0415-XEL-01 150 500 Xeloda Tablets 150mg 500mg Capecitabine 1. 150 500 2. 150 capecitabine Lactose anhydrous Crosscarmellose sodium Hypromellose Cellulose microcrystalline Magnesium stearate Opadry Pink 03A14309 500 capecitabine Lactose anhydrous Crosscarmellose sodium Hypromellose Cellulose microcrystalline Magnesium stearate Opadry Pink 03A14380 3. 150Xeloda 500Xeloda 4. 4.1 : Xeloda docetaxel anthracycline Xeloda taxane anthracycline anthracycline Xeloda Xeloda 1
Xeloda platinum 4.2 Xeloda Xeloda 30 Xeloda 1250 / 1000 / 1 2 5.1 Xeloda 14 1250 / 2500 / 7 III 6 irinotecan ) Xeloda 800 1000 / 14 7 625 / 5.1 irinotecan (XELIRI)Xeloda 800 / 14 7 3 1 irinotecan 200 / 5.1 Xeloda Xeloda cisplatin cisplatin cisplatin Xeloda oxaliplatin oxaliplatin 6 docetaxel Xeloda 14 1250 / 7 3 1 75 / docetaxel Xeloda docetaxel docetaxel docetaxel dexamethasone Xeloda 1 Xeloda 1250 / 2
1250/ 1250/ 150 / 75% 500 950/ 150 500 50% 625/ 1.26 1500-3 1150 800 1.27-1.38 1650 1 3 1300 800 1.39-1.52 1800 2 3 1450 950 1.53-1.66 2000-4 1500 1000 1.67-1.78 2150 1 4 1650 1000 1.79-1.92 2300 2 4 1800 1150 1.93-2.06 2500-5 1950 1300 2.07-2.18 2650 1 5 2000 1300 2.19 2800 2 5 2150 1450 2 Xeloda 1000 / 1000/ 150 / 500 75% 50% 1000/ 750/ 500/ 150 500 1.26 1150 1 2 800 600 1.27-1.38 1300 2 2 1000 600 1.39-1.52 1450 3 2 1100 750 1.53-1.66 1600 4 2 1200 800 1.67-1.78 1750 5 2 1300 800 1.79-1.92 1800 2 3 1400 900 1.93-2.06 2000-4 1500 1000 2.07-2.18 2150 1 4 1600 1050 2.19 2300 2 4 1750 1100 Xeloda / 3
Xeloda Xeloda 3 Xeloda 3 * / % 1 2 100% 75% 0-1 50% 3 75% 0-1 50% 4 50% 0-1 * National Cancer Institute of Canada Clinical Trial Group NCIC CTG US National Cancer Institute Cancer Therapy Evaluation Program Common Terminology Criteria for Adverse Events CTCAE 4.4 < 1.5 x 10 9 // < 100 x 10 9 / Xeloda 1.0 x 10 9 / 75 x 10 9 / Xeloda 3 Xeloda 3 Xeloda 3 Xeloda Xeloda, Xeloda Xeloda Xeloda Xeloda 4
Xeloda Xeloda 3 Xeloda Xeloda 30 / [ Cockcroft-Gault ] 30-50 / 3 4 Xeloda 1250 / 75% 1000 / 51-80 / 2 3 4 3 30 / Xeloda. 18 Xeloda 60 3 4 Xeloda 65 3 4 60 - docetaxel 60 3 4 5.1 60 Xeloda 75% 950 / 60 Xeloda docetaxel Xeloda 1250 / 4.3 fluoropyrimidine ; capecitabine fluorouracil ; dihydropyrimidine dehydrogenase (DPD) deficiency ( 4.4 ); ; ; 5
; 30 /; sorivudine brivudine 4.5 ; 4.4 loperamidencic CTC 2 4 6 3 7 9 4 10 4.2 Xeloda ( 4.8 ) 2 Xeloda 4.2 1 / 2 3 2 3 Xeloda 1 3 Xeloda Xeloda cisplatin B6 pyridoxine cisplatin Xeloda dexpanthenol Fluoropyrimidine QT Xeloda ( [torsade de pointes] ) 4.8 6
Xeloda 4.8 4.8 Xeloda Coumarin warfarin S- warfarin AUC +57% capecitabine P450 2C9 Xeloda coumarin- INR 4.5 Xeloda 3.0 ULN ALT AST 2.5 ULN Xeloda 3.0 ULN 2.5 ULN Xeloda 30-50 / 3 4 4.2 4.3 (DPD) 5-FU ( ) DPD DPD 5-FU DPD Xeloda ( 4.3 ) DPD Xeloda ( 4.9 ) 2 4 Xeloda (Stevens- Johnson syndrome SJS) (Toxic Epidermal Necrolysis TEN) ( 4.8 ) Xeloda Xeloda Lapp - 4.5 7
P-450 2C9 warfarin capecitabine CYP2C9 Capecitabine 2C9 ( phenytoin) coumarin 4.4 Coumarin Xeloda coumarin warfarin phenprocoumon / Xeloda Xeloda warfarin 20 Xeloda S-warfarin AUC 57% INR 91% R-warfarin capecitabine 2C9 1A2 3A4 coumarin Xeloda PT INR Phenytoin Xeloda phenytoin phenytoin phenytoin phenytoin Xeloda phenytoin Folinic acid Xeloda folinic acid folinic acid Xeloda folinic acid Xeloda folinic acid Xeloda MTD 3000 / Xeloda folinic acid 30 2000 / Sorivudine sorivudine 5-FU - sorivudine dihydropyrimidine dehydrogenase fluoropyrimidine Xeloda sorivudine brivudine 4.3 sorivudine brivudine Xeloda 4 capecitabine capecitabine 5 -DFCR 5 -DFUR 5-FU FBAL Allopurinol 5-FU allopurinol 5-FU allopurinol Xeloda α α-2a 3 MIU/ Xeloda MTD 2000 / Xeloda 3000 / Xeloda MTD 3000 / 6 Xeloda MTD 2000 / Oxaliplatin capecitabine oxaliplatin oxaliplatin bevacizumab capecitabine Bevacizumaboxaliplatin bevacizumab capecitabine 30 Xeloda Xeloda 8
capecitabine 5.2 4.6 / capecitabine capecitabine capecitabine capecitabine capecitabine fluoropyrimidine Xeloda capecitabine capecitabine Xeloda Xeloda Xeloda ( 5.3 ) 4.7 Xeloda Xeloda 4.8 Xeloda 3000 Xeloda Xeloda 5.1 /ADRs / 9
Xeloda 4 Xeloda 5 Xeloda 1/10 1/100 <1/10 1/1,000 <1/100 ( 1/10,000 <1/1,000), (<1/10,000) Xeloda 4 Xeloda 1900 ( M66001 SO14695 SO14796) 4 Xeloda - 3-4 - - - (INR) / - - 10
- - - 3-4 - - - - - - 11
- - 3-4 (Radiation recall syndrome) - - - - (Rigors) Xeloda 12
5 3000 Xeloda Xeloda Xeloda 4 Xeloda Xeloda / docetaxel oxaliplatin bevacizumab Xeloda 5 Xeloda Xeloda Xeloda - + + + + + + - - - - / +, - 13
- + + - + + 3 4 6 Xeloda,,,, QT, (Torsade de pointes),, (Vasospasm), ( 4.4 ) ( 4.4 ) Toxic leukoencephalopathy 14
4.4 3 14 capecitabine 1250 / capecitabine HFS 53% 60% capecitabine/docetaxel 63% 3 14 capecitabine 1000 / capecitabine HFS 22% 30% 14 4700 capecitabine capecitabine capecitabine 239 [95% CI 201 288] 2066 43% HFS HFS capecitabine capecitabine 0.1* 6 10 ECOG 0 v.s 1 4.4 Xeloda 50% 14 4700 capecitabine capecitabine 10 capecitabine 0.1* 6 4.4 4 5 7 949 2 5 2 Xeloda 0.1% 4 5 7 Xeloda 0.1% 4.2 Xeloda 60 Xeloda docetaxel 60 3 4 60 60 60 Xeloda docetaxel 15
14 4700 capecitabine 10 HFS 14 4700 capecitabine HFS 4.2 4.4 5.2 : Xeloda 3 4 36% 268 41% 257 54% 59 5.2 33% 32%44% 5% 8% 21% 2 4.9 5. 5.1 ATC L01BC06 Capecitabine fluoropyrimidine carbamate 5-fluorouracil 5-FUCapecitabine 5.2 thymidine phosphorylase ThyPase 5-FU capecitabine docetaxel docetaxel 5-FU deoxyuridylic acid thymidylic acid DNA 5-FU RNA DNA RNA 5-FU DNA RNA 5-FU Xeloda 16
III Dukes C III Xeloda XACT M66001 1987 Xeloda 3 2 1250 / 1 24 5-FU leucovorin Mayo Clinic 28 1 5 20 / leucovorin(bolus)425 / 5-FU 24 Xeloda 5-FU/LV 0.92 95% CI 0.80-1.06 Xeloda 5-FU/LV 0.88 95% CI 0.77-1.01 p=0.068 0.86 95% CI 0.74-1.01 p=0.060 6.9 Cox Xeloda bolus 5-FU/LV CEA 5-FU/LV Xeloda 0.849 95% CI 0.739-0.976 p = 0.0212 0.828 95% CI 0.705-0.971 p = 0.0203 Dukes C III NO16968 Xeloda oxaliplatin XELOX 944 Xeloda 3 2 1000 / 1 24 oxaliplatin 3 1 2 130 / 942 bolus 5-FU leucovorin ITTDFS XELOX 5-FU/LV 0.8095% CI 0.69; 0.93 p=0.0045xelox 71% 5-FU/LV 67%RFS XELOX 5-FU/LV HR=0.78 95% CI 0.67; 0.92 p=0.0024 XELOX 0.87 95% CI 0.72; 1.05 p=0.1486os 13% XELOX 78% 5-FU/LV 74% ITT 5-FU/LV 9% XELOX 21% XELOX 0.80 95% CI 0.69, 0.93; p=0.0038 0.78 95% CI 0.67, 0.91; p=0.0015 XELOX OS rate 73% 5-FU/LV 67% 2 3% 6% Xeloda III SO14695 SO14796 Xeloda 603 Xeloda 3 2 1250 / 1 604 5-FU leucovorin Mayo 28 1 5 20 / leucovorin(bolus)425 / 5-FU 25.7% Xeloda 16.7% Mayo p<0.0002 17
140 Xeloda 144 Mayo 392 Xeloda 391 Mayo Xeloda III NO16966 Xeloda oxaliplatin oxaliplatin bevacizumab 2 634 XELOX FOLFOX-4 2x2 1401 XELOX FOLFOX-4 XELOX bevacizumab FOLFOX-4 bevacizumab 7 7 FOLFOX-4 FOLFOX-4 + Bevacizumab NO16966 mcrc Oxaliplatin 2 85 / Leucovorin 2 200 / 5-Fluorouracil 400 / 22 600 / 2 1 oxaliplatin 2 1 2 leucovorin 2 1 2 / 5- fluorouracil XELOX XELOX+ Bevacizumab Bevacizumab 30-90 5 / Oxaliplatin 2 130 / Capecitabine 1000 / 2 1 FOLFOX-4 3 1 oxaliplatin 2 capecitabine 1 Bevacizumab 30-90 7.5 / 3 1 XELOX 5-Fluorouracil leucovorin FOLFOX- 4 XELOX non-inferiority 8 XELOX FOLFOX-4 8 XELOX bevacizumab FOLFOX-4 bevacizumab XELOX bevacizumab FOLFOX-4 bevacizumab 1.01 97.5% CI 0.84, 1.22 1.5 8 PFS PFS OS XELOX FOLFOX-4 1.24 97.5% CI1.07-1.44 PFS 18
8 NO16966 XELOX/XELOX+P/ XELOX+BV EPP*: N=967; ITT**: N=1017 EPP ITT EPP ITT EPP ITT EPP ITT 241 244 577 581 242 244 600 602 *EPP= ; **ITT= FOLFOX-4/FOLFOX-4+P/ FOLFOX-4+BV EPP*: N = 937; ITT**: N= 1017 259 259 549 553 259 259 594 596 97.5% CI 1.05 0.94; 1.18 1.04 0.93; 1.16 0.97 0.84; 1.14 0.96 0.83; 1.12 97.5% CI 1.02 0.92; 1.14 1.01 0.91; 1.12 1.00 0.88; 1.13 0.99 0.88; 1.12 III (CAIRO) capecitabine( 1000 / 2 3 1 ) irinotecan 820 (n = 410) (n = 410) capecitabine ( 1250 / 14 ) irinotecan ( 1 350 / ) capecitabine ( 1000 / 14 ) oxaliplatin ( 1 130 /) (XELIRI) capecitabine ( 1000 / 14 ) irinotecan ( 1 250 / ) capecitabine ( 1000 / 14 ) oxaliplatin ( 1 130 /) 3 capecitabine 5.8 (95% CI 5.1-6.2 ) XELIRI 7.8 (95% CI 7.0 8.3 p = 0.0002) XELIRI (XELIRI capecitabine 26% 11%) 3 XELIRI 5-FU + irinotecan (FOLFIRI) XELIRI 3 1 14 capecitabine 1000 / 1 irinotecan 250 / (BICC-C) FOLFIRI (n = 144) 5-FU (mifl) (n = 145) XELIRI (n = 141) celecoxib 19
FOLFIRI (PFS) 7.6 mifl 5.9 ( FOLFIRI p = 0.004) XELIRI 5.8 (p = 0.015) FOLFIRI (OS) 23.1 mifl 17.6 (p = 0.09) XELIRI 18.9 (p = 0.27) FOLFIRI XELIRI FOLFIRI (XELIRI FOLFIRI 48% 14%) EORTC FOLFIRI (n = 41) XELIRI (n = 44) celecoxib FOLFIRI XELIRI (PFS)(OS) (PFS 9.6 5.9 OS 19.9 14.8 ) XELIRI (XELIRI 41% FOLFIRI 5.1%) Skof FOLFIRI XELIRI XELIRI 49% FOLFIRI 48% (p = 0.76) XELIRI 37% FOLFIRI 26% FOLFIRI Montagnani FOLFIRI XELIRI mcrc FOLFIRI [ 0.76 95% CI 0.62 0.95 P < 0.01] XELIRI (Souglakos 2012 ) FOLFIRI + bevacizumab XELIRI + bevacizumab PFS OS FOLFIRI bevacizumab (A n = 167) XELIRI bevacizumab (B n = 166) B XELIRI 14 2 capecitabine 1000 / + 1 irinotecan 250 / FOLFIRI-Bev XELIRI-Bev (PFS) 10.0 8.9 p = 0.64 25.7 27.5 p = 0.55 45.5 39.8% p = 0.32 XELIRI + bevacizumab FOLFIRI + bevacizumab II (AIO KRK 0604) 3 800 / capecitabine 2 irinotecan bevacizumab 120 XELIRI capecitabine ( 2 800 / 2 7 ) irinotecan ( 3 1 30 200 /) bevacizumab ( 3 1 30 90 7.5 /) 127 capecitabine ( 2 1000 / 2 7 ) oxaliplatin ( 3 1 2 130 /) bevacizumab ( 3 1 30 90 7.5 /) 26.6 9 AIO KRK (ITT: N=127) 6 XELOX + bevacizumab XELIRI+ bevacizumab (ITT: N= 120) 95% CI P 20
ITT 76% 95% CI 69-84% ITT 10.4 95% CI 9.0-12.0 ITT 95% CI 24.4 19.3-30.7 84% 77-90% 12.1 10.8-13.2 25.5 21.0-31.0-0.93 0.82-1.07 P=0.30 0.90 0.68-1.19 P=0.45 ( ) XELIRI+bevacizumab 56% XELOX+ bevacizumab 53% NO16967 Xeloda oxaliplatin 627 irinotecan fluoropyrimidine XELOX FOLFOX-4 XELOX FOLFOX-4 bevacizumab 7 XELOX FOLFOX-4 9 XELOX FOLFOX-4 9 2.1 9 6 10 NO16967 XELOX PPP*: N=251; ITT**: N=313 FOLFOX-4 PPP*: N = 252; ITT**: N= 314 95% CI PPP ITT 154 144 168 146 1.03 0.87; 1.24 0.97 0.83; 1.14 PPP ITT 388 363 401 382 1.07 0.88; 1.31 1.03 0.87; 1.23 95% CI PPP ITT PPP ITT 154 143 393 363 *PPP= ; **ITT= 166 146 402 382 1.04 0.87; 1.24 0.97 0.83; 1.14 1.05 0.88; 1.27 1.02 0.86; 1.21 : 21
III ML17032 Xeloda 160 Xeloda 2 2 1000 / 7 cisplatin 3 2 80 / 156 5-FU 3 1 5 800 / cisplatin 3 1 2 80 / Xeloda cisplatin 5-FU cisplatin 0.81; 95% CI 0.63-1.04 5.6 Xeloda + cisplatin 5.0 5-FU + cisplatin 0.85 95% CI 0.64-1.13 10.5 Xeloda + cisplatin 9.3 5-FU + cisplatin capecitabine 5-FU oxaliplatin cisplatin REAL2 Xeloda 1002 2x2 ECF: epirubicin 50 / cisplatin 60 / 5-FU 200 / ECX: epirubicin 50 / cisplatin 60 / Xeloda 625 / EOF: epirubicin 50 / oxaliplatin 130 / 5-FU 200 / EOX: epirubicin 50 / oxaliplatin 130 / Xeloda 625 / capecitabine5-fu 0.86 95%CI 0.8-0.99oxaliplatincisplatin 0.92 95%CI 0.80-1.1 capecitabine 10.9 5-FU 9.6 cisplatin 10.0 oxaliplatin 10.4 Xeloda oxaliplatin Xeloda Xeloda 6 SO14695 SO14796 M66001 NO16966 NO16967 M17032Xeloda 5-FU 3097 Xeloda 3074 5-FU Xeloda 22
703 95% CI 671 745 5-FU 683 95% CI 646 715 Xeloda 0.94 95% CI 0.89 1.00 p=0.0489 5-FU Xeloda docetaxel III Xeloda docetaxel anthracycline 255 Xeloda 2 2 1250 / 1 3 1 docetaxel 75 / 256 docetaxel 3 1 100 / Xeloda + docetaxel p=0.0126 442 Xeloda+docetaxel 352 docetaxel 41.6% Xeloda + docetaxel 29.7% docetaxelp=0.0058xeloda + docetaxel p<0.0001 186 Xeloda + docetaxel 128 docetaxel taxanes anthracycline anthracycline Xeloda II taxanes anthracycline anthracycline Xeloda 236 Xeloda 2 2 1250 / 1 20% 25% 93 98 384 373 14 4700 Xeloda Xeloda Xeloda HFS HFS 1100 95%CI 1007; 1200 691 95%CI 638; 754 0.61 95%CI 0.56; 0.66 5.2 502-3514 // capecitabine 1 14 capecitabine 5'-deoxy-5-fluorocytidine 5'- DFCR 5'-deoxy-5-fluorouridine 5'-DFUR 14 5-FU AUC 30%-35% capecitabine 5-FU 23
capecitabine 5'-DFCR 5'-DFUR capecitabine 5'-DFUR AUC 5-FU AUC 1250 / 14 capecitabine 5'-DFCR 5'-DFUR 5-FU FBAL C max / 4.67 3.05 12.1 0.95 5.46 t max 1.50 2.00 2.00 2.00 3.34 AUC 0 / 7.75 7.24 24.6 2.03 36.3 capecitabine 5'-DFCR 5'-DFUR 5-FU 54% 10% 62% 10% (Biotransformation) Capecitabine carboxylesterase 5'-DFCR cytidine deaminase 5'-DFUR ThyPase 5'-DFUR Capecitabine 5-FU 5-FU 5-FU capecitabine 5-FU 3.2 0.9 8.0 5-FU 21.4 3.9 59.9, n=8 5-FU 8.9 3.0 25.8 n=8 4 5-FU dihydropyrimidine dehydrogenase DPD dihydro-5-fluorouracil FUH 2 5-fluoroureidopropionic acid FUPA β-ureido-propionase FUPA α-fluoroβ-alanine FBAL DPD DPD capecitabine 4.3 4.4 capecitabine 5'-DFCR 5'-DFUR 5-FU FBAL t 1/2 0.85 1.11 0.66 0.76 3.23 Capecitabine 95.5% capecitabine 2.6% FBAL 57% 3% Xeloda docetaxel paclitaxel Xeloda docetaxel paclitaxel C max AUC docetaxel paclitaxel 5'- DFUR 24
505 Xeloda 1250 / Karnofsky Performance status ASAT ALAT 5'-DFUR 5-FU FBAL capecitabine 5-FU : 5-FU 5'-DFUR 50%AUC 35% FBAL 50% AUC 114%FBAL : 27 86 234 46% 65 5'-DFUR 5-FU FBAL AUC 20% FBAL AUC 15% 14 825 / capecitabine n=18 capecitabine C max AUC n=22 36% 24% FBAL C max AUC 25% 34% 5'-DFCR 5'-DFUR 5-FU 5.3 capecitabine fluoropyrimidines capecitabine / Capecitabine 100 / PR QT 1379 // capecitabine capecitabine 13 ( 4.6 ) Ames V79/HPRT capecitabine 5- FUcapecitabine 25
6 6.1 30 C 6.2 150 8-1000 500 20-1000 150 500 022408 022409 CDS 12_EU 2014 12 0115-XEL-3B01 F. Hoffmann-La Roche Ltd., Grenzacherstrasse 124, CH-4070 Basel, Switzerland. Productos Roche, S.A. de C.V.. Via Isidro Fabela Nte. No.1536-B, CP 50030, Toluca, Mexico. F. Hoffmann-La Roche Ltd. Wurmisweg, CH-4303 Kaiseraugst, Switzerland. 3 134 9 02-2715-3111 Xeloda 26