1016-TAM-01 30 45 75 ( ) 75 () Capsules 30 mg Capsules 45 mg Capsules 75 mg Oseltamivir phosphate 1. 1.1 / 1.2 30 ROCHE 30 mg 45 ROCHE 45 mg 75 ROCHE 75 mg 1.3 1.4 / 1
1.5 : Oseltamivir phosphate 30 39.4 oseltamivir phosphate 30 oseltamivir 45 59.1 oseltamivir phosphate 45 oseltamivir 75 98.5 oseltamivir phosphate 75 oseltamivir pregelatinized starch talc povidone (K 30) croscarmellose sodium sodium stearyl fumarate 30 titanium dioxide (E171) iron oxide yellow (E172) iron oxide red (E172) gelatin 45 titanium dioxide (E171) black iron oxide (E172) gelatin 75 titanium dioxide (E171) black iron oxide (E172) iron oxide yellow (E172) iron oxide red (E172) gelatin Printing ink dehydrated alcohol shellac glaze n-butyl alcohol titanium dioxide FD & C Blue 2 (E132) SDA-3A alcohol 1.6 Oseltamivir carboxylate (cell culture assays) oseltamivir carboxylate 50% 90% (EC 50 EC 90 ) 0.0008 μm >35 μm 0.004 μm >100 μm(1 μm=0.284 μg/ml) oseltamivir carboxylate oseltamivir carboxylate A oseltamivir carboxylate (neuraminidase) (hemagglutinin) A N1 I222T H274YA N2 I222T R292K A N9 E119V R292K R305Q A H3N2A28T R124M H1N9 H154Q 2
1 12oseltamivir carboxylate 1.3% (4/301) 8.6% (9/105)A N1 H274YN2 E119V R292K zanamivir oseltamivir oseltamivir zanamivir oseltamivir (E119V H274Y R292K) zanamivir (E119G/A/D R152K R292K) 2. 2.1 30 45 75 2.2.1 2.4 3.3 1 2.2 3.2 13 75 2 5 13 75 2 5 4.2 3
40 75 2 30 45 2 4.2 1 5 (6 mg/ml) 15 30 2 5.0 2 > 15-23 45 2 7.5 2 > 23-40 60 2 10.0 2 > 40 75 2 12.5 2 1 0 12 3 mg/kg 5 0-12 3mg/kg 36 1 * 5 (6 mg/ml) 3 9 2 1.5 2 4 12 2 2.0 2 5 15 2 2.5 2 6 18 2 3.0 2 7 21 2 3.5 2 8 24 2 4.0 2 9 27 2 4.5 2 10 30 2 5.0 2 4
( 4.2 ) 75 10 75 6 1 40 75 30 45 10 4.2 1 10 (6 mg/ml) 15 30 1 5.0 1 > 15-23 45 1 7.5 1 > 23-40 60 1 10.0 1 > 40 75 1 12.5 1 ( 4.2 ) 2.2.1 (creatinine clearance) 60 / 30 60 / 30 5 10 30 / 30 5 30 30 5
CAPD (continuous ambulatory peritoneal dialysis) APD (automated peritoneal dialysis) oseltamivir carboxylate CAPD APD CAPD 3.2.5 2.4 ( < 10 / ) oseltamivir 60 / 30 60 / 30 10-30 / 30 30 30 7 30 CAPD (continuous ambulatory peritoneal dialysis) APD (automated peritoneal dialysis) oseltamivir carboxylate CAPD APD CAPD 3.2.5 2.4 ( < 10 / ) oseltamivir 3.2.5 3.2.5 1 3.2.5 0-12 3 mg/kg 2.1 2.3 oseltamivir phosphate 2.4 6
( 2.6.2 ) () A B 2.2.1 ( 3.2.5 ) Neuropsychiatric Events 10 2.4.1 live attenuated influenza vaccine, LAIV 48 LAIV oseltamivir phosphate Oseltamivir phosphate esterases Oseltamivir oseltamivir phosphate P450 glucuronyl transferase ( 3.2 ) Cimetidine cytochrome P450 oseltamivir 7
( ) probenecid 2 probenecid amoxicillin paracetamol oseltamivir paracetamol oseltamivir paracetamol cimetidine ( ) warfarin rimantadine amantadine oseltamivir ACE (enalapril captopril) thiazide (bendrofluazide) (penicillin cephalosporin azithromycin erythromycin doxycycline) H2 (ranitidine cimetidine) beta-(propranolol) xanthines (theophylline) (pseudoephedrine) opioids (codeine)(corticosteroids) (inhaled bronchodilators) (aspirin ibuprofen paracetamol) 2.5 2.5.1 oseltamivir 15-20% oseltamivir ( 3.2.5 ) /( 3.3 ) 2.5.2 oseltamivir oseltamivir oseltamivir 8
oseltamivir oseltamivir oseltamivir 2.5.3 2.2.1 3.2.5 2.5.4 2.2.1 3.2.5 2.5.5 2.2.1 3.2.5 2.5.6 2.2.1 3.2.5 2.6 2.6.1 2647 / 858 1945 / 148 / (ADRs) 1-2 / / ( 75 5 75 6 ) ( 1%) 1% / ( 9
) (75 6 ) ( ) oseltamivir ( 1%)( 1%) a Oseltamivir (75 ) N=2647 N=1977 Oseltamivir (75 ) N=1945 N=1588 10% 6% 8% 4% 8% 3% 2% 1% 2% 1% 17% 16% <1% <1% 4% 3% a oseltamivir ( 1/10)( 1/100 < 1/10) (n=2647) (n=1945) oseltamivir 1% oseltamivir <1% ( ) - (6% 7%)(2% 3%) - (3% 4%) (2% 2%) (1% 1%) ( ) - (3% 4%)(1% 1%)(1% 1%) - (4% 4%) (3% 3%)(2% 3%) ( ) - ( 2% 3%) - (7% 7%)(2% 2%)(1% 2%)(1% 1%) (1% <1%) ( ) - (1% <1%) - (1% <1%) 10
( ) - (2% 2%) (1% 1%) - (7% 7%) (5% 5%)(5% 6%) (1% 1%) ( ) - (2% 3%) (1% 2%)(1% 1%) ( ) - (3% 3%) 942 ( 65 ) 475 ( 18 1-12 ) 12 238 1 1480 1 12 6 12 oseltamivir 858 oseltamivir oseltamivir 1 12 (n=858) 1% (n=622) 1% (oseltamivir 16% 8%) (n=99) 6 (n=49) 148 (oseltamivir 8% 2%) oseltamivir (n=858) 1% (n=148) 5%/ oseltamivir / <1% ( ) - (9% 9%)(4% 4%)(3% 3%) ( ) - (5% 8%) (2% 3%)(1% 3%)(1% 2%) ( ) 11
- ( 3% 4%) (2% 2%) - (12% 26%) (11% 20%) ( ) - ( 1% 2%) ( ) - (1% <1%) ( ) - ( 1% <1%) ( ) - (<1% 1%), ( ) - (<1% 1%) 1 124 1 oseltamivir ( 3.2.5 ) 36 ( 2400 ) 1 1 1 2.6.2 ( ) / Stevens-Johnson oseltamivir / ( 12
) 2.6.2.1 oseltamivir ( 2.6.2 ) 2.7 ( 2.6 ) 3. 3.1 3.1.1 Oseltamivir phosphate oseltamivir carboxylate OC OC A B (neuraminidase enzymes) (neuraminidase) Oseltamivir carboxylate A B 50% (IC50) OC (nanomolar) OC 3.1.2 / 13
(inactivated vaccine) 1997-1998 40 97% A 3% B 32 38% 50% (secondary endpoint) (AUC of viral titres) 75 2 5 13 / 1 2 4 (>100 F/37.8 C) ( ) 1 12 ( 5.3 ) 67% A 33% B 48 35.8 40% 2 334 6 12 53.6% oseltamivir 6 ( ) oseltamivir (FEV 1 ) 10.8% 4.7% (p=0.0148) A B 14
2 7 92% 18-65 76% 42 80% 92% 86% 42 1% 1-12 1-12 30-75 10 21% (15/70) 4% (2/47) 475 ( 18 1-12 ) RT-PCR >99.0 F/37.2 C ( ) ( 24 ) 3.0% (7/231) 0.4% (1/232) (neuraminidase) oseltamivir oseltamivir 15
(%) * * 4/1245 (0.32%) 5/1245 (0.4%) (1-12 ) 19/464 (4.1%) 25/464 (5.4%) * (7 ) (10 ) (42 ) 12 oseltamivir A B oseltamivir 2008 2008 H1N1 >99% oseltamivir H275Y 2009 H1N1 ( ) oseltamivir oseltamivir oseltamivir H1N1 oseltamivir oseltamivir oseltamivir oseltamivir N1 N2 ( WHO ( ) ) 3.2 3.2.1 oseltamivir phosphate oseltamivir (esterase) 30 2-3 (prodrug)( 20 ) 75% oseltamivir 5% ( 2) ( 2.2 ) 75 oseltamivir oseltamivir carboxylate (CV%)(n=20) 16
Oseltamivir Oseltamivir carboxylate (ng/ml) 65.2 (26) 348 (18) 0-12 (ng h/ml) 112 (25) 2719 (20) 3.2.2 oseltamivir phosphate (mean volume of distribution V ss ) 23 oseltamivir phosphate ( 3%) 42% 3.2.3 Oseltamivir phosphate (esterase) oseltamivir cytochrome P450 ( 2.4.1 3.2.4 oseltamivir ( 90%) 6-10 ( 99%) (18.8 / ) (7.5 / 20% 3.2.5 17
100 2 5 oseltamivir oseltamivir carboxylate 3 oseltamivir carboxylate 75 75 150 < 10 / >10 <30 / (CAPD) 75 75 30 30 30 48 259* 348* 705* 766 850 1638 1175 655 39* 138* 288* 62 48 864 209 346 7476* 10876* 21864* 17381 12429 62636 21999 25054 * 48 (creatinine clearance) 60 / 30 60 / 30 5 10-30 / 30 5 30 30 CAPD (continuous ambulatory peritoneal dialysis) APD (automated peritoneal dialysis) oseltamivir carboxylate CAPD APD CAPD 2.2.1 2.4 ( < 10 / ) oseltamivir 18
60 / 30 60 / 30 10~30 / 30 30 30 7 30 CAPD (continuous ambulatory peritoneal dialysis) APD (automated peritoneal dialysis) oseltamivir carboxylate CAPD APD CAPD 2.2.1 2.4 ( < 10 / ) oseltamivir oseltamivir 2.2.1 ( 65-78 ) 25-35% 2.2.1 2.2 ( 30% ) ( 3.2.5 ) 1 1-16 3 12 / 2.2 2 / ( 30 45 ) oseltamivir carboxylate 75 1 / Oseltamivir 12 19
1 1 (124 ) 1 0-12 3 mg/kg 3.3 3.3.1 ( oseltamivir Tg:AC ) oseltamivir phosphate 400 / 500 / oseltamivir phosphate oseltamivir carboxylate AUC 130 320 oseltamivir carboxylate 15 50 3.3.2 Oseltamivir Oseltamivir (Ames test) (human lymphocyte chromosome assay)(mouse micronucleus test) (Syrian Hamster Embryo (SHE) cell transformation test) Oseltamivir carboxylate L5178Y (L5178Y mouse lymphoma assay) 3.3.3 1500 / / 20
6 oseltamivir 50 250 1500 / / oseltamivir oseltamivir carboxylate ( 0 24 ) 100 3.3.4 1500 / / 500 / / / 1500 / / (500 / / ) oseltamivir 480 44 15 20% 3.3.5 oseltamivir oseltamivir 0.01 0.3 (maximization test) oseltamivir 50% oseltamivir phosphate 7 657 500 ( 7 21 500 / / ) 4. 4.1 25 C 4.2 / 21
EXP ( 6 mg/ml) (6 mg/ml) (6 mg/ml) 6 mg/ml 5 30 mg 45 mg 75 mg (sodium benzoate) 0.05% w/v (6 mg/ml) 5 ( ) ( ) < 5 kg 25 ml 5 < 6 kg 30 ml 6 < 7 kg 50 ml 7 10 kg 50 ml 10 15 kg 50 ml > 15 23 kg 75 ml > 23 40 kg 100 ml > 40 kg 125 ml (6 mg/ml)( 25mL 30 ml 50 ml 75 ml 100 ml 125 ml) ( sodium benzoate 0.05% w/v ) (6 mg/ml) ( oseltamivir ) 22
75 mg 45 mg 30 mg 25 ml 2 (150 mg) 30mg 75mg * 5 (150 mg) 24.5 ml 30 ml 30mg 45mg * 4 (180 mg) 6 (180 mg) 29.5 ml 50 ml 4 (300 mg) 30mg 75mg * 10 (300 mg) 49.5 ml 60 ml 30mg 45mg * 8 (360 mg) 12 (360 mg) 59.5 ml 75 ml 6 (450 mg) 10 (450 mg) 15 (450 mg) 74 ml 90 ml 30mg 45mg * 12 (540 mg) 18 (540 mg) 89 ml 100 ml 8 (600 mg) 30mg 75mg * 20 (600 mg) 98.5 ml 120 ml 30mg 45mg * 16 (720 mg) 45mg 75mg * 118.5 ml 125 ml 10 (750 mg) 30mg 75mg * 25 (750 mg) 123.5 ml * (6 mg/ml) 1. sodium benzoate () 2. 3. 4. 5. ( ) (6 mg/ml) 10 25 C 2 C - 8 C 17 23
(6 mg/ml) 2.2 ( ) 5. 30 4-1000 45 4-1000 75 4-1000 30 45 024860 024861 : Roche S.p.A. : Via Morelli 2, 20090 Segrate (Milan, Italy) : F. Hoffmann-La Roche Ltd. : Wurmisweg, CH-4303, Kaiseraugst, Switzerland 75 ( ) 025771 : Roche S.p.A. : Via Morelli 2, 20090 Segrate (Milan, Italy) : F. Hoffmann-La Roche Ltd. : Wurmisweg, CH-4303, Kaiseraugst, Switzerland ( ) 1 91 75 () 025285 Cenexi SAS : 52 Rue Marcel et Jacques Gaucher, 94120 Fontenay-sous-bois, France. F. Hoffmann-La Roche Ltd. : Wurmisweg, CH-4303, Kaiseraugst, Switzerland. 24
F. Hoffmann-La Roche Ltd., Grenzacherstrasse 124, CH-4070 Basel, Switzerland. CDS13.0 2014 3 06.14-TAM-3B01 : : 134 9 : (02)27153111 25