A MIMS Supplement 1 NEW PRODUCT FEATURE Pg.pdf · 4 New Product Feature† MIMS Hong Kong 4th Issue...

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MIMS Hong Kong 4th Issue 2011

Scientifi c Prescribing Information of Pradaxa® an Oral Anticoagulant

Scientific Prescribing Information of Pradaxa® an Oral Anticoagulant

NEW PRODUCT FEATUREA MIMS Supplement

PRADAXABoehringer IngelheimDabigatran etexilate.

Cap 75 mg

Cap 110 mg Cap 150 mg

PRESENTATIONCap 75 mg (light blue, opaque cap and cream-coloured, opaque body of size 2 fi lled with yellowish pellets, imprinted with the Boehringer Ingelheim company symbol, the body with “R75”) x 30’s. 110 mg (light blue, opaque cap and cream-coloured, opaque body of size 1 fi lled with yellowish pellets, imprinted with the Boehringer Ingelheim company symbol, the body with ”R110”) x 30’s. 150 mg (light blue, opaque cap and cream-coloured, opaque body size 0 fi lled with yellowish pellets, imprinted with the Boehringer Ingelheim company symbol, the body with “R150”) x 30’s.

DESCRIPTIONEach 75-, 110- and 150-mg capsule contains dabigatran etexilate mesilate 86.48, 126.83 and 172.95 mg corresponding to dabigatran etexilate base 75, 110 and 150 mg, respectively.It also contains the following excipients: Tartaric acid, acacia, hypromellose, dimethicone 350, talc, hydroxypropyl cellulose. HPMC Capsule Shell: Carrageenan, potassium chloride, titanium dioxide, sunset yellow (E110), indigo carmine (E132), hypromellose, purifi ed water. Printing Ink: Shellac, black iron oxide, propylene glycol.Each capsule contains INN: Ethyl 3-[[[2-[[[4- [[[(hexyloxy)carbonyl]amino]iminomethyl] phenyl] amino]methyl]-1-methyl-1H-benzimidazol-5-yl]carbonyl](pyridin-2-yl)amino]propanoate; IUPAC: Ethyl N-{[2-({[4-((E)-amino{[(hexyloxy)carbonyl] imino} methyl)phenyl]amino}methyl)-1-methyl-1H-benzimidazol-5-yl]carbonyl}-N-pyridin-2-yl-ß-alaninate methanesulfonate; CAS: β-Alanine, N-[[2-[[[4-[[[(hexyloxy)carbonyl]amino] iminomethyl]phenyl]amino]methyl]-1-methyl-1H-benzimidazol-5-yl]carbonyl]-N-2-pyridinyl-, ethyl ester, methanesulfonate. Its molecular formula is C34H41N705-CH4S03 and has a molecular weight of 723.86 g/mol (salt) and 627.75 g/mol (free base).Chirality: Dabigatran etexilate mesilate has no chiral centres and therefore, does not form enantiomers. Geometric isomers (tautomers) are possible.Physical Appearance: Yellow-white to yellow powder. The crystals have a rod-like habit.Melting Point: 180±3°C (DSC: 10 K min-1 heating rate).

New Product Feature2 •


A MIMS Supplement

Dissociation Constants: pKa1=4±0.1; pKa2=6.7±0.1.Apparent Partition Coeffi cient: The partition coeffi cient of the neutral form (free base) is log P=3.8.Hygroscopicity: Nonhygroscopic.pH-Solubility Profi le: Solubility is strongly pH-dependent with increased solubility at acidic pH. The solubility in water is 1.8 mg/mL.Solubility in Organic Solvents of Dabigatran Etexilate Mesilate: Methanol: Freely soluble (>250 mg/mL). Ethanol: Soluble (approximately 50 mg/mL). Isopropanol: Sparingly soluble (approximately 10 mg/mL). Acetone: Very slightly soluble (approximately 0.3 mg/mL). Ethyl Acetate, Toluene, n-Hexane and Diisopropylether: Practically insoluble (<0.1 mg/mL).

ACTIONSPharmacology: Intravenous administration of BIBR 953 ZW (dabigatran) and oral administration of BIBR 1048 MS (dabigatran mesilate) result in potent antithrombotic activity in animal models of thrombosis.Dabigatran inhibits purifi ed thrombin in vitro with a Ki of 4.5 nanomolar. Its selectivity is apparent through the lack of eff ect on other serine proteases involved in coagulation. It is active in coagulation assays that simulate intrinsic, extrinsic and common pathway activation, not only in human plasma, but in other species as well. Platelet aggregation is not aff ected by dabigatran, unless the aggregation stimulus is thrombin.Anticoagulant activity ex vivo is prolonged in a dose-dependent manner in mice (investigated only in toxicology studies), rats, rabbits and Rhesus monkeys and the activated partial thromboplastin time (aPTT) is a particularly sensitive assay. Anticoagulation after oral administration of higher doses of dabigatran mesilate could be detected up to 5 hrs p.a.. Antithrombotic activity in venous stasis models in both rats and rabbits showed 50% reduction of thrombus formation with dabigatran 33 and 66 mcg/kg after IV dosing. There was a good correlation between reduction of clot size and increasing aPTT. Similar eff ects could be shown after oral dosing with dabigatran mesilate, with maximal thrombus inhibition 30 min and 2 hrs post-dosing in rats and rabbits, respectively.Dabigatran had no eff ect on hERG-mediated potassium current in concentrations up to 30 micromolar. In addition, there was no eff ect on the action potential confi guration in guinea

pig papillary muscle in concentrations up to 10 micromolar. In vivo studies were performed in pigs and Rhesus monkeys, with no eff ect on any ECG parameter. Thus these data suggest that the risk for proarrhythmic events is very low.Cardiovascular studies in rats, rabbits and Rhesus monkeys, after both IV and oral routes of administration showed very little eff ect.There was no eff ect on locomotor activity. Further testing in rats in doses up to 300 mg/kg oral showed no eff ect except for a slight reduction in body temperature at the highest dose. In doses >100 mg/kg in mice, there was a dose-dependent increase in the number of deaths due to bleeding.Eff ects on the gastrointestinal tract were minimal. There was no eff ect on gastrointestinal transit with either IV or oral routes of administration.Mechanism of Action: Dabigatran etexilate is a prodrug which does not exhibit anticoagulant activity itself. Following oral administration, dabigatran etexilate is rapidly absorbed and converted to dabigatran by esterase-catalysed hydrolysis in plasma and in the liver.Dabigatran is a competitive, reversible direct thrombin inhibitor and is the main active principle in plasma. Since thrombin (serine protease) enables the conversion of fi brinogen into fi brin during the coagulation cascade, its inhibition prevents the development of thrombus. Dabigatran also inhibits free thrombin, fi brin-bound thrombin and thrombin-induced platelet aggregation.In vivo and ex vivo animal studies have demonstrated antithrombotic effi cacy and anticoagulant activity of dabigatran after IV administration and of dabigatran etexilate following oral administration in various animal models of thrombosis.Pharmacodynamics: There is a clear correlation between plasma dabigatran concentration and degree of anticoagulant eff ect. The maximum eff ect (Emax) of dabigatran on pharmacodynamic (PD) parameters occurred at the same time as Cmax, indicating that thrombin inhibition by dabigatran is a direct eff ect, linked to the central plasma compartment.At recommended doses of dabigatran etexilate, dabigatran prolongs the aPTT and prothrombin time (PT), as measured by international normalized ratio (INR), but these tests are relatively insensitive to the activity of dabigatran and are not suitable alone as measures of anticoagulant activity. However, in patients who are bleeding, aPTT may help determine an excess of anticoagulant activity.Pharmacokinetic/Pharmacodynamic analyses

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suggested marked diff erences between the various assays in terms of sensitivity and precision with varying dabigatran plasma concentrations.A curvilinear relationship was shown between dabigatran plasma concentrations and aPTT. The fl attening of the aPTT-plasma concentration response curve indicated that this assay was associated with low sensitivity at dabigatran plasma concentrations >100 ng/mL, and well within the range observed following oral doses shown to be eff ective in the pivotal phase III studies.The data suggest a linear relationship between plasma concentration and INR (<2); however, this assay lacked sensitivity within the clinically-relevant dabigatran plasma concentration range and showed high variability.The thrombin time (TT) assay exhibited a linear relationship with plasma concentration with a high level of sensitivity. Thrombin time might be too sensitive to dabigatran plasma concentrations in the clinically relevant plasma concentration range. At dabigatran concentrations >600 ng/mL, the thrombin clotting time frequently exceeded the maximum measurement time of the coagulometer. Hence, the TT assay may serve as a sensitive method for determining if any dabigatran is present. However, since the reagents used for determining TT at diff erent laboratories are not standardised, the clinical utility of this test during dabigatran dosing remains to be established.The ecarin clotting time (ECT) assay displayed a linear relationship with drug plasma concentrations

in the clinically-relevant drug concentration range and exhibited adequate sensitivity and precision. However, given lack of uniform standardisation of this assay, the clinical utility of this test remains to be established.Clinical Trials: Prevention of Venous Thromboembolic Events (VTE) Following Hip- or Knee-Replacement Surgery. (See Table 1.)The clinical trial inclusion and exclusion criteria were uniform across the phase III programme, and were designed with the goal of being representative of the population of patients undergoing major orthopaedic surgery. Consistent with this goal, the mean age was >65 years, about 60% were female and the mean body mass index (BMI) was >29. Some important patient subgroups excluded by protocol were: Patients with known hepatic disease with potential impact on survival or with baseline elevation of liver function tests >2 x ULN, patients with severe renal insuffi ciency [creatinine clearance (CrCl) <30 mL/min], patients who were or had the potential to become pregnant during the study period and patients <40 kg.Each of the trials in the phase III programme were noninferiority studies with scientifi cally justifi ed noninferiority margins, and the pre-specifi ed primary effi cacy endpoint was total VTE and all-cause mortality. In recognition of the importance of the composite endpoint major VTE and VTE-related death, a meta-analysis of this endpoint including the 3 phase III studies was pre-specifi ed. This analysis shows that there are no clinically relevant diff erences with regard to major VTE and VTE-related death between any of the 3 treatment

Table 1. Summary of Patient Demographics for Phase III Clinical Trials in Primary Prevention of VTE following Major Orthopaedic Surgery.

Study # Trial designDosage*, route

of administration and duration

Study subjects n=number(dose)**

Mean age Gender

1160.48(Renovate)

Randomised, double-blind, parallel group, total hipreplacement

Dabigatran etexilate 220 mg once dailyDabigatran etexilate 150 mg once dailyEnoxaparin 40 mg once dailyFor 28-42 days

N=1157 (D220)N=1174 (D150)N=1162 (E)N=3494(Total)

Mean age 64 Female 54%

Male 46%

1160.25(Remodel)

Randomised, double-blind, parallel group, total knee replacement

Dabigatran etexilate 220 mg once dailyDabigatran etexilate 150 mg once dailyEnoxaparin 40 mg once dailyFor 6-10 days

N=693 (D220)N=708 (D150)N=699 (E)N=2100 (total)


Male 35%

1160.24(Remobilize)

Randomised, double-blind, parallel group, total knee replacement

Dabigatran etexilate 220 mg once dailyDabigatran etexilate 150 mg once dailyEnoxaparin 30 mg twice dailyFor 12-15 days

N=862 (D220)N=877 (D150)N=876 (E)N=2615 (total)


Male 44%

*Dabigatran etexilate dose - 220 mg once daily and 150 mg once daily, each initiated with a half dose on the day of surgery. Enoxaparin dose - 40 mg once daily, beginning the night prior to surgery; 30 mg twice daily beginning 12-24 hrs post-operatively.**D220-Dabigatran etexilate 220 mg; D150-Dabigatran etexilate 150 mg; E-Enoxaparin.



A MIMS Supplement

regimens tested in this programme. The 95% confi dence intervals (CI) of the individual trial and combined trial risk diff erence point estimates for all dabigatran etexilate treatments all overlap zero. (See Table 2.)The composite of major VTE and VTE-related death was a pre-specifi ed secondary endpoint of each of the phase III trials, as were also each of the individual components of the 2 composite endpoints, total VTE and all-cause mortality, and major VTE and VTE-related mortality. (See Tables 3 and 4 on page 5.)Prevention of Stroke and Systemic Embolism in Patients with Atrial Fibrillation (AF). (See Table 5 on page 6.)The primary clinical evidence for the eff ectiveness of dabigatran etexilate is derived from the randomised evaluation of long-term anticoagulant therapy (RELY) study a multicenter, multinational, randomised, parallel-group study of 2 blinded doses of

dabigatran (110 and 150 mg twice daily), compared to open-label warfarin in patients with atrial fi brillation 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, total stroke and systemic embolic events.In the RELY study, a total of 18,113 patients were randomised, 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. RELY had a median treatment of 20 months with dabigatran etexilate given as fi xed-dose without coagulation monitoring. In addition to documented, non-valvular AF ie, paroxysmal, persistent or permanent AF, patients had 1 of the following additional risk factors for stroke: Previous stroke, transient ischemic attack or systemic embolism; left ventricular ejection

Table 2. Analysis of Total VTE and All-Cause Mortality During Treatment Period for FAS in Phase III Orthopaedic Surgery Studies.

Study Treatment+ FAS* Incidence%

Difference%

95% CI(%)a

Difference vs Enoxaparin

Lower bound of 95% CI

placebo-enoxaparin

Enoxaparin effect

preserved b,c

(%)

p-valuea

1160.48 (Renovate)

DE 220 mg 880 53 (6) -0.7 (-2.9, 1.6) 23% 93 <0.0001

DE 150 mg 874 75 (8.6) 1.9 (-0.6, 4.4) 23% 81 <0.0001

Enox 40 mg once daily

897 60 (6.7)

1160.25(Remodel)

DE 220 mg 503 183 (36.4) -1.3 (-7.3, 4.6) 27.7% 83.3 0.0003

DE 150 mg 526 213 (40.5) 2.8 (-3.1, 8.7) 27.7% 68.5 0.0173


512 193 (37.7)

1160.24(Remobilize)

DE 220 mg 604 188 (31.1) 5.8 (0.8, 10.8) 27.7% 61.1 0.0895

DE 150 mg 649 219 (33.7) 8.4 (3.4, 13.3) 27.7% 51.8 0.3749

Enox 30 mg twice daily

643 163 (25.3)

1160.48 &1160.25

DE 220 mg 1383 236 (17.1) -0.7e (-2.9, 1.4)d

DE 150 mg 1400 288 (20.6) 2e (-0.3, 4.3)d


1409 253 (18)

1160.481160.251160.24

DE 220 mg 1987 424 (21.3) 0.2e (-1.7, 2.2)d

DE 150 mg 2049 507 (24.7) 3.1e (1.1, 5.2)d

Enox 2052 416 (20.3)+DE=Dabigatran Etexilate; Enox=Enoxaparin.*Full analysis set.aProbability for testing difference vs enoxaparin >MID. Calculation was based on normal approximation of independent binomial distribution.bCalculated as [lower bound (placebo-enoxaparin) - upper bound (dabigatran-enoxaparin)] / lower bound (placebo-enoxaparin).cMinimum important difference (MID) was defi ned to preserve 2/3 of the enoxaparin effect size based on the lower bound of the 95% confi dence interval. MID was 9.2% for 1160.25, 7.7% for 1160.48 and 9.2% for 1160.24.dBased on the fi xed model approach of meta-analysis, assuming that the summary statistic from each study follows an independent normal distribution with a fi xed mean. In combining studies, the weight was given as the inverse of the variance of the summary statistic.eDifference is determined prior to the rounding of individual incidence percentages and then rounded. The difference was calculated as a weighted difference.

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fraction <40%; symptomatic heart failure, NYHA class ≥2; age ≥75 years; age ≥65 years associated with 1 of the following: Diabetes mellitus, coronary artery disease (CAD) or hypertension.The concomitant diseases of patients in this trial included hypertension 79%, diabetes mellitus 23%, and CAD 28%. Fifty percent (50%) of the patient population was VKA-naive defi ned as

<2 months total lifetime exposure. Thirty-two percent (32%) of the population had never been exposed to a VKA. For those patients randomised to warfarin, the time in therapeutic range (INR 2-3) for the trial was a median of 67%.Concomitant medications during the study included aspirin (25% of patients used acetylsalicylic acid (ASA) at least 50% of the time

Table 3. Analysis of Total VTE and All-Cause Mortality During Treatment Period in Risk Ratio Scale for Fas-Major in Phase III Orthopaedic Surgery Studies and Summary of Individual Components Contributing to Major VTE and VTE-Related Mortality During Treatment Period for FAS-Major in Phase III Orthopaedic Surgery Studies.

Study Treatment+ FAS-Major*

IncidenceN %

Proximal DVT

N (%)

PEN (%)

VTE related deathc

N (%)Risk ratio

95% CI (%)a

1160.48 (Renovate)

DE 220 mg 909 28 (3.1) 22 (2.4) 0 (0) 0 (0) 0.78 (0.48, 1.27)

DE 150 mg 888 38 (4.3) 35 (3.9) 1 (0.2) 1 (0.2) 1.09 (0.7, 1.7)


917 36 (3.9) 33 (3.6) 3 (0.3) 0 (0)

1160.25(Remodel)

DE 220 mg 506 13 (2.6) 13 (2.6) 0 (0) 0 (0) 0.73 (0.36, 1.47)

DE 150 mg 527 20 (3.8) 18 (3.4) 1 (0.2) 1 (0.2) 1.08 (0.58, 2.01)


511 18 (3.5) 17 (3.3) 0 (0) 1 (0.2)

1160.24(Remobilize)

DE 220 mg 618 21 (3.4) 14 (2.3) 6 (1) 1 (0.2) 1.51 (0.79, 2.91)

DE 150 mg 656 20 (3) 20 (3) 0 (0) 0 (0) 1.36 (0.7,2.63)

Enox 30 mg twice daily

668 15 (2.2) 10 (1.5) 5 (0.7) 0 (0)

1160.48 &1160.25

DE 220 mg 1415 41 (2.9) 35 (2.5) 5 (0.4) 1 (0.1) 0.77 (0.51, 1.14)b

DE 150 mg 1415 58 (4.1) 53 (3.7) 1 (0.2) 4 (0.3) 1.09 (0.76, 1.56)b


1428 54 (3.8) 50 (3.5) 3 (0.2) 1 (0.1)

1160.481160.251160.24

DE 220 mg 2033 62 (3) 49 (2.4) 11 (0.5) 2 (0.1) 0.92 (0.66, 1.3)b

DE 150 mg 2071 78 (3.8) 73 (3.5) 1 (0) 4 (0.2) 1.14 (0.83, 1.57)b

Enox 2096 69 (3.3) 60 (2.9) 8 (0.4) 1 (0)

+DE=Dabigatran Etexilate; Enox=Enoxaparin.*Full analysis set - major.aBased on normal approximation of log relative risk.bBased on the fi xed model approach of meta-analysis, assuming that the log of the summary statistic from each study follows an independent normal distribution with a fi xed mean. In combining studies, the weight was given as the inverse of the summary statistic.cPatients were counted only one in the most severe category in order of death >PE >proximal DVT.

Table 4. Major Bleeding Events (MBE) and any Bleeding Events by Treatment in the Phase III (REMODEL, RENOVATE and REMOBILIZE) Studies.

Trial Dabigatran Etexilate220 mg

Dabigatran Etexilate150 mg

Enoxaparin

RENOVATE (hip) Treated patients N Number of MBE N (%)

114623 (2)

116315 (1.3)

1154*18 (1.6)

REMODEL (knee) Treated patients N Number of MBE N (%)

67910 (1.5)

7039 (1.3)

694*9 (1.3)

REMOBILIZE (knee)Treated patients, NNumber of MBE, N (%)

8575 (0.6)

8715 (0.6)

868**12 (1.4)

*Enoxaparin dose 40 mg once daily.**Enoxaparin dose 30 mg twice daily.



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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%).This study demonstrated that dabigatran etexilate, at a dose of 110 mg twice daily, is noninferior to warfarin in the prevention of stroke and systemic embolism in patients with atrial fi brillation. The dose of 150 mg twice daily was shown to be superior to warfarin with respect to stroke and systemic embolism. The dose of dabigatran 110 mg demonstrated a signifi cantly lower risk of major bleeding compared to warfarin. (See Table 6; Table 7 on page 7; Tables 8, 9 and 10 on page 8; Figure 1 on page 7.)For the randomised set, there was an imbalance in adjudicated myocardial infarction (MI) with an increased frequency observed in the dabigatran etexilate treatment groups compared to the warfarin treatment group. The all-MI hazard ratios for dabigatran etexilate 110 mg twice daily and dabigatran etexilate 150 mg twice daily versus warfarin were 1.29 (p=0.0929) and 1.27 (p=0.124), respectively, with CI that included unity. The increased hazard was not dose-related and did not reach statistical signifi cance. The imbalance could not be explained by diff erences in baseline risk factors or concomitant treatments. Twenty-one

(21%) percent of all MI occurred off study drug. Most of those patients were receiving a non-study drug anticoagulant, either orally or parenterally, at the visit prior to their infarct event. It should be noted that, in the RELY trial, treatment with dabigatran etexilate or warfarin in patients that sustained MI, was discontinued as per protocol. Given the diff erent half-life (t½) of these drugs, diff erential anticoagulant eff ect cannot be ruled out within a period of about 72 hrs after discontinuation.In the RELY study, potential abnormalities of liver function tests (LFT), are presented as follows. (See Tables 11, 12 and 13 on page 9; Tables 14 and 15 on page 10; Figures 2 and 3 on page 11.)Pharmacokinetics: After oral administration of dabigatran etexilate in healthy volunteers, the pharmacokinetic profi le of dabigatran in plasma is characterised by a rapid increase in plasma concentrations with Cmax attained within 0.5 and 2 hrs post-administration. After Cmax, plasma concentrations of dabigatran showed a biexponential decline with a mean terminal t½ of approximately 11 hrs in healthy elderly subjects. Following administration of multiple doses, a terminal t½ of about 12-14 hrs was observed, with the t½ independent of dose. Cmax and AUC were dose-proportional. Food does not aff ect the bioavailability of dabigatran etexilate but delays the time to peak plasma concentrations by 2 hrs.Half-life is prolonged if renal function is impaired as shown in Table 16. (See Table 16 on page 10.)

Table 5. Summary of Patient Demographics for the RELY Trial, a Phase III Clinical in Atrial Fibrillation.

Study # Trial Design

Dosage, Route of Administration

and Duration

Study Subjects n=number(dose)** Mean Age Gender

1160.26(RELY)

Multicenter, Multinational, randomised

parallel group study

2 blinded doses of dabigatran: 110 mg twice

daily and 150 mg twice daily compared to open

label warfarin

N=18,113 (total)N=6015 (DE110)N=6076 (DE150)

71.5 Male 64%

Female 36%

**DE110-Dabigatran etexilate 110 mg twice daily. DE150-Dabigatran etexilate 150 mg twice daily.

Table 6. Analysis of First Occurrence of Stroke or Systemic Embolism (Primary Endpoint) During the Study Period in the RELY Study.

Dabigatran Etexilate 110 mg Twice Daily

Dabigatran Etexilate150 mg Twice Daily Warfarin+

Patients randomised 6015 6076 6022

Total Stroke and/or SEE** No. of events (%)* Hazard ratio over warfarin (95% CI) p-value superiority

183 (1.54)0.9 (0.74, 1.1)

p=0.2943

134 (1.11)0.65 (0.52, 0.81)

p=0.0001

202 (1.71)

*% Refers to yearly event rate.**SEE: Systemic Embolic Event.+Dose adjusted, INR 2-3.

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The absolute bioavailability of dabigatran following oral administration of dabigatran etexilate was approximately 6.5%. (See Table 17 on page 12.)The oral bioavailability may be increased by 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 Pradaxa. Therefore, patients should be advised not to open the capsules and take the pellets alone (eg, sprinkled over food or into beverages) (see Dosage & Administration).Absorption: A study evaluating post-operative absorption of Pradaxa, 1-3 hrs following surgery, demonstrated relatively slow absorption compared with that in healthy volunteers, showing a smooth plasma concentration-time profi le without high peak plasma concentrations. Peak plasma

Table 7. Analysis of First Occurrence of Ischemic or Haemorrhagic Strokes During the Study Period in the RELY Study.



Subjects randomised 6015 6076 6022

Total Stroke No. of events (%) Hazard ratio vs warfarin (95% CI) p-value, superiority

171 (1.44) 0.92 (0.75, 1.14)

0.443

122 (1.01) 0.64 (0.51, 0.81)

<0.001

186 (1.58)

SEE No. of events (%) Hazard ratio vs warfarin (95% CI) p-value

15 (0.13)0.73 (0.37, 1.46)

0.378

13 (0.11)0.67 (0.33, 1.36)

0.271

21 (0.18)

Ischemic Stroke No. of events (%) Hazard ratio vs warfarin (95% CI) p-value

152 (1.28)1.14 (0.91, 1.44)

0.258

103 (0.86)0.76 (0.58, 0.98)

0.034

134 (1.14)

Hemorrhagic Stroke No. of events (%) Hazard ratio vs warfarin (95% CI) p-value

14 (0.12)0.31 (0.17, 0.56)

<0.001

12 (0.1)0.26 (0.14, 0.49)

<0.001

45 (0.38)

+Dose adjusted, INR 2-3.% Refers to yearly event rate.



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concentrations are reached at 6 hrs following administration, or at 7-9 hrs following surgery. It is noted however that contributing factors eg, anaesthesia, gastrointestinal paresis and surgical eff ects 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

Table 9. Frequency and Annualized Event Rate (%) of Major and Other Bleeding Events from the RELY Study.

Dabigatran Etexilate110 mg Twice Daily

N (%)


N (%)Warfarin

N (%)

Number of Patients 6015 6076 6022

Patient-years 11,899 12,033 11,794

Major bleeding events (MBE)* 342 (2.87) 399 (3.32) 421 (3.57)

Hazard ratio vs warfarin(95% CI) 0.8 (0.7, 0.93) 0.93 (0.81, 1.07)

p-value 0.0026 0.3146

Life-threatening MBE 147 (1.24) 179 (1.49) 218 (1.85)


p-value 0.0001 0.0305

Intracranial hemorrhage (ICH)+ 27 (0.23) 38 (0.32) 90 (0.76)


p-value <0.0001 <0.0001

Any bleeding eventa 1754 (14.74) 1993 (16.56) 2166 (18.37)


p-value <0.0001 0.0016

*Adjudicated bleeds.+ICH consists of adjudicated hemorrhagic stroke and subdural and/or subarachnoid hemorrhage.aInvestigator-reported bleeding events.

Table 10. Other Measures Evaluated in the RELY Study.


N (%)


N (%)Warfarin

N (%)


Myocardial Infarction* No. of Events (%) Hazard ratio vs warfarin (95% CI) p-value

98 (0.82)1.29 (0.96, 1.75)

0.0929

97 (0.81)1.27 (0.94, 1.71)

0.124

75 (0.64)

*Myocardial infarction including silent MI.% Refers to yearly event rate.

Table 8. Analysis of All-Cause Mortality and Cardiovascular Mortality During the Study Period in the RELY Study.




All-cause mortality No. of events (%) Hazard ratio vs warfarin (95% CI) p-value

446 (3.75)0.91 (0.8, 1.03)

0.1308

438 (3.64)0.88 (0.77, 1)

0.0516

487 (4.13)

Vascular Mortality* No. of events (%) Hazard ratio vs warfarin (95% CI) p-value

289 (2.43)0.9 (0.77, 1.06)

0.2093

274 (2.28)0.85 (0.72, 0.99)

0.043

317 (2.69)

+Dose adjusted, INR 2-3.% Refers to yearly event rate.*Vascular Mortality: Cardiac death (includes sudden and non-sudden cardiac death, eg, pump failure), and mortality due to stroke, pulmonary embolus, peripheral embolus, aortic dissection/rupture, hemorrhage and deaths of unknown cause.

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with peak plasma concentrations attained 2 hrs after drug administration.Distribution: Low (34-35%) concentration-independent binding of dabigatran to human plasma proteins was observed. The volume of distribution of dabigatran of 60-70 L exceeded the volume of total body water indicating moderate tissue distribution of dabigatran.Metabolism: 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 <10% of total dabigatran in plasma. Traces of other metabolites were only detectable with highly sensitive analytical methods.

Table 11. Liver Function Tests in the RELY Trial.


N (%)


N (%)Warfarin+

N (%)

Total treatedALT or AST >3 x ULNALT or AST >5 x ULNALT or AST >3 x ULN + Bilirubin >2 x ULN

5983 (100)118 (2)36 (0.7)

11 (0.2)

6059 (100)106 (1.7)45 (0.7)

14 (0.2)

5998 (100)125 (2.1)50 (0.8)

21 (0.4)+Dose adjusted, INR 2-3.

Table 12. Yearly Event Rates and Hazard Ratios for Stroke/SEE by Age Groups in the RELY Trial.



Warfarin+

N (%)

Patients <65 years, N=2981

Annual event rate (%/year) 1.47 0.69 1.35

Hazard ratio vs warfarin (95% Cl) 1.1 (0.64, 1.87) 0.51 (0.26, 0.98)

Hazard ratio DE 110 vs DE 150 (95% Cl) 2.16 (1.14, 4.09)

Patients >65 to <75 years, N=7894




Patients ≥75 years, N=7238



Hazard ratio DE 110 vs DE 150 (95% Cl) 1.32 (0.96, 1.81)+Dose adjusted , INR 2-3.

Table 13. Yearly Event Rates and Hazard Ratios for MBE* by Age Groups in the RELY Trial.



Warfarin+

Patients <65 years, N=2981



Hazard ratio DE 110 vs DE 150 (95% Cl) 0.92 (0.47,1.8)

Patients >65 to <75 years, N=7894


Hazard ratio vs warfarin (95% Cl) 0.7 (0.56, 0.89) 0.8 (0.64, 1)






*MBE-major bleeding events.+Dose adjusted , INR 2-3.



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Excretion: 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.Dabigatran is eliminated primarily in the unchanged form in the urine, at a rate of approximately 100 mL/min corresponding to the glomerular fi ltration rate.Special Populations: Paediatrics: Dabigatran has not been studied in the paediatric population.Geriatrics: Specifi c pharmacokinetic studies with elderly subjects in phase I studies showed an increase of 40-60% in the AUC and about 25% in Cmax, compared to young subjects. The AUCτ,ss and

Cmax,ss in male and female elderly subjects (>65 years) 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 eff ect of age on exposure to dabigatran was confi rmed in the RELY trial, with about 31% increase of trough concentration for subjects ≥75 years, and about 22% lower trough concentration for subjects <65 years, compared to subjects between 65 and 75 years.Gender: Drug exposure in the primary VTE prevention studies was about 40-50% higher in female patients than in male patients.In atrial fi brillation patients, females had on average 30% higher trough and post-dose concentrations.Race: The pharmacokinetics of dabigatran were investigated in Caucasian and Japanese volunteers after single and multiple doses. Ethnic origin does not aff ect the pharmacokinetics of dabigatran in a clinically relevant manner. Only limited pharmacokinetic data in Black patients are available.

Table 14. Yearly Event Rates and Hazard Ratios for Stroke/SEE by Age Groups (Below And Above 80 Years) in the RELY Trial.



Warfarin*

Patients <80 years, N=15,097






Hazard ratio vs warfarin (95% Cl) 0.68 (0.44, 1.05) 0.65 (0.43, 1)


*Dose adjusted , INR 2-3.

Table 15. Yearly Event Rates and Hazard Ratios for MBE* by Age Groups (Below And Above 80 Years) in the RELY Trial.

Dabigatran Etexilate(DE) 110 mg Twice Daily

Dabigatran Etexilate(DE) 150 mg Twice Daily Warfarin+

Patients <80 years, N=15,097








*MBE-major bleeding events.+Dose adjusted , INR 2-3.

Table 16. Half-Life of Total Dabigatran in Relation to Renal Function.

Glomerular FiltrationRate (CrCl)[mL/min]

gMean (gCV%; range) half-life

[hr]

>80>50 to ≤80>30 to ≤50

≤30

13.4 (25.7%; 11-21.6)15.3 (42.7%; 11.7-34.1)18.4 (18.5%; 13.3-23)27.2 (15.3%; 21.6-35)

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Hepatic Insuffi ciency: No change in dabigatran exposure was seen in 12 subjects in a phase I study with moderate hepatic insuffi ciency (Child-Pugh B) compared to 12 controls.Dabigatran is metabolised in the liver by conjugation with activated glucuronic acid. CYP-450 metabolic enzymes are not involved in dabigatran metabolism. Hepatic elimination via the bile represents a minor elimination pathway of dabigatran (approximately 20% of the dose is eliminated biliary).Patients with moderate and severe hepatic impairment (Child-Pugh 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 for prevention of VTE after hip- or knee-replacement surgery.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 for prevention of stroke and systemic embolism.Renal Insuffi ciency: 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



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moderate renal insuffi ciency (CrCl between 30-50 mL/min), than in those without renal insuffi ciency.In a small number of volunteers with severe renal insuffi ciency (CrCl 10-30 mL/min), the exposure (AUC) to dabigatran was approximately 6 times higher and the t½ approximately 2 times longer than that observed in a population without renal insuffi ciency (see Renal Impairment under Dosage & Administration, Contraindications and Renal under Precautions).Body Weight (BW): 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 patients in the RELY trial were in the ≥50 and <100 kg category with no clear diff erence detected. Limited data in patients ≤50 kg are available.Cardioversion: A total of 1255 subjects had cardioversions performed during the RELY study, 409 (6.8%), 415 (6.8%) and 431 (7.2%) in the dabigatran etexilate 110 mg, dabigatran etexilate 150 mg and warfarin treatment groups, respectively. The rate of stroke occurring within 30 days of cardioversion was low and similar across all treatment groups ie, dabigatran etexilate 110 mg (0.03%), dabigatran etexilate 150 mg (0.03%) and warfarin (0.02%) (see Cardioversion under Dosage & Administration).Pharmacokinetic Interactions: 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 DEA were essentially unchanged. The dabigatran AUC and Cmax were increased by about 60% and 50%, respectively (see P-glycoprotein Inhibitors under Dosage & Administration and Table 23: Summary of Drug-Drug Interactions under Interactions on page 23).In the RELY study, concomitant administration of amiodarone and dabigatran did not appear to increase the relative risk of bleeding compared to

subjects on warfarin and amiodarone. Therefore, no dose adjustment is necessary in patients with atrial fi brillation treated for prevention of stroke and systemic embolism.Verapamil: When dabigatran etexilate was co-administered 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 1st dose of an immediate-release formulation of verapamil administered 1 hr prior to dabigatran etexilate intake (increase of Cmax by about 180% and AUC by about 150%). The eff ect was progressively decreased with administration of 240 mg of an extended-release formulation of verapamil given concurrently (increase of Cmax by about 90% and AUC by about 70%), or after 3 days of administration of multiple doses of verapamil at 120 mg twice daily ie, steady-state conditions, (increase of Cmax by about 60% and AUC by about 50%). There was no meaningful interaction observed when verapamil was given 2 hrs after dabigatran etexilate (increase of Cmax by about 10% and AUC by about 20%). This is likely explained by complete absorption of dabigatran etexilate after 2 hrs. Therefore, close clinical surveillance (looking for signs of bleeding or anaemia) is required when dabigatran is co-administered with verapamil (see P-glycoprotein Inhibitors under Dosage & Administration).No data are available for the parenteral application of verapamil. However, based on the known mechanism of the interaction, no meaningful interaction is expected.In the RELY study, patients treated concomitantly with verapamil had on average a trough and 2 hrs post-dose dabigatran plasma concentration increase of only 16% and 20%, respectively. Annualised major bleeding rates in patients who had used verapamil at least once together with warfarin, dabigatran etexilate 110 or 150 mg twice daily were reported at 3.33%, 3.09% and 3.92%,

Table 17. Summary of Pharmacokinetic Parameters After Single and Repeated Oral Administration in Humans.

Cmax t½ (hr) AUC Clearance,Excretion

Volume ofDistribution

Healthy Volunteers 0.8 - 1.4 ng/mL/mg 11 hrs 6-10 ng*hr/mL/mg Urine (85%)Fecal (6%)

Total Clearance(IV): about

120 mL/min

Vss=60-70L

Patients treated for prevention of VTE after hip- or knee- replacement surgery

Cmax: 1.22 ng/mL/mgTmax: 7-9 hrs following

surgery

14-17 hrs 9.7 ng*hr/mL/mg n/a (no IV data) n/a (no IV data)

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respectively. Therefore, no dose adjustment has been deemed necessary in most patients with atrial fi brillation co-treated with verapamil and Pradaxa for prevention of stroke and systemic embolism.Ketoconazole: Ketoconazole increased total dabigatran AUC0-∞ and Cmax values by 138% and 135%, respectively, after a single oral dose of 400 mg, and 153% and 149%, respectively, after multiple dosing of ketoconazole 400 mg once daily. The time-to-peak, terminal t½ and mean residence time were not aff ected by ketoconazole.Clarithromycin: When clarithromycin 500 mg twice daily was administered orally 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 orally every 2 hrs 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 AUCτ,ss and Cmax,ss were increased on average by 53% and 56%, respectively, with concomitant quinidine.In the RELY study, concomitant administration of quinidine and dabigatran etexilate did not appear to increase the relative risk of bleeding compared to subjects on warfarin and amiodarone (see Table 23, Summary of Drug-Drug Interactions under Interactions on page 23).Co-Medication with P-gp Inducers: Rifampicin: Predosing 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. Following discontinuation of rifampicin treatment, the inducing eff ect was diminished resulting in dabigatran exposure close to the reference after 7 days. No further increase in bioavailability was observed after another 7 days (see Table 23, Summary of Drug-Drug Interactions under Interactions on page 23).Co-Medication with Platelet-Inhibitors: From the data gathered in the phase III study, RELY, it was observed that ASA or clopidogrel co-medication with dabigatran etexilate at dosages of 110 or 150 mg twice daily increased the risk of major bleeding by about 2-fold. This higher rate of bleeding events by ASA or clopidogrel co-medication was, however, also observed for warfarin (see Bleeding under Precautions).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 eff ect, aPTT, ECT or TT (anti-FIIa) or the inhibition of platelet aggregation (IPA) as measure of clopidogrel eff ect remained essentially unchanged comparing combined treatment and the respective monotreatments. With a loading dose of clopidogrel 300 or 600 mg, dabigatran AUCτ,ss and Cmax,ss were increased by about 30-40%.Nonsteroidal Anti-Infl ammatory Drugs (NSAIDs): When Pradaxa was co-administered with diclofenac, the plasma exposure of both drug products remained unchanged, indicating a lack of a pharmacokinetic interaction between dabigatran etexilate and diclofenac. However, due to the risk of hemorrhage, especially gastrointestinal hemorrhage, notably with NSAID with elimination half-lives >12 hrs, caution is required and close observation for signs of bleeding is recommended.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 eff ect were minor (fractional decrease in bioavailability not signifi cant for antacids and 14.6% for PPIs).In the phase III study, RELY, PPI co-medication did not result in lower trough levels and on average only slightly reduced post-dose concentrations (-11%).Co-Medication with Low Molecular Weight Heparin (LMWH): Low Molecular Weight Heparin: The concomitant use of LMWHs eg, enoxaparin and dabigatran has not been specifi cally investigated. After switching from 3-day treatment of once daily enoxaparin 40 mg SC, 24 hrs after the last dose of enoxaparin, the exposure to dabigatran was slightly lower upon administration of a single-dose of dabigatran etexilate 220 mg, than that after administration of same dose of dabigatran etexilate alone. A higher anti-Xa/IIa activity was observed after dabigatran administration with enoxaparin pre-treatment compared to that after treatment with dabigatran alone. This is considered to be due to the carry-over eff ect of enoxaparin treatment, and regarded as not clinically relevant. Other dabigatran-related anticoagulation tests were not changed signifi cantly by the pre-treatment of enoxaparin.Toxicology: Acute Toxicity: Acute oral toxicity studies were conducted in rats and mice. In both species, the approximate lethal dose after single



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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.Chronic Toxicity: 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 fi rst 4-6 hrs after administration and are directly related to the pharmacodynamic activity of dabigatran.Reproductive Toxicity: Teratology studies were performed with up to 200 mg/kg (free base equivalent) in rats and rabbits. A slight eff ect on the morphogenesis of foetuses was observed in rats at 200 mg/kg (free base equivalent). No teratogenic eff ects were noted in rabbits.In the fertility study in rats, no toxicologically remarkable parental fi ndings 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.Carcinogenicity/Mutagenicity: Comprehensive in vitro and in vivo studies revealed no evidence of a mutagenic potential.Two-year carcinogenicity studies were conducted in male and female mice and rats given oral doses of dabigatran etexilate of 30, 100 and 200 mg/kg/day. In both studies, no evidence for carcinogenic potential of dabigatran etexilate was observed.

INDICATIONSPrevention of venous thromboembolic events (VTE) in patients who have undergone elective total hip-replacement surgery or total knee-replacement surgery.Prevention of stroke and systemic embolism in patients with atrial fi brillation, in whom anticoagulation is appropriate.

DOSAGE & ADMINISTRATIONRecommended Dose and Dosage Adjustment:VTE Prevention Following Elective Knee Replacement Surgery: 220 mg daily, taken orally as 2 capsules of 110 mg once daily in patients with intact renal function. Treatment should normally

be initiated within 1-4 hrs of completed surgery once haemostasis is secured. Start with a single capsule of 110 mg, and continue 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 for whatever reason, then treatment should be initiated with 2 capsules at once.VTE Prevention Following Elective Hip Replacement Surgery: 220 mg daily, taken orally as 2 capsules of 110 mg once daily in patients with intact renal function. Treatment should normally be initiated within 1-4 hrs of completed surgery once haemostasis is secured. Start with a single capsule of 110 mg, and continue 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 for whatever reason, then treatment should be initiated with 2 capsules at once.Prevention of Stroke and Systemic Embolism in Patients with Atrial Fibrillation: 300 mg daily, taken orally as one 150 mg capsule twice a day.Elderly: VTE Prevention Following Orthopedic Surgery: In patients (>75 years)treated for prevention of VTE after hip- or knee-replacement surgery, Pradaxa should be used with caution, and a dose of 150 mg daily should be considered, taken as 2 capsules of 75 mg daily, since age-related compromise of renal function is frequently encountered (see Renal and Use in the elderly under Precautions).Prevention of Stroke and Systemic Embolism in Patients with Atrial Fibrillation: Patients ≥80 years should be treated with a dose of Pradaxa 220 mg daily, taken orally as one 110 mg capsule twice daily (see Clinical Trials: Prevention of Stroke and Systemic Embolism in Patients with Atrial Fibrillation; Tables 14 and 15 under Pharmacology under Actions on page 10).The usual recommended dose for most geriatric patients <80 years is 300 mg daily, taken orally as one 150 mg capsule twice a day (see Clinical Trials: Prevention of Stroke and Systemic Embolism in Patients with Atrial Fibrillation; Tables 14 and 15 under Pharmacology under Actions on page 10). However, in geriatric patients, especially those >75 with at least 1 other risk factor for bleeding (see Bleeding under Precautions), the administration of a dose of Pradaxa 220 mg daily, taken orally as one 110 mg capsule twice a day, may be considered. It should be noted, however,

15



that the eff ectiveness of stroke prevention may be expected to be lessened with this dosage regimen, compared to that of the usual one of Pradaxa 300 mg daily. As with any anticoagulant, caution is required when prescribing Pradaxa to the elderly (see Contraindications and Bleeding under Precautions).Patients at risk of Bleeding: Prevention of Stroke and Systemic Embolism in Patients with Atrial Fibrillation: Patients with an increased risk of bleeding (see Bleeding under Precautions), should be closely monitored clinically (looking for signs of bleeding or anaemia). In such patients, a dose of 220 mg, given as 110 mg twice daily may be considered. A coagulation test eg, aPTT (see Monitoring and Laboratory Tests under Precautions), may help to identify patients with an increased bleeding risk caused by excessive dabigatran exposure.As for any anticoagulant, Pradaxa is not indicated in patients at excessive risk of bleeding (see Contraindications).Renal Impairment: Following oral dosing with dabigatran etexilate, there is a direct correlation of systemic exposure to dabigatran with degree of renal impairment (see Renal under Precautions). The kidneys account for 85% of dabigatran clearance.There are no data to support use in patients with severe renal impairment (CrCl<30 mL/min). Given the substantial increase in dabigatran exposure observed in this patient population, treatment with Pradaxa is not recommended (see Renal Insuffi ciency under Special Populations under Pharmacokinetics under Actions and Contraindications).Patients treated for prevention of VTE after hip- or knee-replacement surgery with moderate renal impairment (CrCl 30-50 mL/min) exposed to dabigatran etexilate appear to be at higher risk of bleeding. Accordingly, treatment with Pradaxa should be initiated orally in these patients within 1-4 hrs of completed surgery once haemostasis is secured, at an initial dose of 75 mg, taken as a single capsule, and then continued at 150 mg, taken as 2 capsules of 75 mg once daily thereafter.Patients with atrial fi brillation treated for prevention of stroke and systemic embolism having moderate renal impairment (CrCl 30-50 mL/min): No dose adjustment is recommended (see Prevention of Stroke and Systemic Embolism in Patients with Atrial Fibrillation under Clinical Trials under Pharmacology under Actions). Patients with moderate renal impairment (CrCl 30-50 mL/min)

should be treated with a daily dose of Pradaxa at 300 mg taken orally as one 150 mg capsule twice daily, with caution. Regular assessment of renal status is required in these patients (see Contraindications and Renal under Precautions). A coagulation test eg, 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:

Creatinine Clearance (mL/min) =

Males: [140 - age (years)] x weight (kg) 72 x serum creatinine (mg/100 mL)

Females: 0.85 x [140 - age (years)] x weight (kg) 72 x serum creatinine (mg/100 mL)

P-Glycoprotein (P-gp) Inhibitors: P-gp inhibitors like verapamil, quinidine and amiodarone may be expected to increase systemic exposure to dabigatran. Combination use with oral ketoconazole is contraindicated (see Contraindications).Patients Treated for Prevention of VTE after Hip- or Knee-Replacement Surgery: Treatment initiation with verapamil should be avoided in patients who are already treated with Pradaxa for prevention of VTE after hip- or knee-replacement surgery. Simultaneous initiation of treatment with Pradaxa and verapamil should also be avoided.Dosing should be reduced to Pradaxa 150 mg daily, taken as 2 capsules of 75 mg, in patients treated for prevention of VTE after hip- or knee-replacement surgery who concomitantly receive amiodarone, quinidine or verapamil. Caution should be exercised (see Precautions and P-glycoprotein Inhibitors under Interactions). In patients with moderate renal impairment, and concomitantly treated with dabigatran etexilate and verapamil, a dose reduction of Pradaxa to 75 mg taken once daily should be considered.Patients with Atrial Fibrillation Treated for Prevention of Stroke and Systemic Embolism: No dose adjustment is recommended in patients concomitantly receiving amiodarone, quinidine or verapamil (see Special Populations under Pharmacokinetics under Actions and Table 23: Summary of Drug-Drug Interactions under Interactions on page 23). Patients should be treated with a daily dose of Pradaxa 300 mg taken orally as one 150 mg capsule twice daily.



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To minimise potential for interaction, Pradaxa should be given at least 2 hrs before verapamil (see Special Populations under Pharmacokinetics under Actions). Caution should be exercised. Close clinical surveillance is recommended.Drugs that Increase Gastric pH eg, Antacids, Protein-Pump Inhibitors (PPI): Diminished clinical eff ect for antacids may occur (see Table 23: Summary of Drug-Drug Interactions under Interactions on page 23). Although no dosage adjustment is generally necessary, administer Pradaxa at least 2 hrs before antacids, if possible, to minimise interaction potential. No dose adjustment is required for pantoprazole or other PPIs.Concomitant Antithrombotic Use: Concomitant use of ASA or clopidogrel with Pradaxa in patients with atrial fi brillation approximately doubled the risk of major bleed, irrespective of dose of Pradaxa used. A similar increase was noted with such concomitant use with the study comparator, warfarin. These observations contrasted with little apparent additional improvement in stroke and systemic embolic events with combined antithrombotic use and Pradaxa (or warfarin).Concomitant use of Pradaxa with an antithrombotic is not recommended for prevention of cardiogenic thromboembolic stroke in patients with atrial fi brillation. Concomitant use of ASA or other antiplatelet agents based on medical need to prevent MI should be undertaken with caution. Close clinical surveillance is recommended.Acute Myocardial Infarction (AMI): Consideration should be given to discontinuing Pradaxa in the setting of AMI should the treatment of myocardial infarction involve invasive procedures eg, percutaneous coronary revascularization or coronary artery bypass surgery. Similar consideration should be given if thrombolytic therapy is to be initiated, because bleeding risk may increase. Patients with AMI should be treated according to current clinical guidelines for that disorder. In this setting, Pradaxa may be resumed for the prevention of stroke and systemic embolism upon completion of these revascularization procedures.Children: Since Pradaxa has not been investigated in patients <18 years, treatment is not recommended.Patient Body Weight: Population PK modelling shows that patients with a body weight of about 120 kg have about 20% lower drug exposure. Patients with a body weight of about 48 kg have about 25% higher drug exposure compared to

patients with average weight. No dose adjustment deemed necessary.Switching from Pradaxa Treatment to Parenteral Anticoagulant: In Patients Treated for Prevention of VTE after Hip- or Knee-Replacement Surgery: Wait 24 hrs after the last dose of Pradaxa before switching to a parenteral anticoagulant.In Patients with Atrial Fibrillation Treated for Prevention of Stroke and Systemic Embolism: Wait 12 hrs after the last dose of Pradaxa before switching to a parenteral anticoagulant.Switching from Parenteral Anticoagulants Treatment to Pradaxa: If deemed medically appropriate, treatment with Pradaxa should be initiated 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 Vitamin K antagonists to Pradaxa: If deemed medically appropriate, Pradaxa should only be started after vitamin K antagonists have been discontinued, and the patient’s INR found to be <2.Cardioversion: Patients can be maintained on Pradaxa while being cardioverted.Missed Dose: Prevention of Venous Thrombo-embolism in Patients following Orthopaedic Surgery: Patients can continue with their remaining daily doses of Pradaxa at the same time of the next day. Patients should not take a double dose to make up for missed individual doses.Prevention of Stroke and Systemic Embolism in Patients with Atrial Fibrillation: If the prescribed dose of Pradaxa is not taken at the scheduled time, the dose should be taken as soon as possible on the same day. 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 on, the missed dose should be omitted. Patients should not take a double dose to make up for missed individual doses. For optimal eff ect and safety, it is important to take Pradaxa regularly twice a day, at approximately 12-hr intervals.Administration: Pradaxa should be taken orally, with the entire capsule to be swallowed whole. The capsule should not be chewed, broken or opened. Should be taken regularly, as prescribed to ensure optimal eff ectiveness. All temporary discontinuations should be avoided, unless medically indicated.Pradaxa may be taken with food or on an empty stomach with water.

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OVERDOSAGEThere is no antidote to dabigatran etexilate or dabigatran. 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 the transfusion of fresh frozen plasma.As protein-binding is low, dabigatran can be dialysed, although there is limited clinical experience in using dialysis in this setting.Activated prothrombin complex concentrates (eg, 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 eff ect of dabigatran but their usefulness in clinical settings has not yet been clearly 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 should be given according to the physician’s judgement.

CONTRAINDICATIONSHypersensitivity to dabigatran or dabigatran etexilate or to any of the excipients of Pradaxa.Patients with severe renal impairment (CrCl <30 mL/min). Haemorrhagic manifestations, bleeding diathesis or patients with spontaneous or pharmacological impairment of haemostasis. Lesions at risk of clinically signifi cant bleeding eg, extensive cerebral infarction (hemorrhagic or ischemic) within the last 6 months, active peptic ulcer disease with recent bleeding. Concomitant treatment with strong P-gp inhibitors ie, oral ketoconazole (see Interactions).

PRECAUTIONSBleeding: As with all anticoagulants, Pradaxa should be used with caution in circumstances associated 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. Patients at high risk of bleeding should not be prescribed Pradaxa (see Contraindications).Close clinical surveillance (looking for signs of bleeding or anaemia) is recommended throughout the treatment period, especially if risk factors are combined.Factors which Increase Haemorrhagic Risk, as Identifi ed in Clinical Studies: Factors Increasing Dabigatran Plasma Levels: Moderate renal impairment (CrCl 30-50mL/min); P-gp inhibitor co-medication.Pharmacodynamic Interactions: Acetylsalicylic acid; NSAID; clopidogrel.Diseases/Procedures with Special Haemorrhagic Risks: Congenital or acquired coagulation disorders; thrombocytopenia or functional platelet defects; active ulcerative gastrointestinal disease; recent gastrointestinal bleeding; recent biopsy or major trauma; recent intracranial haemorrhage; brain, spinal or ophthalmic surgery; bacterial endocarditis.Others: Age ≥75 years.The measurement of dabigatran-related anticoagulation may be helpful to avoid excessive high exposure to dabigatran in the presence of additional risk factors.In patients who are bleeding, an aPTT test may be useful to assist in determining an excess of anticoagulant activity, despite its limited sensitivity. An aPTT >80 sec at trough ie, when the next dose is due, is associated with a higher risk of bleeding (see Monitoring and Laboratory Tests as follows).Should severe bleeding occur, treatment with Pradaxa must be discontinued and the source of bleeding investigated promptly.Agents that may enhance the risk of haemorrhage should not be administered concomitantly with Pradaxa or, if necessary, should only be administered with caution. (see Pharmacology and Pharmacokinetics under Actions and Interactions). Treatment that should not be administered concomitantly with Pradaxa due to increase in bleeding risk, includes unfractionated heparin and heparin derivatives, low molecular weight heparins (LMWH), fondaparinux, bivalirudin, thrombolytic agents, GPIIb/IIIa receptor antagonists, ticlopidine, sulfi npyrazone and vitamin K antagonists eg, warfarin.



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The concomitant use of Pradaxa with the following treatments has not been studied and may increase the risk of bleeding: rivaroxaban, prasugrel and the strong P-gp inhibitors itraconazole, tacrolimus, cyclosporine, ritonavir, tipranavir, nelfi navir and saquinavir.Unfractionated heparin may be administered at doses necessary to maintain a patent central venous or arterial catheter.In patients with atrial fi brillation treated for the prevention of stroke and systemic embolism, the co-administration of oral antiplatelet (including aspirin and clopidogrel) and NSAID therapies increases the risk of bleeding, by about 2-fold (see Special Populations under Pharmacokinetics under Actions). If necessary, co-administration of low-dose ASA ie, ≤100 mg daily with Pradaxa may be considered for other indications than stroke prevention in atrial fi brillation. Note that in the RELY trial, there is no evidence that the addition of ASA or clopidogrel to dabigatran, or its comparator warfarin, improved outcomes in respect of stroke (see Stroke Prevention in Atrial Fibrillation under Clinical Trials under Pharmacology under Actions).Treatment initiation with verapamil should be avoided in patients following orthopedic surgery who are already treated with Pradaxa. Simultaneous initiation of treatment with Pradaxa and verapamil should also be avoided at any time (see P-glycoprotein inhibitors under Interactions).Interaction with P-glycoprotein 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 as follows and Interactions).Surgery/Procedural Interventions: Patients on Pradaxa who undergo surgery or invasive procedures are at increased risk for bleeding. In these circumstances, temporary discontinuation of Pradaxa may be required.Pre-Operative Phase: In advance of invasive or surgical procedures Pradaxa should be stopped temporarily due to an increased risk of bleeding. If possible, Pradaxa should be discontinued at least 24 hrs before invasive or surgical procedures. In patients at higher risk of bleeding (see Dosage & Administration) or in major surgery where complete haemostasis may be required consider stopping Pradaxa 2-4 days before surgery. Clearance of dabigatran in patients with renal insuffi ciency may take longer (see Renal under Dosage & Administration). This should be considered in advance of any procedures.

Pradaxa is contraindicated in patients with severe renal dysfunction (CrCl <30 mL/min). Should acute renal failure occur before surgery is required, Pradaxa should generally be stopped at least 5 days before major surgery.If acute intervention is required, Pradaxa should be temporarily discontinued, due to increased risk of bleeding. Surgery or procedural interventions should be delayed if possible until at least 12 hrs after the last dose of Pradaxa, with risk of bleeding weighed against the urgency of the needed intervention. Perioperative Spinal/Epidural Anaesthesia, Lumbar Puncture: Procedures eg, spinal anesthesia may require complete haemostatic function.In patients treated with Pradaxa for VTE prevention following major orthopedic surgery and who undergo spinal or epidural anesthesia, or in whom lumbar puncture is performed in follow-up to surgery, the formation of spinal or epidural haematomas that may result in long-term or permanent paralysis cannot be excluded.In the case of these peri-spinal procedures, administration of the 1st dose of Pradaxa should occur after haemostasis has been obtained and no sooner than 2 hrs following puncture or removal of catheters related to these procedures.The risk of these rare events may be higher with post-operative use of indwelling epidural catheters or the concomitant use of other products aff ecting haemostasis. Accordingly, the use of Pradaxa is not recommended in patients undergoing anesthesia with post-operative indwelling epidural catheters.Postprocedural Period: Resume treatment with Pradaxa as soon as complete haemostasis is achieved.Renal: Pradaxa is contraindicated in cases of severe renal impairment (CrCl <30 mL/min). Patients who develop acute renal failure while on Pradaxa should discontinue such treatment.Patients Treated for Prevention of VTE after Hip- or Knee-Replacement Surgery: Following oral dosing with dabigatran etexilate, there is a direct correlation of systemic exposure to dabigatran with degree of renal impairment. Severe renal insuffi ciency (CrCl <30 mL/ min) has been shown to increase exposure to dabigatran 6-fold (see Contraindications) while moderate renal impairment (CrCl 30-50 mL/min) increased exposure 2.7-fold. While the standard dose of Pradaxa for patients treated for prevention of VTEs after hip- or knee-replacement surgery with intact renal function is 220 mg daily (taken as two 110 mg capsules once daily), for patients with moderate renal impairment (CrCl 30-50 mL/min), the

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recommended daily dose is 150 mg daily (taken as two 75 mg capsules once daily). (see Renal Impairment under Dosage & Administration).As dose selection of Pradaxa for patients treated for prevention of VTE after hip- or knee-replacement surgery is based on renal function, creatinine clearance should be evaluated before initiating treatment, and during treatment as appropriate (see Renal impairment under Dosage & Administration).Patients with Atrial Fibrillation Treated for Prevention of Stroke and Systemic Embolism: Since no dose adjustment is necessary for most atrial fi brillation patients with moderate renal impairment (CrCl 30-50 mL/min), a standard daily dose of 300 mg, taken orally as one 150 mg capsule twice daily is recommended (see Renal Impairment under Dosage & Administration).Patients of Low Body Weight (<50 kg): Since limited data are available in these patients, Pradaxa should be used with caution.Monitoring and Laboratory Tests: At recommended doses of Pradaxa, dabigatran prolongs coagulation time as measured by the aPTT, TT and ECT. In patients who are bleeding due to excess activity of dabigatran, these coagulation tests would be expected to be elevated and may be helpful in assessing anticoagulant activity of dabigatran, if necessary (see Pharmacodynamics under Pharmacology under Actions). The aPTT is generally less sensitive to anticoagulant activity than either TT or ECT (see Drug-Laboratory Interactions under Interactions).However, the aPTT test is widely available and provides an approximate indication of the anticoagulation intensity achieved with dabigatran. In patients who are bleeding, the aPTT test maybe useful to assist in determining an excess of anticoagulant activity, despite its limited sensitivity. An aPTT >80 sec at trough (when the next dose is due) is associated with a higher risk of bleeding. In circumstances where there is no excess of anticoagulant activity, the utility of aPTT is limited in monitoring anticoagulant status of patients taking Pradaxa.Eff ect on the Ability to Drive or Operate Machinery: The eff ect of Pradaxa on the ability to drive and use machines has not been investigated. However, no such interaction is to be expected.Use in pregnancy: Since there are no studies of Pradaxa in pregnant women, the potential risk in these patients is unknown. Animal reproductive studies did not show any adverse eff ects on fertility or postnatal development of the neonate. Women of childbearing potential should avoid

pregnancy during treatment with Pradaxa and when pregnant, women should not be treated with Pradaxa unless the expected benefi t is greater than the risk.Use in lactation: Breastfeeding during treatment with Pradaxa is not recommended.There are no clinical data available on the excretion of dabigatran into breast milk.Use in children: The safety and effi cacy of Pradaxa have not been established in children <18 years. Therefore, Pradaxa is not recommended in this patient population.Use in the elderly: Clinical studies have been conducted in patients with a mean age >65 years. Safety and effi cacy data are available (see Clinical Trials under Pharmacology under Actions).Pharmacokinetic studies in older subjects demonstrate an increase in exposure to dabigatran in most of those patients, usually in association with age-related decline of renal function. (see Renal Impairment under Dosage & Administration).Patients Treated for Prevention of VTE after Hip- or Knee-Replacement Surgery: In general, patients should be treated with a standard dose of Pradaxa 220 mg daily (taken as two 110 mg capsules once daily). In patients >75 years, Pradaxa should be used with caution, and a dose of 150 mg daily (taken as 2 capsules of 75 mg once daily) should be considered since age-related decrease of renal function is frequently encountered (see Renal). Regardless of age, in those patients with moderate renal impairment (CrCl 30-50 mL/min), because of an increased risk of bleeding, the recommended dose of Pradaxa is 150 mg daily (taken as 2 capsules of 75 mg once daily) (see Renal Impairment under Dosage & Administration).Patients with Atrial Fibrillation Treated for Prevention of Stroke and Systemic Embolism: Patients ≥80 years should be treated with a daily dose of 220 mg taken orally as one 110 mg capsule twice daily. This alternate dosing may also be considered for other geriatric patients (see Elderly under Dosage & Administration). Use with caution.

ADVERSE REACTIONSThe safety of Pradaxa has been evaluated overall in 22,126 patients.A total of 10,084 patients were exposed to at least one dose of dabigatran as study medication in 4 active-controlled clinical trials conducted to evaluate the safety and eff ectiveness of dabigatran etexilate in the prevention of VTE following major elective orthopedic surgery. Of these 5419 were



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treated with Pradaxa 150 or 220 mg daily, while 389 received doses of <150 mg daily and 1168 received doses in excess of 220 mg daily.In the RELY trial investigating the prevention of stroke and systemic embolism in patients with atrial fi brillation, a total of 12,042 patients were exposed to Pradaxa. Of these 6059 were treated with dabigatran etexilate 150 mg twice daily while 5983 received doses of 110 mg twice daily.Nine percent (9%) of patients treated with

dabigatran and about 10% of patients treated with enoxaparin for VTE prevention after elective hip or knee surgery (short-term treatment up to 42 days) experienced adverse reactions. About 21% of patients with atrial fi brillation treated with dabigatran and about 16% of patients treated with warfarin for the prevention of stroke and systemic embolism (long-term treatment for up to 3 years) experienced adverse events considered related to treatment.

Table 18. Number (%) of Patients Experiencing Bleeding Events During the Treatment Period for VTE Prevention in the REMODEL and RENOVATE Trials, According to Dose.

Dabigatran Etexilate150 mgN (%)

Dabigatran Etexilate 220 mgN (%)

Enoxaparin40 mg Once Daily

N (%)

TreatedMajor bleeding*Any bleeding

1866 (100)24 (1.3)

258 (13.8)

1825 (100)33 (1.8)

251 (13.8)

1848 (100)27 (1.5)

247 (13.4)

*Major Bleeding: Major bleeding was defi ned as clinically overt bleeding associated with ≥20 g/L fall in hemoglobin; clinically overt bleeding leading to transfusion of ≥2 units packed cells or whole blood; fatal, retroperitoneal, intracranial, intraocular or intraspinal bleeding; bleeding warranting treatment cessation or leading to reoperation. Major bleeding included those events occurring at the surgical site.

Table 19. Number (%) of Patients Experiencing Bleeding Events During the Treatment Period for VTE Prevention in the REMOBILIZE Trial, According to Dose.



Enoxaparin30 mg Twice Daily

N (%)

TreatedMajor bleeding*Any bleeding

871 (100)5 (0.6)72 (8.3)

857 (100)5 (0.6)74 (8.6)

868 (100)12 (1.4)84 (9.7)

*Major Bleeding: Major bleeding was defi ned as clinically overt bleeding associated with ≥20 g/L fall in hemoglobin; clinically overt bleeding leading to transfusion of ≥2 units packed cells or whole blood; fatal, retroperitoneal, intracranial, intraocular or intraspinal bleeding; bleeding warranting treatment cessation or leading to reoperation. Major bleeding included those events occurring at the surgical site.

Table 20. Frequency and Annualized Event Rate (%) of Bleeding Events from the RELY Trial.


N (%)


N (%)Warfarin**

N (%)


Patient-years 11,899 12,033 11,794

Major bleeding event (MBE)* 342 (2.87) 399 (3.32) 421 (3.57)


p-value 0.0026 0.3146

Life-threatening MBE 147 (1.24) 179 (1.49) 218 (1.85)


p-value 0.0001 0.0305

Intracranial hemorrhage (ICH)+ 27 (0.23) 38 (0.32) 90 (0.76)


p-value <0.0001 <0.0001

Any bleeding eventa 1754 (14.74) 1993 (16.56) 2166 (18.37)


p-value <0.0001 0.0016

*Adjudicated bleeds.**Dose-adjusted warfarin to an INR of 2-3.+ICH consists of adjudicated hemorrhagic stroke and subdural and/or subarachnoid hemorrhage.aInvestigator-reported bleeding events.

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Bleeding: Bleeding is the most relevant side eff ect of Pradaxa. 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 16.5% of patients with atrial fi brillation treated for the prevention of stroke and systemic embolism.Although rare in frequency in clinical trials, major or severe bleeding may occur and, regardless of location, may lead to disabling, life-threatening or even fatal outcomes.Since the patient populations treated with Pradaxa for diff erent indications are not interchangeable, a summary description of major and total bleeding is provided by indication in Tables 18, 19 and 20 on page 20.

Table 20 shows the number of patients experiencing major and total bleeding event rates during the treatment period in the RELY study, conducted in patients with atrial fi brillation. In Table 20, the category of major bleeds includes both life-threatening and non-life-threatening bleeds. Within life-threatening, intracranial bleeds is a subcategory of life-threatening bleeds.Intracranial bleeds include intracerebral (haemorrhagic stroke), subarachnoid and subdural bleeds. For this reason, these events may be counted in multiple categories.Major Bleeding Fulfi lled ≥1 of the following Criteria: Bleeding associated with a reduction in hemoglobin of at least 20 g/L or leading to a

Table 21. Common Adverse Reactions Observed in ≥1% of Dabigatran-Treated Patients in Active-Controlled VTE Prevention Trials.



Enoxaparinb

N (%)

2737 (100) 2682 (100) 3108 (100)

Blood and Lymphatic System

AnemiaGastrointestinal hemorrhageHematomaHematuriaWound hemorrhage

110 (4)33 (1.2)38 (1.4)34 (1.2)35 (1.3)

117 (4.4)17 (0.6)37 (1.4)31 (1.2)28 (1)

141 (4.5)20 (0.6)55 (1.8)25 (0.8)31 (1)

Procedural Complications

Wound secretionPostprocedural hematomaPostprocedural hemorrhagePostoperative anemiaTraumatic hematomaPostprocedural discharge

130 (4.7)66 (2.4)28 (1.5)37 (1.4)37 (1.4)31 (1.1)

130 (4.8)45 (1.7)43 (2.4)54 (2)

41 (1.5)34 (1.3)

93 (3)78 (2.5)32 (1.7)56 (1.8)51 (1.6)31 (1)

Laboratory Investigations

ALT ≥3 x ULNDecreased hemoglobin

68 (2.5)45 (1.6)

58 (2.2)35 (1.3)

95 (3.5)a

74 (2.4)aBased on N=2716.bEnoxaparin 40 mg once daily or 30 mg twice daily.

Table 22. Common Adverse Reactions Observed in ≥1% of Dabigatran-Treated Patients with Atrial Fibrillation in the Active-Controlled Trial, RELY.



WarfarinN (%)

5983 (100) 6059 (100) 5998 (100)

Bleeding and Anemia* 599 (10) 747 (12.3) 825 (13.8)

AnemiaEpistaxisGastrointestinal hemorrhageUrogenital hemorrhage

73 (1.22)66 (1.1)

196 (3.28)66 (1.1)

97 (1.6)67 (1.11)277 (4.57)84 (1.39)

74 (1.23)107 (1.78)155 (2.58)96 (1.6)

Gastrointestinal Disorders* 735 (12.3) 772 (12.7) 220 (3.7)

Abdominal painDiarrhoeaDyspepsiaNausea

135 (2.25)75 (1.25)250 (4.18)58 (0.97)

134 (2.21)71 (1.17)234 (3.9)73 (1.2)

15 (0.25)11 (0.18)13 (0.22)12 (0.2)

*Aggregate incidence presented for all adverse reactions within the body system, including those reactions occurring <1% and not listed in the table above.



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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 Classifi ed as Life-Threatening if they Fulfi lled ≥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 intervention.Clinical Trial Adverse Drug Reactions: Because clinical trials are conducted under very specifi c conditions the adverse reaction rates observed in the clinical trials may not refl ect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug. Adverse drug reaction information from clinical trials is useful for identifying drug-related adverse events and for approximating rates. (See Tables 21 and 22 on page 21.)Gastrointestinal adverse reactions occurred more often with dabigatran etexilate than warfarin. These were related to dyspepsia (including upper abdominal pain, abdominal pain, abdominal discomfort, epigastric discomfort) or gastritis-like symptoms (including GERD, esophagitis, erosive gastritis, gastric hemorrhage, hemorrhagic gastritis, hemorrhagic erosive gastritis, gastrointestinal ulcer).Gastrointestinal hemorrhage occurred at a higher frequency with Pradaxa compared to warfarin (see Table 22 on page 21). Gastrointestinal adjudicated major bleeds were reported at 1.14%, 1.57% and 1.07% (annualized rates) in the dabigatran etexilate 110 mg, dabigatran etexilate 150 mg and warfarin groups, respectively. Gastrointestinal life-threatening bleeds occurred with a frequency of 0.57%, 0.79% and 0.49% in the dabigatran etexilate 110 mg, dabigatran etexilate 150 mg and warfarin groups, respectively. Any gastrointestinal bleeds occurred with frequency of 5.41%, 6.13% and 4.02% in the dabigatran etexilate 110 mg, dabigatran etexilate 150 mg and warfarin groups, respectively. The underlying mechanism of the increased rate of gastrointestinal bleeding has not been established (see Prevention of Stoke and Systemic Embolism in Patients with Atrial Fibrillation under Clinical Trials under Pharmacology under Actions).Allergic reactions or drug hypersensitivity including urticaria, bronchospasm, rash and pruritus have been reported in patients who received dabigatran etexilate. Rare cases of anaphylactic reactions have also been reported.

Liver Function Tests (LFT): In the long-term RELY study, observed abnormalities of LFT are presented in Table 11. (See Table 11 in Clinical Trials under Pharmacology under Actions on page 9.)Less Common Clinical Trial Adverse Drug Reactions (<1%): Observed with exposure to dabigatran 150 mg and 220 mg/day during active-controlled venous thromboembolic prevention trials in the context of major orthopedic surgery: Blood and Lymphatic System: Thrombocytopenia.Gastrointestinal Disorders: Hemorrhoidal hemorrhage, rectal hemorrhage.General: Bloody discharge, catheter site hemorrhage.Hepatobiliary Disorders: Increased alanine aminotransferase, aspartate aminotransferase, hepatic enzyme and transaminases, abnormal hepatic function abnormal/liver function test.Injury, Poisoning and Procedural Complications: Incision site hemorrhage.Laboratory Investigations: Occult blood positive, blood present in the urine, decreased hematocrit.Musculoskeletal and Cumulative Tissue Disorders: Hemarthrosis.Respiratory and Thoracic System: Epistaxis.Skin and Subcutaneous Tissue: Ecchymosis.Surgical and Medical Procedures: Postprocedural drainage, wound drainage.Vascular Disorders: Hemorrhage.Observed with exposure to dabigatran 110 and 150 mg twice daily during the RELY trial, an active-controlled clinical trial for the prevention of stroke and systemic embolism in patients with atrial fi brillation: Blood and Lymphatic System Disorders: Thrombocytopenia.Vascular Disorders: Hematoma, hemorrhage.Gastrointestinal Disorders: Gastrointestinal ulcer, gastroesophagitis, GERD, vomiting, dysphagia.Hepatobiliary Disorders: Abnormal hepatic function/liver function test, increased hepatic enzyme.Skin and Subcutaneous Tissue Disorder: Skin hemorrhage, urticaria, rash, pruritus.Musculoskeletal and Connective Tissue and Bone Disorders: Hemarthrosis.Renal and Urinary Disorders: Hematuria.General Disorders and Administration Site Conditions: Injection site hemorrhage, catheter site hemorrhage.Injury, Poisoning and Procedural Complications: Incision site hematoma, traumatic hematoma, Incision site hemorrhage.

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Table 23. Summary of Drug-Drug Interactions.

Proper Name Ref* Effect Clinical comment

Amiodarone CT Dabigatran exposure in healthy subjects was increased by 60% in the presence of amiodarone (see Pharmacology and Special Populations and Pharmacokinetic Interactions under Pharmacokinetics under Actions).

Adjust dosing for patients treated for prevention of VTE after hip- or knee-replacement surgery to 150 mg daily Pradaxa with amiodarone. Caution should be exercised.

No dose adjustment is generally recommended for AF patients. Use with caution. Occasional testing of aPTT may be considered to rule out excessive anticoagulant effect.

Antacids (aluminumcompounds, sodium bicarbonate, calcium and/or magnesium compounds, or combinations of these)

CT In population PK analyses, a reduction in dabigatran exposure by 35% was seen over the fi rst 24 hrs following surgery. Thereafter, (24 hrs after surgery), a reduction of about 11% was observed.

Diminished clinical effect may occur, as may be expected for any drug resulting in an increase in gastric pH during Pradaxa administration. Pradaxa should be administered at least 2 hrs before taking an antacid.

Co-administration with Pradaxa should be avoided within 24 hrs after orthopedic surgery.

Atorvastatin CT When dabigatran etexilate was co-administered with atorvastatin, exposure of atorvastatin, and atorvastatin metabolites was not signifi cantly changed. Dabigatran concentrations were decreased about 20%.

No dose adjustment is recommended.

Clarithromycin CT Dabigatran exposure in healthy subjects was increased by about 15% in the presence of clarithromycin (see Special Population and Pharmacokinetic Interactions under Pharmacokinetics under Actions).

No dose adjustment is recommended. Caution should be exercised.

Diclofenac CT When dabigatran etexilate was co-administered with diclofenac, pharmacokinetics of both drugs appeared unchanged.

No dose adjustment is recommended. Use with caution. (See Bleeding under Precautions.)

Digoxin CT When dabigatran etexilate was co-administered with digoxin, no PK-interaction was observed.

No dose adjustment is recommended.

Ketoconazole CT Dabigatran exposure was increased 150% after single and multiple doses of ketoconazole (see Special Population and Pharmacokinetic Interactions under Pharmacokinetics under Actions).

Co-administration with Pradaxa is contraindicated (see Contraindications).

Pantoprazole CT When dabigatran etexilate was co-administered with pantoprazole, a decrease in dabigatran AUC of about 30% was observed.

In the phase III study, RELY, PPI co-medication did not result in lower trough levels and on average only slightly reduced post-dose concentrations (-11%). (See Pharmacology and Special Populations and Pharmacokinetic Interactions under Pharmacokinetics under Actions.)

No dose adjustment is recommended. Diminished clinical effect may occur, as may be expected for any drug resulting in an increase in gastric pH during Pradaxa administration.

Rifampicin CT After 7 days of treatment with rifampicin 600 mg once daily total dabigatran AUC0-∞ and Cmax were reduced by 67% and 66% compared to the reference treatment, respectively (see Special Population and Pharmacokinetic Interactions under Pharmacokinetics under Actions.)

Concomitant use of Pradaxa with rifampicin should, in general, be avoided. Concomitant use would be expected to result in substantially diminished anticoagulant effect of Pradaxa.

Verapamil CT When dabigatran etexilate given at 150 mg once daily, was coadministered with moderate doses of oral verapamil, the Cmax and AUC of dabigatran were increased but the magnitude of this change varied depending on the timing of administration and the formulation of verapamil used (see Special Population and Pharmacokinetic Interactions under Pharmacokinetics under Actions.)

Dosing should be reduced to Pradaxa 150 mg daily in patients treated for prevention of VTE after hip- or knee-replacement surgery who concomitantly receive dabigatran etexilate and verapamil. To minimise potential for interaction, Pradaxa should be given at least 2 hrs before verapamil.

Caution should be exercised. Although no dose adjustment is recommended for AF patients, to minimise potential for interaction, Pradaxa should be given at least 2 hrs before verapamil.

Caution should be exercised.

Quinidine CT Dabigatran exposure in healthy subjects was increased by 53% in the presence of quinidine.

Adjust dosing for patients treated for prevention of VTE after hip- or knee-replacement surgery to Pradaxa 150 mg daily.


Although no dose adjustment is recommended for AF patients, to minimise potential for interaction, Pradaxa should be given at least 2 hrs before quinidine, if possible.


*C=Case Study; CT=Clinical Trial; PK=Pharmacokinetic; T=Theoretical



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Immune System Disorder: Drug hypersensitivity.Respiratory Disorders: Hemoptysis, bronchospasm.

Nervous System Disorders: Intracranial hemorrhage.

INTERACTIONSBased on in vitro evaluation, neither dabigatran etexilate nor its active moiety, dabigatran, have been shown to be metabolised by the human cytochrome P-450 system, nor did they exhibit eff ects on human CYP P-450 isozymes.Concomitant use of Pradaxa with treatment that interfere with haemostasis or coagulation increases bleeding risk (see Bleeding under Precautions). Co-administration of Pradaxa with other anticoagulants has not been adequately studied and is not recommended.In the RELY trial, conducted in patients with atrial fi brillation, a 2-fold increase in major bleeding was seen in both dabigatran study treatment arms, as well as that of the comparator, warfarin, when ASA was administered concomitantly (see Special Population under Pharmacokinetics under Actions and Dosage & Administration).Drug-Drug Interactions: Transporter Interactions: Dabigatran etexilate, but not dabigatran, is a substrate with moderate affi nity for the effl ux P-gp transporter. Therefore, potent P-gp inducers or inhibitors may be expected to impact exposure to dabigatran.P-glycoprotein Inhibitors: P-gp inhibitors like verapamil, quinidine and amiodarone may be expected to increase systemic exposure to dabigatran, see Table 23 on page 23. The strong P-gp inhibitor ketoconazole, when administered orally, is contraindicated (see Contraindications). If not otherwise specifi cally described, close clinical surveillance (looking for signs of bleeding or anaemia), along with a sense of caution is required when dabigatran is co-administered with strong P-gp inhibitors.P-glycoprotein Inducers: The concomitant use of Pradaxa with the strong P-gp inducer rifampicin, reduces dabigatran plasma concentration. Other P-gp inducers eg, carbamazepine and St. John’s wort are also expected to reduce the systemic exposure of dabigatran. Less potent inducers eg, tenofovir can potentially reduce systemic exposure. Caution is advised when co-administering these drug products.P-glycoprotein Substrates: Dabigatran etexilate is not expected to have a clinically meaningful

interaction with P-gp substrates that do not also act as inhibitors or inducers of P-gp.Drug-Food Interactions: Food does not aff ect the bioavailability of Pradaxa but delays the time-to-peak plasma concentrations by 2 hrs.Drug-Herb Interactions: Drug-herb interactions have not been investigated. Potent P-gp inducers eg, St John’s wort (Hypericum perforatum) may be expected to aff ect systemic exposure of dabigatran. Co-administration of these products is not recommended.Drug-Laboratory Interactions: No single test (aPTT, TT, ECT) is adequate to reliably assess the anticoagulant activity of dabigatran following Pradaxa administration. At therapeutic levels of dabigatran, TT is the best measure of the pharmacodynamic eff ect of dabigatran because of its linear and sensitive relationship with dabigatran exposure (see Pharmacodynamics under Pharmacology under Actions and Monitoring and Laboratory Test under Precautions).The aPTT test is widely available and provides an approximate indication of the anticoagulation intensity achieved with dabigatran. In patients who are bleeding, the aPTT test maybe useful to assist in determining an excess of anticoagulant activity, despite its limited sensitivity. An aPTT >80 sec at trough (when the next dose is due) is associated with a higher risk of bleeding.Note that a PT (INR) test is not useful to assess the anticoagulant activity of Pradaxa.Drug-Lifestyle Interactions: No direct interaction between dabigatran etexilate and alcohol was demonstrated in animal models or has been hypothesised.

STORAGEStore below 30°C. Protect from moisture.

[70791-01]

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