patients originally randomly assigned to receive dabigatran etexilate in RELY 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.
In an exploratory study the efficacy of two gastrointestinal symptoms (GIS)-management strategies was tested: taking Pradaxa within 30 minutes after a meal and adding pantoprazole 40 mg daily.
In total n=1067 patients on Pradaxa entered the study; 117 patients developed GIS and were randomized to one of two treatments.
Both initial management strategies (taking Pradaxa after a meal and adding pantoprazole 40 mg daily) provided complete relief of the primary GIS in over 55% of patients who reported GIS (Pradaxa after a meal: 55.9%; pantoprazole: 67.2%).
As a single GIS management strategy, adding pantoprazole 40 mg daily provided complete resolution of their symptoms in 67.2% of patients after 4 weeks of treatment while taking Pradaxa after a meal resulted in 55.9% of patients having complete resolution of symptoms. After 1 week of treatment, complete resolution of symptoms was achieved in 51.7% pantoprazole vs. 39.0% Pradaxa taken after a meal.
Patients who did not have a complete response to the initial strategy after 4 weeks were to receive the alternate strategy in addition (= combined strategies) for another 4 weeks.
Complete or partial effectiveness after 4 weeks of the combined management strategies (8 weeks, total treatment) was reported by 12 of 14 (85.7%) patients taking Pradaxa after a meal in the first part of the trial and 12 of 15 (80.0%) patients taking pantoprazole in the first part of the trial.
Ultimately, 92 (78.6%) patients (79 with complete effectiveness and 13 with partial effectiveness) experienced positive outcomes using the two GIS management strategies, 45 in the Pradaxa after a meal group (39 complete effectiveness + 6 partial effectiveness) and 47 in the pantoprazole group (40 complete effectiveness + 7 partial effectiveness).
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. An imbalance in thromboembolic and total (mainly minor) bleeding events in disfavour of dabigatran etexilate was observed in this trial. 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) and prevention of related death: 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, RE-COVER 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 Table 7.)


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Other Measures Evaluated: Treatment of acute deep vein thrombosis (DVT) and/or pulmonary embolism (PE) and prevention of related death: Myocardial infarction occurred at a low frequency in all four of the VTE studies for all treatment groups. Cardiac death occurred in one patient in the warfarin treatment group.
In the three active controlled studies a higher rate of myocardial infarction was reported in patients who received dabigatran etexilate (20; 0.5%) than in those who received warfarin (5; 0.1%).
In the RE-SONATE study, which compared dabigatran etexilate to placebo, there was 1 MI event in each of the treatment groups, resulting in MI rates with dabigatran equal to MI rates with placebo.
Liver Function Tests: Treatment of acute deep vein thrombosis (DVT) and/or pulmonary embolism (PE) and prevention of related death: 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.
Clinical trials in Prevention of recurrent of deep vein thrombosis (DVT) and/or pulmonary embolism (PE) and related death: 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).
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).
Table 9 displays details of key results of the RE-SONATE study. (See Table 9.)


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Other Measures Evaluated: Reduction in the Risk of Recurrence of Deep Venous Thrombosis and Pulmonary Embolism: Myocardial infarction occurred at a low frequency in all four of the VTE studies for all treatment groups. Cardiac death occurred in one patient in the warfarin treatment group.
In the three active controlled studies a higher rate of myocardial infarction was reported in patients who received dabigatran etexilate (20; 0.5%) than in those who received warfarin (5; 0.1%).
In the RE-SONATE study, which compared dabigatran etexilate to placebo, there was 1 MI event in each of the treatment groups, resulting in MI rates with dabigatran equal to MI rates with placebo.
Liver Function Tests: Reduction in the Risk of Recurrence of Deep Venous Thrombosis and Pulmonary Embolism: 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 (Cmax) attained within 0.5 and 2.0 hours post administration. Cmax and the area under the plasma concentration-time curve (AUC) were dose proportional. After Cmax, 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 in 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 I study was approximately 3-fold higher in volunteers with moderate renal insufficiency (CrCL between 30-50 mL/min) than in those without renal insufficiency.
In a small number of volunteers with severe renal insufficiency (CrCL 10-30 mL/min), the exposure (AUC) to dabigatran was approximately 6 times higher and the half-life approximately 2 times longer than that observed in a population without renal insufficiency (see Dosage & Administration 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. 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 SEE in adult patients with NVAF with one or more risk factors (SPAF): 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) and prevention of related death: The median CrCL in the RE-COVER study was 100.43 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 30-50 mL/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.
Reduction in the Risk of Recurrence of Deep Venous Thrombosis and Pulmonary Embolism: 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 Cmax compared to young subjects.
The AUCτ,ss and Cmax,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.
Prevention of Venous Thromboembolic Events in patients who have undergone elective total hip 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 SEE in adult patients with NVAF with one or more risk factors (SPAF): 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) and prevention of related death: 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.
Reduction in the Risk of Recurrence of Deep Venous Thrombosis and Pulmonary Embolism: 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: Drug exposure in the primary VTE prevention studies was about 1.4- to 1.5-fold (+40% to 50%) higher in female patients. 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 inblack patients are available which suggest no relevant differences.
Indications/Uses
Prevention of venous thromboembolic events in adult patients who have undergone elective total hip or total knee replacement surgery.
Prevention of stroke and systemic embolism in adult patients with non-valvular atrial fibrillation (NVAF), with one or more risk factors, such as prior stroke or transient ischemic attack (TIA); age ≥75 years; heart failure (NYHA Class ≥ II); diabetes mellitus; hypertension.
Treatment of acute deep vein thrombosis (DVT) and/or pulmonary embolism (PE) and prevention of related death.
Reduction in the Risk of Recurrence of Deep Venous Thrombosis and Pulmonary Embolism.
Dosage/Direction for Use
PRADAXA hard capsules can be taken with or without food. PRADAXA should be taken 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. Do not open the capsule.
Adults: Prevention of Venous Thromboembolic Events in patients who have undergone elective total hip or total knee replacement surgery: Prevention of Venous Thromboembolism (VTE) following knee replacement surgery: Treatment with PRADAXA should be initiated orally within 1-4 hours of completed surgery with a single capsule (110 mg) and continuing with 2 capsules once daily thereafter for a total of 10 days. If haemostasis is not secured, initiation of treatment should be delayed. If treatment is not started on the day of surgery then treatment should be initiated with 2 capsules once daily.
Prevention of Venous Thromboembolism (VTE) following hip replacement surgery: Treatment with PRADAXA should be initiated orally within 1-4 hours of completed surgery with a single capsule (110 mg) and continuing with 2 capsules once daily thereafter for a total of 28-35 days. If haemostasis is not secured, initiation of treatment should be delayed. If treatment is not started on the day of surgery then treatment should be initiated with 2 capsules once daily.
Prevention of stroke and SEE in adult patients with NVAF with one or more risk factors (SPAF): The recommended daily dose of PRADAXA is 300 mg taken orally as 150 mg hard capsules twice daily. Therapy should be continued life-long.
Treatment of acute deep vein thrombosis (DVT) and/or pulmonary embolism (PE) and prevention of related death: The recommended daily dose of PRADAXA is 300 mg taken orally as 150 mg hard capsules twice daily following treatment with a parenteral anticoagulant for at least 5 days. Therapy should be continued for up to 6 months.
Reduction in the Risk of Recurrence of Deep Venous Thrombosis and Pulmonary Embolism: The recommended daily dose of PRADAXA is 300 mg taken orally as 150 mg hard capsules twice daily. Therapy could be continued life-long depending on the individual patient risk.
Children: Prevention of Venous Thromboembolic Events in patients who have undergone elective total hip or total knee replacement surgery: PRADAXA has not been investigated in patients <18 years of age. Treatment of children with PRADAXA is not recommended.
Prevention of stroke and SEE in adult patients with NVAF with one or more risk factors (SPAF): PRADAXA has not been investigated in patients <18 years. Treatment of children with PRADAXA is not recommended.
Treatment of acute deep vein thrombosis (DVT) and/or pulmonary embolism (PE) and prevention of related death: The safety and efficacy in children has not yet been established. Treatment of children with PRADAXA is therefore not recommended.
Reduction in the Risk of Recurrence of Deep Venous Thrombosis and Pulmonary Embolism: The safety and efficacy in children has not yet been established. Treatment of children with PRADAXA is therefore not recommended.
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 <30 mL/min). There are no data to support use in patients with severe renal impairment (<30 mL/min creatinine clearance); 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.
Prevention of Venous Thromboembolic Events in patients who have undergone elective total hip or total knee replacement surgery: Dosing should be reduced to 150 mg PRADAXA taken once daily as 2 capsules of 75 mg in patients with moderate renal impairment (30-50 mL/min creatinine clearance).
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 once daily.
Prevention of stroke and SEE in adult patients with NVAF with one or more risk factors (SPAF): In patients with moderate renal impairment (CrCL 30-50 mL/min) the renal function should be assessed at least once a year.
No dose adjustment necessary, patients should be treated with a daily dose of 300 mg taken orally as 150 mg hard capsules twice daily.
However, for patients with high risk of bleeding, a dose reduction of Pradaxa to 220 mg taken as one 110 mg capsule twice daily should be considered (see Pharmacology: Pharmacokinetics under Actions and Precautions). Close clinical surveillance is recommended in patients with renal impairment.
Treatment of acute deep vein thrombosis (DVT) and/or pulmonary embolism (PE) and prevention of related death: No dose adjustment necessary in patients with renal function over CrCl 30 mL/min. Patients should be treated with a daily dose of 300 mg taken orally as 150 mg hard capsules twice daily.
However, for patients with high risk of bleeding, a dose reduction of Pradaxa to 220 mg taken as one 110 mg capsule twice daily should be considered (see Pharmacology: Pharmacokinetics under Actions and Precautions). Close clinical surveillance is recommended in patients with renal impairment.
Reduction in the Risk of Recurrence of Deep Venous Thrombosis and Pulmonary Embolism: In patients with moderate renal impairment (CrCL 30-50 mL/min) the renal function should be assessed at least once a year.
No dose adjustment necessary in patients with renal function over CrCL 30 mL/min. Patients should be treated with a daily dose of 300 mg taken orally as 150 mg hard capsules twice daily.
However, for patients with high risk of bleeding, a dose reduction of Pradaxa to 220 mg taken as one 110 mg capsule twice daily should be considered (see Pharmacology: Pharmacokinetics under Actions and Precautions). Close clinical surveillance is recommended in patients with renal impairment.
Elderly: Prevention of Venous Thromboembolic Events in patients who have undergone elective total hip or total knee replacement surgery: 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 Pharmacology: Pharmacokinetics under Actions and Precautions).
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 <30 mL/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).
Prevention of stroke and SEE in adult patients with NVAF with one or more risk factors (SPAF): 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 <30 mL/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).
Patients between 75-80 years should be treated with a daily dose of 300 mg taken as one 150 mg capsule twice daily.
A dose of 220 mg taken as one 110 mg 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 (see Precautions).
Patients aged 80 years or above should be treated with a daily dose of 220 mg taken orally as 110 mg hard capsules twice daily.
Treatment of acute deep vein thrombosis (DVT) and/or pulmonary embolism (PE) and prevention of related death: 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 <30 mL/min). The renal function should also be assessed in patients treated with PRADAXA 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).
Patients between 75-80 years should be treated with a daily dose of 300 mg taken as one 150 mg capsule twice daily.
A dose of 220 mg taken as one 110 mg 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 (see Precautions).
Patients aged 80 years or above should be treated with a daily dose of 220 mg taken orally as 110 mg hard capsules twice daily.
Reduction in the Risk of Recurrence of Deep Venous Thrombosis and Pulmonary Embolism: 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 <30 mL/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).
Patients between 75-80 years should be treated with a daily dose of 300 mg taken as one 150 mg capsule twice daily.
A dose of 220 mg taken as one 110 mg 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 (see Precautions).
Patients aged 80 years or above should be treated with a daily dose of 220 mg taken orally as 110 mg hard capsules twice daily.
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: Prevention of Venous Thromboembolic Events in patients who have undergone elective total hip or total knee replacement surgery: Patients with elevated liver enzymes >2 upper limit of normal (ULN) were excluded in clinical trials investigating the VTE prevention following elective hip or knee replacement surgery. No treatment experience is available for this subpopulation of patients, and therefore the use of Pradaxa is not recommended in this population (see Pharmacology: Pharmacokinetics under Actions and Precautions). Hepatic impairment or liver disease expected to have any impact on survival is contraindicated (see Contraindications).
Prevention of stroke and SEE in adult patients with NVAF with one or more risk factors (SPAF): Patients with elevated liver enzymes >2 upper limit of normal (ULN) were excluded in the main trials. No treatment experience is available for this subpopulation of patients, and therefore the use of Pradaxa is not recommended in this population (see Pharmacology: Pharmacokinetics under Actions and Precautions). Hepatic impairment or liver disease expected to have any impact on survival is contraindicated (see Contraindications).
Treatment of acute deep vein thrombosis (DVT) and/or pulmonary embolism (PE) and prevention of related death: Patients with elevated liver enzymes >2 upper limit of normal (ULN) were excluded in the main trials. No treatment experience is available for this subpopulation of patients, and therefore the use of Pradaxa is not recommended in this population (see Pharmacology: Pharmacokinetics under Actions and Precautions). Hepatic impairment or liver disease expected to have any impact on survival is contraindicated (see Contraindications).
Reduction in the Risk of Recurrence of Deep Venous Thrombosis and Pulmonary Embolism: Patients with elevated liver enzymes >2 upper limit of normal (ULN) were excluded in the main trials. No treatment experience is available for this subpopulation of patients, and therefore the use of Pradaxa is not recommended in this population (see Pharmacology: Pharmacokinetics under Actions and Precautions). Hepatic impairment or liver disease expected to have any impact on survival is contraindicated (see Contraindications).
Weight: Prevention of Venous Thromboembolic Events in patients who have undergone elective total hip or total knee replacement surgery: There is very limited clinical experience in patients with a body weight <50 kg or >110 kg at the recommended posology. Given the available clinical and kinetic data no adjustment is necessary (see Pharmacology: Pharmacokinetics under Actions), but close clinical surveillance is recommended (see Precautions).
Prevention of stroke and SEE in adult patients with NVAF with one or more risk factors (SPAF): Given the available clinical and kinetic data, no dose adjustment is necessary (see Pharmacology: Pharmacokinetics under Actions), but close clinical surveillance is recommended in patients with a body weight <50 kg (see Precautions).
Treatment of acute deep vein thrombosis (DVT) and/or pulmonary embolism (PE) and prevention of related death: Given the available clinical and kinetic data, no dose adjustment is necessary (see Pharmacology: Pharmacokinetics under Actions), but close clinical surveillance is recommended in patients with a body weight <50 kg (see Precautions).
Reduction in the Risk of Recurrence of Deep Venous Thrombosis and Pulmonary Embolism: Given the available clinical and kinetic data, no dose adjustment is necessary (see Pharmacology: Pharmacokinetics under Actions), but close clinical surveillance is recommended in patients with a body weight <50 kg (see Precautions).
Concomitant use of PRADAXA with strong P-glycoprotein inhibitors, i.e. amiodarone, quinidine or verapamil: Prevention of Venous Thromboembolic Events in patients who have undergone elective total hip or total knee replacement surgery: Dosing should be reduced to PRADAXA 150 mg taken once daily as 2 capsules of 75 mg 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 elective total hip or total knee replacement 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 once daily.
Prevention of stroke and SEE in adult patients with NVAF with one or more risk factors (SPAF): No dose adjustment necessary, patients should be treated with a daily dose of 300 mg taken orally as 150 mg hard capsules twice daily.
Treatment of acute deep vein thrombosis (DVT) and/or pulmonary embolism (PE) and prevention of related death: No dose adjustment necessary, patients should be treated with a daily dose of 300 mg taken orally as 150 mg hard capsules twice daily.
Reduction in the Risk of Recurrence of Deep Venous Thrombosis and Pulmonary Embolism: No dose adjustment necessary, patients should be treated with a daily dose of 300 mg taken orally as 150 mg hard capsules twice daily.
Patients at risk of bleeding: Prevention of stroke and SEE in adult patients with NVAF with one or more risk factors (SPAF): The presence of the following factors may increase the risk of bleeding: e.g. age ≥75 years, moderate renal impairment (30-50 CrCL mL/min), concomitant treatment with strong P-gp inhibitors (see Pharmacology: Pharmacokinetics under Actions), antiplatelets or previous gastro-intestinal bleed (see Precautions). For patients with one or more than one of these risk factors, a reduced daily dose of 220 mg given as 110 mg twice daily may be considered at the discretion of the physician.
Treatment of acute deep vein thrombosis (DVT) and/or pulmonary embolism (PE) and prevention of related death: The presence of the following factors may increase the risk of bleeding: e.g. age ≥75 years, moderate renal impairment (30-50 mL/min CrCL) or previous gastro-intestinal bleed (see Precautions).
No dose adjustment is necessary for patients with single risk factors.
Limited clinical data are available for patients with multiple risk factors.
In these patients, PRADAXA should only be given if the expected benefit outweighs bleeding risks.
Reduction in the Risk of Recurrence of Deep Venous Thrombosis and Pulmonary Embolism: The presence of the following factors may increase the risk of bleeding: e.g. age ≥75 years, moderate renal impairment (30-50 mL/min CrCL) or previous gastro-intestinal bleed (see Precautions).
No dose adjustment is necessary for patients with single risk factors.
Limited clinical data are available for patients with multiple risk factors.
In these patients, PRADAXA should only be given if the expected benefit outweighs bleeding risks.
Switching from PRADAXA treatment to parenteral anticoagulant: Prevention of Venous Thromboembolic Events in patients who have undergone elective total hip or total knee replacement surgery: Wait 24 hours after the last dose before switching from PRADAXA to a parenteral anticoagulant.
Prevention of stroke and SEE in adult patients with NVAF with one or more risk factors (SPAF): Wait 12 hours after the last dose before switching from PRADAXA to a parenteral anticoagulant.
Treatment of acute deep vein thrombosis (DVT) and/or pulmonary embolism (PE) and prevention of related death: Wait 12 hours after the last dose before switching from PRADAXA to a parenteral anticoagulant.
Reduction in the Risk of Recurrence of Deep Venous Thrombosis and Pulmonary Embolism: 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 SEE in adult patients with NVAF with one or more risk factors (SPAF): The Vit. K antagonist should be stopped. PRADAXA can be given as soon as the INR is <2.0.
Treatment of acute deep vein thrombosis (DVT) and/or pulmonary embolism (PE) and prevention of related death: The Vit. K antagonist should be stopped. PRADAXA can be given as soon as the INR is <2.0.
Reduction in the Risk of Recurrence of Deep Venous Thrombosis and Pulmonary Embolism: 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: Prevention of stroke and SEE in adult patients with NVAF with one or more risk factors (SPAF): The starting time of the VKA should be adjusted according to the patient's 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.
Treatment of acute deep vein thrombosis (DVT) and/or pulmonary embolism (PE) and prevention of related death: The starting time of the VKA should be adjusted according to the patient's 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.
Reduction in the Risk of Recurrence of Deep Venous Thrombosis and Pulmonary Embolism: The starting time of the VKA should be adjusted according to the patientss 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.
Cardioversion: Prevention of stroke and SEE in adult patients with NVAF with one or more risk factors (SPAF): Patients can stay on PRADAXA while being cardioverted.
Missed dose: Prevention of Venous Thromboembolic Events in patients who have undergone elective total hip or total knee replacement surgery: Continue with your 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 SEE in adult patients with NVAF with one or more risk factors (SPAF): 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.
Treatment of acute deep vein thrombosis (DVT) and/or pulmonary embolism (PE) and prevention of related death: 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.
Reduction in the Risk of Recurrence of Deep Venous Thrombosis and Pulmonary Embolism: 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.
Overdosage
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 case of an overdose suspicion, coagulation tests can help to determine a bleeding risk (see Pharmacology: Pharmacokinetics under Actions and Precautions). A calibrated quantitative (dTT) test or repetitive dTT measureme nts allow prediction of the time by when certain dabigatran levels will be reached (see Pharmacology under Actions), also in case additional measures e.g. dialysis have been initiated.
Excessive anticoagulation may require discontinuation of PRADAXA.
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 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. Coagulation tests may become unreliable following administration of suggested reversing medicinal products. 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: Pharmacokinetics under Actions).
Contraindications
Known hypersensitivity to dabigatran or dabigatran etexilate or to one of the excipients of the product.
Severe renal impairment (CrCL <30 mL/min).
Haemorrhagic manifestations, patients with a bleeding diathesis, or patients with spontaneous or pharmacological impairment of haemostasis.
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 systemic ketoconazole, cyclosporine, itraconazole and dronedarone.
Concomitant treatment with any other anticoagulants e.g. unfractionated heparin (UFH), low molecular weight heparins (enoxaparin, dalteparin etc), heparin derivatives (fondaparinux etc), oral anticoagulants (warfarin, rivaroxaban, apixaban etc) except under the circumstances of switching therapy to or from Pradaxa or when UFH is given at doses necessary to maintain an open central venous or arterial catheter.
Mechanical prosthetic heart valve replacement.
Hepatic impairment or liver disease expected to have any impact on survival.
Special Precautions
Hepatic impairment: Patients with elevated liver enzymes >2 ULN were excluded in the main trials. No treatment experience is available for this subpopulation of patients, and therefore the use of Pradaxa is not recommended in this population.
Haemorrhagic risk: As with all anticoagulants, PRADAXA should be used with caution in conditions with an increased risk of bleeding and in situations with concomitant use of drugs affecting haemostasis by inhibition of platelet aggregation. 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 Overdosage, Surgery and Interventions, and Pre-operative Phase as follows).
PRADAXA treatment does not require routine anticoagulant monitoring.
However, the measurement of dabigatran related anticoagulation may be helpful to avoid excessive high exposure to dabigatran in the presence of additional risk factors.
The INR test is unreliable in patients on PRADAXA and false positive INR elevations have been reported. Therefore INR tests should not be performed.
Diluted thrombin time (dTT), ecarin clotting time (ECT) and activated partial thromboplastin time (aPTT) may provide useful information, but the tests are not standardised, and results should be interpreted with caution (see Pharmacology under Actions).
Table 11 shows coagulation test thresholds at trough that may be associated with an increased risk of bleeding (see Pharmacology under Actions). (See Table 11.)


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Prevention of stroke and SEE in adult patients with NVAF with one or more risk factors (SPAF): 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.
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.
Limited data is available in patients <50 kg (see Pharmacology: Pharmacokinetics under Actions).
When severe bleedings occur treatment must be discontinued and the source of bleeding investigated (see Overdosage).
Medicinal products that may enhance the risk of haemorrhage should not be administered concomitantly or should be administered with caution with Pradaxa (see Interactions).
Factors, such as decreased renal function (CrCL 30-50 mL/min), age ≥75 years, low body weight <50 kg, or mild to moderate P-gp-inhibitor comedication (e.g. amiodarone, quinidine or verapamil) 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 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).
Table 12 summarises factors which may increase the haemorrhagic risk. Please also refer to Contraindications. (See Table 12.)


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The presence of lesions, conditions, procedures and/or pharmacological treatment (such as NSAIDs, antiplatelets, SSRIs and SNRIs, see Interactions), which significantly increase the risk of major bleeding requires a careful benefit risk assessment. Pradaxa should only be given if the benefit outweighs bleeding risks.
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.
Prevention of Venous Thromboembolic Events in patients who have undergone elective total hip 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 SEE in adult patients with NVAF with one or more risk factors (SPAF): In a study of prevention of stroke and SEE in adult patients with NVAF, dabigatran etexilate was associated with higher rates of major gastrointestinal (GI) bleeding which was statistically significant for dabigatran etexilate 150 mg twice daily. This increased risk was seen in the elderly (≥75 years). Use of acetylsalicylic acid (ASA), clopidogrel or non steroidal antiinflammatory drug (NSAID), as well as the presence of esophagitis, gastritis or gastroesophageal reflux increase the risk of GI bleeding. In these atrial fibrillation patients a dosage of 220 mg dabigatran given as 110 mg capsule twice daily should be considered and posology recommendations in Dosage & Administration be followed. The administration of a PPI can be considered to prevent GI bleeding.
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 (Hypericum perforatum) or carbamazepine, or phenytoin are also expected to reduce dabigatran plasma concentrations, and should be co-administered with caution (see Pharmacology: Pharmacokinetics under Actions and Interactions).
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).
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.
Caution should be exercised when treatment is temporarily discontinued for interventions and anticoagulant monitoring is warranted. Clearance of dabigatran in patients with renal insufficiency may take longer (see Pharmacology: Pharmacokinetics under Actions).
This should be considered in advance of any procedures. In such cases a coagulation test (see Pharmacology: Pharmacokinetics under Actions and Precautions) may help to determine whether haemostasis is still impaired.
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: Dabigatran etexilate should be temporarily discontinued.
The specific reversal agent (PRAXBIND, idarucizumab) of PRADAXA is available for the rapid reversal of the anticoagulation effect (see Surgery and Interventions on previous text).
Reversing dabigatran therapy exposes patients to the thrombotic risk of their underlying disease. Pradaxa treatment can be re-initiated 24 hours after administration of Praxbind (idarucizumab), if the patient is clinically stable and adequate haemostasis has been achieved.
Subacute Surgery/Intervention: 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. This risk of bleeding should be weighed against the urgency of intervention (for cardioversion see Dosage & Administration).
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).


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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 (for cardioversion see Dosage & Administration).
Spinal Anesthesia/Epidural Anesthesia/Lumbar Puncture: Procedures such as spinal anesthesia may require complete hemostatic function.
The risk of spinal or epidural hematoma 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 1 hour 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.
Postoperative phase: Resume treatment after complete haemostasis is achieved.
Dabigatran etexilate should be restarted after the invasive procedure or surgical intervention as soon as possible provided the clinical situation allows and adequate haemostasis has been established. Patients at risk for bleeding or patients at risk of overexposure, notably patients with moderate renal impairment (CrCL 30-50 mL/min), should be treated with caution (see Pharmacology: Pharmacokinetics under Actions and Precautions).
Patients with bioprosthetic valves: The use of dabigatran etexilate has not been evaluated in patients with bioprosthetic valves and use cannot be recommended for such patients.
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.
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: Prevention of stroke and SEE in adult patients with NVAF with one or more risk factors (SPAF): In the phase III study RE-LY (see Pharmacology under Actions) the overall rate of myocardial infarction (MI) was 0.82, 0.81, and 0.64%/year for dabigatran etexilate 110 mg twice daily, dabigatran etexilate 150 mg twice daily and warfarin, respectively, an increase in relative risk for dabigatran of 29% and 27% compared to warfarin. Irrespective of therapy, the highest absolute risk of MI was seen in the following subgroups, with similar relative risk: patients with previous MI, patients ≥65 years with either diabetes or coronary artery disease, patients with left ventricular ejection fraction <40%, and patients with moderate renal dysfunction. Furthermore a higher risk of MI was seen in patients concomitantly taking ASA plus clopidogrel or clopidogrel alone.
Treatment of acute deep vein thrombosis (DVT) and/or pulmonary embolism (PE) and prevention of related death: 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.
Reduction in the Risk of Recurrence of Deep Venous Thrombosis and Pulmonary Embolism: 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: Treatment of acute deep vein thrombosis (DVT) and/or pulmonary embolism (PE) and prevention of related death: The efficacy and safety have not been established for DVT/PE patients with active cancer.
Reduction in the Risk of Recurrence of Deep Venous Thrombosis and Pulmonary Embolism: The efficacy and safety have not been established for DVT/PE patients with active cancer.
Colorants: Pradaxa hard capsules contain the colorant sunset yellow (E110), which may cause allergic reactions.
Effects on ability to drive and use machines: No studies on the effects on the ability to drive and use machines have been performed.
Use In Pregnancy & Lactation
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.
Adverse Reactions
The safety of PRADAXA has been evaluated overall in 38,141 patients treated in 11 clinical trials; thereof 23,393 patients were treated with PRADAXA.
Prevention of Venous Thromboembolic Events in patients who have undergone elective total hip or total knee replacement surgery: In the primary VTE prevention trials after elective total hip 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 (150 mg qd, 220 mg qd, enoxaparin). 6,684 of the 10,795 patients were treated with 150 or 220 mg once daily of dabigatran etexilate.
Prevention of stroke and SEE in adult patients with NVAF with one or more risk factors (SPAF): In the RE-LY 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.
Treatment of acute deep vein thrombosis (DVT) and/or pulmonary embolism (PE) and prevention of related death: 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.
Reduction in the Risk of Recurrence of Deep Venous Thrombosis and Pulmonary Embolism: 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.
In total, about 9% of patients treated for elective hip or knee surgery (short-term treatment for up to 42 days) and 22% of patient with atrial fibrillation treated for the prevention of stroke and systemic embolism (long-term treatment for up to 3 years), 14% of patients treated for acute DVT/PE treatment (long-term treatment up to 6 months) 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; dependent of the indication bleeding of any type or severity occurred in approximately 14% of patients treated short-term for elective hip or knee replacement surgery and in long-term treatment in yearly 16.6% of patient with atrial fibrillation treated for the prevention of stroke and systemic embolism.
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.
Prevention of Venous Thromboembolic Events in patients who have undergone elective total hip or total knee replacement surgery: Overall bleeding rates were similar between treatment groups and not significantly different.
Prevention of stroke and SEE in adult patients with NVAF with one or more risk factors (SPAF): Major bleeding fulfilled one or more of the following criteria: Bleeding associated with a reduction in hemoglobin of at least 20 grams per liter 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 liter; 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 150 mg 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 110 mg twice daily had a signficantly 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) and prevention of related death: 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 a symptomatic 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.
Reduction in the Risk of Recurrence of Deep Venous Thrombosis and Pulmonary Embolism: 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 a symptomatic 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 was higher with dabigatran etexilate compared with placebo (5.3% vs. 2.0%).
Adverse reactions classified by SOC and MedDRA preferred terms reported from any treatment group per population of all controlled studies are shown in Tables 14 and 15. Table 14 lists identified side effects applicable to four indications. Table 15 lists indication specific side effects identified.
Side effects are generally associated to the pharmacological mode of action of dabigatran etexilate and represent bleeding associated events that may occur in different anatomical regions and organs.
Prevention of Venous Thromboembolic Events in patients who have undergone elective total hip or total knee replacement surgery: In patients treated for VTE prevention after hip or knee replacement surgery the observed incidences of side effects of dabigatran etexilate were in the range of enoxaparin.
Prevention of stroke and SEE in adult patients with NVAF with one or more risk factors (SPAF): The observed incidences of side effects of dabigatran etexilate in patients treated for stroke prevention in patients with atrial fibrillation were in the range of warfarin except gastrointestinal disorders which appeared at a higher rate in the dabigatran etexilate arms.
Treatment of acute deep vein thrombosis (DVT) and/or pulmonary embolism (PE) and prevention of related death: The overall frequency of side effects in patients receiving PRADAXA for acute DVT/PE treatment was lower for PRADAXA compared to warfarin (14.2% vs. 18.9%).
Reduction in the Risk of Recurrence of Deep Venous Thrombosis and Pulmonary Embolism: The overall frequency of side effects in patients treated for recurrent DVT/PE prevention was lower for PRADAXA compared to warfarin (14.6% vs. 19.6%); compared to placebo the frequency was higher (14.6% vs. 6.5%). (See Tables 14 and 15.)


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Click on icon to see table/diagram/image

Drug Interactions
The concomitant use of PRADAXA with treatments that act on haemostasis or coagulation including Vitamin K antagonists can markedly increase the risk of bleeding (see Precautions).
Dabigatran etexilate and dabigatran are not metabolized by the cytochrome P450 system and had no effects in vitro on human cytochrome P450 enzymes. Therefore related drug-drug interactions are not expected with dabigatran etexilate or dabigatran (see Pharmacology: Pharmacokinetics under Actions).
Anticoagulants and antiplatelet aggregation medicinal products: There is no or only limited experience with the following treatments which may increase the risk of bleeding when used concomitantly with Pradaxa: anticoagulants such as unfractionated heparin (UFH), low molecular weight heparins (LMWH), and heparin derivatives (fondaparinux, desirudin), thrombolytic medicinal products, and vitamin K antagonists, rivaroxaban or other oral anticoagulants, and platelet aggregation medicinal products such as GPIIb/IIIa receptor antagonists, ticlopidine, prasugrel, ticagrelor, dextran, and sulfinpyrazone.
From the limited data collected in the phase III study RE-LY in patients with atrial fibrillation it was observed that the concomitant use of other oral or parenteral anticoagulants increases major bleeding rates with both dabigatran etexilate and warfarin by approximately 2.5-fold, mainly related to situations when switching from one anticoagulant to another.
UFH can be administered at doses necessary to maintain a patent central venous or arterial catheter.
Clopidogrel and ASA: From the data collected in the phase III study RE-LY it was observed that the concomitant use of antiplatelets, ASA or clopidogrel approximately doubles major bleeding rates with both dabigatran etexilate and warfarin.
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 compared to clopidogrel monotherapy. In addition, dabigatran AUCτ,ss and Cmax,ss and the coagulation measures for dabigatran effect or the inhibition of platelet aggregation as measure of clopidogrel effect remained essentially unchanged comparing combined treatment and the respective mono-treatments. With a loading dose of 300 mg or 600 mg clopidogrel, dabigatran AUCτ,ss and Cmax,ss were increased by about 30-40% (see ASA as follows).
ASA: The effect of concomitant administration of dabigatran etexilate and ASA on the risk of bleeds was studied in patients with atrial fibrillation in a phase II study in which a randomized ASA co-administration 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.
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 half-lives >12 hours, close observation for signs of bleeding is recommended.
LMWH: The concomitant use of LMWHs, such as enoxaparin and dabigatran etexilate has not been specifically investigated. After switching from 3-day treatment of once daily 40 mg enoxaparin s.c., 24 hours after the last dose of enoxaparin the exposure to dabigatran was slightly lower than that after administration of dabigatran etexilate (single dose of 220 mg) alone. A higher anti-FXa/FIIa activity was observed after dabigatran etexilate administration with enoxaparin pre-treatment compared to that after treatment with dabigatran etexilate alone. This is considered to be due to the carry-over effect of enoxaparin treatment, and regarded as not clinically relevant. Other dabigatran related anti-coagulation tests were not changed significantly by the pre-treatment of enoxaparin.
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.
Prevention of Venous Thromboembolic Events in patients who have undergone elective total hip or total knee replacement surgery: For the concomitant use of P-gp inhibitors and dosing of PRADAXA in this indication, see Pharmacology: Pharmacokinetics under Actions and Dosage & Administration.
Prevention of stroke and SEE in adult patients with NVAF with one or more risk factors (SPAF): For the other P-gp inhibitors listed previously no dose adjustments are required for PRADAXA in this indication.
Treatment of acute deep vein thrombosis (DVT) and/or pulmonary embolism (PE) and prevention of related death: For P-gp inhibitors listed previously no dose adjustments are required for PRADAXA in this indication.
Reduction in the Risk of Recurrence of Deep Venous Thrombosis and Pulmonary Embolism: For P-gp inhibitors listed previously no dose adjustments are required for PRADAXA in this indication.
Amiodarone: Dabigatran exposure in healthy subjects was increased by 1.6 fold (+60%) in the presence of amiodarone (see Pharmacology: Pharmacokinetics under Actions).
Prevention of stroke and SEE in adult patients with NVAF with one or more risk factors (SPAF): 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 (150 mg) was coadministered with oral verapamil, the Cmax 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 under Actions).
Prevention of stroke and SEE in adult patients with NVAF with one or more risk factors (SPAF): 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 under Actions).
Clarithromycin: Dabigatan exposure in healthy subjects was increased by about 19% in the presence of clarithromycin without any clinical safety concern (see Pharmacology: Pharmacokinetics under Actions).
Ketoconazole: Dabigatran exposure was increased by 2.5 fold (+150%) after single and multiple doses of systemic ketoconazole (see Pharmacology: Pharmacokinetics under Actions and Contraindications).
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 under Actions).
Ticagrelor: When a single dose of 75 mg 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 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 AUCτ,ss and Cmax,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 AUCτ,ss and Cmax,ss was reduced to 1.27-fold and 1.23-fold (+27% and 23%), respectively, compared with dabigatran etexilate given alone. This staggered intake is the recommended administration for start of ticagrelor with a loading dose.
Concomitant administration of 90 mg ticagrelor BID (maintenance dose) with 110 mg dabigatran etexilate increased the adjusted dabigatran AUCτ,ss and Cmax,ss 1.26-fold and 1.29-fold, respectively, compared with dabigatran etexilate given alone.
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 under Actions).
Co-medication with selective serotonin re-uptake inhibitors (SSRIs) or selective serotonin norepinephrine re-uptake inhibitors (SNRIs): SSRIs and SNRIs increased the risk of bleeding in RE-LY in all treatment groups.
Gastric pH: Pantoprazole: When Pradaxa was co-administered with pantoprazole, a decrease in the dabigatran area under the plasma concentration-time curve of approximately 30% was observed. Pantoprazole and other proton-pump inhibitors (PPI) were co-administered with Pradaxa in clinical trials, and concomitant PPI treatment did not appear to reduce the efficacy of Pradaxa.
Ranitidine: Ranitidine administration together with Pradaxa had no clinically relevant effect on the extent of absorption of dabigatran.
P-glycoprotein inducers: After 7 days of treatment with 600 mg rifampicin qd total dabigatran AUC0-∞ and Cmax were reduced by 67% and 66% compared to the reference treatment, respectively.
The concomitant use with P-gp inducers (e.g., rifampicin) reduces exposure to dabigatran and should be avoided (see Pharmacology: Pharmacokinetics under Actions and Precautions).
Caution For Usage
Instructions for Use/Handling: Blister: When removing a hard capsule from the blister, please 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.
Storage
Store in the original package in order to protect from moisture.
Do not store 30°C.
Do not put the capsules in pill boxes or pill organizers, unless capsules can be maintained in the original package.
Shelf Life: 36 months since manufactured date.
MIMS Class
Anticoagulants, Antiplatelets & Fibrinolytics (Thrombolytics)
ATC Classification
B01AE07 - dabigatran etexilate ; Belongs to the class of direct thrombin inhibitors. Used in the treatment of thrombosis.
Presentation/Packing
Cap 75 mg x 10's, 30's, 60's. Tab 110 mg x 10's, 30's, 60's. Tab 150 mg x 30's.
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