Pradaxa

Dabigatran etexilate.

Each 75-, 110- and 150 mg cap contains β-alanine, N-[[2-[[[4(hexyloxy)carbonyl]amino]iminomethyl]phenyl]amino]methyl]-1-methyl-1H-benzimidazol-5-yl]carbonyl]-N-2-pyridinyl-,ethyl ester, methane-sulfonate, being the methane sulfonic acid salt 86.48 mg, 126.83 mg or 172.95 mg corresponding to dabigatran etexilate base form 75 mg, 110 mg or 150 mg, respectively.
It also contains the following excipients: Tartaric acid, acacia, hypromellose, dimethicone 350, talc, hydroxypropyl cellulose. HPMC Capsule Shell: Carragenan, potassium chloride, titanium dioxide, sunset yellow (E110), indigo carmine (E132), hypromellose. Printing Ink: Shellac, N-butyl alcohol, isopropyl alcohol, industrial methylated spirit, black iron oxide (E172), purified water, propylene glycol.

Pharmacotherapeutic Group: Oral direct thrombin inhibitor. ATC Code: B01AE07.
Pharmacology: Pharmacodynamics: 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 IV 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 activated partial thromboplastin time (aPTT), ecarin clotting time (ECT) and thrombin time (TT).
Clinical Trials in Primary Venous Thromboembolism (VTE) Prevention Following Major Joint Replacement Surgery: In 2 large, randomized, parallel group, double-blind, dose-confirmatory trials, patients undergoing elective major orthopaedic surgery (1 for knee replacement surgery and 1 for hip replacement surgery) received dabigatran etexilate 75 mg or 110 mg within 1-4 hrs of surgery followed by 150 mg or 220 mg once daily thereafter, haemostasis having been secured, or enoxaparin 40 mg on the day prior to surgery and 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. A total of 2,076 patients (knee) and 3,494 (hip) were treated, respectively.
The results of the knee study (RE-MODEL) with respect to the primary endpoint, total including asymptomatic 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 endpoint 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 3rd 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 hrs of surgery followed by 150 mg and 220 mg once daily thereafter. The treatment duration was 12-15 days. In total, 2,615 patients were randomized and 2,596 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 randomization to the respective study medication was done pre-surgery, and in the RE-MOBILIZE and the Japanese placebo-controlled trial, the randomization 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 randomized trials in Table 1.
Data for the major VTE and VTE-related mortality endpoint and adjudicated major bleeding endpoints are shown in Table 1 as follows. (See Table 1.)
Venous thromboembolism was defined as the composite incidence of deep vein thrombosis and pulmonary embolism.

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Clinical Trials in Prevention of Stroke and Systemic Embolism in Patients with Atrial Fibrillation (AF): The clinical evidence for the efficacy of dabigatran etexilate is derived from the RE-LY (Randomized Evaluation of Long-Term Anticoagulant Therapy) study, a multicenter, multinational, randomized, parallel group study of 2 blinded doses of dabigatran etexilate (110 mg and 150 mg twice daily) compared to open-label warfarin in patients with AF 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 AF (eg, 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, ≥ New York Heart Association (NYHA) Class 2; age ≥75 years; age ≥65 years associated with one of the following: Diabetes mellitus, coronary artery disease (CAD) or hypertension.
The concomitant diseases of patients in this trial included hypertension 79%, diabetes 23% and CAD 28%. Fifty percent (50%) of the patient population was vitamin K antagonist (VKA)-naive defined as <2 months total lifetime exposure. Thirty-two percent (32%) of the population had never been exposed to a VKA. For those patients randomized to warfarin, the time in therapeutic range (INR 2-3) for the trial was a median of 67%.
Concomitant medications included aspirin (ASA) (25% of the subjects used at least 50% of the time in study), clopidogrel (3.6%), ASA + clopidogrel (2%), nonsteroidal anti-inflammatory drugs (NSAIDs) (6.3%), β-blockers (63.4%), diuretics (53.9%), statins (46.4%), angiotensin-converting enzyme (ACE) inhibitors (44.6%), angiotensin-receptor blockers (26.1%), oral hypoglycemics (17.5%), insulin (5.2%), digoxin (29.4%), amiodarone (11.3%), diltiazem (8.9%), verapamil (5.4%) and proton-pump inhibitors (PPIs) (17.8%).
For the primary endpoint, stroke and systemic embolism, no subgroups (ie, age, weight, gender, renal function, ethnicity) 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 AF, with a reduced risk of intracranial hemorrhage and total bleeding. The higher dose of 150 mg twice daily significantly reduces 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 (see Figure 1 and Tables 2-6).

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The net clinical benefit (NCB) as measured by the unweighted composite clinical endpoint of stroke, systemic embolism, pulmonary embolism, acute myocardial infarction, vascular deaths and major bleeds was assessed and is presented as part of Table 5. The yearly event rates for the dabigatran etexilate groups were lower compared to the warfarin group. The risk reduction for this composite endpoint was 8% and 10% for the dabigatran etexilate 110 mg and 150 mg twice daily treatment groups.
Other components evaluated included all hospitalizations which had statistically significant fewer hospitalizations at dabigatran etexilate 110 mg twice daily compared to warfarin (7% risk reduction, 95% CI 0.87, 0.99, p=0.021).

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In the RE-LY study, potential abnormalities of liver function tests (LFTs) occurred with a comparable or lower incidence in dabigatran etexilate versus warfarin-treated patients. (See Table 6.)

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Clinical Trials for the Prevention of Thromboembolism in Patients With Prosthetic Heart Valves: A phase II study examined dabigatran etexilate and warfarin in a total of 252 patients with recent mechanical heart valve replacement surgery (ie, within the current hospital stay) and in patients who received a mechanical heart valve replacement >3 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 postoperative patients, major bleeding manifested predominantly as haemorrhagic pericardial effusions, specifically in patients who started dabigatran etexilate early (ie, 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 2 multicenter, randomised, double-blind, parallel group, replicate studies RE-COVER and RE-COVER II. These studies compared dabigatran etexilate (150 mg twice daily) with warfarin (target INR 2-3) 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%, CAD 6.8% and gastric or duodenal ulcer 4.1%.
The duration of treatment with fixed-dose of dabigatran was 174 days without coagulation monitoring. For patients randomized to warfarin, the median time in therapeutic range (INR 2-3) was 60.6%. Concomitant medications included vasodilators 28.5%, agents acting on the renin-angiotensin system 24.7%, lipid-lowering agents 19.1%, β-blockers 14.8%, calcium channel blockers 9.7%, nonsteroidal anti-inflammatory drugs (NSAIDs) 21.7%, aspirin 9.2%, antiplatelet agents 0.7%, P-gp inhibitors 2% (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 etixilate 150 mg twice daily as compared with those receiving warfarin. (See Figure 2 and 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 4 of the VTE studies for all treatment groups. Cardiac death occurred in 1 patient in the warfarin treatment group.
In the 3 active controlled-studies, a higher rate of myocardial infarction was reported in patients who received dabigatran etexilate (20; 05%) than in those who received warfarin (5; 0.1%).
In the RE-SONATE study, which compared dabigatran etexilate to placebo, there was 1 myocardial infarction event in each of the treatment groups, resulting in myocardial infarction rates with dabigatran equal to myocardial infarction rates with placebo.
Liver Function Tests: Treatment of acute DVT and/or 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 versus 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 3-12 months with the need for further anticoagulant treatment and RE-SONATE, the placebo-controlled study, enrolled patients already treated for 6-18 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 twice daily) to warfarin (target INR 2-3) 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%, Caucasian 90.1%, Asian 7.9%, Blacks 2%. Co-morbidities included hypertension 38.6%, diabetes mellitus 9%, coronary artery disease (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%, β-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 exilate treatment ranged from 6-36 months (median-534 days). For patients randomized to warfarin, the median time in therapeutic range (INR 2-3) 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%); most frequent were verapamil (1.2% overall) and amiodarone (0.4% overall). (See Figure 3 and 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 6-18 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%, Asian 9.3%, Blacks 1.7%. Co-morbidities included hypertension 38.8%, diabetes mellitus (DM) 8%, coronary artery disease (CAD) 6% 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%, β-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% 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% versus 10.7% among the placebo group [hazard ratio 0.61 (0.42, 0.88), p=0.0082]. (See Figure 4 and Table 9.)

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Other Measures Evaluated: Prevention of recurrent DVT and/or PE and Related death: Myocardial infarction occurred at a low frequency in all 4 of the VTE studies for all treatment groups. Cardiac death occurred in 1 patient in the warfarin-treatment group. In the 3 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 myocardial infarction event in each of the treatment groups, resulting in myocardial infarction rates with dabigatran equal to myocardial infarction rates with placebo.
Liver Function Tests: Prevention of recurrent DVT and/or PE and 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 versus warfarin-treated patients. In RE-SONATE, there was no marked difference between the dabigatran- and placebo groups with regard to possible clinically significant abnormal LFT values.
Pharmacokinetics: After oral administration of dabigatran etexilate in healthy volunteers, the pharmacokinetic profile of dabigatran in plasma is characterized by a rapid increase in plasma concentrations with peak concentration (C_max) attained within 0.5 and 2 hrs post-administration.
Peak plasma concentration (C_max) and the area under the plasma concentration-time curve (AUC) were dose-proportional. After C_max, plasma concentrations of dabigatran showed a biexponential decline with a mean terminal half-life (t_½) of approximately 11 hrs in healthy elderly subjects. After multiple doses, a terminal t_½ of about 12-14 hrs was observed. The t_½ was independent of dose. However, half-life is prolonged if renal function is impaired as shown below (see Table 10).

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The absolute bioavailability of dabigatran following oral administration of dabigatran etexilate as HPMC capsule was approximately 6.5%.
Food does not affect the bioavailability of dabigatran etexilate but delays the time-to-peak plasma concentrations by 2 hrs.
The oral bioavailability may be increased by about 1.8-fold (+75%) 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 (eg, sprinkled over food or into beverages). (See Dosage & Administration.)
A study evaluating postoperative absorption of dabigatran etexilate, 1-3 hrs following surgery, demonstrated relatively slow absorption compared with that in healthy volunteers, showing a smooth plasma concentration-time profile without high C_max. Peak plasma concentrations are reached at 6 hrs following administration, or at 7-9 hrs following surgery (BISTRO Ib). It is noted, however, that contributing factors eg, 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, the absorption of dabigatran is rapid with C_max attained 2 hrs after drug administration.
Metabolism and excretion of dabigatran were studied following a single IV dose of radiolabeled dabigatran in healthy male subjects. After an IV 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 hrs 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 (4) positional isomers, 1-O, 2-O, 3-O, 4-O-acylglucuronide exist, each accounts for <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 60-70 L of dabigatran 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 [creatinine clearance (CrCl) between 30-50 mL/min] than 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 t_½ 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, 4-hr 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 pharmacokinetic/pharmacodynamic (PK/PD) relationship was not affected by the procedure.
Prevention of Stroke, Systemic Embolism and Reduction of Vascular Mortality in Patients with Atrial fibrillation: The median CrCl in RE-LY was 68.4 mL/min. Almost ½ (45.8%) of the RE-LY patients had a CrCl >50 to <80 mL/min. Patients with moderate renal impairment (CrCl between 30-50 mL/min) had, on average, 2.29- and 1.8-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 100.4 mL/min. Twenty-one and seven tenths percent (21.7%) of patients had mild renal impairment (CrCl >50 to <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 1.8-fold and 3.6-fold higher steady-state dabigatran trough concentrations compared with patients with CrCl >80 mL/min. Similar values for CrCl were found in RE-COVER II.
Prevention of Recurrent DVT and/or PE and Related Death: The median CrCl in the RE-MEDY and RE-SONATE studies were 99 mL/min and 99.7 mL/min, respectively. Twenty-two and nine tenths percent (22.9%) and 22.5% of the patients had a CrCl >50 to <80 mL/min, and 4.1% and 4.8% had a CrCl between 30-50 mL/min in in the RE-MEDY and RE-SONATE studies.
Elderly: Specific pharmacokinetic studies with elderly subjects in phase I studies showed an increase of 1.4- to 1.6-fold (+40-60%) in the AUC and of >1.25-fold (+25%) in C_max compared to young subjects.
The AUC_τ,ss and C_max,ss in male and female elderly subjects (>65 yrs) were approximately 1.9- and 1.6-fold higher for elderly females compared to young females, and 2.2- and 2-fold higher for elderly males than in male subjects of 18-40 years.
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 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 65-75 years.
Hepatic Insufficiency: No change in dabigatran exposure was seen in 12 subjects in a phase I study with moderate hepatic insufficiency (Child Pugh B) compared to 12 controls.
Prevention of VTE Events in Patients Who Have Undergone Major Orthopaedic 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 of normal (ULN) were excluded in clinical trials.
Prevention of Stroke, Systemic Embolism and Reduction of Vascular Mortality in Patients with Atrial Fibrillation: Patients with active liver disease including but not limited to the persistent elevation of liver enzymes ≥2 ULN or hepatitis A, B or C were excluded in clinical trials.
Treatment of Acute DVT and/or 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 ULN were excluded in clinical trials.
Prevention of Recurrent DVT and/or PE and 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 ULN were excluded in clinical trials.
Body Weight: The dabigatran trough concentrations were about 20% lower in patients with a body weight >100 kg compared with 50-100 kg. The majority (80.8%) of the subjects were in the ≥50 kg and <100 kg category, with no clear difference detected. Limited data in patients ≤50 kg are available.
Gender: Prevention of Stroke, Systemic Embolism and Reduction of Vascular Mortality in Patients with Atrial Fibrillation: In atrial fibrillation patients, females had an average 1.3-fold (+30%) higher trough and post-dose concentrations. This finding had no clinical relevance.
Prevention of Venous Thromboembolic Events (VTE) in Patients Who Have Undergone Major Orthopedic Surgery: Drug exposure in the primary VTE prevention studies was about 1.4- to 1.5-fold (+40-50%) higher in female patients. This finding had no clinical relevance.
Ethnic Origin: The pharmacokinetics of dabigatran was investigated in Caucasian and Japanese volunteers after single and multiple doses. Ethnic origin does not affect the pharmacokinetics of dabigatran in a clinically relevant manner.
Limited pharmacokinetic data in Black patients are available which suggest no relevant differences.
Pharmacokinetic Interactions: In vitro interaction studies did not show any inhibition or induction of cytochrome P-450. This has been confirmed by in vivo studies in healthy volunteers, who did not show any interaction between dabigatran etexilate treatment and the following drugs: Atorvastatin (CYP3A4) and diclofenac (CYP2C9).
Atorvastatin: When dabigatran etexilate was co-administered with atorvastatin, a CYP3A4 substrate, exposure of atorvastatin, atorvastatin metabolites and of dabigatran were unchanged indicating a lack of interaction.
Diclofenac: When dabigatran etexilate was co-administered with diclofenac, a CYP2C9 substrate, pharmacokinetics of both drugs remained unchanged indicating a lack of interaction between dabigatran etexilate and diclofenac.
P-glycoprotein (P-gp) Inhibitor/Inducer Interactions: The prodrug dabigatran etexilate, but not dabigatran, is a substrate of the efflux transporter P-gp. Therefore, co-medications with P-gp transporter inhibitors and inducers have been investigated.
Co-Medication with P-gp Inhibitors: Amiodarone: When dabigatran etexilate was co-administered with a single oral dose of amiodarone 600 mg, the extent and rate of absorption of amiodarone and its active metabolite diethanolamine (DEA) were essentially unchanged. The dabigatran AUC and C_max were increased by about 1.6- and 1.5-fold (+60% and 50%), respectively.
Prevention of Stroke, Systemic Embolism and Reduction of Vascular Mortality in Patients with Atrial Fibrillation: In the population pharmacokinetics study from RE-LY, no important changes in dabigatran trough levels were observed in patients who received amiodarone (see Interactions).
Dronedarone: When dabigatran etexilate and dronedarone were given at the same time, total dabigatran AUC_0-∞ and C_max values increased by about 2.4- and 2.3-fold (+136% and 125%), respectively, after multiple dosing of dronedarone 400 mg twice daily, and about 2.1- and 1.9-fold (+114% and 87%), respectively, after a single dose of 400 mg. The terminal t_½ and renal clearance of dabigatran were not affected by dronedarone. When single and multiple doses of dronedarone were given 2 hrs after dabigatran etexilate, the increases in dabigatran AUC_0-∞ were 1.3- and 1.6-fold, respectively.
Verapamil: When dabigatran etexilate was co-administered with oral verapamil, the C_max and AUC of dabigatran were increased depending on timing of administration and formulation of verapamil.
The greatest elevation of dabigatran exposure was observed with the 1st dose of an immediate-release formulation of verapamil administered 1 hr prior to dabigatran etexilate intake [increase of C_max by about 2.8-fold (+180%) and AUC by about 2.5-fold (+150%)]. The effect was progressively decreased with administration of an extended-release formulation [increase of C_max by about 1.9-fold (+90%) and AUC by about 1.7-fold (+70%)] or administration of multiple doses of verapamil [increase of C_max by about 1.6-fold (+60%) and AUC by about 1.5-fold (+50%)]. This can be explained by the induction of P-gp in the gut by chronic verapamil treatment.
There was no meaningful interaction observed when verapamil was given 2 hrs after dabigatran etexilate (increase of C_max by about 10% and AUC by about 20%). This is explained by completed dabigatran absorption after 2 hrs (see Dosage & Administration).
No data are available for the parenteral application of verapamil; based on the mechanism of the interaction, no meaningful interaction is expected.
Prevention of Stroke, Systemic Embolism and Reduction of Vascular Mortality in Patients with Atrial Fibrillation: In the population pharmacokinetic study from RE-LY, no important changes in dabigatran trough levels were observed in patients who received verapamil (see Interactions).
Ketoconazole: Systemic ketoconazole increased total dabigatran AUC_0-∞ and C_max values by about 2.4-fold (+138% and 135%), respectively, after a single dose of 400 mg and about 2.5-fold (+153% and 149%), respectively, after multiple dosing of ketoconazole 400 mg once daily. The time-to-peak, terminal t_½ and mean residence time were not affected by ketoconazole.
Clarithromycin: When clarithromycin 500 mg twice daily was administered together with dabigatran etexilate, no clinically relevant pharmacokinetic interaction was observed (increase of C_max by about 15% and AUC by about 19%).
Quinidine: Quinidine was given as a 200-mg dose every 2nd hr up to a total dose of 1000 mg. Dabigatran etexilate was given twice daily over 3 consecutive days, on the 3rd day either with or without quinidine. Dabigatran AUC_τ,ss and C_max,ss were increased, on average, by about 1.5-fold (+53% and 56%), respectively, with concomitant quinidine.
Ticagrelor: When a single dose of dabigatran etexilate 75 mg was co-administered simultaneously with a loading dose of ticagrelor 180 mg, the dabigatran AUC and C_max were increased by 1.73- and 1.95-fold (+73% and 95%), respectively. After multiple doses of ticagrelor 90 mg twice daily, the increase of dabigatran exposure is reduced to 1.56- and 1.46-fold (+56% and 46%) for C_max and AUC, respectively.
Co-Medication with P-gp Substrates: Digoxin: When dabigatran etexilate was co-administered with digoxin, a P-gp substrate, no PK interaction was observed. Neither dabigatran nor the prodrug dabigatran etexilate is a clinically relevant P-gp inhibitor.
Co-Medication with P-gp Inducers: Rifampicin: Pre-dosing of the probe inducer rifampicin at a dose of 600 mg once daily for 7 days decreased total dabigatran peak and total exposure by 65.5% and 67%, respectively. The inducing effect was diminished resulting in dabigatran exposure close to the reference by day 7 after cessation of rifampicin treatment. No further increase in bioavailability was observed after another 7 days.
Co-Medication with Platelet Inhibitors: Acetylsalicylic Acid (ASA): The effect of concomitant administration of dabigatran etexilate and ASA on the risk of bleeding 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 dabigatran etexilate 150 mg twice daily may increase the risk for any bleeding from 12-18% and 24% with ASA 81 mg and 325 mg, respectively.
From the data gathered in the phase III study RE-LY, it was observed that ASA or clopidogrel co-medication with dabigatran etexilate at dosages of 110 mg or 150 mg twice daily may increase the risk of major bleeding. The higher rate of bleeding events by ASA or clopidogrel co-medication was, however, also observed for warfarin.
Nonsteroidal anti-inflammatory drugs (NSAIDs) given for short-term perioperative analgesia have been shown not to be associated with increased bleeding risk when given in conjunction with dabigatran etexilate. There is limited evidence regarding the use of regular NSAID medication with t_½ of <12 hrs during treatment with dabigatran etexilate and this has not suggested additional bleeding risk.
Prevention of Stroke, Systemic Embolism and Reduction of Vascular Mortality in Patients with Atrial Fibrillation: Nonsteroidal anti-inflammatory drugs increased the risk of bleeding in RE-LY in all treatment groups.
Clopidogrel: In a phase I study in young healthy male volunteers, the concomitant administration of dabigatran etexilate and clopidogrel resulted in no further prolongation of capillary bleeding times (CBT) compared to clopidogrel monotherapy. In addition, dabigatran AUC_τ,ss, C_max,ss and the coagulation measures for dabigatran effect, activated partial thromboplastin time (aPTT), electroconvulsive therapy (ECT) or thrombolytic therapy (TT) (anti-FIIa) or the inhibition of platelet aggregation (IPA) as measure of clopidogrel effect remained essentially unchanged comparing combined treatment and the respective mono-treatments. With a loading dose of clopidogrel 300 mg or 600 mg, dabigatran AUC_τ,ss and C_max,ss were increased by about 1.3- to 1.4-fold (+30-40%) (see previous discussion on ASA).
Antiplatelets or Other Anticoagulants: The concomitant use of dabigatran etexilate and antiplatelets, or other anticoagulants may increase the risk of bleeding (see Precautions).
Co-Medication with Selective Serotonin Reuptake Inhibitors (SSRIs): Selective serotonin reuptake inhibitors (SSRIs) increase the risk of bleeding in RE-LY in all treatment groups.
Co-Medication with Gastric pH-Elevating Agents: The changes in dabigratan exposure determined by population pharmacokinetic analysis caused by proton-pump inhibitors (PPIs) and antacids were not considered clinically relevant because the magnitude of the effect were minor (fractional decrease in bioavailability not significant for antacids and 14.6% for PPIs.
Pantoprazole: When dabigatran etexilate was co-administered with pantoprazole, a decrease in dabigatran AUC of approximately 30% was observed.
Pantoprazole and other PPIs were co-administered with dabigatran etexilate in clinical trials and no effects on bleeding or efficacy were observed.
Prevention of Stroke, Systemic Embolism and Reduction of Vascular Mortality in Patients with Atrial Fibrillation: In the phase III study, RE-LY, PPI co-medication did not result in lower trough levels and on average, only slightly reduced post-dose concentrations (-11%). Accordingly, PPI co-medication seemed to be not associated with a higher incidence of stroke or SEE, especially in comparison with warfarin, and hence, the reduced bioavailability by pantoprazole co-administration seemed to be of no clinical relevance.
Ranitidine: Ranitidine administration, together with dabigatran etexilate, had no meaningful effect on the extent of absorption of dabigatran.
Toxicology: Acute oral toxicity studies were conducted in rats and mice. In both species, the approximate lethal dose after single oral administration was >2000 mg/kg. In dogs and Rhesus monkeys, oral administration of dabigatran etexilate 600 mg/kg did not induce any toxicologically meaningful changes.
In repeat-dose toxicity studies over a maximum of 26 weeks in rats and 52 weeks in Rhesus monkeys, dosages up to 300 mg/kg (free-base equivalent) were used. Generally, these doses were tolerated remarkably well by both rats and Rhesus monkeys. Bleeding problems were observed in association with traumata (eg, blood sampling) within the first 4-6 hrs after administration and are directly related to the pharmacodynamic activity of dabigatran.
Teratology studies were performed with up to 200 mg/kg (free-base equivalent) in rats and rabbits. A slight effect on the morphogenesis of foetuses was observed in rats at 200 mg/kg (free-base equivalent). No teratogenic effects were noted in rabbits.
In the fertility study in rats, no toxicologically remarkable parental findings were noted. With respect to litter parameters, a slight decrease in corpora lutea and an increase in pre-implantation loss led to a decrease in the mean number of implantations in the 200 mg/kg (free-base equivalent) dose group.
Comprehensive in vitro and in vivo studies revealed no evidence of a mutagenic potential.
In lifetime toxicology studies in rats and mice, there was no evidence for a tumorigenic potential of dabigatran up to maximum doses of 200 mg/kg (free-base equivalent).

Prevention of venous thromboembolic events in patients who have undergone orthopaedic surgery for knee or hip replacement.
Prevention of stroke, systemic embolism and reduction of vascular mortality in patients with atrial fibrillation.
Treatment of acute deep vein thrombosis (DVT) and/or pulmonary embolism (PE) and prevention of related death.
Prevention of recurrent DVT and/or PE and related death.

Adults: Primary Prevention of Venous Thromboembolism (VTE): Prevention of VTE Following Knee Replacement Surgery: Treatment with Pradaxa should be initiated orally within 1-4 hrs 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 VTE Following Hip Replacement Surgery: Treatment with Pradaxa should be initiated orally within 1-4 hrs of completed surgery with 1 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, Systemic Embolism and Reduction of Vascular Mortality in Patients with Atrial Fibrillation: The recommended daily dose of Pradaxa is 300 mg taken orally as 150 mg hard capsule 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.
Prevention of Recurrent DVT and/or PE and Related Death: 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.
Renal Impairment: Renal function should be assessed by calculating the CrCl prior to initiation of treatment with Pradaxa to exclude patients for treatment with severe renal impairment (ie, CrCl <30 mL/min). There are no data to support the use in patients with severe renal impairment (CrCl <30 mL/min); 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 (eg, hypovolemia, dehydration and with certain co-medications).
Dabigratan can be dialysed; there is limited clinical experience to demonstrate the utility of this approach in clinical studies.
Prevention of VTE Events in Patients Who Have Undergone Major Orthopaedic Surgery: Dosing should be reduced to Pradaxa 150 mg taken once daily as 2 capsules of 75 mg in patients with moderate renal impairment (CrCl 30-50 mL/min).
Prevention of Stroke, Systemic Embolism and Reduction of Vascular Mortality in Patients with Atrial Fibrillation: 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 is necessary. Patients should be treated with a daily dose of 300 mg taken orally as 150 mg hard capsule twice daily.
Treatment of Acute DVT and/or 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.
Prevention of Recurrent DVT and/or PE and Related Death: 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.
Elderly: Prevention of VTE in Patients Who Have Undergone Major Orthopaedic Surgery and Treatment of Acute DVT and/or 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 CrCl prior to initiation of treatment with Pradaxa to exclude patients for treatment with severe renal impairment (ie, 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 (eg, hypovolemia, dehydration and with certain co-medications).
No dose adjustment necessary. Patients should be treated with Pradaxa 220 mg taken once daily as 2 capsules of 110 mg or with a daily dose of 300 mg taken orally as 150 mg hard capsules twice daily.
Prevention of Stroke, Systemic Embolism and Reduction of Vascular Mortality in Patients with Atrial Fibrillation and Recurrent DVT and/or PE and Related Death: As renal impairment may be frequent in the elderly (>75 years), renal function should be assessed by calculating CrCl prior to initiation of treatment with Pradaxa to exclude patients for treatment with severe renal impairment (ie, 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 (eg, hypovolemia, dehydration and with certain co-medications). Patients aged ≥80 years should be treated with a daily dose of 220 mg taken orally as 110 mg hard capsules or 300 mg taken orally as 150 mg hard capsules twice daily. No dose adjustment is necessary. Pharmacokinetic studies in older subjects demonstrate an increase in drug exposure in those patients with age-related decline of renal function. (See Renal Impairment in previous text.)
Weight: No dose adjustment necessary.
Concomitant use of Pradaxa with Strong P-glycoprotein Inhibitors ie, Amiodarone, Quinidine or Verapamil: Prevention of Venous Thromboembolic Events in Patients Who Have Undergone Major Orthopaedic 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 major orthopaedic surgery who are already treated with Pradaxa. Simultaneous initiation of treatment with Pradaxa and verapamil should also be avoided.
Prevention of Stroke, Systemic Embolism and Reduction of Vascular Mortality in Patients with Atrial Fibrillation and Treatment of Acute DVT and/or 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.
Prevention of Recurrent DVT and/or PE and 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.
Patients at Risk of Bleeding: Prevention of Stroke, Systemic Embolism and Reduction of Vascular Mortality in Patients with Atrial Fibrillation: The presence of the following factors may increase the risk of bleeding [eg, patients ≥75 years, moderate renal impairment (CrCl 30-50 mL/min), concomitant treatment with strong P-gp inhibitors (see Special Populations under Pharmacokinetics under Actions), antiplatelets or previous gastrointestinal bleed (see Precautions).
For patients with ≥1 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 and Prevention of Acute or Recurrent DVT and/or PE and Prevention of Related Death: The presence of the following factors may increase the risk of bleeding: Eg, age ≥75 years, moderate renal impairment (CrCl 30-50 mL/min) or previous gastrointestinal 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 VTE Events in Patients Who Have Undergone Major Orthopaedic Surgery: Wait 24 hrs after the last dose before switching from Pradaxa to a parenteral anticoagulant.
Prevention of Stroke, Systemic Embolism and Reduction of Vascular Mortality in Patients with Atrial Fibrillation: Wait 12 hrs after the last dose before switching from Pradaxa to a parenteral anticoagulant.
Treatment and Prevention of Acute or Recurrent DVT and/or PE and Prevention of Related Death: Wait 12 hrs 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 hrs 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 [eg, IV unfractionated heparin (UFH)].
Switching from VKA to Pradaxa: Prevention of Stroke, Systemic Embolism and Reduction of Vascular Mortality in Patients with Atrial Fibrillation: The VKA should be stopped. Pradaxa can be given as soon as the international normalized ratio (INR) is <2.
Treatment and Prevention of Acute or Recurrent DVT and/or PE and Prevention of Related Death: The VKA should be stopped. Pradaxa can be given as soon as the international normalized ratio (INR) is <2.
Switching from Pradaxa to VKA: Prevention of Stroke, Systemic Embolism and Reduction of Vascular Mortality in Patients with Atrial Fibrillation: 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 to <50 mL/min, start VKA 2 days before discontinuing dabigatran etexilate.
Treatment and Prevention of Acute or Recurrent DVT and/or 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 to <50 mL/min, start VKA 2 days before discontinuing dabigatran etexilate.
Cardioversion: Prevention of Stroke, Systemic Embolism and Reduction of Vascular Mortality in Patients with Atrial Fibrillation: Patients can stay on Pradaxa while being cardioverted.
Missed Dose: Prevention of VTE Events in Patients Who Have Undergone Major Orthopaedic Surgery: Continue with the remaining daily doses of Pradaxa at the same time of the next day.
Do not take a double dose to make up for the missed individual doses.
Prevention of Stroke, Systemic Embolism and Reduction of Vascular Mortality in Patients with Atrial Fibrillation: A forgotten Pradaxa dose may still be taken up to 6 hrs prior to the next scheduled dose. From 6 hrs prior to the next scheduled dose, the missed dose should be omitted.
Do not take a double dose to make up for the missed individual doses.
Treatment and Prevention of Acute or Recurrent DVT and/or PE and Prevention of Related Death: A forgotten Pradaxa dose may still be taken up to 6 hrs prior to the next scheduled dose. From 6 hrs prior to the next scheduled dose, the missed dose should be omitted.
Do not take a double dose to make up for the missed individual doses.
Administration: 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. Do not open the capsule.

Overdose following administration of Pradaxa may lead to haemorrhagic complications due to its pharmacodynamic properties. A specific antidote antagonising the pharmacodynamic effect of Pradaxa is not available. Doses of Pradaxa beyond those recommended expose the patient to increased risk of bleeding. 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.
Appropriate standard treatment (eg, surgical haemostasis) as indicated and blood volume replacement should be undertaken. In addition, consideration may be given to the use of fresh whole blood or fresh frozen plasma. As protein-binding is low, dabigatran is dialysable; however, there is limited clinical experience in using dialysis in this setting (see Special Populations under Pharmacokinetics under Actions).
Activated prothrombin complex concentrates [eg, factor eight inhibitor bypass activity (FEIBA)] or recombinant factor VIIa or concentrates of coagulation factors II, IX or X may be considered. There is some experimental evidence to support the role of these agents in reversing the anticoagulant effect of dabigatran, but their usefulness in clinical settings has not yet been systematically demonstrated. Consideration should also be given to the 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.

Known hypersensitivity to dabigatran or dabigatran etexilate or to any of the excipients of Pradaxa.
Patients with severe renal impairment (CrCl <30 mL/min); haemorrhagic manifestations, with a bleeding diathesis or spontaneous or pharmacological impairment of haemostasis; organ lesions at risk of clinically significant bleeding, including haemorrhagic stroke within the last 6 months; concomitant treatment with systemic ketoconazole (see Interactions). Prosthetic heart valve replacement.

Haemorrhagic Risk: As with all anticoagulants, Pradaxa should be used with caution in conditions with an increased risk of bleeding. Bleeding can occur at any site during therapy with Pradaxa. An unexplained fall in hemoglobin and/or hematocrit or blood pressure should lead to a search for a bleeding site.
Pradaxa treatment does not require anticoagulant monitoring. The INR test is unreliable in patients on Pradaxa and false positive INR elevations have been reported. Therefore, INR tests should not be performed.
Tests of anticoagulant activity eg, thrombin time (TT), ecarin clotting time (ECT) and activated partial thromboplastin time (aPTT) are available to detect excessive dabigatran activity.
Dabigatran-related anticoagulation can be assessed by ECT or TT. If ECT or TT is not available, the aPTT test provides an approximation of the anticoagulant activity of Pradaxa.
Prevention of Stroke, Systemic Embolism and Reduction of Vascular Mortality in Patients with Atrial Fibrillation: In atrial fibrillation patients in RE-LY treated with 150 mg twice daily, an aPTT of >2- to 3-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.
Factors [eg, decreased renal function (CrCl 30-50 mL/min), patients ≥75 years or strong P-gp inhibitor co-medications 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 the central venous or arterial catheter) and heparin derivatives, low molecular weight heparins (LMWH), fondaparinux, desirudin, thrombolytic agents, glycoprotein IIb/IIIa (GPIIb/IIIa) receptor antagonists, ticlopidine, dextran, sulfinpyrazone, rivaroxaban, prasugrel, VKA 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 Special Populations under 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 reuptake inhibitors (SSRIs) or selective serotonin norepinephrine reuptake inhibitors (SNRIs).
Use of Fibrinolytic Agents for the Treatment of Acute Ischemic Stroke: The use of fibrinolytic agents for the treatment of acute ischemic stroke may be considered if the patient presents with TT, ECT or aPTT not exceeding the ULN according to the local reference range.
In situations where there is an increased haemorrhagic risk (eg, recent biopsy or major trauma, bacterial endocarditis), close observation (ie, looking for signs of bleeding or anaemia) is generally required.
Prevention of VTE Events in Patients Who Have Undergone Major Orthopaedic Surgery: Nonsteroidal anti-inflammatory drugs (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 t_½ of <12 hrs during treatment with Pradaxa and this has not suggested additional bleeding risk.
Prevention of Stroke, Systemic Embolism and Reduction of Vascular Mortality in Patients with Atrial Fibrillation: Co-administration of antiplatelet (including aspirin and clopidogrel) and NSAID therapies increase the risk of bleeding. Specifically, with concomitant intake of antiplatelets or strong P-gp inhibitors in patients ≥75 years, the risk of major bleeding including gastrointestinal bleeding increases. If bleeding is clinically suspected, appropriate measures (eg, testing for occult blood in stool or testing for a drop in hemoglobin) is suggested.
Interaction with P-gp Inducers: The concomitant use of Pradaxa with the strong P-gp inducer rifampicin reduces dabigatran plasma concentrations. Other P-gp inducers eg, St. John's Wort or carbamazepine are also expected to reduce dabigatran plasma concentrations and should be co-administered with caution (see Special Populations under 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 Pharmacokinetics under Pharmacology under Actions).
Preoperative Phase: Due to an increased risk of bleeding, Pradaxa may be stopped temporarily in advance of invasive or surgical procedures. If possible, Pradaxa should be discontinued at least 24 hrs 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 11 and Pharmacology: Pharmacokinetics under Actions).

Click on icon to see table/diagram/image

Pradaxa is contraindicated in patients with severe renal dysfunction (CrCl <30 mL/min), but should this occur, Pradaxa should be stopped at least 5 days before major surgery.
If an acute intervention is required, Pradaxa should be temporarily discontinued. A surgery/intervention should be delayed if possible until at least 12 hrs after the last dose. If surgery cannot be delayed, there may be an increase in the risk of bleeding. This risk of bleeding should be weighed together with the urgency of intervention. (For cardioversion, see Dosage & Administration).
Spinal Anesthesia/Epidural Anesthesia/Lumbar Puncture: Procedures (eg, 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 hr should elapse before the administration of the 1st dose of Pradaxa. These patients require frequent observation for neurological signs and symptoms of spinal or epidural hematoma.
Postprocedural Period: Resume treatment after complete haemostasis is achieved.
Excipients: Pradaxa contains the excipient sunset yellow (E110) which may cause allergic reactions.
Effects on the Ability to Drive or Operate Machinery: No studies on the effects on the ability to drive and use machines have been performed.
Impairment of Fertility: No clinical data are available. Nonclinical reproductive studies did not show any adverse effects on fertility or postnatal development of the neonate.
Use in Pregnancy: No clinical data on exposed pregnancies are available. The potential risk for humans is unknown.
Women of childbearing 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.
Use in Lactation: No clinical data are available. As a precaution, breastfeeding should be stopped.
Use in Children: Prevention of VTE Events in Patients Who Have Undergone Major Orthopaedic Surgery and Prevention of Stroke, Systemic Embolism and Reduction of Vascular Mortality in Patients with Atrial Fibrillation: Pradaxa has not been investigated in patients <18 years. Treatment of children with Pradaxa is not recommended.
Treatment and Prevention of Acute or Recurrent DVT and/or PE and Prevention of Related Death: Pradaxa is under investigation in patients <18 years. The safety and efficacy in children has not yet been established. Treatment of children with Pradaxa is therefore not recommended

Use in Pregnancy: No clinical data on exposed pregnancies are available. The potential risk for humans is unknown.
Women of childbearing 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.
Use in Lactation: No clinical data are available. As a precaution, breastfeeding should be stopped.

The safety of Pradaxa has been evaluated overall in 38,008 patients in 11 clinical trials; thereof 23,352 Pradaxa patients were investigated.
Prevention of VTE Events in Patients Who Have Undergone Major Orthopaedic Surgery: In the primary VTE prevention trials after major orthopaedic surgery, a total of 10,795 patients were treated in 6 controlled-studies with at least 1 dose of dabigatran etexilate (enoxaparin 150 mg and 220 mg once daily). Of these, 6684 of the 10,795 were treated with dabigatran etexilate 150 mg or 220 mg once daily.
Prevention of Stroke, Systemic Embolism and Reduction of Vascular Mortality in Patients with Atrial Fibrillation: 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 randomized to dabigatran etexilate. Of these, 6,059 were treated with dabigatran etexilate 150 mg twice daily, while 5,983 received doses of 110 mg twice daily.
Treatment of Acute DVT and/or PE and Prevention of Related Death: In the acute DVT/PE treatment trials (RE-COVER, RE-COVER II) a total of 2,456 patients were included in the safety analysis for dabigatran etexilate. All patients were treated with dabigatran etexilate 150 mg twice daily.
Prevention of Recurrent DVT and/or PE and Related Death: 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 twice daily.
In total, about 9% of the patients treated for elective hip or knee surgery (short-term treatment for up to 42 days) and 22% of the patients with atrial fibrillation treated for the prevention of stroke and systemic embolism (long-term treatment for up to 3 yrs).
Fourteen percent (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 the patients treated short-term for elective hip or knee-replacement surgery, and in long-term treatment in yearly 16.5% of patient with atrial fibrillation treated for the prevention of stroke and systemic embolism and in 14.4% of patients with acute DVT and/or PE. In the recurrent DVT/PE trial RE-MEDY 19.4% and in the RE-SONATE trial 10.5% of patients experienced any bleeding.
Although rare in frequency in clinical trials, major or severe bleeding may occur and, regardless of location, may lead to disabling, life-threatening or even fatal outcomes.
Prevention of VTE Events in Patients Who Have Undergone Major Orthopaedic Surgery: Overall bleeding rates were similar between treatment groups and not significantly different.
Prevention of Stroke, Systemic Embolism and Reduction of Vascular Mortality in Patients with Atrial Fibrillation: Major bleeding fulfilled ≥1 of the following criteria: Bleeding associated with a reduction in hemoglobin of at least 20 g/L 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 IM with compartment syndrome, retroperitoneal bleeding, intra-articular bleeding or pericardial bleeding.
Major bleeds were classified as life-threatening if they fulfilled ≥1 of the following criteria: Fatal bleed; symptomatic intracranial bleed; reduction in hemoglobin of at least 50 g/L; transfusion of at least 4 units of blood or packed cells; a bleed associated with hypotension requiring the use of IV inotropic agents; a bleed that necessitated surgical interventions.
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 also had a statistically significant lower total bleed rate. Subjects randomized to dabigatran etexilate 110 mg twice daily had a significantly lower risk for major bleeds compared with warfarin (hazard ratio 0.8, p=0.0026).
Treatment of Acute DVT and/or 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 categorized as an MBE if it fulfilled at least 1 of the following criteria: Fatal bleeding; symptomatic bleeding in a critical area or organ eg, intracranial, intraspinal, intraocular, retroperitoneal, intra-articular or pericardial, or IM 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 leading to transfusion of ≥2 units of whole blood or red cells.
In a pooled analysis of the 2 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 0.6 (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 versus warfarin.
Bleeding events for both treatments are counted from the 1st intake of dabigatran etexilate or warfarin after the parenteral therapy has been discontinued (only oral treatment period). This includes all bleeding events which occurred during dabigatran therapy. All bleeding events which occurred during warfarin therapy are included except for those during the overlap period between warfarin and parenteral therapy.
Prevention of Recurrent DVT and/or PE and Related Death: The definition of MBEs followed the recommendations of the International Society on Thrombosis and Haemostasis. A bleeding in RE-MEDY event was categorized as an MBE if it fulfilled at least 1 of the following criteria: Fatal bleeding, symptomatic bleeding in a critical area or organ eg, intracranial, intraspinal, intraocular, retroperitoneal, intra-articular or pericardial, or IM 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 leading to transfusion of ≥2 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 categorized as an MBE if it fulfilled at least 1 of the following criteria: Fatal bleeding associated with a fall in haemoglobin of ≥2 g/dL led to the transfusion of ≥2 units packed cells or whole blood.
Occurred in a critical site: Intracranial, intraspinal, intraocular, pericardial, intra-articular, IM with compartment syndrome, retroperitoneal.
In RE-SONATE, the rates of MBE were low [2 patients with MBEs (0.3%) for dabigatran etexilate vs 0 patients with MBE (0%) for placebo]. The rate of major bleeding events or clinically relevant bleeding events were higher with dabigatran etexilate compared with placebo (5.3% vs 2%).
Adverse reactions classified by System Organ Class (SOC) and MedDRA preferred terms reported from any treatment group per population of all controlled studies are shown as follows. Side effects applicable to all 4 indications and additional lists of specific side effects are 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 VTE Events in Patients Who Have Undergone Major Orthopaedic 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, Systemic Embolism and Reduction of Vascular Mortality in Patients with Atrial Fibrillation: 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 DVT and/or 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%).
Prevention of Recurrent DVT and/or PE and Related Death: 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%).
Side Effects Identified From The Primary VTE Prevention Studies After Major Orthopaedic Surgery Program, The Prevention of Thromboembolic Stroke and Systemic Embolism in Patients with Atrial Fibrillation, Treatment of Acute DVT and/or PE and Prevention of Related Death, and Prevention of Recurrent DVT and/or PE and Related Death: Blood and Lymphatic System Disorders: Anaemia, thrombocytopenia.
Immune System Disorders: Drug hypersensitivity including pruritus, rash and urticaria, bronchospasm, angioedema, anaphylactic reaction.
Nervous System Disorders: Intracranial haemorrhage.
Vascular Disorders: Haematoma, haemorrhage.
Respiratory, Thoracic and Mediastinal Disorders: Epistaxis, haemoptysis.
Gastrointestinal Disorders: Gastrointestinal haemorrhage, abdominal pain, diarrhoea, dyspepsia, nausea, gastrointestinal ulcer (including oesophageal ulcer), gastroesophagitis, gastroesophageal reflux disease, vomiting, dysphagia.
Hepatobiliary Disorders: Abnormal hepatic function.
Skin and Subcutaneous Tissue Disorders: Skin haemorrhage.
Musculoskeletal, Connective Tissue and Bone Disorders: Haemarthrosis.
Renal and Urinary Disorders: Urogenital haemorrhage.
General Disorders and Administration Site Conditions: Injection site haemorrhage, catheter-site haemorrhage.
Injury, Poisoning and Procedural Complications: Traumatic haemorrhage, incision-site haemorrhage.
Additional Specific Side Effects Identified Per Indication: Prevention of VTE Events in Patients Who Have Undergone Major Orthopaedic Surgery: Vascular Disorders: Wound haemorrhage.
General Disorders and Administration Site Conditions: Bloody discharge.
Injury, Poisoning and Procedural Complications: Postprocedural haematoma, haemorrhage and discharge; postoperative anaemia, wound secretion.
Surgical and Medical Procedures: Wound drainage, postprocedural drainage.
Prevention of Stroke, Systemic Embolism and Reduction of Vascular Mortality in Patients with Atrial Fibrillation: None.
Treatment and Prevention of Acute or Recurrent DVT and/or PE and Prevention of Related Death: None.

The concomitant use of Pradaxa with treatments that act on haemostasis or coagulation including VKA can markedly increase the risk of bleeding. (See Precautions.)
Dabigatran etexilate and dabigatran are not metabolized by the cytochrome P-450 system and had no effects in vitro on human cytochrome P-450 enzymes. Therefore, related drug-drug interactions are not expected with dabigatran etexilate or dabigatran (see Special Populations under Pharmacokinetics under Actions).
P-gp Interactions: P-gp Inhibitors: Dabigatran etexilate is a substrate for the efflux transporter P-gp. Concomitant administration of P-gp inhibitors (eg, 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 VTE Events in Patients Who Have Undergone Major Orthopaedic Surgery: For the concomitant use of P-gp inhibitors and dosing of Pradaxa in this indication (see Dosage & Administration and Special Precautions under Pharmacokinetics under Actions).
Prevention of Stroke, Systemic Embolism and Reduction of Vascular Mortality in Patients with Atrial Fibrillation: For the other P-gp inhibitors listed previously, no dose adjustments are required for Pradaxa in this indication.
Treatment and Prevention of Acute or Recurrent DVT and/or PE and Prevention of Related Death: 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 Special Populations under Pharmacokinetics under Actions).
Prevention of Stroke, Systemic Embolism and Reduction of Vascular Mortality in Patients with Atrial Fibrillation: In patients in the RE-LY trial, concentrations were increased by no more than 14% and no increased risk of bleeding was observed.
Verapamil: When Pradaxa 150 mg was co-administered with oral verapamil, the C_max and AUC of dabigatran were increased, but the magnitude of this change differs depending on the timing of administration and formulation of verapamil (see Special Populations under Pharmacokinetics under Actions).
Prevention of Stroke, Systemic Embolism and Reduction of Vascular Mortality in Patients with Atrial Fibrillation: In patients in the RE-LY trial, concentrations were increased by no more than 21% and no increased risk of bleeding was observed.
Quinidine: Dabigatran exposure in healthy subjects was increased by 1.5-fold (+53%) in the presence of quinidine (see Special Populations under Pharmacokinetics under Actions).
Clarithromycin: Dabigatran exposure in healthy subjects was increased by about 19% in the presence of clarithromycin without any clinical safety concern (see Special Populations under Pharmacokinetics under Actions).
Ketoconazole: Dabigatran exposure was increased by 2.5-fold (+150%) after single and multiple doses of systemic ketoconazole (see Special Populations under 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 Special Populations under Pharmacokinetics under Actions).
Ticagrelor: Dabigatran exposure in healthy subjects was increased by 1.46 fold (+46%) in the presence of ticagrelor at steady state or by 1.73 fold (+73%) when a loading dose of ticagrelor was administered simultaneously with a single dose of dabigatran etexilate 75 mg.
P-gp Substrate: Digoxin: In a study performed with 24 healthy subjects, when Pradaxa was co-administered with digoxin, no changes on digoxin and no clinical relevant changes on dabigatran exposure have been observed (see Special Populations under Pharmacokinetics under Actions).
P-gp Inducers: After 7 days of treatment with rifampicin 600 mg once daily, the total dabigatran AUC_0-∞ and C_max were reduced by 67% and 66% compared to the reference treatment, respectively.
The concomitant use with P-gp inducers (eg, rifampicin) reduces exposure to dabigatran and should be avoided (see Special Populations under Pharmacokinetics under Actions and Precautions).

Store below 30°C. Protect from moisture.

Anticoagulants, Antiplatelets & Fibrinolytics (Thrombolytics)

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

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