1

TM 50/500 50/850 50/1000

JANUMET 50/500 mg Film-Coated Tablets, 50/850 mg Film-Coated Tablets, 50/1000 mg Film-Coated Tablets

(sitagliptin phosphate/metformin HCl, MSD)

WPC-JMT-T-052007 MK0431A-TWN-2009-000014

JANUMET 1 (sitagliptin/metformin HCl) sitagliptin metformin hydrochloride Sitagliptin Sitagliptin 4 (dipeptidyl peptidase 4DPP-4)Sitagliptin JANUMET sitagliptin phosphate monohydrate 7-[(3R)-3-amino-1-oxo-4-(2,4,5-trifluorophenyl)butyl]-5,6,7,8- tetrahydro-3-(trifluoromethyl)-1,2,4-triazolo[4,3-a]pyrazine phosphate (1:1) monohydrate C16H15F6N5OH3PO4H2O 523.32

F

F

F

N

N

N

N

CF3

OH NH2

. H3PO4 . H2O

Sitagliptin phosphate monohydrate N,N-dimethyl formamide acetonitrile Metformin hydrochloride Metformin hydrochloride (N,N-dimethylimidodicarbonimidic diamide hydrochloride)

Metformin hydrochlorideC4H11N5HCl165.63Metformin hydrochloride

MetforminpKa12.4metformin hydrochloride 1%pH6.68

JANUMET JANUMET 64.25 sitagliptin phosphate monohydrate metformin hydrochloride 50 sitagliptin 500 metformin hydrochloride (JANUMET 50 /500 )850 metformin hydrochloride (JANUMET 50 /850 ) 1000 metformin hydrochloride (JANUMET 50 /1000 ) JANUMET microcrystalline cellulose polyvinylpyrrolidonesodium lauryl sulfate sodium stearyl fumarate polyvinyl alcoholpolyethylene glycoltalctitanium dioxidered iron oxide black iron oxide

1 Registered trademark of MERCK & CO., Inc., Whitehouse Station, New Jersey, 08889 USA TM Trademark of MERCK & CO., Inc., Whitehouse Station, New Jersey, 08889 USA COPYRIGHT 2007 MERCK & CO., Inc. All right reserved

50/500 025043 50/850 025041 50/1000 025040

2

JANUMET JANUMET (sitagliptin phosphate/metformin HCl) sitagliptin phosphate 4 (dipeptidyl peptidase 4DPP-4) metformin hydrochloride (biguanide) Sitagliptin phosphate Sitagliptin phosphate DPP-4 DPP-4 (incretin) DPP-4 sitagliptin -1 (glucagonlike peptide-1GLP-1) (glucose-dependent insulinotropic polypeptideGIP)Incretins GLP-1 GIP (insulin)GLP-1 (glucagon)sulfonylureas sulfonylureas sulfonylurea Sitagliptin DPP-4 DPP-8 DPP-9 Sitagliptin GLP-1 sulfonylureas meglitinides biguanides (peroxisome proliferator-activated receptor gammaPPAR) amylin Metformin hydrochloride Metformin Metformin

sulfonylureas metformin (Metformin hydrochloride) metformin

JANUMET JANUMET sitagliptin phosphate 4 (DPP-4) metformin hydrochloride Sitagliptin phosphate Sitagliptin phosphate 4 (DPP-4)

-1 (GLP-1)(GIP)Incretins GLP-1 GIP AMP(c-AMP)

3

GLP-1 DPP-4 GLP-1 glucagonGlucagons GLP-1 GIP GLP-1 glucagon GLP-1 GIP GLP-1 glucagon GLP-1 GIP DPP-4 Sitagliptin DPP-4 GLP-1 GIP Sitagliptin glucagon sulfonylureas sulfonylureas

glucagon A1c (HbA1c)Sitagliptin DPP-4 DPP-8 DPP-9 Metformin hydrochloride MetforminMetformin

sulfonylureasmetformin2(Metformin hydrochloride)metformin

JANUMET JANUMET (sitagliptin/metformin hydrochloride) 50 /500 50 /1000 sitagliptin phosphate (JANUVIA) metformin hydrochloride sitagliptin/metformin 50 /850 (FDC) Sitagliptin phosphate Sitagliptin 87%Sitagliptin phosphate sitagliptin Metformin hydrochloride metformin hydrochloride 50050-60%50015008502550metformin hydrochloride

850metformin(Cmax)40%

4

(AUC)25%(Tmax)35metformin Sitagliptin phosphate 100198Sitagliptin(38%) Metformin hydrochloride 850metformin hydrochloridemetformin(V/F)65435890%sulfonylureasmetforminmetforminmetformin hydrochloridemetformin24-48

5

90%246.217.6 Sitagliptin phosphate Sitagliptin Metformin hydrochloride metformin metformin JANUMET JANUMET () Sitagliptin phosphate sitagliptin AUC 2 ESRD 4 Metformin hydrochloride ()metformin Sitagliptin phosphate (Child-Pugh 7 9 ) 100 sitagliptin phosphate sitagliptin AUC Cmax 21%13% (Child-Pugh >9)sitagliptin sitagliptin Metformin hydrochloride metformin Sitagliptin phosphate

6

I II sitagliptin (65 80 ) sitagliptin 19% Metformin hydrochloride metformin

metformin Sitagliptin phosphate I II sitagliptin (65 80 ) sitagliptin 19% Metformin hydrochloride

metformin Cmax metformin ( GLUCOPHAGE -) 80 JANUMET ( Metformin hydrochloride) JANUMET Sitagliptin phosphate I I II sitagliptin Metformin hydrochloride metformin metformin (n=249)(n=51)(n=24) (Body Mass Index; BMI) Sitagliptin phosphate IIII

7

sitagliptin Sitagliptin phosphate sitagliptin 24 DPP-4 GLP-1 GIP 2 3 C

18 24 III 100 sitagliptin HOMA- (-) II sitagliptin 50 sitagliptin 100 (double-dummy) sitagliptin metformin GLP-1 GLP-1 sitagliptin metformin sitagliptin metformin 4 GLP-1 2 Sitagliptin metformin GLP-1 GLP-1 4 sitagliptin GLP-1 DPP-4 metformin GLP-1 GLP-1 GLP-1 sitagliptin GIP metformin sitagliptin ()(II ) sitagliptin sitagliptin 100 sitagliptin 24 2 79 sitagliptin 100 sitagliptin 800 ( 8 ) 100 QTc 800 3 QTc 8.0 800 sitagliptin 100 11

8

sitagliptin 100 (N=81) sitagliptin 200 (N=63) ECG QTc

JANUMET JANUMET sitagliptin metformin Sitagliptin 50150 500 // sitagliptin 500 / AUC 60 (100 /) 150 /( 20 ) 50125250 500 // sitagliptin500 / 70 (Ames bacterial mutagenicity assay)(Chinese hamster ovary chromosome aberration assay)(in vitro cytogenetics assay) DNA (in vitro rat hepatocyte DNA alkaline elution assay) (in vivo micronucleus assay)sitagliptin (clastogenic) () 125250 1000 / 125 /( AUC 12 100 /)( AUC 25 100 ) Metformin hydrochloride 900 // 1500 // 104 91 4 2000 metformin metformin 900 //(benign stromal uterine polyps) Metformin (S. typhimurium)()() 600 // metformin ( 3 )

Sitagliptin metformin glimepiride JANUMET JANUMET sitagliptin metformin

9

SitagliptinMetformin 1,09124sitagliptinmetformin(N=541)12(washout)(HbA1c 7.5%11%)(run-in)(N=550)(HbA1c 7.5%11%)100sitagliptin (JANUVIA)5001000metformin50sitagliptin5001000metforminglyburide (glibenclamide) metforminsitagliptinsitagliptinmetforminHbA1cFPG2PPG(11)HbA1cHbA1cHbA1c-1.1%100sitagliptin-1.1%500metformin-1.2%1000metformin-1.6%50sitagliptin500metformin -1.9%50sitagliptin1000metformin-0.2%sitagliptinmetforminmetformin

1 Sitagliptin

Metformin(24)

Sitagliptin 100 q.d.Metformin

500 b.i.d.

Metformin 1000

b.i.d.

Sitagliptin 50 b.i.d. + Metformin

500 b.i.d.

Sitagliptin 50 b.i.d. + Metformin 1000

b.i.d. HbA1c (%) N=165 N=175 N=178 N=177 N=183 N=178

() 8.7 8.9 8.9 8.7 8.8 8.8 () 0.2 -0.7 -0.8 -1.1 -1.4 -1.9 () (95% CI)

- -0.8 (-1.1, -0.6)

-1.0 (-1.2, -0.8)

-1.3 (-1.5, -1.1)

-1.6 (-1.8, -1.3)

-2.1 (-2.3, -1.8)

HbA1c

10

0 6 12 18 24 Week

-2.0

-1.5

-1.0

-0.5

0.0 L

S M

ean

Cha

nge

from

Bas

elin

e

Placebo Metformin 1000 mg b.i.d.

Sitagliptin 100 mg q.d. Sitagliptin 50 mg b.i.d. + Metformin 500 mg b.i.d.

Metformin 500 mg b.i.d. Sitagliptin 50 mg b.i.d. + Metformin 1000 mg b.i.d.

(HbA1c >11%>280 mg/dL) (N=117)sitagliptin 50metformin 1000HbA1cFPG2PPG11.2 %314 mg/dL441 mg/dL24HbA1cFPG2PPG-2.9%-127 mg/dL-208 mg/dL Metformin Sitagliptin 70124sitagliptin metformin 1500 metformin (N=431)100sitagliptinmetformin(N=229)(8N=41)metformin(1500)10pioglitazone sitagliptinmetforminHbA1cFPG2PPG(2)sitagliptin5%14%

2 SitagliptinMetformin(24)

Sitagliptin 100 q.d. +

Metformin +

Metformin HbA1c (%) N=453 N=224

() 8.0 8.0

11

() -0.7 -0.0 +metformin() (95% CI)

-0.7 (-0.8, -0.5)

HbA1c

12

Sitagliptin Glipizide Metformin sitagliptin 52 glipizide metformin (1500 mg/day) 12 metformin (HbA1c 6.5% 10%) 1:1 100 sitagliptin glipizide 52 glipizide 5 mg/day 18 20 mg/day glipizide glipizide 10 52 HbA1c sitagliptin glipizide ( 4)( 2)sitagliptin glipizide HbA1c ( 70% HbA1c

13

Sitagliptin (4.9%) glipizide(32.0%) sitagliptin glipizide (-1.5 +1.1 )

sitagliptinmetforminsitagliptinmetformin

JANUMET sitagliptin 100 metformin 2000 JANUMET metformin (GI) JANUMET JANUMET

50 sitagliptin/500 metformin hydrochloride 50 sitagliptin/850 metformin hydrochloride 50 sitagliptin/1000 metformin hydrochloride

metformin metformin JANUMET 50 ( 100 ) sitagliptin metformin sitagliptin sitagliptin JANUMET 50 sitagliptin/500 metformin hydrochloride 50 sitagliptin/1000 metformin hydrochloridesitagliptin sitagliptin JANUMET () sitagliptin metformin sitagliptin metformin sitagliptin metformin JANUMET sitagliptinmetformin sulfonylurea JANUMET 50 ( 100 ) sitagliptin metformin metformin () metformin (GI) sulfonylurea sulfonylurea () JANUMET

14

JANUMET (sitagliptin phosphate/metformin HCl)

1. 1.5 mg/dL []1.4 mg/dL []()

2. sitagliptin phosphatemetformin hydrochlorideJANUMET(Sitagliptin phosphate).

3. JANUMET( Metformin hydrochloride)

JANUMET JANUMET Metformin sitagliptin metformin

JANUMET JANUMET JANUMET

JANUMET Sulfonylureasulfonylureasitagliptinmetforminsulfonylureametforminsulfonylurea()(sulfonylureameglitinide)sulfonylurea()JANUMET Sitagliptin phosphate JANUMET sitagliptin

sitagliptin sitagliptin JANUMET () Metformin hydrochloride JANUMET (sitagliptin phosphate/metformin HCl)metformin50%()

15

(>5 mmol/L)pH/metforminmetformin>5 g/mL metformin hydrochloride ( 1000 0.03 1000 0.015 )metformin 20,000 ()/

metformin metformin 80 Metformin

metforminmetformin metformin metformin hydrochloride metformin

metformin pH metformin metformin () metformin 5 mmol/L

() metformin metformin hydrochloride ( 170 mL/min) metformin() metformin (sulfonylureas )

metformin metformin ( Metformin hydrochloride)

16

((CT)) metformin () JANUMET 48 ()

JANUMET ( ) JANUMET metformin JANUMET JANUMET B12 29 metformin 7% B12 B12- B12 metformin B12 JANUMET ( B12 ) B12 B12 JANUMET ()

pH metformin JANUMET

JANUMET JANUMET JANUMET

JANUMET JANUMET JANUMET JANUMET JANUMET sitagliptin metformin

17

Sitagliptin phosphate 250 mg/kg125 mg/kg(100 mg/day3222)sitagliptin1000 mg/kg/day(100 mg/day100)()1000 mg/kg/day

Metformin hydrochloride 600 mg/kg/day metformin

2,000 2 6 metformin

JANUMETsitagliptinmetforminsitagliptinJANUMET

JANUMET18

JANUMET sitagliptin metformin JANUMET () Sitagliptin phosphate sitagliptin 65 (

18

JANUMET JANUMET (sitagliptin phosphate metformin hydrochloride) Sitagliptin phosphate SitagliptinCYP3A42C82C92D61A22C192B6CYPCYP3A4SitagliptinPP (p-glycoprotein)digoxinsitagliptin Sitagliptin- Sitagliptin ( ) sitagliptin metformin glyburide simvastatin rosiglitazonewarfarinCYP3A4CYP2C8CYP2C9(OCT)sitagliptindigoxin Sulfonylureassitagliptinglyburide (CYP2C9)glyburideCYP2C9sulfonylurea(glipizidetolbutamideglimepiride) Simvastatinsitagliptinsimvastatin (CYP3A4)sitagliptinCYP3A4 ThiazolidinedionessitagliptinrosiglitazonesitagliptinCYP2C8pioglitazoneCYP2C8CYP3A4pioglitazone Warfarinsitagliptinwarfarin(S(-)R(+) warfarin)(INR)S(-) warfarinCYP2C9sitagliptinCYP2C9 sitagliptinnorethindroneethinyl estradiol DigoxinSitagliptindigoxin100.25digoxin100JANUVIAdigoxinAUC11%Cmax18% sitagliptin sitagliptin Cyclosporinecyclosporine (P)sitagliptin 100 JANUVIA 600 cyclosporinesitagliptinAUCCmax29%68%sitagliptinsitagliptinP

19

sitagliptin ( statinsfibratesezetimibe)( clopidogrel)( ACE hydrochlorothiazide) ( naproxen diclofenaccelecoxib)( bupropionfluoxetinesertraline)(cetirizine)( omeprazolelansoprozole)( sildenafil) Metformin hydrochloride Glyburide metformin glyburide metformin Glyburide AUC Cmax glyburide Furosemide metformin-furosemide Furosemide metformin Cmax Cmax 22% AUC 15%metformin metformin furosemide Cmax AUC 31% 12% 32% furosemide metformin furosemide Nifedipine metformin-nifedipine nifedipine metformin Cmax AUC 20% 9%Tmax Nifedipine metformin Metformin nifedipine ( amiloridedigoxinmorphineprocainamidequinidinequinineranitidinetriamterenetrimethoprim vancomycin) metformin metformin-cimetidine metformin cimetidine metformin 60%metformin AUC AUC 40%Metformin cimetidine ( cimetidine ) JANUMET () thiazides phenothiazinesphenytoin isoniazid JANUMET metformin propranolol metformin ibuprofen sulfonylureasmetformin salicylatessulfonamideschloramphenicol probenecid

20

sitagliptin metformin sitagliptin metformin metformin Sitagliptin Metformin 5 24 sitaglipitin metformin (5%)()

5 Sitagliptin Metformin

5% ()()

(%) Sitagliptin

100 q.d. Metformin

500 1000 b.i.d. Sitagliptin 50 b.i.d.

+Metformin 500 1000 b.i.d.

N = 176 N = 179 N = 364 N = 372 7 (4.0) 5 (2.8) 28 (7.7) 28 (7.5) 9 (5.1) 8 (4.5) 19 (5.2) 23 (6.2) 5 (2.8) 2 (1.1) 14 (3.8) 22 (5.9)

metformin

Sitagliptin Metformin metformin sitagliptin 100 24 5% ( sitagliptin metformin 1.9% metformin 2.5%)

0.6% sitagliptin 0.6% metformin 0.8% sitagliptin metformin 1.6% metformin sitagliptin 1.3% 2.1% sitagliptin metformin metformin 6

6 Sitagliptin Metformin

() (%)

Sitagliptin Metformin Metformin Sitagliptin

Sitagliptin + Sitagliptin 100

21

Sitagliptin 100 q.d.

Metformin 500 1000 b.i.d.

50 b.i.d. + Metformin

500 1000 b.i.d.

Metformin 1500

q.d.+ Metformin 1500

N = 176 N = 179 N = 364 N = 372 N= 237 N= 464 7 (4.0) 5 (2.8) 28 (7.7) 28 (7.5) 6 (2.5) 11 (2.4) 2 (1.1) 2 (1.1) 20 (5.5) 18 (4.8) 2 (0.8) 6 (1.3) 1 (0.6) 0 (0.0) 2 (0.5) 8 (2.1) 2 (0.8) 5 (1.1)

4 (2.3) 6 (3.4) 14 (3.8) 11( 3.0) 9 (3.8) 10 (2.2) metformin

Sitagliptin Metformin Glimepiride metformin glimepiride sitagliptin 100 (sitagliptin N=116 N=113) 24 sitagliptin 5%(sitagliptin 16.4%0.9%)(6.9%2.7%) sitagliptin metformin ECG ( QTc ) sitagliptin 5% metformin (5%)/ JANUMETsitagliptin

(Sitagliptin phosphate, )

Sitagliptin phosphate sitagliptinmetformin(7.6%)metformin(8.7%)(WBC200 cells/microLWBC6600 cells/microL)() Metformin hydrochloride 29 metformin 7%B12 B12- B12 metformin B12 ( Metformin hydrochloride)

22

Sitagliptin phosphate 800 sitagliptin 800 sitagliptin QTc () 800 I 400 sitagliptin 28 600 sitagliptin 10

() sitagliptin3413.5%sitagliptin Metformin hydrochloride metformin hydrochloride 50 10% metformin hydrochloride 32% metformin (Metformin hydrochloride)Metformin 170 mL/min metformin

30C (86F)

50/500 "575" 50/850 "515" 50/1000 "577"

2-1000 Patheon Puerto Rico, Inc. Villa Blanca Industrial Park, State Rd. 1, Km. 34.8, Jose Garrido, Caguas, Puerto

Rico 00725 Frosst Iberica, S.A. Via Complutense, 140 28805 Alcala de Henares, Madrid, Spain 216 14