ケイセントラ_製品情報概要_H1-4_収載_新発売

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2 CONTENTS K KVKA K K VKA VKA K - PT-INR KC S 1996VKA VKA 3 KK CS K VKA 12VKAFDA Kcentra in vitro VKA PT-INR CSL214 VKA PT-INRVKA PT-INR K

3 IU 1. K CS PCC Prothrombin Complex Concentrate p p K 4 4-Factor PCC p12 29 HBsHCVHIV-1HIV-2 HIV-1 HBV HCV HAVNAT B19 NAT p % PT-INR 2.9% % 1 DIC p8 3 DIC IU 2 4 3IU 4 8mg 8 4IU 6 12mg 45 92mg 2mL 1 1 1,IU 2 8 6IU 8 16mg 16 8IU 12 24mg mg 4mL C S 2 3p9 3 5

4 2 ph K HIT heparin-induced thrombocytopenia p7 3 B19 4 B19 2 PT-INR kg 25IU/kg 35IU/kg 5IU/kg 1kg 25IU 35IU 5IU 1HBsHCVHIV-1 HIV-2 HIV-1 HBV HCVHAV NAT B19 NAT K 6 1 B19 2 vcjd vcjd HIT heparin-induced thrombocytopenia 6 7

5 % PT-INR 2.9% % % 2 3DIC DIC 2.5% 7 DIC /1 p IU/kg/21IU/ / B

6 5/

7 p PT-INR1.3 KVKA VKA PT-INR VKA PT-INR Day45 K PT-INR IU/kg kg1kg 5,IU 3 PT-INR 1 2 PT-INR PT-INR 24 modified Rankin Scale mrs Day45 predicted blood loss PBL actual blood loss ABL Day14 Day45 FAS PT-INR / Kaplan-MeierPT-INR CT2% / 2 1% packed red blood cells PRBC 8 1g/dL 8 1g/dLPRBC / PRBC / CT2%35% / 2 1%2PRBC8 1g/dL 8 1g/dLPRBC 2 / PRBC 4 / 1 4 / CT35% / 2 2% PRBC8 1g/dL 8 1g/dLPRBC 2 / PRBC 1 24 /PRBC 11g/dL 3% 24/ 2 /% 12 13

8 3 PT-INR 11PT-INR % PT-INR PT-INR Mean SD 3PT-INR Mean SD n=6 n=5 n= PT-INR PT-INR PT 1 PT-INR PT-INR PT Preferred term 23PT-INR 1.3PT-INR PT-INR 1.3PT-INR PT-INR PT-INR 3PT-INR PT-INR PT-INR PT-INR 1 PT-INR

9 PT-INR PT-INR % 24PT-INR PT-INR 1.3PT-INR 31.3 PT-INR n= Day43 n= n= n=4 1 3PT-INR 1 PBL ABL ABLPBL PBL Predicted blood loss 2 ABL Actual blood loss mL 83.3% 5/6 1% 5/5 18.2% 2/111 2 PBL 1 mln= ABL 2 mln= mrsday mrs5 Day454 1 mrs2 Day

10 KVKAK CS VKA CS Intention-to-treatITT-E Intention-to-treatITT-S PT-INR Day9K K PT-INR 1 IU/kg 1 ml/kg mL 25IU 24 PT-INR PT-INR packed red blood cells PRBC PRBC1 24 /PRBC Day45 PT-INR 95% Farrington and Manning 1% 95% 1% 3/ Cochran-Mantel-Haenszel PT-INR 3 ITT-E 1 1kg1kg 2 3PT-INR PT-INRPT-INR / CT2% 3/ % PRBC 8 1g/dL 8 1g/dLPRBC / CT2%35% 3/ %2PRBC8 1g/dL 8 1g/dLPRBC 2 / 3 4 / 1 4 / CT35% 3/ % PRBC8 1g/dL 8 1g/dLPRBC 2 / 3 CT 1% / 2 24 /PRBC 11g/dL 3% 3PRBC PRBC 11g/dL 3% 24 / 18 19

11 % 65.4%7.1% 95%5.8, %1% %67.3%6.2% 95% 6.5, %1% % n= ,19.9 n=14 95 % n=98 95Farrington and Manning ,18.8 n= Farrington and Manning PT-INR PT-INR 3PT-INR %9.6% 52.6% 95% 39.4, % 1% PT-INR / % 3.52,11.9 % 1 8 PT-INR n=98 95Farrington and Manning , n=14 95 PT-INR PT-INR PT-INR % PT-INR PT-INR PT-INR 88%58% PT-INR n=98 n=14 Kaplan-Meier

12 PT-INR 3 12 PT-INR 5 n=98 n=14 4 p<.5 Wilcoxon 3 2 PT-INR 1 PRBC PRBC1 PRBCMean SD Wilcoxon PRBC149% 48/9845% 47/14 PRBC 1 1g/dL3% 24 /PRBC BL PRBC/ Mean SD Wilcoxon Day45 Day45 95 Day45 / %.66,5.5 ITT-S %96% ITT-S n=13 n=19 PT-INR IU/kg mL/kg 1.4mL/kg 2.mL/kg n % mL25IU ITT-S n= ml IU/ ml/ IU/kg ml/kg ml/kg n % n= Mean SD 64.1% 66/ % 71/19 9.7% 1/ % 23/19 PT-INR21.9% 3 2.8% 1.9% 2/13 3.7% 4/

13 KVKAK CS VKA CS Intention-to-treatITT-E Intention-to-treatITT-S PT-INR Day9K K PT-INR mL 25IU 1 IU/kg ml/kg PT-INR 3 PT-INR 24packed red blood cells PRBC 24 PRBC PT-INR 12 95% Newcombe-Wilson 1% 95% 1% PT-INR 4 ITT-E 1actual blood loss:ablpredicted blood loss:pbl5ml / PRBC ABLPBL 2% PRBC ABLPBL 2%3% / ABL PBL 3% PRBC PRBC / ABL PBL 3% ABL PBL/ 2 ABLPBL5mL / ABL PBL/ PRBC ABL PBL 2 PRBC ABLPBL 2% / PRBC PRBC / 1 1kg1kg FDA 33PT-INR PT-INRPT-INR 24 25

14 89.7% 75.3%14.3% 95% 2.8, % 1% PT-INR PT-INR PT-INR % PT-INR PT-INR PT-INR 87%48% 95Newcombe-Wilson% n= , n= PT-INR n=87 n= Kaplan-Meier PT-INR PT-INR 3PT-INR %9.9% 45.3% 95% 31.9, % 1% PT-INR 3 24 PT-INR % 1 8 PT-INR , PT-INR n=87 n=81 p<.5 Wilcoxon n=87 95Newcombe-Wilson 9.9 n=81 BL

15 55.749/ /88 9.1% 8/88 17.% 15/ % 3/ % 11/ % 3/88 3.4% 3/ Day PRBC PRBC 16.1% 14/8714.8% 12/81 Fisher ITT-S %98% PRBC PRBC PRBC Wilcoxon ITT-S 1mL25IU Mean SD n=88 PT-INR IU/kg mL/kg 1.4mL/kg 2.mL/kg ml/kg n % n % n=88 ITT-S ml IU/ ml/ IU/kg ml/kg n= n=

16 % PT-INR 2.9% % PT-INR PT-INR 32 n= % 3 2.9% 1 1.% 1 1.% 1 1.% 5 4.9% 2 1.9% 1 1.% 1 1.% 1 1.% 1 1.% 1 1.% 2 1.9% 1 1.% 1 1.% 1 1.% 1 1.% 1 1.% 1 1.% 8 9.1% 2 2.3% 2 2.3% 2 2.3% 3 3.4% 33 n= n= n= MedDRA Ver / MedDRA Ver / MedDRA / J Ver.18. n= IU/kg 5 Cmax Cmax 162%S 278%Ct1/ CS Mean SD % C S

17 C S , , , , , , IVR9% 2 IVR3 IU/kg IVRt1/2 CmaxAUC CLMRTVss IVRIU/dL / IU/kg 2 t1/2 hn=14 t1/2 h Cmax % AUC kg h/dl CL ml/ kg h MRT h Vss ml/kg IVRIU/dL / IU/kg 2 t1/2 h Cmax % AUC kg h/dl CL ml/ kg h MRT h Vss ml/kg IVRIU/dL / IU/kg 2 t1/2 hn=12 t1/2 h Cmax % AUC kg h/dl CL ml/ kg h MRT h Vss ml/kg IVRIU/dL / IU/kg 2 t1/2 h Cmax % AUC kg h/dl CL ml/ kg h MRT h Vss ml/kg IVRIU/dL / IU/kg 2 t1/2 hn=12 t1/2 h Cmax % AUC kg h/dl CL ml/ kg h MRT h Vss ml/kg IVRIU/dL / IU/kg 2 t1/2 h t1/2 h Cmax % AUC kg h/dl CL ml/ kg h MRT h Vss ml/kg 2 K34 1 K 3IVR IU/dL / IU/kg IU/dL / IU/kg.868 IU/dL / IU/kg IU/dL / IU/kg 3 CS n=6 n=5 C S %normal 3 %normal %normal 3 %normal CS IVRIVR 1 IVRIU/dL / IU/kg= IU/dL/ IU/kg 2IVR % = 1 / IVR n=6 n=5 C S IVR 1 [IU/dL]/[IU/kg] IVR 2 % IVR 1 [IU/dL]/[IU/kg] IVR 2 %

18 3 KK CS 33 3 K CS 3 5% p.5 Wilcoxon36 24 CS BL n=87 n=81 BL n=87 n=81 BL C n=87 n=81 2 n=87 n=81 BL n=87 2 n=87 n=81 n=81 BL BL S C S C S 34 35

19 K K in vitro 6 PCC rf a PT PCC PT PT in vitro PT-INR PCC U/mL rf a nm Marcumar 2.5mg/kg PCC 5U/kg rf a 1 g/kg 15 PTaPTT PT PCCrF a p.5 Wilcoxon PT PCCrF apcc appt p.1 Wilcoxon PT aptt aptt aptt vs F a vs PCC F a vs PCC aptt p , , , aptt 48 aptt vs F a vs PCC F a vs PCC aptt p , , , PT-INR3.6in vitro nm PT-INR3.6 PCC.72U/mL PT-INR3.6 PCC.4U/mL PT-INR3.6 PCC.2U/mL PT-INR3.6 rf a 6nM PT-INR3.6 PT PT L1 1 vs F a vs PCC F a vs PCC PT p , , , p 3 2 vs F a , vs PCC , F a vs PCC , PT PT L 15 1 vs F a vs PCC F a vs PCC vs F a vs PCC F a vs PCC PT p , , , p , , , n=5 rf a (n=5) PCC (n=5) n=5 rf a (n=5) PCC (n=5) 1 PT aptt 2 95Hodges-Lehmann 3 Wilcoxon 36 37

20 8 35IU/kg IU/animal 9 1 IU/kg IU/kg 2IU/kg IU/kg IU/kg 2646 g/kg 3 NOAEL1IU/kg

/ / 1 25 2 6% 5%RH 4 2 C 75 5%RH 25 6%RH 36 6 12 lux 2W hr/m 2 C S 25 3 2 5 1

21 / / % 5%RH 4 2 C 75 5%RH 25 6%RH lux 2W hr/m 2 C S mL mL AMX AMX

22 / Tanaka K.A., et al.: Thromb Res. 122, 117, 28 7 Dickneite, G: Thromb Res. 119, 643, CSL CSL

125 2 P 1st washout 2 PB P mg/dL nd washout 2 P 5.5mg/dL< mg/dL <2.5mg/dL P P 2 D D 3 Ca 10

125 2 P 1st washout 2 PB P mg/dL nd washout 2 P 5.5mg/dL< mg/dL <2.5mg/dL P P 2 D D 3 Ca 10 . (1) 125 1 125 Renagel PB-94 P intact-pth P 1 b c a b 1 18 2 3 3 3 1 P 4 D 1 5 6 7 2 1HIV 2 3 4 5Hb 8.0g/dL ALT 48IU/L 6 7 PB-94 440mg 403mg 1-196 125 2 P 1st washout 2 PB-94 1 2 4 4 P 2.5 5.5mg/dL 1