1.

75 110 150 Pradaxa Capsules 75 mg 026233 110 mg 025459 150 mg 025458

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) Tartaric acid, acacia, hypromellose, dimeticone, talc, hydroxypropylcellulose. HPMC capsule shell: Carrageenan, potassium chloride, titanium dioxide, Sunset Yellow, Indigo Carmin, hypromellose. Printing ink: Shellac, butyl alcohol, isopropyl alcohol, industrial methylated spirit, Iron oxide black , purified water, propylene glycol. 75 1.

(VTE)

110 1. 2.

(VTE)

150 1.

Pradaxa (VTE):

2.

Pradaxa 150 mg ( 75 mg ) 220 mg 110 mg 1-4 2 10 Pradaxa 150 mg ( 75 mg ) 220 mg 110 mg 1-4 2 28-35

Pradaxa 150 mg ( 75 mg ) [CrCL]30-50 mL/min[

] verapamilamiodaronequinidine [ Pradaxa P- (P-gp)

amidaronequinidine verapamil] 75 []

2 Pradaxa CrCL

CrCL< 30 mL/min Pradaxa

[hypovolemia]

Pradaxa CrCLmL/min Cockgroft-Gault

mol/L 1.23(140-[])[] (0.85)

[mol/L] mg/dL

(140-[])[] (0.85) 72[mg/dL]

Pradaxa CrCL< 30 mL/min Pradaxa CrCL30-50 mL/min150 mg75 mg PRADAXAP-amiodaronequinidineverapamil (VTE)

3.

PRADAXA amiodaronequinidine verapamil PRADAXA 150 mg 75 mg PRADAXA PRADAXA verapamil PRADAXA verapamil >75150 mg75 mg >75PradaxaCrCLCrCL< 30 mL/min

[hypovolemia]

ULN2 Pradaxa 50110 Pradaxa 24Pradaxa Pradaxa 02[unfractionated heparinUFH]dabigatran etexilate Pradaxa (VTE) dabigatran etexilate

4.

110~150 mg 110 mg75CHADS 2> 375 Pradaxa CrClCrCl< 30 mL/min Pradaxa [hypovolemia]

PRADAXA 220 mg 110mg aPTT dabigatran [(5)] PRADAXA 2 AB C 18 PRADAXA PRADAXA PRADAXA CrClCrCl< 30 mL/min

5.

< 30 mL/min PRADAXA PRADAXA

[hypovolemia] Dabigatran 30-50ml/min PRADAXAP-amiodaronequinidineverapamil 300 mg ( 150 mg ) PRADAXA 12 PRADAXA PRADAXA PRADAXA 0 2 [unfractionated heparin UFH] K PRADAXA K INR< 2.0 PRADAXA PRADAXA K (VKA) CrCL K CrCL50 ml/min dabigatran etexilate 3 VKA CrCL30 < 50 ml/min dabigatran etexilate 2 VKA CrCL

6.

6 ketoconazole, cyclosporine, itraconazole

2 PRADAXA PRADAXA 1

dabigatran ( 30-50 mL/min) P

(Acetylsalicylic acid ) (NSAID) Clopidogrel

75 Pradaxadabigatrandabigatran Pradaxa(INR)INRINRdiluted thrombin timedTTecarin clotting timeECTactivated partial thromboplastin timeaPTT 2

7.

dTT [ng/mL] > 67 > 200

ECT [x-] > 3

aPTT [x-] > 1.3 > 2

INR

RE-LY 150mg () aPTT 2.0 3.0

PRADAXA (CrCL < 30 mL/min) PRADAXA 30-50 ml/min CrCL75 50 kg P- dabigatran PRADAXA

LMWHfondaparinuxdesirudinGPIIbIIIa ticlopidinedextransulfinpyrazonerivaroxabanprasugrel K P-itraconazoletacrolismusritonavirtipranavirnelfinavir saquinavir dronedarone dabigatran ticagrelor dabigatran selective serotonin re-uptake inhibitors SSRIselective serotonin norepinephrine re-uptake inhibitors SNRIs

8.

fibrinolytic agents TTECTaPTTULNfibrinolytic agents

(VTE) NSAID PRADAXA PRADAXA 12 NSAID

aspirin Clopidogrel(NSAID) 50%PRADAXA ASA( 100 mg)RE-LY dabigatran warfarin ASA Clopidogrel 75P-

9.

PRADAXA PRADAXA 24

2-4 PRADAXA dabigatran 3 3

[CrCl]mLmin

dabigatran

80 ~13* 2 24 50-

10.

P-P-gp P- Dabigatran etexilate efflux transporterP-P-gpP- amiodaroneverapamilquinidine ketoconazoledronedaroneticagrelor clarithromycin dabigatran P-: ketoconazole cyclosporineitraconazole P-( amiodarone, quinidine, verapamil ticagrelor) P-(VTE) Amiodarone RE-LY 14% amiodarone dabigatran 1.6 60 % VTE dabigatran etexilate amiodarone Pradaxa 150 mg2 75 mg dabigatran etexilate amiodarone Verapamil PRADAXA (150 mg) verapamil dabigatran Cmax AUC verapamil RE-LY 21% dabigatran verapamil dabigatran Cmax 180%AUC 150% verapamil Cmax 90%AUC 70% verapamil Cmax 60%AUC 50% dabigatranverapamildabigatran etexilateverapamilPradaxa150 mg275 mgdabigatran etexilateverapamilPradaxa75 mg dabigatran etexilate verapamil Pradaxa 220 mg 1 110 mg dabigatran etexilate verapamil

11.

dabigatran etexilate 2 verapamil Cmax 10%AUC 20% 2 dabigatran Quinidine quinidine dabigatran 1.5 53 %

dabigatran etexilatequinidinePradaxa 150 mg2 75 mgDabigatran etexilatequinidine Clarithromycin clarithromycin dabigatran 19 % dabigatran clarithromycin dabigatran etexilate clarithromycin Ketoconazole ketoconazoledabigatran 2.5 150% ketoconazole Dronedarone dronedarone dabigatran 2.1 114% 2.4 136% dronedarone Ticagrelor ticagrelor Dabigatran 1.46 + 46%loading dose ticagrelor 75 mg dabigatran etexilate 1.73 +73% Pketoconazole ItraconazolecyclosporinePradaxa posaconazolePradaxa P- Digoxin 24 Pradaxa digoxin digoxin dabigatran P-

12.

600 mg rifampicin7dabigatran AUC0-Cmax67%66%P-rifampicin(Hypericum perforatum)carbamazepine phenytoindabigatran P- : ritonavirP-Pradaxa : C PRADAXA PRADAXAPradaxa 70 mg/kg 5

5 10 4 PRADAXA 10,795 6 6,684 150 220 Pradaxa RE-LY 12,042 dabigatran etexilate 6,059 150 mg dabigatran etexilate 5,983 110 mg

13.

42 9 % 3 22 %

14 % 16.5 % 2System Organ ClassesSOC56

4

( 1/10) ( 1/100, < 1/10) ( 1/1,000, < 1/100) ( 1/10,000,< 1/1,000)(< 1/10,000)

SOC

-

14.

-

- - - - -

- -

5% Dabigatran etexilate

150 mg N%

Dabigatran etexilate 220 mg N%

Enoxaparin N%

1,866100.0 1,825100.0 1,848100.0 241.3 331.8 271.5 25813.8 25113.8 24713.4

15.

RE-NOVATERE-MODEL 20gL1.24 mmol/L; 2g/dl 2 [CT] [] 6 RE-LY 6RE-LY (%)

Dabigatran etexilate110 mg

N (%)

Dabigatran etexilate 150 mg

N (%) Warfarin**

N (%) 6,015 6,076 6,022

- 11,899 12,033 11,794 (MBE)* 342 (2.87) 399 (3.32) 421 (3.57)

Warfarin 95%

0.80 (0.700.93) 0.93 (0.811.07)

P- 0.0026 0.3146 147 (1.24) 179 (1.49) 218 (1.85)

Warfarin 95%

0.67 (0.540.82) 0.80 (0.660.98)

P- 0.0001 0.0305 (ICH)+ 27 (0.23) 38 (0.32) 90 (0.76)

Warfarin 95%

0.30 (0.190.45) 0.41 (0.280.60)

P- < 0.0001 < 0.0001 a 1,754 (14.74) 1,993 (16.56) 2,166 (18.37)

Warfarin 95%

0.78 (0.730.83) 0.91 (0.850.96)

P- < 0.0001 0.0016 * ** warfarin INR 2 3 + (ICH) a (major bleeding)

16.

20gL (2 g/dl) 2

(compartment syndrome)

50gL (5 g/dl) 4

PRADAXA 150 mgwarfarin75PRADAXA1.295%1.01.4

warfarindabigatran etexilate

GERD warfarinPRADAXA 7dabigatran etexilate 110mg dabigatran etexilate 150mg warfarin 1.14%1.57% 1.07%dabigatran etexilate 110mg dabigatran etexilate 150mg warfarin 0.57%0.79% 0.49% dabigatran etexilate 110mgdabigatran etexilate 150mg warfarin 5.41%6.13% 4.02% 7: RE-LY dabigatran

(1%)

Dabigatran etexilate

110 mg N (%)

Dabigatran

etexilate

150 mg N (%)

Warfarin

N (%)

5,983 (100) 6,059 (100) 5,998 (100)

* 599 (10.0) 747 (12.3) 825 (13.8)

73 (1.22) 97 (1.60) 74 (1.23)

66 (1.10) 67 (1.11) 107 (1.78)

196 (3.28) 277 (4.57) 155 (2.58)

66 (1.10) 84 (1.39) 96 (1.60)

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

17.

135 (2.25) 134 (2.21) 15 (0.25)

75 (1.25) 71 (1.17) 11 (0.18)

250 (4.18) 234 (3.90) 13 (0.22)

58 (0.97) 73 (1.20) 12 (0.20)

*, 5xULN 36 (0.7) 45 (0.7) 50 (0.8) ALT AST > 3xULN + >2xULN

11 (0.2) 14 (0.2) 21 (0.4)

PRADAXA PRADAXA PRADAXA dabigatran

dabigatran FEIBA VIIa IIIX X dabigatran

(Coagulation tests) dabigatran

18.

ATC B01AE07 - dabigatran etexilate Dabigatran etexilate dabigatran etexilate esterase dabigatranDabigatran fibrinogenfibrinDabigatran

dabigatran dabigatran etexilate dabigatran Dabigatran aPTTECT TT 220 mg dabigatran etexilate23dabigatran70.8 ng/ml35.2-162 ng/ml2575220 mg dabigatran24dabigatran22.0 ng/ml13.0-35.7 ng/ml2575

220 mg dabigatran etexilate 20-28 dabigatran 90 67 ng/mL

20-28 aPTT 90 51 1.3

220 mg dabigatran etexilate ECT VTE:

1 - 4Pradaxa 75 110Pradaxa 150(75 mg 2)220(110 mg 2)enoxaparin 40 RE-MODEL6-10RE-NOVATE28-35 2076 3494

19.

[PE][DVT]()

Pradaxa 220 mg150 mgenoxaparinPradaxa 150 mgenoxaparin9220 mgPradaxaenoxaparin9 >65

RE-MODELRE-NOVATE5,53951%9%9%20%dabigatran

9

10

11 9RE-MODELRENOVATE Dabigatran etexilate Dabigatran etexilate Enoxaparin 220 mg

150 mg 40 mg

RE-NOVATE N 909 888 917 % 283.1 384.3 363.9 enoxaparin

0.78 1.09

95% CI 0.481.27 0.701.70 Re-MODEL N 506 527 511 % 132.6 203.8 183.5 enoxaparin

0.73 1.08

95% CI 0.361.47 0.582.01 10RE-MODELRENOVATE Dabigatran etexilate Dabigatran etexilate Enoxaparin 220 mg

150 mg 40 mg

20.

RE-NOVATE N 880 874 897 % 536.0 758.6 606.7 enoxaparin

0.9 1.28

95% CI 0.631.29 0.931.78 RE-MODEL N 503 526 512 % 18336.4 21340.5 19337.7 enoxaparin

0.97 1.07

95% CI 0.821.13 0.921.25 11RE-MODELRENOVATE Dabigatran etexilate

220 mg Dabigatran etexilate 150 mg

Enoxaparin 40 mg

RE-NOVATE n 1,146 1,163 1,154 n% 232.0 151.3 181.6

RE-MODEL n 679 703 694 n% 101.5 91.3 91.3 PRADAXA RE-LY[Randomized Evaluation of Long-term Anticoagulant Therapy]

PRADAXA 110 mg 150 mg warfarin INR 2 3

TIA

21.

PRADAXA 50% warfarin

18,113 2 71.5 CHADS2 2.1 64%70%16%1%20%TIA K VKA 2 50% K 32% 79% 23% 28%40%6% clopidogrel warfarin INR 2 3 64%INR 4 1.5 2% 5%

warfarin PRADAXA 110 mgPRADAXA 150 mg 12 1PRADAXA 110 mg () warfarin 12 RELY (SEE) Dabigatran

etexilate 110 mg

Dabigatran etexilate

150 mg

Warfarin+

6,015 6,076 6,022 SEE **

(%) * 183 (1.54) 134 (1.11) 202 (1.71) Warfarin 95%

0.90 (0.741.10) 0.65 (0.520.81)

P- p = 0.2943 p = 0.0001 P- p < 0.0001 p < 0.0001 * % ** SEE + INR 2.0 3.0

1 RELY Kaplan-Mayer

22.

PRADAXA 150 mg () 13 RELY Dabigatran

etexilate 110 mg

Dabigatran etexilate 150

mg

Warfarin+

6,015 6,076 6,022

(%) * 171 (1.44) 122 (1.01) 186 (1.58) Warfarin 95%

0.92 (0.751.14) 0.64 (0.510.81)

P- 0.443

23.

(%) * 14 (0.12) 12 (0.10) 45 (0.38) Warfarin 95%

0.31 (0.170.56) 0.26 (0.140.49)

P-

24.

16RELY (SEE)

Dabigatran etexilate

110 mg

Dabigatran etexilate

150 mg

Warfarin+

< 65 N = 2,981

% 1.47 0.69 1.35

Warfarin 95% 1.10 (0.641.87) 0.51 (0.260.98)

65

25.

17RELY (major bleeding events)

Dabigatran etexilate

110 mg

Dabigatran etexilate

150 mg

Warfarin+

< 65 N = 2,981

% 0.81 0.88 2.43

Warfarin 95% 0.33 (0.190.59)

0.36 (0.210.62)

> 65 -

26.

CHADS =1 1.88%2.20% 2.90%CHADS2 =2 2.98%3.04% 3.31%CHADS 3 3.80%4.86 % 4.61% 19 (SEE)(%) Dabigatran

etexilate 110 N (%)

Dabigatran etexilate 150

N (%)

Warfarin

N (%) 545 552 551 - 1071 1076 1055

(SEE) 20 (1.87) 19 (1.77) 24 (2.28)

19 (1.77) 19 (1.77) 22 (2.09) 15 (1.40) 16 (1.49) 16 (1.52) 1 (0.09) 3 (0.28) 6 (0.57) 3 (0.28) 2 (0.19) 1 (0.09) (SEE) 1 (0.09) 0 (0.00) 3 (0.28) -=( +1)/365.25 (%) =/-* 100 20 Dabigatran

etexilate 110 N (%)

Dabigatran etexilate 150

N (%)

Warfarin

N (%)

545 552 551

- 1071 1076 1055 26 (2.43) 21 (1.95) 34 (3.22) 11 (1.03) 14 (1.3) 19 (1.80) 15 (1.40) 10 (0.93) 17 (1.61)

252 dabigatran etexilate warfarin dabigatran etexilate 3 dabigatran etexilate

27.

Dabigatran etexilate mesylate dabigatran etexilate dabigatranDabigatran 4 acyl glucuronides glucuronides dabigatran dabigatran glucuronides 10 400 mg dabigatran dabigatran etexilate dabigatran absolute bioavailability 3 7%Dabigatran etexilate P-efflux transporter dabigatran etexilate Cmax 1 PRADAXA Cmax 2 dabigatran PRADAXA dabigatran etexilate 75% PRADAXA Dabigatran 35%Dabigatran 0.3Dabigatran 50-70 L 10-400 mg dabigatran dabigatran accumulation factor 2 Dabigatran dabigatran 80% dabigatran 7%86%Dabigatran 12 17 dabigatran etexilate dabigatranDabigatran etexilate esterase dabigatranDabigatran CYP450 Dabigatran acyl glucuronides 4 positional isomers1-O2-O3-O 4-O-acyl glucuronides dabigatran 10% 30 50 ml/mindabigatran etexilate dabigatran 3 10 - 30 ml/min dabigatran 6 2

28.

7 ESRDdabigatran 700 ml/min 4 200 ml/min 350 390 ml/min 50% 60% dabigatran 300 ml/minDabigatran / RE-LY 68.4 ml/minRE-LY 45.8 %> 50 < 80 ml/min80 ml/min 30-50 ml/min dabigatran 2.29 1.81 AUC 1.4 1.6 40 60%Cmax 1.25 25 % > 65 AUC,ss Cmax,ss 1.9 1.6 AUC,ss Cmax,ss 18 40 2.2 2.0 dabigatran dabigatran RE-LY 75 1.3 ( 31 %)< 65 65 75 22 % 12 Child Pugh B 12 dabigatran (VTE): Child-Pugh B C 2 ULN : 2 AB C > 100 dabigatran 50 100 20%80.8% 50 < 100 50

29.

1.3 30 % 1.4 1.5 40 50 % dabigatran dabigatran

dabigatran P450cytochrome P450dabigatran atorvastatinCYP3A4 diclofenacCYP2C9 AtorvastatinDabigatran etexilate atorvastatinCYP3A4atorvastatinatorvastatin dabigatran DiclofenacDabigatran etexilate diclofenacCYP2C9 dabigatran etexilate diclofenac P- dabigatran etexilate dabigatranefflux transporterP- P-

P- AmiodaroneDabigatran etexilate 600 mg amiodarone amiodarone DEA Dabigatran AUC Cmax 1.6 1.5 60 % 50 % RE-LY amiodarone dabigatran DronedaroneDabigatran etexilate dronedarone 400 mg dronedarone dabigatran AUC0- Cmax 2.4 2.3 136 % 125% 400 mg 2.1 1.9 114% 87%Dabigatran dronedarone dabigatran etexilate 2 dronedarone dabigatran AUC0- 1.3 1.6 dronedarone

30.

VerapamilDabigatran etexilate verapamil dabigatran Cmax AUC verapamil dabigatran verapamil dabigatran Cmax 2.8 [ 180%]AUC 2.5 [ 150%] verapamil Cmax 1.9 [ 90%]AUC 1.7 [70%] verapamil Cmax 1.6 [ 60%]AUC 1.5 [ 50%] verapamil P- dabigatran etexilate 2 verapamilCmax 10%AUC 20% 2 dabigatran RE-LY verapamil dabigatran verapamil Ketoconazole ketoconazole400 mg dabigatran AUC0- Cmax 2.4 138 % 135% 400 mg ketoconazole 2.5 153% 149%Dabigatran ketoconazole ketoconazole Clarithromycin clarithromycin 500 mg dabigatran etexilateCmax 15 %AUC 19% QuinidineQuinidine 2 200 mg 1000 mgdabigatran etexilate 3 3 quinidinequinidine dabigatran AUC,ss Cmax,ss 1.5 53% 56% Ticagrelor 75mg dabigatran etexilate 180 mg ticagrelor dabigatran AUC Cmax 1.73 1.95 +73% 95% ticagrelor 90 mgdabigatran AUC Cmax 1.56 1.46+56% 46% P- Digoxin24Pradaxadigoxindigoxindabigatran P-

31.

Rifampicin rifampicin 600 mg 7 dabigatran 65.5% 67% rifampin 7dabigatran 7 Acetylsalicylic acid ASA dabigatran etexilateASA ASA ASA 150 mg dabigatran etexilate 81 mg 325 mg ASA 12 %-18 % 24% RE-LYASA clopidogrel dabigatran etexilate110 150 mg ASA clopidogrel warfarin NSAID dabigatran etexilate dabigatran etexilate 12 NSAID RE-LY NSAID Clopidogrelclopidogrel dabigatran etexilate clopidogrel capillary bleeding times CBTdabigatran AUC,ss Cmax,ss dabigatran aPTTECT TT FIIa clopidogrel inhibition of platelet aggregation IPA 300 600 mg clopidogrel dabigatran AUCt,ss Cmax,ss 1.3 1.4 30 40% ASA Dabigatran etexilate LMWHLMWH enoxaparindabigatran etexilate40 mg enoxaparin3dabigatran etexilateenoxaparin24dabigatrandabigatran etexilate 220 mgdabigatran etexilateenoxaparindabigatran etexilate-FXa/FIIaenoxaparincarry-over effectdabigatranenoxaparin (SSRIs)(SNRIs) SSRI SNRIs RE-LY

32.

pH PantoprazoleDabigatran etexilate pantoprazoledabigatran - 30 %Pantoprazole dabigatran etexilate RanitidineRanitidine dabigatran etexilate dabigatran dabigatran

14.6 % RE-LY dabigatran - 11 % warfarin pantoprazole

dabigatran 70 mg/kg5

5104 200 mg/kg dabigatran 30C 30C 4 / Boehringer Ingelheim Pharma GmbH & Co. KG Binger Strasse 173, D-55216 Ingelheim am Rhein, Germany

33.

Boehringer Ingelheim International GmbH Ingelheim am Rhein, Germany 49/51 12 20121211