Microsoft Word - Tarceva ex Segrate_CDS 14.0_0615-TAR-01_excipient_clean

0615-TAR-01 TARCEVA Film-coated Tablets 25mg, 100mg, 150mg Italy Erlotinib hydrochloride 25 1 025076 100 025077 150 025071 1.1 TARCEVA EGFR-TK (NSCLC) 1.2 TARCEVA 4 platinum-based EGFR, 1.3 TARCEVA NSCLC 3 TARCEVA [carboplatin paclitaxel gemcitabine cisplatin] 2 2.1 EGFR-TK : (NSCLC) TARCEVA EGFR TARCEVA 150 1 2 TARCEVA 1

: TARCEVA 150 1 2 TARCEVA 2.2 TARCEVA ILD TARCEVA [ (4.1)] TARCEVA loperamide loperamide TARCEVA TARCEVA TARCEVA TARCEVA bullous blister / 50 TARCEVA TARCEVA CYP3A4 ( atazanavir clarithromycin indinavir itraconazole ketoconazole nefazodone nelfinavir ritonavir saquinavir telithromycin troleandomycin (TAO) voriconazole ) TARCEVA CYP3A4 CYP1A2 ciprofloxacin TARCEVA [ (6)] CYP3A4 rifampicin erlotinib AUC 2/3 4/5 CYP3A4 TARCEVA TARCEVA rifampicin 450 TARCEVA rifampicin CYP3A4 rifabutin rifapentine phenytoin carbamazepine phenobarbital St. John's Wort [ (6)] erlotinib TARCEVA 300 2

> 14 TARCEVA [ (10.2)] Erlotinib erlotinib Child-Pugh B TARCEVA > (ULN) Child-Pugh A B C [ (4.2)] TARCEVA > 3 x ULN / TARCEVA / > 3 x ULN / > 5 x ULN TARCEVA[ (4.2, 4.3) (5.2) (7.7)] 3 4 4.1 TARCEVA NSCLC (ILD-like events)( ) NSCLC [ (12.1)] TARCEVA ( 0.8%) ( ) 4900 TARCEVA 0.7% TARCEVA 5 9 ( 39 ) (parenchymal lung disease) TARCEVA ILD TARCEVA [ (2.2)] 4.2 Child-Pugh B 15 10 TARCEVA 30 1 8 3

10 6 > 3 x ULN TARCEVA > 3 x ULN TARCEVA > ULN Child-Pugh A B C / TARCEVA [ (10.2) (2.2)] 4.3 TARCEVA ( ) / > 3 x ULN / > 5 x ULN TARCEVA[ (5.2) (2.2)] 4.4 / TARCEVA [ (5.2) (2.2)] 4.5 TARCEVA NSAIDs / taxane [ (5.2)] TARCEVA 4.6 Stevens-Johnson syndrome / toxic epidermal necrolysis [ (5.2)] TARCEVA 4.7 TARCEVA TARCEVA / [ (5.2)] 4

/ TARCEVA 4.8 D TARCEVA erlotinib ( 150 AUCs) / / 150 0.3 0.7 erlotinib [ (7.1)] 4.9 (INR) (INR) ( ) warfarin warfarin coumarin INR [ (5.2)] 5 TARCEVA 1200 150 TARCEVA TARCEVA NSCLC ( ) [( (4) (2.2)] 5.1 TARCEVA TARCEVA 150 10% 3% ( ) NCI-CTC (2.0 ) 1 TARCEVA 150 TARCEVA 3/4 9% 6% TARCEVA 1% 6% 1% 8 12 5

1 TARCEVA 3% TARCEVA 10% TARCEVA 150 mg N=485 N=242 NCI CTC 3 4 3 4 MedDRA Preferred Term % % % % % % 75 8 <1 17 0 0 54 6 <1 18 <1 0 52 8 1 38 5 <1 52 14 4 45 16 4 41 17 11 35 15 11 33 4 0 29 2 0 33 3 0 24 2 0 24 4 0 15 2 0 23 2 <1 19 2 0 17 <1 0 3 0 0 13 <1 0 5 0 0 12 0 0 4 0 0 12 <1 0 2 <1 0 12 0 0 3 0 0 11 2 <1 7 1 <1 TARCEVA 150 ( (ALT) (AST) ) 2 (>2.5 5.0 x ULN) ALT TARCEVA 4% <1% TARCEVA 3 (>5.0 20.0 x ULN) TARCEVA[ (2.2)] 889 BO18192 BO18192 TARCEVA 49% 20% 1 2 3 6% 2% 4 1% < 1% 8.3% 3% 6

154 (ML20650) 75 TARCEVA EGFR-TK (NSCLC) ML20650 TARCEVA 80% 57% 1 2 3 9% 4% 4 1% 11% 7% 5.2 TARCEVA [ (4.5)] warfarin NSAID [ (4.9)] ( ) [ (4.4)] TARCEVA TARCEVA [ (4.3)] TARCEVA TARCEVA [ (4.7)] / TARCEVA NCI- CTC 3 [ (14)] Stevens-Johnson syndrome / toxic epidermal necrolysis [ (4.6)] 7

NCI-CTC 3 4 / TARCEVA / TARCEVA 65 65 [ (7.4)] TARCEVA 5.3 : : / (uveitis) 6 Erlotinib CYP3A4 CYP3A4 CYP3A4 ketoconazole erlotinib AUC 2/3 TARCEVA ciprofloxacin CYP3A4 CYP1A2 erlotinib [AUC] [Cmax] 39% 17% TARCEVA ketoconazole CYP3A4 ( atazanavir clarithromycin indinavir itraconazole nefazodone nelfinavir ritonavir saquinavir telithromycin troleandomycin[tao] voriconazole ) [ (2.2)] TARCEVA CYP3A4 rifampicin erlotinib AUC 2/3 4/5 30 50 rifampicin 11 8 TARCEVA 450 erlotinib AUC rifampicin TARCEVA 150 57.6%[ (2.2)] CYP3A4 TARCEVA TARCEVA rifampicin CYP3A4 rifabutin rifapentine phenytoin 8

carbamazepine phenobarbital St. John's Wort [ (2.2)] TARCEVA coumarin warfarin INR coumarin INR TARCEVA statin statin erlotinib TARCEVA TARCEVA [ (2.2) (10.2)] TARCEVA CYP3A4 midazolam AUC 24% gemcitabine erlotinib erlotinib gemcitabine ph erlotinib TARCEVA omeprazole erlotinib AUC 46% TARCEVA ph TARCEVA TARCEVA H2 blockers erlotinib TARCEVA [ (10.2)] 7 7.1 D [ (4.8)] ( 150 AUCs) erlotinib / ( AUC ) / 30 / / 60 / / ( / 0.3 0.7 ) erlotinib erlotinib 600 / / 150 / 60 / 9

/ / 150 / 0.7. TARCEVA TARCEVA 2 TARCEVA [ (4.8)] 7.2 erlotinib TARCEVA 7.3 TARCEVA 7.4 62% 65 38% 65 ( ) [ 65 HR = 0.75 (95% CI: 0.6, 0.9) 65 HR = 0.79 (95% CI: 0.6, 1.0)] 7.5 65% 35% [ HR = 0.76 (95% CI: 0.6, 0.9) HR = 0.80 (95% CI: 0.6, 1.1)] 7.6 78% 12% [ HR = 0.79 (95% CI: 0.6, 1.0) HR = 0.61 (95% CI: 0.4, 1.0)] 10

7.7 TARCEVA > ULN Child-Pugh A B C TARCEVA > 3 x ULN [ (4.2) (5.2) (2.2)] erlotinib erlotinib Child-Pugh B [ (2.2) (10.2)] 7.8 9% 8. 1,000 TARCEVA 1,600 200 TARCEVA [ (2)] TARCEVA 9. TARCEVA (erlotinib) tyrosine kinase inhibitor quinazolinamine N-(3-ethynylphenyl)-6,7-bis(2- methoxyethoxy) -4-quinazolinamine TARCEVA erlotinib Erlotinib C 22 H 23 N 3 O 4 HCl 429.90 25 pka 5.42 Erlotinib (acetonitrile) Erlotinib ph ph 5 ph 1.4 9.6 0.4 / ph 2 11

TARCEVA 25 100 150 erlotinib erlotinib (27.3 109.3 163.9 ) : cellulose microcrystalline lactose monohydrate sodium starch glycolate magnesium stearate sodium laurilsulfate hypromellose hydroxypropyl cellulose titanium dioxide macrogol 400 10 10.1 Erlotinib Erlotinib (EGFR) (tyrosine kinase) EGFR 10.2 Erlotinib 60% 100% 4 Erlotinib ph erlotinib ph TARCEVA omeprazole erlotinib AUC Cmax 46% 61% [ (6)] 93% erlotinib α-1 (AAG) Erlotinib 232 591 TARCEVA 36.2 7-8 erlotinib 24% CYP450 erlotinib CYP3A4 CYP1A2 CYP1A1 100 91% 83% ( 1% ) 8% ( 0.3% ) erlotinib erlotinib 1/2 erlotinib apparent plasma clearance 24% erlotinib AUC 0- / 1/3 1/2 N= 35 12

TARCEVA 150 300 erlotinib [ (6) (14)] TARCEVA > ULN Child-Pugh A B C TARCEVA > 3 x ULN [ (4.2) (5.2) (2.2)] erlotinib erlotinib Child-Pugh B 9% 11 11.1 erlotinib ( ) erlotinib erlotinib Erlotinib 12 12.1 (NSCLC) - TARCEVA EGFR-TK TARCEVA EGFR (NSCLC) (ML20650, EURTAC) EGFR (exon 19 exon 21 ) (NSCLC)( IIIB-IV ) 1 1 TARCEVA 150 4 PFS (n 153) TARCEVA (n 77) (n 76) 13

0.42 (95 % CI, 0.27-0.64) (p<0.0001) 58% TARCEVA 9.4 5.2 (ORR) 54.5% 10.5% PFS (independent review of the scans) TARCEVA 10.4 5.4 0.47 95% CI, 0.27-0.78 p 0.003 Jan 26, 2011 TARCEVA 19.3 (95% CI 15.9-26.8) 19.5(16.1-not assessable) (HR 1.04, 95% CI 0.65-1.68; P=0.87) (76%) EGFR TARCEVA BO18192 889 1 1 TARCEVA150 EGFR IHC PFS 2 ITT (PFS) (OS) 2 BO18192 ITT ( ) (95%CI) Tarceva 150mg N=438 N=451 2.8 2.6 (2.8, 3.1) (1.9, 2.7) 12.0 11.0 (10.6, 13.9) (9.9, 12.1) (1) Univariate Cox regression model (2) Unstratified log-rank test (1) (95% CI) 0.71 (0.62, 0.82) 0.81 (0.70, 0.95) P (2) p < 0.0001 0.0088 EGFR IHC PFS OS 0.69(95% CI:0.58, 0.82) 0.77(95%CI:0.64, 0.93) EGFR IHC PFS OS 0.77(95%CI:0.51, 1.14) 0.91(95%CI:0.59, 1.38) OS 0.77(95%CI:0.61, 0.97) OS 0.86(95%CI: 0.68, 1.10) 14

/ 731 (NSCLC) TARCEVA 2:1 150 TARCEVA (488 TARCEVA 243 ) (PFS) 17 3 了 ECOG (performance status PS) 2 9% ECOG PS 3 50% 3 15

4 4 TARCEVA (1) 95% CI p 6.7 4.7 0.73 0.61 0.86 <0.001 (2) 1 31.2% 21.5% 9.9 7.9 0.59 0.50 0.70 <0.001 (2) 16

(CR+PR) 8.9% 0.9% <0.001 (3) 34.3 15.9 (1) Cox (Cox regression model) ECOG (2) ECOG (Log-Rank test) (3) 精 (Fisher s exact test) 1 Kaplan-Meier PFS ECOG : Kaplan-Meier HR Cox ECOG P ECOG 12.2 NSCLC - TARCEVA 1000 TARCEVA [carboplatin paclitaxel (TARCEVA N=526) gemcitabine cisplatin (TARCEVA N=580)] 17

13 30 C TARCEVA EXP 14 [ (4) (5) (2.2)] TARCEVA 精 TARCEVA [ (4.8) (7.1)] TARCEVA erlotinib [ (10.2)] 25 ( 025076 ) 12-1000 100 ( 025077 ) 3-1000 150 ( 025071 ) 2-1000 US 2009 4 / CDS 14.0 08.13-TAR-3B01 F. Hoffmann-La Roche Ltd. Grenzacherstrasse 124, CH-4070 Basel, Switzerland. 18

Roche S.p.A. Via Morelli 2, IT-20090, Segrate (Milano), ITALIA. F. Hoffmann-La Roche Ltd. Wurmisweg, CH-4303 Kaiseraugst, Switzerland. 3 134 9 (02)27153111 TARCEVA OSI 19