150 500 Xeloda TM Tablets 150mg 500mg Capecitabine Capecitabine 150 500 Capecitabine fluoropyrimidine carbamate capecitabine 5-fluorouracil (5-FU) 5-FU (tumour-associated angiogenic factorthymidine phosphorylase (dthdpase) 5-FU Capecitabine 5-FU 5-FU (N=8) capecitabine 5-FU 3.2 ( 0.9 8.0 5-FU 21.4 ( 3.9 59.9)5-FU 8.9 ( 3.0 25.8) thymidine 4 thymidine ( 5 -DFUR [5'-deoxy-5-fluorouridine] 5-FU 5-FU 5-fluoro-2-deoxyuridine monophosphate (FdUMP5-fluorouridine triphosphate (FUTP) FdUMP N 5-10 -methylenetetrahydrofolate thymidylate (TS uracil thymidylate thymidylate DNA thymidine triphosphate RNA FUTP uridine triphosphate (UTP RNA Xeloda 603 Xeloda (1250 / 2 1 3 604 5-FU leucovorin (Mayo leucovorin 20 / 5-FU 425 / 28 ( 25.7% (Xeloda16.7% (Mayo p<0.0002 140 (Xeloda144 (Mayo ) 392 (Xeloda) 391 (Mayo anthracycline 255 Xeloda (1250 / 2 1 ) docetaxel(75 / 1 3 256 (100 / 1 3 Xeloda docetaxel docetaxel (p=0.0126) 442 (Xeloda+docetaxel352 (docetaxel ( 41.6% (Xeloda+docetaxel29.7% (docetaxel p=0.0058 Xeloda docetaxel docetaxel (p<0.001) (median 186 (Xeloda+docetaxel128 (docetaxel Xeloda taxane anthracycline anthracycline 236 Xeloda (1250 / 2 1 ) ( 20%( ) 25%( ) 93 1
98 384 373 capecitabine 5'-deoxy-5-fluorocytidine (5'-DFCR) 5'-DFUR capecitabine 5'-DFUR 5-FU (AUCs) 1250 / 14 capecitabine 5'-DFCR 5'-DFUR 5-FU FBAL (C max / 4.47 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% Capecitabine carboxylesterase 5'-DFCR cytidine deaminase 5'-DFUR 5-FU dthdpase 5-FU 5-FU AUC 5-FU ( 600 / 6 22 Capecitabine 5-FU ( 5-FU dihydroyrimidine dehydrogenase (DPD) dihydro-fluoruracil (FUH2) 5-fluoro-ureido-propionic acid (FUPAα-fluoro-β alanine(fbal Capecitabine 5'-DFCR 5'-DFUR 5-FU FBAL (t 1/2 0.85 1.11 0.66 0.76 3.23 capecitabine 502 3514 / / 1 14 capecitabine 5'-DFCR 5'-DFUR 5-FU AUC 14 30%-35% ( 22 ) 5-FU capecitabine capecitabine 95.5% capecitabine (2 6% FBAL 57% 3% Xeloda docetaxel paclitaxel Xeloda docetaxel paclitaxel (C max AUC docetaxel paclitaxel 5'-DFUR(capecitabine ) 505 Xeloda 1250 / Karnofsky Performance Status ASAT ALAT 5'-DFUR 5-FU FBAL capecitabine ( 5-FU 5'-DFUR( 50% AUC 35%FBAL( 50% AUC 114%) FBAL 5'-DFUR 5-FU ( (27 86 234 (46%) 65 5'-DFUR 5-FU FBAL AUC ( 20% FBAL AUC 15% ( 455 (90.1% 22 (4.4%28 ethnicity (5.5%) 2
Xeloda docetaxel anthracycline Xeloda (taxaneanthracycline anthracycline Xeloda Xeloda 1250 / ( 2500 / 14 7 Xeloda 30 docetaxel Xeloda 1250 / 2 1 docetaxel 75 / 1 3 Xeloda docetaxel docetaxel docetaxel Xeloda 1 Xeloda 1250 / / 150 mg 500 mg 150 mg 500 mg ( ) ( ) = 1.26 1500-3 - 3 1.27-1.38 1650 1 3 1 3 1.39-1.52 1800 2 3 2 3 1.53-1.66 2000-4 - 4 1.67-1.78 2150 1 4 1 4 1.79-1.92 2300 2 4 2 4 1.93-2.06 2500-5 - 5 2.07-2.18 2650 1 5 1 5 =2.19 2800 2 5 2 5 Xeloda / Xeloda ( ) Xeloda 50% capecitabine ( Xeloda ( National Cancer Institute Canada Common Toxicity Criteria 1994 12 2 Xeloda NCIC * (% ) 1 2 0-1 100 % 0-1 75 % 0-1 50 % 3 0-1 75 % 0-1 50 % 3
4 50 % 0-1 * National Cancer Institute of Canada Common Toxicity Criteria ( Xeloda docetaxel 3 Xeloda docetaxel 2 3 4 NCIC * 2 Xeloda 14 2 Xeloda 14 50% Xeloda Xeloda 0-1 0-1 Xeloda Xeloda Xeloda Xeloda Xeloda/docetaxel Xeloda/docetaxel 2 3 0-1 100% 0-1 Xeloda docetaxel 3 0-1 75% Xeloda 55 / docetaxel 4
2 Xeloda 14 3 Xeloda 14 Xeloda Xeloda 0-1 0-1 75% Xeloda 50% Xeloda Xeloda Xeloda Xeloda/docetaxel Xeloda/docetaxel 3 2 0-1 0-1 3 2 2 0-1 0-1 50% 75% Xeloda Xeloda docetaxel 55 / docetaxel 5
2 Xeloda 14 Xeloda 0-1 50% Xeloda Xeloda Xeloda/docetaxel 2 0-1 2 0-1 50% Xeloda docetaxel * National Cancer Institute of Canada Common Toxicity Criteria ( docetaxel Xeloda / docetaxel ( docetaxel Xeloda docetaxel Xeloda docetaxel Xeloda Xeloda 1.5 x 10 9 / (0-1 0.5 x 10 9 / (4 ) 1 (>38 ) docetaxel 75 / 55 / docetaxel 55 / 4 docetaxel 1.5 x 10 9 / / 1.0 x 10 9 / Xeloda docetaxel ( 20 / 2 docetaxel 55 / 3 docetaxel Xeloda docetaxel (3 4 ) docetaxel Xeloda docetaxel ASAT ALAT / docetaxel 4 docetaxel ASAT / ALAT Docetaxel 6
=1.5 UNL =5 UNL >1.5 UNL - =2.5 UNL =2.5 UNL >2.5 UNL - =5 UNL =2.5 UNL 25% ( 55 / ) >1.5 UNL - =5 UNL >2.5 UNL - =5 UNL 25% ( 55 / ) >5 UNL >5 UNL( 2 ) docetaxel docetaxel docetaxel docetaxel 2 ( Xeloda Xeloda 75% 50% Xeloda Xeloda docetaxel 75% 50% 5 Xeloda 75% 1250 / / 150 mg 500 mg 150 mg 500 mg ( ) ( ) =1.26 1150 1 2 1 2 1.27-1.38 1300 2 2 2 2 1.39-1.52 1450 3 2 3 2 1.53-1.66 1500-3 - 3 1.67-1.78 1650 1 3 1 3 1.79-1.92 1800 2 3 2 3 1.93-2.06 1950 3 3 3 3 2.07-2.18 2000-4 - 4 =2.19 2150 1 4 1 4 6 Xeloda 50% 1250 / / 150 mg 500 mg 150 mg 500 mg ( ) ( ) =1.38 800 2 1 2 1 1.39-1.52 950 3 1 3 1 1.53-1.66 1000-2 - 2 1.67-1.78 1000-2 - 2 1.79-1.92 1150 1 2 1 2 1.93-2.06 1300 2 2 2 2 2.07-2.18 1300 2 2 2 2 =2.19 1450 3 2 3 2 7
( ( 30-50 / [Cockroft Gault]) 75% ( 51-80 / 2 3 4 ( 5 Xeloda Xeloda 80 3 4 Xeloda docetaxel 60 3 4 60 Xeloda docetaxel Xeloda 75%(950 / 5 Xeloda capecitabine Xeloda fluoropyrimidine fluorouracil fluoropyrimidine Xeloda DPD Xeloda sorivudine brivudine( Xeloda ( 30 / ) Docetaxel Xeloda docetaxel Xeloda 2-4 31 3 4 4.5 2 3 4 Xeloda 1 3 4 Xeloda ( ) ( loperamide Xeloda ( Xeloda fluorinated pyrimidine (dysrhythmias 5-fluorouracel ( ) dihydropyrimidine dehydrogenase (DPD) 5-fluorouracil Xeloda 5-FU ( 30-50 / ) 3 4 ( 30-50 / [Cockroft Gault]) 75% ( 51-80 / 2 3 4 60-79 Xeloda 80 80 3 4 ( Xeloda docetaxel 60 60 3 4 60 8
Xeloda ( - erythrodysesthesia ( 79 11 360 ) 1 3 1 / / 2 / / 3 / / 2 3 Xeloda 1 3 Xeloda ( Xeloda (hyperbilirubinemia) 3.0 x ULN (ALT AST 2.5 x ULN Xeloda 3.0 x ULN 2.5 x ULN Xeloda Xeloda ( warfarin S-warfarin AUC (+57% capecitabine P450 2C9 Xeloda coumarin- (INR ) Xeloda Xeloda Xeloda capecitabine flroropyrimidine capecitabine Xeloda Xeloda Xeloda Xeloda Xeloda capecitabin Xeloda Xeloda Xeloda 2 % (N=949) (N=319 (N=630) ( ) 7 949 Xeloda =2 % / Xeloda 1250 / / N = 949 3 4 N (%) N (%) N (%) 470 (50) 107 (11) 18 (2) 412 (40) 35 (4) 261 (28) 31 (3) 3 (<1) ( )* 238 (25) 38 (4) 1 (<1) 112 (12) 28 (3) 1 (<1) 79 (8) 5 (1) 62 (7) 7 (1) 55 (6) 1 (<1) 35 (4) 36 (4) 1 (<1) 22 (2) 503 (53) 151 (16) 93 (10) 3 (<1) 66 (7) 1 (<1) 57 (6) 1 (<1) 9
47 (5) 32 (3) 2 (<1) 18 (2) 32 (3) 1 (<1) ( ) NOS 23 (2) 59 (6) 7 (1) 36 (4) 6 (1) 36 (4) 1 (<1) 28 (3) 1 (<1) 52 (5) 4 (<1) 47 (5) ( vertigo) 45 (5) 1 (<1) 41 (4) 2 (<1) 35 (4) 54 (6) 20 (2) 32 (3) 101 71 229 86 (11) (7) (24) (9) 13 4 30 2 (1) (<1) (3) (<1) 4 (<1) 58 (6) 20 (2) NOS 27 (3) 38 (4) 3 (<1) 18 (2) 1 (<1) 24 (3) 22 (2) 18 (2) 4 (<1) 35 (4) 21 (2) 3 (<1) NOS 18 (2) * (N = 949) 2% Xeloda fluoropyrimidine (N = 949 2% Xeloda / / (extrasystoles / ( ) ( recall ( ) ( ( ) 10
Xeloda 949 Xeloda 8 Xeloda Xeloda 1250 / / N = 949 3/4 1 2 3 4 (%) (%) (%) (%) 3.1 41.4 40.7 0.7 3.6 18.7 15.6 3.1 0.2 1.9 1.7 0.2 44.4 58.2 53.1 5.1 2.0 20.4 18.8 1.6 17.7 36.9 21.6 15.3 ALAT (SGPT) 0.5 16.7 16.3 0.4 ASAT (SGOT) 1.1 25.1 24.8 0.3 0.5 9.8 9.4 0.4 3.5 27.2 27.2 0.0 4.4 40.1 39.2 0.9 Xeloda docetaxel Xeloda Xeloda docetaxel anthracycline docetaxel 9 Xeloda docetaxel =5 % /Xeloda 1250 / / Docetaxel 100 / 2 docetaxel 75 /3 / /3 (N = 251) (N = 255) 3/4 3/4 (%) (%) (%) (%) 67 18 42 5 64 14 45 5 43 6 35 2 33 4 22 1 14 1 12-14 2 9 1 12-5 <1 9-6 1 5-4 - * 63 24 7 1 41 6 42 7 ( 14 2 15-8 - 9 1 8 <1 4 - ( 6-4 <1 onycholysis 5 1 5 1 11
23 3 22 5 21 1 29 <1 21 4 25 5 13 1 9 2 9 <1 8 <1 6-5 1 6-2 - 15 <1 14 <1 11 <1 15 1 9-6 <1 7 <1 8 1 5-10 1 8 2 5 1 6-4 - 12 10 1-10 4 1-12 - 5-14 2 24 2 11 1 18 2 7 1 6 1 14 1 12 1 11 2 7 <1 7 1 9 <1 6 <1 9-5 <1 5-6 <1 7 <1 * 3 10 Xeloda docetaxel 3/4 1 2 3 4 (%) (%) (%) (%) Xeloda 1250 / docetaxel 75 / /3 (N=251) 9.6 65.4 61.8 3.6 63.3 80.8 17.9 62.9 6.4 7.6 1.2 6.4 88.8 64.6 57.4 7.2 2.8 37.9 35.1 2.8 8.8 22.0 14.0 8.0 ALAT (SGPT) 1.6 19.1 18.3 0.8 ASAT (SGOT) 2.8 22.3 20.7 1.6 0.4 5.6 5.2 0.4 12
0.8 25.5 25.5 0.0 13.9 58.2 52.2 6.0 Docetaxel (100 / /3 (N=255) 5.9 70.2 68.2 2.0 72.2 82.8 11.0 71.8 5.5 5.9 0.4 5.5 83.9 65.5 58.4 7.1 2.8 20.4 18.4 2.0 3.1 5.8 3.1 2.7 ALAT (SGPT) 2.4 18.8 18.4 0.4 ASAT (SGOT) 3.5 18.8 18.0 0.8 0.0 3.5 3.5 0.0 2.0 21.2 20.8 0.4 7.8 52.1 48.6 3.5 NOS Coumarin Xeloda coumarin warfarin phenprocoumon / Xeloda Xeloda warfarin 20 Xeloda S-warfarin AUC 57% INR 91% coumarin Xeloda (PT INR) P-450 capecitabine P-450 2C9 Xeloda Phenytoin Xeloda phenytoin phenytoin phenytoin capecitabine P-450 2C9 ( Coumarin phenytoin Xeloda phenytoin - 30 Xeloda Xeloda (Maaloxcapecitabine Xeloda (5 DFCR) (5 DFUR 5-FU FBAL) Leucovorin leucovorin capecitabine leucovorin capecitabine Sorivudine sorivudine 5-FU - sorivudine dihydropyrimidine dehydrogenase fluoropyfimidine Xeloda sorivudine brivudine( mucositis 150 8-1000 13
500 20-1000 150 022408 500 022409 2001 9 Made for F. Hoffmann-La Roche Ltd, CH-4070, Basel Switzerland. By F. Hoffmann-La Roche Inc., 340 Kingsland Street, Nutley, NJ 07110, USA. 3 134 9 02-27153111 14