Forxiga Film - coated Tablets 5mg, 10mg

510ForxigaFilmcoatedTablets5mg,10mg

5 026475 10 026476

1

[(14)]

1.1 Forxiga

2

2.1

Forxiga metforminsulfonylureathiazolidinedioneDPP-4 (

metformin)metformin sulfonylurea

Forxiga 5 mg 1 Forxiga 5

mg 1 10 mg 1

Forxiga [ (5.1)

(8.58.6) (17)]

2.2

Forxiga

eGFR 60 mL/min/1.73 m2 Forxiga

(eGFR 60 mL/min/1.73 m2 )

eGFR 60 mL/min/1.73 m2 Forxiga[(5.3)

(8.6)]

3

Forxiga 5mg 51427

Forxiga 10mg 101428

4

Forxiga [(6.1)]

(ESRD)[(8.6)]

5

5.1

Forxiga Forxiga [ (6.1)]

(eGFR 60 mL/min/1.73 m2) (loop

diuretics)

Forxiga

5.2

Forxiga SGLT2 (

) Forxiga

Forxiga

14 mmol/l (250 mg/dl) Forxiga

Forxiga

5.3

Forxiga eGFR

Forxiga [ (6.1)] Forxiga

5.4

Forxiga

[ (6.1)] Forxiga

5.5

Forxiga SGLT2

SGLT2

5.6

Forxiga [

(6.1)]

5.7 (LDL-C)

Forxiga LDL-C [(6.1)] Forxiga LDL-C

5.8

22 Forxiga 10/6045

(0.17%)/ 1/3512 (0.03%)

1 4 Forxiga/

()

Forxiga

Forxiga

Forxiga Forxiga

5.9

Forxiga

6

[(5.1)]

[(5.2)]

[(5.3)]

[(5.4)]

[(5.5)]

[(5.6)]

(LDL-C)[(5.7)]

[(5.8)]

6.1

12 Forxiga 5 10 mg

1 12 12 24 Forxiga 4

8 Forxiga metformin [

(14)]

2338 Forxiga 21

(N=1393)Forxiga 5 mg (N=1145) Forxiga 10 mg (N=1193) 1 55

2% 75 50%81%14%3%

6 A1c(HbA1c) 8.3%21%

92%8%( eGFR 86 mL/min/1.73

m2)

1 Forxiga Forxiga

2% Forxiga 5 mg Forxiga 10 mg

1 Forxiga 2%

%

12

N=1393

Forxiga 5 mg N=1145

Forxiga 10 mg N=1193

* 1.5 8.4 6.9

6.2 6.6 6.3

3.7 5.7 4.3

3.2 3.1 4.2

1.7 2.9 3.8

0.3 2.8 2.7

2.4 2.8 2.5

2.3 2.7 2.3

1.5 2.1 2.5

1.5 2.2 1.9

0.7 1.6 2.1

1.4 2.0 1.7

*

( N =677 Forxiga 5

mg=581Forxiga 10 mg=598)

( N =716 Forxiga 5 mg=564 Forxiga 10

mg=595)

13 Forxiga 10 mg

Forxiga 10 mg

13 3 9

metformin 13 2360 1 Forxiga 10 mg

22 59 4% 75 58%84%

9% 3% 9

HbA1c 8.2%30%88%11%

( eGFR 82 mL/min/1.73 m2)

Forxiga 2 12 13

()[

(5.1)]

2Forxiga * 12 13

Forxiga 5 mg Forxiga 10 mg Forxiga 10 mg

N (%) N=1393 5 (0.4%)

N=1145 7 (0.6%)

N=1193 9 (0.8%)

N=2295 17 (0.7%)

N=2360 27 (1.1%)

n (%)

n=55 1 (1.8%)

n=40 0

n=31 3 (9.7%)

n=267 4 (1.5%)

n=236 6 (2.5%)

eGFR

30

Forxiga eGFR ( 3)

24 eGFR

Forxiga ( 4)

( 4)(eGFR 30 60 mL/min/1.73 m2) eGFR

3 12 Forxiga

eGFR 12

N=1393

Forxiga 5 mg N=1145

Forxiga 10 mg N=1193

(mg/dL) 0.853 0.860 0.847

eGFR (mL/min/1.73 m2) 86.0 85.3 86.7

1 (mg/dL) 0.003 0.029 0.041

eGFR (mL/min/1.73 m2) 0.4 2.9 4.1

24 (mg/dL) 0.005 0.001 0.001

eGFR (mL/min/1.73 m2) 0.8 0.8 0.3

N=84

Forxiga 5 mg N=83

Forxiga 10 mg N=85

(mg/dL) 1.46 1.53 1.52

eGFR (mL/min/1.73 m2) 45.6 44.2 43.9

1 (mg/dL) 0.01 0.13 0.18

eGFR (mL/min/1.73 m2) 0.5 3.8 5.5

24 (mg/dL) 0.02 0.08 0.16

eGFR (mL/min/1.73 m2) 0.03 4.0 7.4

52 (mg/dL) 0.10 0.06 0.15

eGFR (mL/min/1.73 m2) 2.6 4.2 7.3

4

6

( 104)*

9

( 104)

Forxiga 5 mg

Forxiga 10 mg

Forxiga 10 mg

1(%)

n=785 13 (1.7%)

n=767 14 (1.8%)

n=859 16 (1.9%)

n=1956 82 (4.2%)

n=2026 136 (6.7%)

65

1(%)

n=190 4 (2.1%)

n=162 5 (3.1%)

n=159 6 (3.8%)

n=655 52 (7.9%)

n=620 87 (14.0%)

eGFR30

[n (%)] 3 (2.1) 8 (5.5) 9 (6.0)

Metformin Sulfonylurea (24) N=109 N=109

[n (%)] 0 0

[n (%)] 4 (3.7) 14 (12.8)

Pioglitazone* (24) N=139 N=141 N=140

[n (%)] 0 0 0

[n (%)] 0 3 (2.1) 0

DPP4 (24) N=226 N=225

[n (%)] 0 1 (0.4)

[n (%)] 3 (1.3) 4 (1.8)

Insulin OADs(24) N=197 N=212 N=196

[n (%)] 1 (0.5) 1 (0.5) 1 (0.5)

[n (%)] 67 (34.0) 92 (43.4) 79 (40.3)

*

0.33%Forxiga 10 mg 2.30% 24 >55%

0.4%Forxiga 10 mg 1.3%

13 24 Forxiga

( 0.13 0.04 mg/dL) 24 Forxiga

(17-65 5.6 mg/dL 66 5.1 mg/dL)

( 0.9% Forxiga 10 mg1.7%)

13 Forxiga

24 Forxiga 10 mg

0.0% 2.5%LDL 1.0% 2.9%

7

7.1

SGLT2 SGLT2

7.2 1, 5 -(1,5-anhydroglucitol (1,5-AG))

SGLT2 1,5-AG SGLT2 1,5-AG

8

8.1

C

Forxiga

dapagliflozin ( 10

mg 15 )/

Forxiga

(PND)21 PND 90

dapagliflozin 115 75 mg/kg/

AUC 15

1

6 21 115 75

mg/kg/ 75 mg/kg/

( dapagliflozin

1415 137 )

1 mg/kg/(19 ) 1 mg/kg/

19

dapagliflozin

dapagliflozin 75 mg/kg/ 10 mg 1441

150 mg/kg 10 mg

2344

8.3

Forxiga Dapagliflozin

0.49 dapagliflozin

() 2

Forxiga

Forxiga

8.4

Forxiga 18

8.5

Forxiga 21 Forxiga

5936 Forxiga 1424 (24%) 65 207 (3.5%)

75 (eGFR) 65 65

65 Forxiga

[(5.1)(6.1)]

8.6

(eGFR 30 60 mL/min/1.73 m2) Forxiga

Forxiga

[(14.7)][

(2.2)(5.3)(6.1)] Forxiga

Forxiga (eGFR 30 mL/min/1.73 m2)

(ESRD)[(4)]

8.7

dapagliflozin - dapagliflozin

[(12.3)]

10

Forxiga

dapagliflozin

11

Dapagliflozin D-glucitol,1,5-anhydro-1-C-[4-chloro-3- [(4-

ethoxyphenyl)methyl]phenyl]-,(1S)-,compounded with (2S)-1,2-propanediol, hydrate (1:1:1)

C21H25ClO6C3H8O2H2O 502.98

Forxiga 5 mg dapagliflozin dapagliflozin propanediol

10 mg dapagliflozin dapagliflozin propanediol

(crospovidone)

12

12.1

- 2(SGLT2)

Dapagliflozin SGLT2 Dapagliflozin SGLT2

12.2

dapagliflozin (

1) dapagliflozin 5mg 10 mg 12 12

70 dapagliflozin 20 mg

dapagliflozin [(6.1)]

1(T2DM)24

dapagliflozin (Fitted Line)()

dapagliflozin 150 mg ( 15 )

QTc dapagliflozin 500 mg

( 50 ) QTc

12.3

dapagliflozin 2 (Cmax)

Cmax AUC 10 mg dapagliflozin

78%Dapagliflozin Cmax 50% Tmax 1

AUC dapagliflozin

Dapagliflozin 91%

Dapagliflozin UGT1A9CYP Dapagliflozin

dapagliflozin 3-O-glucuronideDapagliflozin 3-O-

glucuronide 50 mg [14C]-dapagliflozin 61%

Dapagliflozin [14C]- dapagliflozin 50 mg

75% 21% 2%

15% Forxiga 10 mg dapagliflozin

(t) 12.9

(dapagliflozin 20 mg 1 7 )( eGFR

)

dapagliflozin 1.45 2.04 3.03

dapagliflozin 24

24

42%80% 90% dapagliflozin

[ (2.2) (5.3) (8.6)

(14.7).]

(Child-Pugh A B ) dapagliflozin 10 mg

dapagliflozin Cmax AUC 12% 36%

(Child-Pugh C )dapagliflozin

Cmax AUC 40% 67%[(8.7)]

dapagliflozin

dapagliflozin dapagliflozin 3-O-glucuronide CYP 1A22C9

2C192D6 3A4 CYP 1A22B6 3A4Dapagliflozin P-(P-gp)

dapagliflozin 3-O-glucuronide OAT3

Dapagliflozin dapagliflozin 3-O-glucuronide P-gpOCT2OAT1

OAT3 dapagliflozin P-gpOCT2OAT1

OAT3

Dapagliflozin

6 dapagliflozin dapagliflozin

6 dapagliflozin

()*

Dapagliflozin ()*

dapagliflozin

(%[90% CI])

Cmax AUC

Metformin (1000 mg) 20 mg

Pioglitazone (45 mg) 50 mg

()*

Dapagliflozin ()*

dapagliflozin

(%[90% CI])

Cmax AUC

Sitagliptin (100 mg) 20 mg

Glimepiride (4 mg) 20 mg

Voglibose (0.2 mg 3) 10 mg

Hydrochlorothiazide (25 mg) 50 mg

Bumetanide (1 mg) 10 mg 1 7

Valsartan (320 mg) 20 mg 12% [3%, 20%]

Simvastatin (40 mg) 20 mg

Rifampin (600 mg 1 6) 10 mg 7% [22%, 11%]

22% [27%, 17%]

Mefenamic Acid ( 500 mg 6

250 mg 14 )

10 mg 13% [3%, 24%]

51% [44%, 58%]

*

AUC = AUC(INF) AUC = AUC(TAU)

= ( 0.80 1.25) =

dapagliflozin ( 0.80 1.25)

Dapagliflozin

7 dapagliflozin Dapagliflozin

7Dapagliflozin

()*

Dapagliflozin ()*

(%[90% CI])

Cmax AUC

Metformin (1000 mg) 20 mg

Pioglitazone (45 mg) 50 mg 7% [25%, 15%]

Sitagliptin (100 mg) 20 mg

Glimepiride (4 mg) 20 mg 13% [0%, 29%]

Hydrochlorothiazide (25 mg) 50 mg

Bumetanide (1 mg) 10 mg 1 7 13% [2%, 31%]

13% [1%, 30%]

Valsartan (320 mg) 20 mg 6% [24%, 16%]

5% [15%, 29%]

Simvastatin (40 mg) 20 mg 19%

Digoxin (0.25 mg) 20 mg

10 mg 1 7

Warfarin (25 mg) 20 mg

10 mg 1 7

*

AUC = AUC(INF) AUC = AUC(TAU)

= ( 0.80 1.25) =

dapagliflozin ( 0.80 1.25)

13

13.1

2 dapagliflozin

515 40 mg/kg/210 20 mg/kg/

0.52 10 mg/kg/ AUC

10 mg 72 () 105 () AUC

10 mg 131 () 186 ()

Dapagliflozin Ames S9 100

g/mL Dapagliflozin DNA

>2100

dapagliflozin

Dapagliflozin 1708 998

14

14.1 Forxiga

Forxiga metformin pioglitazone (glimepiride)

sitagliptin( metformin)metformin sulfonylurea(

)(glipizide)Forxiga

Forxiga metforminglimepiridepioglitazone sitagliptin

24 HbA1c

BMI HbA1c

14.2

840 2 Forxiga

558 24

2 485 HbA1c 7%10% Forxiga 5 mg

Forxiga 10 mg 1 (QAM)(QPM)

24 Forxiga 10 mg QAM HbA1c FPG ( 8)

8 2 Forxiga 24 (LOCF*) (

AM )

Forxiga 10 mg N=70

Forxiga 5 mg N=64

N=75

HbA1c (%)

() 8.0 7.8 7.8

() 0.9 0.8 0.2

() (95% CI)

0.7 (1.0, 0.4)

0.5 (0.8, 0.2)

HbA1c

() 28.8 24.1 4.1

() (95% CI)

24.7 (35.7, 13.6)

19.9 (31.3, 8.5)

* LOCF ()

1

p

Forxiga 10 mg + Metformin XR

Forxiga 10 mg Metformin XR

N=211 N=219 N=208

() 60.4 46.4 34.8

Forxiga () (95% CI)

13.9 (20.9, 7.0)

metformin XR () (95% CI)

25.5 (32.6, 18.5)

11.6# (18.6, 4.6)

(kg)

() 88.6 88.5 87.2

() 3.3 2.7 1.4


2.0 (2.6, 1.3)

1.4 (2.0, 0.7)

* LOCF ()

1

p

603 1 3 Forxiga 5 mg

metformin XR( 2000 mg)Forxiga 5 mg metformin XR( 2000

mg)Metformin XR 500 mg

2000 mg

Forxiga 5 mg metforminXR HbA1c FPG

metformin XR ( 10)

10Forxiga metformin XR 24 (LOCF*)



N=194 N=203 N=201

HbA1c (%)

() 9.2 9.1 9.1

() 2.1 1.2 1.4

Forxiga () (95% CI)

0.9 (1.1, 0.6)


0.7 (0.9, 0.5)

HbA1c



N=194 N=203 N=201

() 193.4 190.8 196.7

() 61.0 42.0 33.6

Forxiga () (95% CI)

19.1 (26.7, 11.4)


27.5 (35.1, 19.8)

(kg)

() 84.2 86.2 85.8

() 2.7 2.6 1.3


1.4 (2.0, 0.7)

* LOCF ()

1

p

Forxiga 10 mg + Metformin

N=135

Forxiga 5 mg + Metformin

N=137

+ Metformin

N=137

() (95% CI)

0.5 (0.7, 0.3)

0.4 (0.6, 0.2)

HbA1c

14.5 metformin Glipizide

52 glipizide 816

(HbA1c >6.5% 10%) Forxiga metformin

metformin 1500 mg 2 glipizide

dapagliflozin ( 5 mg 2.5 mg)18 (FPG

Forxiga + Metformin

N=400

Glipizide + Metformin

N=401

() 0.5 0.5

glipizide + metformin () (95% CI)

0.0 (0.1, 0.1)

(kg)

() 88.4 87.6

() 3.2 1.4

glipizide + metformin () (95% CI)

4.7 (5.1, 4.2)

* LOCF ()

1

glipizide + metformin

p

Thiazolidinedione

420 (HbA1c 7%10.5%) 24

Forxiga pioglitazone( Thiazolidinedione [TZD])

pioglitazone 45 mg ( 30 mg 45 mg) 12

2 pioglitazone Forxiga 510 mg

Forxiga pioglitazone

Forxiga 10 mg pioglitazone pioglitazone 24

HbA1c2 PPGFPG HbA1c

24 Forxiga 5 mg (5.7 IU) 10 mg (

6.2 IU) 1 ( p

Forxiga 10 mg Forxiga 5 mg

() (95% CI)

0.69 (0.89, 0.49)

HbA1c0.7%() 31.8% 11.1%

FPG (mg/dL)

() 167.4 180.3

24 () 34.2 0.8

() (95% CI)

33.5 (43.1, 23.8)

(kg)

() 88.57 90.07

() 2.65 0.58

() (95% CI)

2.07 (2.79, 1.35)

Thiazolidinedione (Pioglitazone)

N=140** N=141** N=139**

HbA1c (%)

() 8.4 8.4 8.3

() 1.0 0.8 0.4

() (95% CI)

0.6 (0.8, 0.3)

0.4 (0.6, 0.2)

HbA1c


() 84.8 87.8 86.4

() 0.1 0.1 1.6

() (95% CI)

1.8 (2.6, 1.0)

1.6 (2.3, 0.8)

DPP4(Sitagliptin) Metformin

N=223 N=224

HbA1c (%)

() 7.90 7.97

() 0.45 0.04

() (95% CI)

0.48 (0.62, 0.34)

HbA1c0.7%() 35.4% 16.6%

FPG (mg/dL)

() 161.7 163.1

24 () 24.1 3.8

() (95% CI)

27.9 (34.5, 21.4)

(kg)

() 91.02 89.23

() 2.14 0.26

() (95% CI)

1.89 (2.37, 1.40)

2

N=194 N=211 N=193

HbA1c (%)

() 8.6 8.6 8.5

() 0.9 0.8 0.3

() (95% CI)

0.6 (0.7, 0.5)

0.5 (0.7, 0.4)

FPG (mg/dL)

() 173.7 NT 170.0

() 21.7 NT 3.3

() (95% CI)

25.0 (34.3, 15.8)

NT


(kg)

() 94.6 93.2 94.2

() 1.7 1.0 0.0

() (95% CI)

1.7 (2.2, 1.2)

1.0 (1.5, 0.5)

* LOCF ()

1

p

Forxiga

HbA1c

Forxiga

Forxiga

Forxiga

Forxiga

Forxiga

Forxiga

Forxiga [

(5.1) ] ()

[ (5.6) ]

Dapagliflozin(

),()[

(5.2) ]

[ (5.5) ]

()

()

()

[ (5.6) ]

Forxiga ()

Forxiga Forxiga AstraZeneca group of companies

2016 5 : BristolMyersSquibbCompany

: 4601Highway62East,MountVernon,Indiana47620,USA

: BristolMyersSquibbS.r.l.

: LocalitaFontanadelCeraso,03012Anagni,Italy

:

: 207 21

Documents

Forxiga Film - coated Tablets 5mg, 10mg