Pradaxa

Pradaxa

dabigatran

Manufacturer:

Boehringer Ingelheim
Full Prescribing Info
Contents
Dabigatran etexilate.
Description
1 Capsule contains 86.48 mg, 126.83 mg or 172.95 mg of beta-alanine, N-[[2-[[[4(hexyloxy)carbonyl]amino]iminomethyl] phenyl]amino]methyl]-1-methyl-1H-benzimidazol-5-yl]carbonyl]-N-2-pyridinyl-,ethyl ester, methane-sulfonate, being the methane sulfonic acid salt (Corresponding to dabigatran etexilate base form 75 mg, 110 mg or 150 mg).
Excipients/Inactive Ingredients: Tartaric acid, acacia, hypromellose, dimethicone 350, talc, hydroxypropyl cellulose.
HPMC capsule shell: Carragenan, potassium chloride, titanium dioxide, Indigo Carmin (E132), hypromellose.
Printing ink: Shellac, N-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 etexilate.
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 PTT, ECT and TT.
However, this can only be measured by a combination of aPTT, prothrombin Time (PT, expressed as INR), thromboplastin time and Ecarin clotting time tests, no single of which provides a complete assessment of the anticoagulant effect of dabigatran. At recommended prophylactic doses of dabigatran etexilate, dabigatran may prolong the activated partial thromboplastin time (aPTT), and the iNR but these tests are relatively insensitive to the activity of dabigatran and are unsuitable alone as measures of anticoagulant activity. However, in patients who are bleeding aPTT tests may help determine an excess of anticoagulant activity.
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 venous thromboembolism (VTE) 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 VTE 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 RENOVATE the randomisation to the respective study medication was done pre-surgery, and in the RE-MOBILIZE and the Japanese placebo controlled trial the randomisation to the respective study medication was done post-surgery. This is of note especially in the safety evaluation of these trials. For this reason the trials are grouped in pre- and post-surgery randomised trials in Table 1.
Data for the major VTE and VTE-related mortality end-point and adjudicated major bleeding endpoints are shown in the Table 1 as follows. VTE was defined as the composite incidence of deep vein thrombosis and Pulmonary Embolism (see Table 1).


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Clinical trials in prevention of stroke and systemic embolism in patients with atrial fibrillation: The clinical evidence for the efficacy of dabigatran etexilate is derived from the randomized evaluation of long-term anticoagulant therapy (RE-LY) study a multicenter, multinational, randomized parallel group study of 2 blinded doses of dabigatran etexilate (110 and 150 mg twice daily) 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 noninferior 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 nonvalvular atrial fibrillation (AF) eg, persistent AF or paroxysmal, patients had 1 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; patient ≥75 years; ≥65 years and associated with 1 of the following: Diabetes mellitus, coronary artery disease 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 VKA naive defined as <2 months total life time 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 (25% of subjects used at least 50% of the time in study), clopidogrel (3.6%), ASA + clopidogrel (2%), NSAIDs (6.3%), β-blockers (63.4%), diuretics (53.9%), statins (46.4%), ACE inhibitors (44.6%), angiotensin-receptor blockers (26.1%), oral hypoglycemics (17.5%), insulin (5.2%), digoxin (29.4%), amiodarone (11.3%), diltiazem (8.9%), verapamil (5.4%) and proton-pump inhibitors (17.8%).
For the primary endpoint, stroke and systemic embolism, no subgroups (ie, age, weight, gender, renal function, ethnicity, etc). were identified with a different risk ratio compared to warfarin.
This study demonstrated that dabigatran etexilate, at a dose of 110 mg twice daily, is non-inferior to warfarin in the prevention of stroke and systemic embolism in subjects with atrial fibrillation, with a reduced risk of intracranial hemorrhage and total bleeding. The higher dose of 150 mg twice daily, reduces significantly the risk of ischemic and hemorrhagic stroke, vascular death, intracranial hemorrhage and total bleeding compared to warfarin. The lower dose of dabigatran has a significantly lower risk of major bleeding compared to warfarin.
Figure 1 and tables 2 - 6 display details of key results: (see Figure 1 and tables 2-6 as follows


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


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In the RE-LY study, potential abnormalities of liver function tests (LFT) occurred with a comparable or lower incidence in dabigatran etexilate vs. warfarin treated patients (see table 6).


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The RE-LY extension study (RELY-ABLE) provided additional safety information for a large cohort of patients which continued the same dose of dabigatran etexilate as assigned in the RE-LY trial. Patients were eligible for the RELY-ABLE trial if they had not permanently discontinued study medication at the time of their final RE-LY study visit. Enrolled patients continued to receive the same double-blind dabigatran etexilate dose randomly allocated in RE-LY, for up to 43 months of follow up after RE-LY (total mean follow-up RE-LY + RELY-ABLE, 4.5 years). There were 5897 patients enrolled, representing 49% of patients originally randomly assigned to receive dabigatran etexilate in RE-LY and 86% of RELY-ABLE-eligible patients.
During the additional 2.5 years of treatment in RELY-ABLE, with a maximum exposure of over 6 years (total exposure in RELY + RELY-ABLE), the long-term safety profile of dabigatran etexilate was confirmed for both test doses. No new safety findings were observed.
The rates of outcome events including, major bleed and other bleeding events were consistent with those seen in RE-LY.
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.
Treatment of acute deep vein thrombosis (DVT) and/or pulmonary embolism (PE): Clinical evidence has demonstrated dabigatran etexilate to be an effective and safe treatment for DVT and/or PE in two multi-centre, 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 etixilate 150 mg twice daily as compared with those receiving warfarin.


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Other Measures Evaluated: Myocardial infarction occurred at a low frequency in RE-COVER and RE-COVER II studies for all treatment groups.
In the two active studies a higher rate of myocardial infarction was reported in patients who received dabigatran etexilate (9; 0.4%) than in those received warfarin (4; 0.2%).
Liver Function Tests: 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 below, in Table 8.


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The absolute bioavailability of dabigatran following oral administration of dabigatran etexilate as HMPC 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 1.8 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 (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 radiolabelled 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 - 50ml/min) than in those without renal insufficiency.
In a small number of volunteers with severe renal insufficiency (CrCL 10 - 30 ml/min), the exposure (AUC) to dabigatran was approximately 6 times higher and the half-life approximately 2 times longer than that observed in a population without renal insufficiency (see Dosage & Administration and Contraindications).
Clearance of dabigatran by hemodialysis was investigated in patients with end- stage renal disease (ESRD) without atrial fibrillation. Dialysis was conducted with 700ml/min dialysate flow rate, four hour duration, a blood flow rate of either 200ml/min or 350 - 390ml/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 systemic embolism in patients with atrial fibrillation with at least one additional risk factor for stroke (i.e., previous ischemic stroke, transient ischemic attack [TIA], or systemic embolism; left ventricular dysfunction): The median CrCL in RE-LY was 68.4 ml/min. Almost half (45.8 %) of the RE-LY patients had a CrCL > 50-< 80 ml/min. Patients with moderate renal impairment (CrCL between 30-50 ml/min) had on average 2.29-fold and 1.81-fold higher pre- and post-dose dabigatran plasma concentrations, respectively, when compared with patients without renal impairment (CrCL ≥80 ml/min).
Treatment of acute deep vein thrombosis (DVT) and/or pulmonary embolism (PE): The median CrCl in the RE-COVER study was 100.3 mL/min. 21.7% of patients had mild renal impairment (CrCl > 50-< 80 mL/min) and 4.5% of patients had a moderate renal impairment (CrCl between 30-50 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.
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 I 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 replacement surgery or total knee replacement surgery: Patients with moderate and severe hepatic impairment (Child-Pugh classification B and C) or liver disease expected to have any impact on survival or with elevated liver enzymes ≥ 2 Upper Limit Normal (ULN) were excluded in clinical trials.
Prevention of stroke and systemic embolism in patients with atrial fibrillation with at least one additional risk factor for stroke (i.e., previous ischemic stroke, transient ischemic attack [TIA], or systemic embolism; left ventricular dysfunction): Patients with active liver disease including but not limited to the persistent elevation of liver enzymes ≥ 2 Upper Limit Normal (ULN), or hepatitis A, B or C were excluded in clinical trials.
Treatment of acute deep vein thrombosis (DVT) and/or pulmonary embolism (PE): Patients with moderate and severe hepatic impairment (Child-Pugh classification B and C) or liver disease expected to have any impact on survival or with elevated liver enzymes ≥ 2 Upper Limit Normal (ULN) were excluded in clinical trials.
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: In atrial fibrillation patients females had on average 1.3-fold (+30%) higher trough and post-dose concentrations. This finding had no clinical relevance.
Drug exposure in the primary VTE prevention studies was about 1.4- to 1.5-fold (+40% to 50%) higher in female patient. This finding had no clinical relevance.
Ethnic origin: The pharmacokinetics of dabigatran was investigated in Caucasian and Japanese volunteers after single and multiple doses. Ethnic origin does not affect the pharmacokinetics of dabigatran in a clinically relevant manner.
Limited pharmacokinetic data in black patients are available which suggest no relevant differences.
Pharmacokinetic interactions: In vitro interaction studies did not show any inhibition or induction of cytochrome P450. This has been confirmed by in vivo studies in healthy volunteers, who did not show any interaction between dabigatran etexilate treatment and the following drugs: atorvastatin (CYP3A4), and diclofenac (CYP2C9).
Atorvastatin: When dabigatran etexilate was coadministered with atorvastatin, a CYP3A4 substrate, exposure of atorvastatin, atorvastatin metabolites and of dabigatran were unchanged indicating a lack of interaction.
Diclofenac: When dabigatran etexilate was coadministered with diclofenac, a CYP2C9 substrate, pharmacokinetics of both drugs remained unchanged indicating a lack of interaction between dabigatran etexilate and diclofenac.
P-gp inhibitor / inducer interactions: The pro-drug dabigatran etexilate but not dabigatran is a substrate of the efflux transporter P-glycoprotein (P-gp). Therefore co-medications with P-gp transporter inhibitors and inducers had been investigated.
Co-medication with P-gp inhibitors: Amiodarone: When dabigatran etexilate was coadministered with a single oral dose of 600 mg amiodarone, the extent and rate of absorption of amiodarone and its active metabolite DEA were essentially unchanged. The dabigatran AUC and Cmax were increased by about 1.6-fold and 1.5-fold (+60 % and 50 %), respectively.
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 AUC0-∞ and Cmax values increased by about 2.4-fold and 2.3-fold (+136 % and 125%), respectively, after multiple dosing of 400 mg dronedarone bid, and about 2.1-fold and 1.9-fold (+114% and 87%), respectively, after a single dose of 400 mg. The terminal half-life and renal clearance of dabigatran were not affected by dronedarone. When single and multiple doses of dronedarone were given 2 h after dabigatran etexilate, the increases in dabigatran AUC0-∞ were 1.3-fold and 1.6 fold, respectively.
Verapamil: When dabigatran etexilate was coadministered with oral verapamil, the Cmax and AUC of dabigatran were increased depending on timing of administration and formulation of verapamil.
The greatest elevation of dabigatran exposure was observed with the first dose of an immediate release formulation of verapamil administered one hour prior to dabigatran etexilate intake (increase of Cmax 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 Cmax by about 1.9-fold (+90%) and AUC by about 1.7-fold (+70%) or administration of multiple doses of verapamil (increase of Cmax by about 1.6-fold (+60%) and AUC by about 1.5-fold (+50%)). This can be explained by the induction of P-gp in the gut by chronic verapamil treatment.
There was no meaningful interaction observed when verapamil was given 2 hours after dabigatran etexilate (increase of Cmax by about 10% and AUC by about 20%). This is explained by completed dabigatran absorption after 2 hours (See Dosage & Administration).
No data are available for the parenteral application of verapamil; based on the mechanism of the interaction, no meaningful interaction is expected.
In the population pharmacokinetics study from RE-LY, no important changes in dabigatran trough levels were observed in patients who received verapamil (see Interactions).
Ketoconazole: Systemic ketoconazole increased total dabigatran AUC0-∞ and Cmax values by about 2.4-fold (+138 % and 135%), respectively, after a single dose of 400 mg, and about 2.5-fold (+153% and 149%), respectively, after multiple dosing of 400 mg ketoconazole qd. The time to peak, terminal half-life and mean residence time were not affected by ketoconazole.
Clarithromycin: When clarithromycin 500 mg twice daily was administered together with dabigatran etexilate no clinically relevant PK-interaction was observed (increased of Cmax by about 15% and AUC by about 19%).
Quinidine: Quinidine was given as 200 mg dose every 2nd hour up to a total dose of 1000 mg. Dabigatran etexilate was given bid over 3 consecutive days, on the 3rd day either with or without quinidine. Dabigatran AUCτ,ss and Cmax,ss were increased on average by about 1.5-fold (+53 % and 56 %), respectively with concomitant quinidine.
Ticagrelor: When a single dose of 75mg dabigatran etexilate was coadministered simultaneously with a loading dose of 180 mg ticagrelor, the dabigatran AUC and Cmax were increased by 1.73-fold and 1.95-fold (+73% and 95%), respectively. After multiple doses of ticagrelor 90 mg b.i.d. the increase of dabigatran exposure is reduced to 1.56-fold and 1.46-fold (+56% and 46%) for Cmax and AUC, respectively.
Concomitant administration of a loading dose of 180 mg ticagrelor and 110 mg dabigatran etexilate (in steady state) increased the dabigatran AUCτ,ss and by 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. Concomitant administration of 90 mg ticagrelor BID (maintenance dose) with 110 mg dabigatran etexilate increased the adjusted dabigatran AUCτ,ss and and Cmax,ss 1.26-fold 1.29-fold, respectively, compared with dabigatran etexilate given alone.
Co-medication with P-gp substrates: Digoxin: When dabigatran etexilate was coadministered with digoxin, a P-gp substrate, no PK-interaction was observed. Neither dabigatran nor the pro-drug dabigatran etexilate is a clinically relevant P-gp inhibitor.
Co-medication with P-gp inducers: Rifampicine: Pre-dosing of the probe inducer rifampicin at a dose of 600 mg qd for 7 days decreased total dabigatran peak and total exposure by 65.5 and 67 %, respectively. The inducing effect was diminished resulting in dabigatran exposure close to the reference by day 7 after cessation of rifampicin treatment. No further increase in bioavailability was observed after another 7 days.
Co-medications with platelet-inhibitors: Acetylsalicylic acid (ASA): The effect of of dabigatran etexilate and acetylsalicylic acid (ASA) on the risk of bleeds was studied in patients with atrial fibrillation in a phase II study in which a randomized ASA coadministration was applied. Based on logistic regression analysis, co-administration of ASA and 150 mg dabigatran etexilate twice daily may increase the risk for any bleeding from 12% to 18% and 24% with 81 mg and 325 mg ASA, respectively.
From the data gathered in the phase III study RE-LY it was observed that ASA or clopidogrel co-medication with dabigatran etexilate at dosages of 110 or 150 mg bid may increase the risk of major bleeding. The higher rate of bleeding events by ASA or clopidogrel co-medication was, however, also observed for warfarin.
NSAIDs: NSAIDs given for short-term perioperative analgesia have been shown not to be associated with increased bleeding risk when given in conjunction with dabigatran etexilate. There is limited evidence regarding the use of regular NSAID medication with half-lives of less than 12 hours during treatment with dabigatran etexilate and this has not suggested additional bleeding risk.
NSAIDs increased the risk of bleeding in RE-LY in all treatment groups.
Clopidogrel: In a phase I study in young healthy male volunteers, the concomitant administration of dabigatran etexilate and clopidogrel resulted in no further prolongation of capillary bleeding times (CBT) compared to clopidogrel monotherapy. In addition, dabigatran AUCτ,ss and Cmax,ss and the coagulation measures for dabigatran effect, aPTT, ECT or TT (anti FIIa), or the inhibition of platelet aggregation (IPA) as measure of clopidogrel effect remained essentially unchanged comparing combined treatment and the respective mono-treatments. With a loading dose of 300 or 600 mg clopidogrel, dabigatran AUCt,ss and Cmax,ss were increased about 1.3 to 1.4 fold (+30 to 40%) (see above subsection on ASA).
Antiplatelets or other anticoagulants: The concomitant use of dabigatran etexilate and antiplatelets or other anticoagulants may increase the risk of bleeding (see Precautions).
Co-medication with selective serotonin re-uptake inhibitors: SSRIs increased the risk of bleeding in RE-LY in all treatment groups.
Co-medication with gastric pH-elevating agents: The changes in dabigatran exposure determined by population pharmacokinetic analysis caused by PPIs and antacids were not considered clinically relevant because the magnitude of the effect were minor (fractional decrease in bioavailability not significant for antacids and 14.6% for PPIs.
Pantoprazole: When dabigatran etexilate was coadministered with pantoprazole, a decrease in dabigatran area under the plasma concentration - time curve of approximately 30 % was observed. Pantoprazole and other proton-pump inhibitors were co-administered with dabigatran etexilate in clinical trials and no effects on bleeding or efficacy were observed.
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 comedication 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 above 2000 mg/kg. In dogs and Rhesus monkeys, oral administration of 600 mg/kg dabigatran etexilate 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 (e.g. blood sampling) within the first 4 - 6 hours 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 etexilate up to maximum doses of 200 mg/kg (free base equivalent).
Indications/Uses
Primary prevention of venous thromboembolic events in adult patients who have undergone elective total hip replacement surgery or total knee replacement surgery.
Prevention of stroke and systemic embolism in patients with atrial fibrillation with at least one additional risk factor for stroke (i.e., previous ischemic stroke, transient ischemic attack [TIA], or systemic embolism; left ventricular dysfunction).
Treatment of acute deep vein thrombosis (DVT) and/or pulmonary embolism (PE).
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. The capsule should not be chewed broken or opened as this may increase the bioavailability of dabigatran.
Primary prevention of venous thromboembolic events in adult patients who have undergone elective total hip replacement surgery or total knee replacement surgery: Adults: VTE prevention 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.
VTE prevention 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.
Children: PRADAXA has not been investigated in patients <18 years of age. Treatment of children with PRADAXA is not recommended.
Hepatic impairment: 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. Therefore the use of dabigatran etexilate is not recommended in this population.
Renal impairment: Renal function should be assessed by calculating the creatinine clearance (CrCl) prior to initiation of treatment with PRADAXA to exclude patients for treatment with severe renal impairment (i.e. CrCl < 30ml/min). There are no data to support use in patients with severe renal impairment (< 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).
After i.v. application 85 % of dabigatran in plasma is cleared through the kidneys. Patients with moderate renal impairment (30-50 ml/min creatinine clearance) appear to be at higher risk of bleeding. Dosing should be reduced to 150 mg PRADAXA taken once daily as 2 capsules of 75 mg in patients with moderate renal impairment.
Regular assessment of renal status is required in these patients (see Contraindications and Renal under Precautions). A coagulation test, such as aPTT (see Monitoring and Laboratory Tests under Precautions), may help to identify patients with an increased bleeding risk caused by excessive dabigatran exposure.
Creatinine clearance can be estimated using the Cockroft-Gault formula as follows:


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Elderly: 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.
As renal impairment may be frequent in the elderly (>75 years), renal function should be assessed by calculating the creatinine clearance (CrCl) prior to initiation of treatment with PRADAXA to exclude patients for treatment with severe renal impairment (i.e. CrCl < 30ml/min ). The renal function should also be assessed in certain clinical situations when it is suspected that the renal function could decline or deteriorate (such as hypovolemia, dehydration, and with certain comedications, etc).
The clinical studies have been conducted in patient population with a mean age > 65 years. In general patients should be treated with 220 mg dabigatran etexilate daily.
Weight: Population PK modelling shows that patients with a body weight of 120 kg have about 20% lower drug exposure and patients with a body weight of 48 kg have about 25% higher drug exposure compared to patients with an average weight (BISTRO II). Since there was no difference in efficacy and bleeding rates, no dose adjustment is necessary.
Concomitant use of PRADAXA with strong P-glycoprotein inhibitors, i.e. amiodarone, quinidine or verapamil: 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 replacement surgery or total knee replacement surgery who are already treated with PRADAXA. Simultaneous initiation of treatment with PRADAXA and verapamil should also be avoided.
Switching from PRADAXA treatment to parenteral anticoagulant: Wait 24 hours after the last dose before switching from PRADAXA to a parenteral anticoagulant.
Switching from parenteral anticoagulants treatment to PRADAXA: No data are available, therefore it is not recommended to start the administration of dabigatran etexilate before the next scheduled dose of the parenteral anticoagulant would have been due.
Missed dose: 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 systemic embolism in patients with atrial fibrillation with at least one additional risk factor for stroke (i.e., previous ischemic stroke, transient ischemic attack [TIA], or systemic embolism; left ventricular dysfunction): Adults : The recommended daily dose of PRADAXA is 300 mg taken orally as 150 mg hard capsules twice daily. Therapy should be continued life-long. In case of intolerability, patients should be instructed to contact their doctor.
Children: PRADAXA has not been investigated in patients <18 years of age. Treatment of children with PRADAXA is not recommended.
Hepatic impairment: 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. Therefore the use of dabigatran etexilate is not recommended in this population.
Renal impairment: Renal function should be assessed by calculating the creatinine clearance (CrCl) prior to initiation of treatment with PRADAXA to exclude patients for treatment with severe renal impairment (i.e. CrCl < 30ml/min). There are no data to support use in patients with severe renal impairment (< 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).
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 with moderate renal impairment (CrCl 30-50 ml/min) should be treated with a daily dose of 300 mg taken orally as 150 mg hard capsules twice daily, with caution.
Regular assessment of renal status is required in these patients (see Contraindications and Renal under Precautions). A coagulation test, such as aPTT (see Monitoring and Laboratory Tests under Precautions), may help to identify patients with an increased bleeding risk caused by excessive dabigatran exposure. Creatinine clearance can be estimated using the Cockroft-Gault formula as follows:


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Elderly: 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.
As renal impairment may be frequent in the elderly (>75 years), renal function should be assessed by calculating the creatinine clearance (CrCl) prior to initiation of treatment with PRADAXA to exclude patients for treatment with severe renal impairment (i.e. CrCl < 30ml/min ). The renal function should also be assessed at least once a year in patients treated with PRADAXA or more frequently as needed in certain clinical situations when it is suspected that the renal function could decline or deteriorate (such as hypovolemia, dehydration, and with certain comedications, etc).
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.
Weight: Population PK modelling shows that patients with a body weight of 120 kg have about 20% lower drug exposure and patients with a body weight of 48 kg have about 25% higher drug exposure compared to patients with an average weight (BISTRO II). Since there was no difference in efficacy and bleeding rates, no dose adjustment is necessary.
Concomitant use of PRADAXA with strong P-glycoprotein inhibitors, i.e. amiodarone, quinidine or verapamil: 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: The presence of the following factors may increase the risk of bleeding, e.g. age ≥ 75 years, moderate renal impairment (30-50 ml CrCL/min), concomitant treatment with strong P-gp inhibitors (see Pharmacology: Pharmacokinetics: Special Population 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 physician.
Switching from PRADAXA treatment to parenteral anticoagulant: Wait 12 hours after the last dose before switching from PRADAXA to a parenteral anticoagulant.
Switching from parenteral anticoagulants treatment to PRADAXA: No data are available, therefore it is not recommended to start the administration of dabigatran etexilate before the next scheduled dose of the parenteral anticoagulant would have been due.
Switching from Vit. K antagonists to PRADAXA: 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: The starting time of the Warfarin should be adjusted according to the patient's Creatinine Clearance as follows: CrCL ≥ 50 ml/min, start Warfarin 3 days before discontinuing dabigatran etexilate;
CrCL ≥ 30-< 50 ml/min, start Warfarin 2 days before discontinuing dabigatran etexilate.
Cardioversion: Patients can stay on PRADAXA while being cardioverted.
Missed dose: A forgotten PRADAXA dose may still be taken up to 6 hours prior to the next scheduled dose. From 6 hours prior to the next scheduled dose on, the missed dose should be omitted.
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): 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.
Children: 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 CrCl); 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.
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: 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).
No dose adjustment necessary, patients should be treated with a daily dose of 300 mg taken orally as 150 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.
Weight: No dose adjustment is necessary.
Concomitant use of PRADAXA with strong P-glycoprotein inhibitors, i.e. amiodarone, quinidine or verapamil: 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: 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: 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: 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: The starting time of the Warfarin should be adjusted according to the patient's Creatinine Clearance as follows: CrCL ≥ 50 ml/min, start Warfarin 3 days before discontinuing dabigatran etexilate;
CrCL ≥ 30-< 50 ml/min, start Warfarin 2 days before discontinuing dabigatran etexilate.
Missed dose: A forgotten PRADAXA dose may still be taken up to 6 hours prior to the next scheduled dose. From 6 hours prior to the next scheduled dose on, the missed dose should be omitted.
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. 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, e.g. 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.
Coagulation factor concentrations (activated or non-activated) or recombinant Factor VIIa may be taken into account. There is some experimental evidence to support the role of these agents in reversing the anticoagulant effect of dabigatran but their usefulness in clinical settings has not yet been systematically demonstrated. Consideration should also be given to administration of platelet concentrates in cases where thrombocytopenia is present or long acting antiplatelet drugs have been used. All symptomatic treatment has to be given according to the physician's judgement.
Contraindications
Known hypersensitivity to dabigatran or dabigatran etexilate or to one of the excipients of the product. Severe renal impairment (CrCl < 30ml/min). Haemorrhagic manifestations, patients with a bleeding diathesis, or patients with spontaneous or pharmacological impairment of haemostasis. Prosthetic heart valve replacement. Hepatic impairment or liver disease expected to have any impact on survival. Concomitant treatment with systemic ketoconazole or dronedarone (see Precautions).
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.
Warnings
PREMATURE DISCONTINUATION OF PRADAXA INCREASES THE RISK OF THROMBOTIC EVENTS: Premature discontinuation of any oral anticoagulant, including PRADAXA, increases the risk of thrombotic events. To reduce this risk, consider coverage with another anticoagulant if PRADAXA is discontinued for a reason other than pathological bleeding or completion of a course of therapy.
SPINAL/EPIDURAL HEMATOMA: Epidural or spinal hematomas may occur in patients treated with PRADAXA who are receiving neuraxial anesthesia or undergoing spinal puncture. These hematomas may result in long-term or permanent paralysis . Monitor patients frequently for signs and symptoms of neurological impairment and if observed, treat urgently. Consider the benefits and risks before neuraxial intervention in patients who are or who need to be anticoagulated.
Special Precautions
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. Fatal bleeding may occur as with any anticoagulant, but there were fewer fatal bleeds with dabigatran etexilate than with warfarin in the RE-LY study. In this study of prevention of stroke and SEE in adult patients with nonvalvular atrial fibrillation, 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) (seeTable 9 as follows).
Close clinical surveillance (looking for signs of bleeding or anaemia) is recommended throughout the treatment period, especially if risk factors are combined.
The following table summarises factors which may increase the haemorrhagic risk as identified in clinical studies (see Table 9).


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PRADAXA treatment does not require anticoagulant monitoring. The INR test is unreliable in patients on PRADAXA and false positive INR elevations have been reported. Therefore INR tests should not be performed.
Tests of anticoagulant activity such as thrombin time (TT), ecarin clotting time (ECT) and activated partial thromboplastin time (aPTT) are available to detect excessive dabigatran activity.
Dabigatran related anticoagulation can be assessed by ECT or TT. If ECT or TT is not available, the aPTT test provides an approximation of PRADAXA's anticoagulant activity.
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 through 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, such as decreased renal function (30 - 50mL/min CrCL), age ≥ 75 years, or strong P-gp-inhibitor comedication are associated with increased dabigatran plasma levels. The presence of one or more than one of these factors may increase the risk of bleeding (see Dosage & Administration).
The concomitant use of PRADAXA with the following treatments has not been studied and may increase the risk of bleeding: unfractionated heparins (except at doses necessary to maintain patency of central venous or arterial catheter) and heparin derivatives, low molecular weight heparins (LMWH), fondaparinux, desirudin, thrombolytic agents, GPIIb/IIIa receptor antagonists, ticlopidine, dextran, sulphinpyrazone rivaroxaban, prasugrel, vitamin K antagonists, and the P-gp inhibitors, itraconazole, tacrolismus, cyclosporine, ritonavir, tipranavir, nelfinavir and saquinavir.
The concomitant use of dronedarone increases exposure of dabigatran and is not recommended.
The concomitant use of ticagrelor increases the exposure to dabigatran and may show pharmacodynamic interaction, which may result in an increased risk of bleeding.
Bleeding risk may be increased in patients concomitantly treated with selective serotonin re-uptake inhibitors (SSRI) or selective serotonin norepinephrine re-uptake inhibitors (SNRIs).
Use of fibrinolytic agents for the treatment of acute ischemic stroke: The use of fibrinolytic agents for the treatment of acute ischemic stroke may be considered if the patient presents with a thrombin time (TT), or Ecarin clotting time (ECT), or activated partial thromboplastin time (aPTT) not exceeding the upper limit of normal (ULN) according to the local reference range.
In situations where there is an increased haemorrhagic risk (e.g. recent biopsy or major trauma, bacterial endocarditis) close observation (looking for signs of bleeding or anaemia) is generally required.
Prevention of Venous Thromboembolic Events in patients who have undergone elective total hip replacement surgery or total knee replacement surgery: NSAIDs given for short-term perioperative analgesia have been shown not to be associated with increased bleeding risk when given in conjunction with PRADAXA. There is limited evidence regarding the use of regular NSAID medication with half-lives of less than 12 hours during treatment with PRADAXA and this has not suggested additional bleeding risk.
Prevention of stroke and systemic embolism in patients with atrial fibrillation with at least one additional risk factor for stroke (i.e., previous ischemic stroke, transient ischemic attack [TIA], or systemic embolism; left ventricular dysfunction): Co-administration of anti-platelet (including ASA and clopidogrel) and NSAID therapies increase the risk of bleeding. Specifically, with concomitant intake of antiplatelets or strong P-gp inhibitors in patients aged ≥75 years, the risk of major bleeding, including gastrointestinal bleeding, increases. If bleeding is clinically suspected, appropriate measures such as testing for occult blood in stool, or testing for a drop in hemoglobin is suggested.
Interaction with P-gp inducers: The concomitant use of PRADAXA with the strong P-gp inducer rifampicin reduces dabigatran plasma concentrations. Other P-gp inducers such as St. John's Wort or carbamazepine are also expected to reduce dabigatran plasma concentrations, and should be co-administered with caution (see Interactions).
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 Pharmacology: Pharmacokinetics 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 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 10 and Pharmacology: Pharmacokinetics under Actions).
Table 10 summarizes discontinuation rules before invasive or surgical procedures (see Table 10).


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PRADAXA is contraindicated in patients with severe renal dysfunction (CrCl <30 mL/min) but should this occur then PRADAXA should be stopped at least 5 days before major surgery.
If an acute intervention is required, PRADAXA should be temporarily discontinued. A surgery / intervention should be delayed if possible until at least 12 hours after the last dose. If surgery cannot be delayed there may be an increase in the risk of bleeding. This risk of bleeding should be weighed together with the urgency of intervention (for cardioversion see Dosage & Administration).
Spinal Anaesthesia/Epidural Anaesthesia/Lumbar Puncture: Procedures such as spinal anesthesia may require complete hemostatic function.
The risk of spinal or epidural haematoma may be increased in cases of traumatic or repeated puncture and by the prolonged use of epidural catheters. After removal of a catheter, an interval of at least 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.
Post Procedural Period: Resume treatment after complete haemostasis is achieved.
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.
Side Effects
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.
In the primary VTE prevention trials after have undergone elective total hip replacement surgery 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, while 522 received doses less than 150 mg once daily and 1168 received doses in excess of 220 mg daily.
Prevention of stroke and systemic embolism in patients with atrial fibrillation with at least one additional risk factor for stroke (i.e., previous ischemic stroke, transient ischemic attack [TIA], or systemic embolism; left ventricular dysfunction): 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 randomized to 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): 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.
Adverse drug reaction for both treatments, dabigatran etexilate and warfarin, are counted from the first intake of dabigatran etexilate of warfarin after the parenteral therapy has been discontinued (oral only treatment period). This includes all adverse drug reactions which occurred during dabigatran therapy. All adverse drug reactions, which occurred during warfarin therapy, are included except for those during the overlap period between warfarin and parenteral therapy.
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), experienced adverse reactions.
Bleeding: Bleeding is the most relevant side effect of PRADAXA; dependant 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 and in 14.4% of patients with acute DVT and/or PE.
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 replacement surgery or total knee replacement surgery: Overall bleeding rates were similar between treatment groups and not significantly different.
Prevention of stroke and systemic embolism in patients with atrial fibrillation with at least one additional risk factor for stroke (i.e., previous ischemic stroke, transient ischemic attack [TIA], or systemic embolism; left ventricular dysfunction): 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.
Treatment of acute deep vein thrombosis (DVT) and/or pulmonary embolism (PE): The definition of major bleeding events (MBEs) followed the recommendations of the International Society on Thrombosis and Haemostasis. A bleeding event was categorised as an MBE if it fulfilled at least one of the following criteria: Fatal bleeding.
Symptomatic bleeding in a critical area or organ, such as intracranial, intraspinal, intraocular, retroperitoneal, intra-articular, or pericardial, or intramuscular with compartment syndrome. In order for bleeding in a critical area or organ to be classified as an MBE it had to be associated with 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.
Table 11 shows bleeding events in the pooled pivotal studies RE-COVER and RE-COVER II Testing the treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE). In the pooled studies the primary safety endpoints of major bleeding, major or clinically relevant bleeding and any bleeding were significantly lower than warfarin at a nominal alpha level of 5% (see Table 11).


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Bleeding events for both treatments are counted from the first intake of dabigatran etexilate or warfarin after the parenteral therapy has been discontinued (oral only treatment period). This includes all bleeding events which occurred during dabigatran therapy. All bleeding events which occurred during warfarin therapy are included except for those during the overlap period between warfarin and parenteral therapy.
Subjects randomized to dabigatran etexilate 110 mg twice daily and 150mg twice daily had a significantly lower risk for life-threatening bleeds, haemorrhagic stroke and intracranial bleeding compared to warfarin [p < 0.05]. Both dose strengths of dabigatran etexilate had also a statistically significant lower total bleed rate. Subjects randomized to dabigatran etexilate 110mg twice daily had a significantly lower risk for major bleeds compared with warfarin (hazard ration 0.81, p= 0.0027) (see Table 12).


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Primary VTE prevention studies after have undergone elective total hip and total knee surgery : Overall bleeding rates were similar between treatment groups and not significantly different.
Table 13 as follows, shows the number (%) of patients experiencing bleeding events during the treatment period in the VTE prevention in the two pivotal clinical trials, according to dose (see Table 13).


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Adverse reactions classified by SOC and MedDRA preferred terms reported from any treatment group per population of all controlled studies are shown in the listings below. Table 14 and 15 lists identified side effects applicable to all indications. Table 16 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.
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.
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.
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%).
Adverse reactions are ranked under headings of frequency, the most frequent first, using the following convention: very common (≥ 1/10); common (≥ 1/100, < 1/10); uncommon (≥ 1/1000, < 1/100); rare ((≥1/10,000, <1/1000); very rare (<1/10,000) (see Table 14, Table 15 and Table 16).


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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.
P-gp interactions: P-glycoprotein inhibitors: Dabigatran etexilate is a substrate for the efflux transporter P-gp. Concomitant administration of P-gp inhibitors (such as amiodarone, verapamil, quinidine, systemic ketoconazole, dronedarone, ticagrelor and clarithromycin) is expected to result in increased dabigatran plasma concentrations.
Concomitant administration of systemic ketoconazole is contraindicated.
Primary prevention of venous thromboembolic events in adult patients who have undergone elective total hip replacement surgery or total knee replacement surgery: For the concomitant use of P-gp inhibitors and dosing of PRADAXA in this indication see Dosage & Administration.
Prevention of stroke and systemic embolism in patients with atrial fibrillation with at least one additional risk factor for stroke (i.e., previous ischemic stroke, transient ischemic attack [TIA], or systemic embolism; left ventricular dysfunction): For the P-gp inhibitors listed above no dose adjustments are required for PRADAXA in this indication.
Treatment of acute deep vein thrombosis (DVT) and/or pulmonary embolism (PE): For the P-gp inhibitors listed above 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.
Prevention of stroke and systemic embolism in patients with atrial fibrillation with at least one additional risk factor for stroke (i.e., previous ischemic stroke, transient ischemic attack [TIA], or systemic embolism; left ventricular dysfunction): 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.
Prevention of stroke and systemic embolism in patients with atrial fibrillation with at least one additional risk factor for stroke (i.e., previous ischemic stroke, transient ischemic attack [TIA], or systemic embolism; left ventricular dysfunction): 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.
Clarithromycin: Dabigatan exposure in healthy subjects was increased by about 19 % in the presence of clarithromycine without any clinical safety concern.
Ketoconazole: Dabigatran exposure was increased by 2.5 fold (+150%) after single and multiple doses of systemic ketoconazole (see Contraindications).
Dronedarone: Dabigatran exposure was increased by 2.1 fold (+114%) after single or 2.4 fold (+136%) after multiple doses of dronedarone, respectively.
Ticagrelor: Dabigatran exposure in healthy subjects was increased by 1.46 fold (+ 46%) in the presence of ticagrelor at steady state or by 1.73 fold (+73%) when a loading dose of ticagrelor was administered simultaneously with a single dose of 75 mg dabigatran etexilate.
Dabigatran steady state exposure in healthy subjects was increased by 1.26 fold (+ 26 %) in the presence of ticagrelor at steady state or by 1.49 fold (+49%) when a loading dose of ticagrelor was administered simultaneously with 110 mg dabigatran etexilate. The increase in exposure was less pronounced when the 180 mg ticagrelor loading dose was given two hours after dabigatran intake (+27%).
P- glycoprotein substrate: Digoxin: In a study performed with 24 healthy subjects, when PRADAXA was coadministered with digoxin, no changes on digoxin and no clinical relevant changes on dabigatran exposure have been observed.
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 Precautions).
Caution For Usage
Instruction for Use / Handling: When removing a hard capsule from the blister, note the following instructions: Tear off one individual blister from the blister card along the perforated line.
Peel off the backing foil and remove the capsule.
The capsule should not be pushed through the blister foil.
Storage
Store below 30°C.
Store in the original package in order to protect from moisture.
Store in a safe place out of the reach of children.
Do not put the capsules in pill boxes or pill organizers, unless capsules can be maintained in the original package.
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 3 x 10's. 110 mg x 3 x 10's. 150 mg x 3 x 10's.
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